Trial Outcomes & Findings for Evaluation of Tolerability and Pharmacokinetics of Roflumilast, 250μg and 500μg, as add-on to Standard COPD Treatment to Treat Severe COPD (NCT NCT02165826)

Last Updated: 2017-04-20

Results Overview

The primary endpoint is the percentage of participants prematurely discontinuing study treatment for any reason during the Main Period from Visit 1 (V1) to Last Visit (Vend). Discontinuation is defined as permanently stopping randomized treatment; participants who resume randomized treatment after an interval will not be counted as having discontinued. The analysis used discontinuations occurring during the Main Period, irrespective of whether a participant subsequently entered into the Down-Titration Period.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1323 participants

Primary outcome timeframe

Baseline to Week 12 (Main Period)

Results posted on

2017-04-20

Participant Flow

Participants took part in the study at 161 investigative sites in Bulgaria, Germany, Greece, Hungary, Korea, Philippines, Poland, Romania, Russia, Slovakia, South Africa, Spain, Thailand, Ukraine and the United Kingdom from 30 April 2014 to 21 October 2015.

Participants with a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) were enrolled equally in 1 of 3 treatment groups in the Main Treatment Period: roflumilast 250 μg then 500 μg once daily (OD), 500 μg every other day (EOD) then 500 μg OD and 500 μg OD. Participants who discontinued received 250 μg in the Down-Titration Period.

Participant milestones

Participant milestones
Measure	Roflumilast 250 μg OD Then 500 μg OD Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.
Main Treatment Period STARTED	441	439	443
Main Treatment Period Safety Analysis Set: Received Study Drug	441	437	443
Main Treatment Period COMPLETED	360	349	334
Main Treatment Period NOT COMPLETED	81	90	109
Down-Titration Period STARTED	27	39	38
Down-Titration Period Safety Analysis Set: Received Study Drug	27	39	38
Down-Titration Period COMPLETED	20	28	31
Down-Titration Period NOT COMPLETED	7	11	7

Reasons for withdrawal

Reasons for withdrawal
Measure	Roflumilast 250 μg OD Then 500 μg OD Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.
Main Treatment Period Pre-treatment Event/Adverse Event	44	57	68
Main Treatment Period Major/Significant Protocol Deviation	0	1	3
Main Treatment Period Lost to Follow-up	4	2	1
Main Treatment Period Voluntary Withdrawal	23	23	21
Main Treatment Period Lack of Efficacy	2	0	0
Main Treatment Period Reason Not Specified	8	5	16
Main Treatment Period Did Not Receive Study Drug	0	2	0
Down-Titration Period Pre-treatment Event/Adverse Event	4	10	3
Down-Titration Period Voluntary Withdrawal	2	1	2
Down-Titration Period Reason Not Specified	1	0	2

Baseline Characteristics

Evaluation of Tolerability and Pharmacokinetics of Roflumilast, 250μg and 500μg, as add-on to Standard COPD Treatment to Treat Severe COPD

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Roflumilast 250 μg OD Then 500 μg OD n=441 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=437 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD n=443 Participants Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Total n=1321 Participants Total of all reporting groups
Age, Continuous	64.2 years STANDARD_DEVIATION 7.81 • n=5 Participants	65.0 years STANDARD_DEVIATION 8.21 • n=7 Participants	64.6 years STANDARD_DEVIATION 8.36 • n=5 Participants	64.6 years STANDARD_DEVIATION 8.13 • n=4 Participants
Age, Customized 40-64 years	242 participants n=5 Participants	202 participants n=7 Participants	224 participants n=5 Participants	668 participants n=4 Participants
Age, Customized 65-84 years	199 participants n=5 Participants	235 participants n=7 Participants	217 participants n=5 Participants	651 participants n=4 Participants
Age, Customized 85 years and over	0 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants	2 participants n=4 Participants
Sex: Female, Male Female	121 Participants n=5 Participants	112 Participants n=7 Participants	105 Participants n=5 Participants	338 Participants n=4 Participants
Sex: Female, Male Male	320 Participants n=5 Participants	325 Participants n=7 Participants	338 Participants n=5 Participants	983 Participants n=4 Participants
Race/Ethnicity, Customized Hispanic or Latino	1 participants n=5 Participants	2 participants n=7 Participants	5 participants n=5 Participants	8 participants n=4 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	428 participants n=5 Participants	423 participants n=7 Participants	426 participants n=5 Participants	1277 participants n=4 Participants
Race/Ethnicity, Customized Missing	12 participants n=5 Participants	12 participants n=7 Participants	12 participants n=5 Participants	36 participants n=4 Participants
Race/Ethnicity, Customized American Indian or Alaskan Native	0 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants
Race/Ethnicity, Customized Asian	32 participants n=5 Participants	30 participants n=7 Participants	32 participants n=5 Participants	94 participants n=4 Participants
Race/Ethnicity, Customized Black or African American	3 participants n=5 Participants	3 participants n=7 Participants	3 participants n=5 Participants	9 participants n=4 Participants
Race/Ethnicity, Customized Native Hawaiian/Other Pacific Islander	1 participants n=5 Participants	4 participants n=7 Participants	3 participants n=5 Participants	8 participants n=4 Participants
Race/Ethnicity, Customized White	405 participants n=5 Participants	399 participants n=7 Participants	405 participants n=5 Participants	1209 participants n=4 Participants
Region of Enrollment Bulgaria	36 participants n=5 Participants	18 participants n=7 Participants	30 participants n=5 Participants	84 participants n=4 Participants
Region of Enrollment Germany	12 participants n=5 Participants	24 participants n=7 Participants	16 participants n=5 Participants	52 participants n=4 Participants
Region of Enrollment Greece	8 participants n=5 Participants	6 participants n=7 Participants	6 participants n=5 Participants	20 participants n=4 Participants
Region of Enrollment Hungary	82 participants n=5 Participants	74 participants n=7 Participants	79 participants n=5 Participants	235 participants n=4 Participants
Region of Enrollment Korea, Republic Of	22 participants n=5 Participants	11 participants n=7 Participants	13 participants n=5 Participants	46 participants n=4 Participants
Region of Enrollment Philippines	7 participants n=5 Participants	13 participants n=7 Participants	10 participants n=5 Participants	30 participants n=4 Participants
Region of Enrollment Poland	60 participants n=5 Participants	68 participants n=7 Participants	71 participants n=5 Participants	199 participants n=4 Participants
Region of Enrollment Romania	54 participants n=5 Participants	46 participants n=7 Participants	44 participants n=5 Participants	144 participants n=4 Participants
Region of Enrollment Russia	37 participants n=5 Participants	48 participants n=7 Participants	55 participants n=5 Participants	140 participants n=4 Participants
Region of Enrollment Slovakia	40 participants n=5 Participants	38 participants n=7 Participants	27 participants n=5 Participants	105 participants n=4 Participants
Region of Enrollment South Africa	17 participants n=5 Participants	18 participants n=7 Participants	26 participants n=5 Participants	61 participants n=4 Participants
Region of Enrollment Spain	2 participants n=5 Participants	2 participants n=7 Participants	1 participants n=5 Participants	5 participants n=4 Participants
Region of Enrollment Thailand	2 participants n=5 Participants	6 participants n=7 Participants	9 participants n=5 Participants	17 participants n=4 Participants
Region of Enrollment Ukraine	56 participants n=5 Participants	58 participants n=7 Participants	54 participants n=5 Participants	168 participants n=4 Participants
Region of Enrollment United Kingdom	6 participants n=5 Participants	7 participants n=7 Participants	2 participants n=5 Participants	15 participants n=4 Participants
Height	169.1 cm STANDARD_DEVIATION 8.73 • n=5 Participants	168.8 cm STANDARD_DEVIATION 8.66 • n=7 Participants	169.1 cm STANDARD_DEVIATION 8.55 • n=5 Participants	169.0 cm STANDARD_DEVIATION 8.64 • n=4 Participants
Weight	75.59 kg STANDARD_DEVIATION 18.627 • n=5 Participants	74.31 kg STANDARD_DEVIATION 17.808 • n=7 Participants	75.68 kg STANDARD_DEVIATION 16.949 • n=5 Participants	75.20 kg STANDARD_DEVIATION 17.804 • n=4 Participants
Body Mass Index (BMI)	26.36 kg/m^2 STANDARD_DEVIATION 5.957 • n=5 Participants	25.98 kg/m^2 STANDARD_DEVIATION 5.614 • n=7 Participants	26.44 kg/m^2 STANDARD_DEVIATION 5.888 • n=5 Participants	26.26 kg/m^2 STANDARD_DEVIATION 5.822 • n=4 Participants
Smoking Classification Current Smoker	213 participants n=5 Participants	198 participants n=7 Participants	196 participants n=5 Participants	607 participants n=4 Participants
Smoking Classification Ex-smoker	228 participants n=5 Participants	239 participants n=7 Participants	247 participants n=5 Participants	714 participants n=4 Participants
Number of Cigarette Pack-Years	38.1 pack-years STANDARD_DEVIATION 17.49 • n=5 Participants	40.2 pack-years STANDARD_DEVIATION 19.22 • n=7 Participants	37.6 pack-years STANDARD_DEVIATION 17.70 • n=5 Participants	38.6 pack-years STANDARD_DEVIATION 18.17 • n=4 Participants
Pre-bronchodilator Forced Expiratory Volume in the First Second (FEV1)	1.022 liters STANDARD_DEVIATION 0.3177 • n=5 Participants	1.028 liters STANDARD_DEVIATION 0.3173 • n=7 Participants	1.018 liters STANDARD_DEVIATION 0.3289 • n=5 Participants	1.023 liters STANDARD_DEVIATION 0.3211 • n=4 Participants
Pre-Bronchodilator Forced Vital Capacity (FVC)	2.304 liters STANDARD_DEVIATION 0.7418 • n=5 Participants	2.303 liters STANDARD_DEVIATION 0.7091 • n=7 Participants	2.314 liters STANDARD_DEVIATION 0.6822 • n=5 Participants	2.307 liters STANDARD_DEVIATION 0.7109 • n=4 Participants

PRIMARY outcome

Timeframe: Baseline to Week 12 (Main Period)

Population: Safety Analysis Set (SAS) included all randomized participants who took at least one dose of study medication.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=441 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=437 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD n=443 Participants Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Percentage of Participants Prematurely Discontinuing Study Treatment Due to Any Reason	18.4 percentage of participants	20.1 percentage of participants	24.6 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline to Week 12 (Main Period)

Population: SAS included all randomized participants who took at least one dose of study medication.

Adverse events of interest to evaluate tolerability are defined as diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=441 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=437 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD n=443 Participants Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Percentage of Participants With Adverse Events of Interest	45.4 percentage of participants	48.3 percentage of participants	54.2 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline (V0DT) [assessment at end of main period] and Final Visit of Down-Titration Period (Up to Day 56)

Population: Participants from the Down-Titration Period Full Analysis Set (FAS), all randomized participants who entered this period, regardless of whether they took study medication, with data available for analysis.

FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using spirometry prior to taking study medication A positive change from Baseline indicates improvement.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=26 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=39 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD n=38 Participants Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Change From Baseline (V0DT) in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) to Final Visit of the Down-Titration Period	0.030 Liters Standard Deviation 0.2294	0.055 Liters Standard Deviation 0.4170	0.007 Liters Standard Deviation 0.3555	—

SECONDARY outcome

Timeframe: Baseline DT (Day 1 of Down-Titration Period) to Week 8 (Down-Titration Period)

Population: Down-Titration Period Full Analysis Set (FAS) included all randomized participants who entered this period, regardless of whether they took study medication.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=27 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=39 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD n=38 Participants Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Percentage of Participants Prematurely Discontinuing Study Treatment Due to Any Reason During Down-Titration Period	25.9 percentage of participants	28.2 percentage of participants	18.4 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline DT (Day 1 of Down-Titration Period) to Days 14, 28 and 56 (Down-Titration Period)

Population: Down-Titration Period Full Analysis Set (FAS) included all randomized participants who entered this period, regardless of whether they took study medication. "n" in each category is the number of participants with data available at the given time-point.

FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using spirometry prior to taking study medication. A positive change from Baseline indicates improvement.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=27 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=39 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD n=38 Participants Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Down-Titration Period Day 14 (n=20, 32, 34)	0.128 Liters Standard Deviation 0.3708	0.223 Liters Standard Deviation 0.4101	0.097 Liters Standard Deviation 0.2532	—
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Down-Titration Period Day 28 (n=20, 29, 31)	0.162 Liters Standard Deviation 0.4274	0.218 Liters Standard Deviation 0.4443	0.070 Liters Standard Deviation 0.2067	—
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Down-Titration Period Day 56 (n=26, 39, 38)	0.162 Liters Standard Deviation 0.3311	0.261 Liters Standard Deviation 0.4616	0.127 Liters Standard Deviation 0.3334	—

SECONDARY outcome

Timeframe: Baseline (Day 1 of Main Period) to Days 15, 29, 57 and 84 (Main Period)

Population: Main Period FAS included all randomized participants, regardless of whether they took study medication. "n" in each of the categories is the number of participants with data available at the given time-point.

FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using spirometry prior to taking study medication. A positive change from Baseline indicates improvement.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=441 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=439 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD n=443 Participants Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period Day 15 (n=409, 406, 386)	0.067 Liters Standard Deviation 0.2299	0.094 Liters Standard Deviation 0.2573	0.094 Liters Standard Deviation 0.2566	—
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period Day 29 (n=402, 389, 365)	0.099 Liters Standard Deviation 0.2605	0.115 Liters Standard Deviation 0.2629	0.116 Liters Standard Deviation 0.2440	—
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period Day 57 (n=376, 367, 352)	0.104 Liters Standard Deviation 0.2659	0.161 Liters Standard Deviation 0.2765	0.133 Liters Standard Deviation 0.2705	—
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period Day 84 (n=402, 411, 409)	0.117 Liters Standard Deviation 0.2690	0.141 Liters Standard Deviation 0.2882	0.122 Liters Standard Deviation 0.2705	—

SECONDARY outcome

Timeframe: Baseline (Day 1 of Main Period) to Days 15, 29, 57 and 84 (Main Period)

Forced vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Pulmonary function testing was performed using spirometry prior to taking study medication. A positive change from Baseline indicates improvement.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=441 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=439 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD n=443 Participants Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period Day 15 (n=409, 406, 386)	0.096 Liters Standard Deviation 0.4053	0.112 Liters Standard Deviation 0.4168	0.104 Liters Standard Deviation 0.4166	—
Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period Day 29 (n=402, 389, 365)	0.139 Liters Standard Deviation 0.3826	0.143 Liters Standard Deviation 0.4172	0.149 Liters Standard Deviation 0.4173	—
Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period Day 57 (n=376, 367, 352)	0.156 Liters Standard Deviation 0.4346	0.194 Liters Standard Deviation 0.4974	0.162 Liters Standard Deviation 0.4341	—
Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period Day 84 (n=402, 411, 409)	0.157 Liters Standard Deviation 0.4746	0.207 Liters Standard Deviation 0.4925	0.147 Liters Standard Deviation 0.4555	—

SECONDARY outcome

Timeframe: Baseline DT (Day 1 of Down-Titration Period) to Days 14, 28 and 56 (Down-Titration Period)

Population: Down-Titration Period Full Analysis Set (FAS) included all randomized participants who entered this period, regardless of whether they took study medication.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=27 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=39 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD n=38 Participants Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Down-Titration Period Day 14 (n=20, 32, 34)	0.087 Liters Standard Deviation 0.5392	0.303 Liters Standard Deviation 0.5103	0.104 Liters Standard Deviation 0.4568	—
Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Down-Titration Period Day 28 (n=20, 29, 31)	0.125 Liters Standard Deviation 0.6151	0.191 Liters Standard Deviation 0.4780	0.067 Liters Standard Deviation 0.3522	—
Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Down-Titration Period Day 56 (n=26, 39, 38)	0.167 Liters Standard Deviation 0.5492	0.113 Liters Standard Deviation 0.5100	0.029 Liters Standard Deviation 0.4628	—

SECONDARY outcome

Timeframe: Baseline (Day 1 of Main Period) to Days 15, 29, 57 and 84 (Main Period)

Participants will be asked to assess their satisfaction with their COPD therapy at each visit. The participants will rate their treatment satisfaction on a 7-point scale where 0=very satisfied, 1=satisfied, 2=somewhat satisfied, 3=neither satisfied nor dissatisfied, 4=somewhat dissatisfied, 5=dissatisfied and 6=very dissatisfied. A negative change from Baseline indicates improvement.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=441 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=439 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD n=443 Participants Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Change From Baseline in Treatment Satisfaction Scores During the Main Period Day 15 (n=410, 408, 386)	-0.4 score on a scale Standard Deviation 1.12	-0.3 score on a scale Standard Deviation 1.15	-0.3 score on a scale Standard Deviation 1.07	—
Change From Baseline in Treatment Satisfaction Scores During the Main Period Day 29 (n=403, 390, 366)	-0.5 score on a scale Standard Deviation 1.23	-0.5 score on a scale Standard Deviation 1.16	-0.5 score on a scale Standard Deviation 1.22	—
Change From Baseline in Treatment Satisfaction Scores During the Main Period Day 57 (n=375, 369, 351)	-0.6 score on a scale Standard Deviation 1.24	-0.6 score on a scale Standard Deviation 1.26	-0.5 score on a scale Standard Deviation 1.29	—
Change From Baseline in Treatment Satisfaction Scores During the Main Period Day 84 (n=407, 416, 412)	-0.5 score on a scale Standard Deviation 1.43	-0.5 score on a scale Standard Deviation 1.51	-0.3 score on a scale Standard Deviation 1.52	—

SECONDARY outcome

Timeframe: Baseline DT (Day 1 of Down-Titration Period) to Days 14, 28 and 56 (Down-Titration Period)

Population: Down-Titration Period Full Analysis Set (FAS) included all randomized participants who entered this period, regardless of whether they took study medication. "n" in each of the categories is the number of participants with data available at the given time-point.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=27 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=39 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD n=38 Participants Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Change From Baseline in Treatment Satisfaction Scores During the Down-Titration Period Day 14 (n=20, 32, 34)	-1.1 score on a scale Standard Deviation 1.85	-0.8 score on a scale Standard Deviation 1.57	-0.8 score on a scale Standard Deviation 1.84	—
Change From Baseline in Treatment Satisfaction Scores During the Down-Titration Period Day 28 (n=20, 29, 31)	-1.2 score on a scale Standard Deviation 2.01	-0.8 score on a scale Standard Deviation 1.75	-0.9 score on a scale Standard Deviation 1.81	—
Change From Baseline in Treatment Satisfaction Scores During the Down-Titration Period Day 56 (n=26, 39, 38)	-0.8 score on a scale Standard Deviation 2.23	-0.3 score on a scale Standard Deviation 2.15	-0.4 score on a scale Standard Deviation 2.26	—

SECONDARY outcome

Timeframe: Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8

Population: Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration.

PK model point estimates for Ka are calculated using all available PK data for all doses of roflumilast combined and are presented for roflumilast and metabolite roflumilast N-oxide. Results are reported for the subgroups defined according to the covariates (weight, age, smoking status and sex) included in the final model.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=1238 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=1238 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide Weight=33.5 kg	0.90 units per hour (1/h)	0.57 units per hour (1/h)	—	—
Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide Weight=70 kg	0.90 units per hour (1/h)	0.57 units per hour (1/h)	—	—
Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide Weight=160 kg	0.90 units per hour (1/h)	0.57 units per hour (1/h)	—	—
Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide Age=40	0.90 units per hour (1/h)	0.57 units per hour (1/h)	—	—
Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide Age=60	0.90 units per hour (1/h)	0.57 units per hour (1/h)	—	—
Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide Age=92	0.90 units per hour (1/h)	0.57 units per hour (1/h)	—	—
Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide Smoking=former	0.90 units per hour (1/h)	0.57 units per hour (1/h)	—	—
Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide Smoking=current	0.90 units per hour (1/h)	0.57 units per hour (1/h)	—	—
Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide Sex=female	0.90 units per hour (1/h)	0.57 units per hour (1/h)	—	—
Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide Sex=male	0.90 units per hour (1/h)	0.57 units per hour (1/h)	—	—

SECONDARY outcome

Timeframe: Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8

Population: Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration.

PK model point estimates for CL/F are calculated using all available PK data for all doses of roflumilast combined and are presented for roflumilast and metabolite roflumilast N-oxide. Results are reported for the subgroups defined according to the covariates (weight, age, smoking status and sex) included in the final model.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=1238 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=1238 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide Weight=33.5 kg	5.64 liters per hour (L/h)	0.73 liters per hour (L/h)	—	—
Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide Weight=70 kg	5.64 liters per hour (L/h)	0.89 liters per hour (L/h)	—	—
Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide Weight=160 kg	5.64 liters per hour (L/h)	1.12 liters per hour (L/h)	—	—
Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide Age=40	7.23 liters per hour (L/h)	1.11 liters per hour (L/h)	—	—
Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide Age=60	5.64 liters per hour (L/h)	0.89 liters per hour (L/h)	—	—
Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide Age=92	4.35 liters per hour (L/h)	0.71 liters per hour (L/h)	—	—
Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide Smoking=former	5.64 liters per hour (L/h)	0.89 liters per hour (L/h)	—	—
Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide Smoking=current	6.50 liters per hour (L/h)	1.03 liters per hour (L/h)	—	—
Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide Sex=female	5.64 liters per hour (L/h)	0.89 liters per hour (L/h)	—	—
Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide Sex=male	5.64 liters per hour (L/h)	0.79 liters per hour (L/h)	—	—

SECONDARY outcome

Timeframe: Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8

Population: Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration.

PK model point estimates for Vc/F are calculated using all available PK data for all doses of roflumilast combined and are presented for roflumilast and metabolite roflumilast N-oxide. Results are reported for the subgroups defined according to the covariates (weight, age, smoking status and sex) included in the final model.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=1238 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=1238 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide Weight=33.5 kg	26.0 liters (L)	4.5 liters (L)	—	—
Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide Weight=70 kg	63.9 liters (L)	11.0 liters (L)	—	—
Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide Weight=160 kg	175.2 liters (L)	30.2 liters (L)	—	—
Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide Age=40	63.9 liters (L)	11.0 liters (L)	—	—
Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide Age=60	63.9 liters (L)	11.0 liters (L)	—	—
Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide Age=92	63.9 liters (L)	11.0 liters (L)	—	—
Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide Smoking=former	63.9 liters (L)	11.0 liters (L)	—	—
Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide Smoking=current	63.9 liters (L)	11.0 liters (L)	—	—
Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide Sex=female	63.9 liters (L)	11.0 liters (L)	—	—
Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide Sex=male	63.9 liters (L)	11.0 liters (L)	—	—

SECONDARY outcome

Timeframe: Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8

Population: Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration.

PK model point estimates for Vp/F are calculated using all available PK data for all doses of roflumilast combined and are presented for roflumilast and metabolite roflumilast N-oxide. Results are reported for the subgroups defined according to the covariates (weight, age, smoking status and sex) included in the final model.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=1238 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=1238 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide Weight=33.5 kg	69.6 L	5.0 L	—	—
Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide Weight=70 kg	171.0 L	12.4 L	—	—
Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide Weight=160 kg	468.8 L	34.0 L	—	—
Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide Age=40	171.0 L	12.4 L	—	—
Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide Age=60	171.0 L	12.4 L	—	—
Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide Age=92	171.0 L	12.4 L	—	—
Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide Smoking=former	171.0 L	12.4 L	—	—
Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide Smoking=current	171.0 L	12.4 L	—	—
Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide Sex=female	171.0 L	12.4 L	—	—
Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide Sex=male	171.0 L	12.4 L	—	—

SECONDARY outcome

Timeframe: Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours post-dose at Days 15 and 57. Down-titration: Pre-dose and 1,2,3,4,6 hours post-dose at Days 1 and 14 and pre-dose at Days 28 and 56.

Population: Participants from the PK Set, all participants who had at least 1 quantifiable PK concentration, with data available. Study design only includes the 250 µg arm for analyses of this outcome measure in the Down-Titration period. Measured values are predicted values reported as median and 90% prediction interval.

tPDE4i was derived using in-vitro constants for protein binding and biochemical activity (IC50). tPDE4i is reported for a set of reference participants defined according to the covariates included in the final model.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=392 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=399 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD n=404 Participants Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration n=101 Participants 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Total PDE4 Inhibitory Activity (tPDE4i) Overall	1.17 unitless Interval 0.366 to 2.05	0.608 unitless Interval 0.227 to 1.03	0.563 unitless Interval 0.157 to 1.01	0.583 unitless Interval 0.21 to 1.24
Total PDE4 Inhibitory Activity (tPDE4i) Age < 65 (n=198,187,229,45)	1.06 unitless Interval 0.323 to 1.85	0.559 unitless Interval 0.237 to 0.998	0.518 unitless Interval 0.16 to 0.958	0.511 unitless Interval 0.205 to 0.984
Total PDE4 Inhibitory Activity (tPDE4i) Age ≥ 65 to < 75 (n=146,159,136,39)	1.24 unitless Interval 0.55 to 2.08	0.660 unitless Interval 0.177 to 1.04	0.614 unitless Interval 0.138 to 1.1	0.683 unitless Interval 0.207 to 1.23
Total PDE4 Inhibitory Activity (tPDE4i) Age ≥ 75 (n=48,53,39,17)	1.24 unitless Interval 0.318 to 2.31	0.676 unitless Interval 0.188 to 1.12	0.616 unitless Interval 0.195 to 1.01	0.712 unitless Interval 0.3 to 1.32
Total PDE4 Inhibitory Activity (tPDE4i) Weight < 60 kg (n=56,78,73,17)	1.34 unitless Interval 0.591 to 2.64	0.755 unitless Interval 0.258 to 1.22	0.653 unitless Interval 0.156 to 1.12	0.934 unitless Interval 0.325 to 1.39
Total PDE4 Inhibitory Activity (tPDE4i) Weight ≥ 60 kg (n=336,321,331,84)	1.12 unitless Interval 0.339 to 1.99	0.592 unitless Interval 0.223 to 1.01	0.552 unitless Interval 0.158 to 0.971	0.538 unitless Interval 0.202 to 1.02
Total PDE4 Inhibitory Activity (tPDE4i) Males (n=300,297,290,66)	1.12 unitless Interval 0.363 to 1.96	0.585 unitless Interval 0.226 to 0.994	0.558 unitless Interval 0.145 to 0.998	0.575 unitless Interval 0.213 to 1.14
Total PDE4 Inhibitory Activity (tPDE4i) Females (n=92,102,114,35)	1.29 unitless Interval 0.468 to 2.38	0.696 unitless Interval 0.26 to 1.15	0.618 unitless Interval 0.189 to 1.01	0.626 unitless Interval 0.217 to 1.25
Total PDE4 Inhibitory Activity (tPDE4i) Current Smoker (n=179,183,200,45)	1.04 unitless Interval 0.327 to 1.88	0.568 unitless Interval 0.247 to 0.976	0.514 unitless Interval 0.101 to 0.949	0.554 unitless Interval 0.228 to 1.21
Total PDE4 Inhibitory Activity (tPDE4i) Former Smoker (n=213,216,204,56)	1.25 unitless Interval 0.416 to 2.15	0.632 unitless Interval 0.186 to 1.09	0.626 unitless Interval 0.196 to 1.1	0.624 unitless Interval 0.207 to 1.3

SECONDARY outcome

Population: PK Set included all participants who had at least 1 quantifiable PK concentration. "n" in the category is the number of participants with available data. Study design only includes the 250 µg OD and 500 µg OD arms for analyses of this outcome measure. Measured values are predicted values reported as median and 90% prediction interval.

tPDE4i was derived using in-vitro constants for protein binding and biochemical activity (IC50). An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. Adverse Events of Interest (AEI) for PK analyses included: headache, diarrhea, nausea, vomiting, abdominal pain, appetite disorders, sleep disorders, angioedema, psychiatric disorders (anxiety, nervousness), psychiatric disorders (depression,suicidal ideation,behaviour) and weight loss.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=1114 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=76 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) At Least 1 AE=No (n=421,0)	1.08 unitless Interval 0.294 to 1.97	NA unitless No participants in this category for this arm.	—	—
Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) All Participants (n=1114,76)	1.17 unitless Interval 0.352 to 2.03	0.611 unitless Interval 0.197 to 1.243	—	—
Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) Discontinuation due to Any AEI=Yes (n=67,62)	1.28 unitless Interval 0.427 to 2.22	0.647 unitless Interval 0.201 to 1.239	—	—
Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) Discontinuation due to Any AEI=No (n=1047,14)	1.16 unitless Interval 0.339 to 2.02	0.436 unitless Interval 0.212 to 1.069	—	—
Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) Discontinuation due to Any AE=Yes (n=77,64)	1.29 unitless Interval 0.464 to 2.1	0.647 unitless Interval 0.204 to 1.237	—	—
Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) Discontinuation due to Any AE=No (n=1037,12)	1.16 unitless Interval 0.337 to 2.02	0.408 unitless Interval 0.209 to 1.006	—	—
Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) Discontinuation Due to Any Reason=Yes (n=106,75)	1.23 unitless Interval 0.416 to 2.06	0.600 unitless Interval 0.197 to 1.243	—	—
Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) Discontinuation Due to Any Reason=No (n=1008,1)	1.16 unitless Interval 0.332 to 2.02	0.626 unitless Interval 0.626 to 0.626	—	—
Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) At Least 1 AEI=Yes (n=536,75)	1.23 unitless Interval 0.453 to 2.09	0.600 unitless Interval 0.197 to 1.243	—	—
Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) At Least 1 AEI=No (578,1)	1.12 unitless Interval 0.297 to 1.98	0.929 unitless Interval 0.929 to 0.929	—	—
Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) At Least 1 AE=Yes (n=693,76)	1.22 unitless Interval 0.416 to 2.07	0.611 unitless Interval 0.197 to 1.243	—	—

SECONDARY outcome

Timeframe: Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours post-dose at Days 15 and 57. AEIs: 12 Weeks

Population: Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration. Number of participants analyzed is the number of participants simulated. Measured values are predicted values.

The PK model predicted the total PDE4 inhibitory activity and the median simulated percentage of participants with Adverse Events of Interest during 12 weeks of treatment based on 1000 participants simulated. Results are reported for the set of reference participants defined according to the covariates \[weight, smoking status, sex, age and long acting muscarinic antagonist (LAMA)\] included in the final model and tPDE4i. Adverse Events of Interest (AEI) for PK analyses included: headache, diarrhea, nausea, vomiting, abdominal pain, appetite disorders, sleep disorders, angioedema, psychiatric disorders (anxiety, nervousness), psychiatric disorders (depression, suicidal ideation, behaviour) and weight loss.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=1000 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=1000 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD n=1000 Participants Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Median Simulated Percentage of Participants With Adverse Events of Interest Weight=48 kg (tPDE4i=0.72,0.72,1.45)	53.2 percentage of participants Interval 0.352 to 2.03	53.2 percentage of participants Interval 0.197 to 1.243	61.8 percentage of participants	—
Median Simulated Percentage of Participants With Adverse Events of Interest Weight=74 kg (tPDE4i=0.65,0.65,1.30)	52.3 percentage of participants Interval 0.427 to 2.22	52.3 percentage of participants Interval 0.201 to 1.239	60.1 percentage of participants	—
Median Simulated Percentage of Participants With Adverse Events of Interest Weight=105 kg (tPDE4i=0.60.0.60,1.19)	51.7 percentage of participants Interval 0.339 to 2.02	51.7 percentage of participants Interval 0.212 to 1.069	58.8 percentage of participants	—
Median Simulated Percentage of Participants With Adverse Events of Interest Former Smoker (tPDE4i=0.65,0.65,1.30)	52.3 percentage of participants Interval 0.464 to 2.1	52.3 percentage of participants Interval 0.204 to 1.237	60.1 percentage of participants	—
Median Simulated Percentage of Participants With Adverse Events of Interest Current Smoker (tPDE4i=0.56,0.56,1.13)	42.5 percentage of participants Interval 0.337 to 2.02	42.5 percentage of participants Interval 0.209 to 1.006	49.2 percentage of participants	—
Median Simulated Percentage of Participants With Adverse Events of Interest Male (tPDE4i=0.65,0.65,1.30)	52.3 percentage of participants Interval 0.416 to 2.06	52.3 percentage of participants Interval 0.197 to 1.243	60.1 percentage of participants	—
Median Simulated Percentage of Participants With Adverse Events of Interest Female (tPDE4i=0.72,0.72,1.45)	53.2 percentage of participants Interval 0.332 to 2.02	53.2 percentage of participants Interval 0.626 to 0.626	61.8 percentage of participants	—
Median Simulated Percentage of Participants With Adverse Events of Interest Age=51 (tPDE4i=0.58,0.58,1.15)	51.4 percentage of participants Interval 0.453 to 2.09	51.4 percentage of participants Interval 0.197 to 1.243	58.4 percentage of participants	—
Median Simulated Percentage of Participants With Adverse Events of Interest Age=64 (tPDE4i=0.65,0.65,1.30)	52.3 percentage of participants Interval 0.297 to 1.98	52.3 percentage of participants Interval 0.929 to 0.929	60.1 percentage of participants	—
Median Simulated Percentage of Participants With Adverse Events of Interest Age=77 (tPDE4i=0.72,0.72,1.44)	53.2 percentage of participants Interval 0.416 to 2.07	53.2 percentage of participants Interval 0.197 to 1.243	61.7 percentage of participants	—
Median Simulated Percentage of Participants With Adverse Events of Interest With LAMA (tPDE4i=0.65,0.65,1.30)	52.3 percentage of participants Interval 0.294 to 1.97	52.3 percentage of participants	60.1 percentage of participants	—
Median Simulated Percentage of Participants With Adverse Events of Interest Without LAMA (tPDE4i=0.65,0.65,1.30)	43.5 percentage of participants	43.5 percentage of participants	51.4 percentage of participants	—

SECONDARY outcome

Timeframe: Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours post-dose at Days 15 and 57. FEV-1: Pre-dose and Weeks 4 and 12

Population: Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration. The number of participants analyzed is the number of participants simulated. Measured values are predicted values.

The PK model predicted the total PDE4 inhibitory activity and the median simulated Change from Baseline (CFB) in FEV1 at Week 4 and the Change from Baseline in FEV1 at Week 12 during 12 weeks of treatment with roflumilast 500 μg OD based on 1000 participants simulated. Results are reported for the set of reference participants defined according to the covariates \[weight, smoking status, sex, age, race, COPD severity, concomitant long acting muscarinic antagonist (LAMA) and Percent FEV1 reversibility\] included in the final model and tPDE4i. FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using spirometry prior to taking study medication. A positive change from Baseline indicates improvement.

Outcome measures

Outcome measures
Measure	Roflumilast 250 μg OD Then 500 μg OD n=1000 Participants Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD n=1000 Participants Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.	Roflumilast 250 µg Down-Titration 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 Weight=33.5 kg (tPDE4i=1.012,1.012)	50 milliliters (mL) Interval 0.197 to 1.243	32 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 Weight=70 kg (tPDE4i=0.839,0.839)	60.5 milliliters (mL) Interval 0.201 to 1.239	56 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 Weight=160 kg (tPDE4i=0.681,0.681)	108 milliliters (mL) Interval 0.212 to 1.069	157 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 Current Smoker (tPDE4i=0.729,0.729)	99.5 milliliters (mL) Interval 0.204 to 1.237	96.5 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 Former/Never Smoker (tPDE4i=0.839,0.839)	60.5 milliliters (mL) Interval 0.209 to 1.006	56 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 Male (tPDE4i=0.839,0.839)	60.5 milliliters (mL) Interval 0.197 to 1.243	56 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 Female (tPDE4i=0.937,0.937)	53.2 milliliters (mL) Interval 0.626 to 0.626	49.8 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 Age=40 years (tPDE4i=0.675,0.675)	57.6 milliliters (mL) Interval 0.197 to 1.243	52.2 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 Age=60 years (tPDE4i=0.839,0.839)	60.5 milliliters (mL) Interval 0.929 to 0.929	56 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 Age=92 years (tPDE4i=1.06,1.06)	56.4 milliliters (mL) Interval 0.197 to 1.243	53.3 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 Asian (tPDE4i=0.839,0.839)	56.1 milliliters (mL)	52 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 non-Asian (tPDE4i=0.839,0.839)	60.5 milliliters (mL)	56 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 COPD_Not Very Severe (tPDE4i=0.839,0.839)	60.5 milliliters (mL)	56 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 COPD_Very Severe (tPDE4i=0.839,0.839)	42.2 milliliters (mL)	39.1 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 LAMA=Yes (tPDE4i=0.839,0.839)	60.5 milliliters (mL)	56 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 LAMA=No (tPDE4i=0.839,0.839)	63.5 milliliters (mL)	58.8 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 %FEV1 Reversibility=-28% (tPDE4i=0.839,0.839)	68.1 milliliters (mL)	63.1 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 %FEV1 Reversibility=10% (tPDE4i=0.839,0.839)	60.5 milliliters (mL)	56 milliliters (mL)	—	—
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 %FEV1 Reversibility=147% (tPDE4i=0.839,0.839)	32.9 milliliters (mL)	30.5 milliliters (mL)	—	—

Adverse Events

Roflumilast 250 μg OD Then 500 μg OD_Main Treatment Period

Serious events: 19 serious events

Other events: 239 other events

Deaths: 0 deaths

Roflumilast 500 μg EOD Then 500 μg OD_Main Treatment Period

Serious events: 22 serious events

Other events: 248 other events

Deaths: 0 deaths

Roflumilast 500 μg OD_Main Treatment Period

Serious events: 20 serious events

Other events: 272 other events

Deaths: 0 deaths

Roflumilast 250 μg OD Then 500 μg OD_Down Titration Period

Serious events: 1 serious events

Other events: 13 other events

Deaths: 0 deaths

Roflumilast 500 μg EOD_Down-Titration Period

Serious events: 0 serious events

Other events: 21 other events

Deaths: 0 deaths

Roflumilast 500 μg OD_Down Titration Period

Serious events: 0 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Roflumilast 250 μg OD Then 500 μg OD_Main Treatment Period n=441 participants at risk Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD_Main Treatment Period n=437 participants at risk Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD_Main Treatment Period n=443 participants at risk Roflumilast 500 μg tablets, orally, once daily for 12 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 250 μg OD Then 500 μg OD_Down Titration Period n=27 participants at risk Participants in the roflumilast 250 μg once daily (OD) then 500 μg OD who were not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD_Down-Titration Period n=39 participants at risk Participants in the roflumilast 500 μg, every other day (EOD) treatment arm who were not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD_Down Titration Period n=38 participants at risk Participants in the roflumilast 500 μg once daily (OD) treatment arm who were not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Cardiac disorders Myocardial infarction	0.23% 1/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Cardiac disorders Myocardial ischaemia	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Cardiac disorders Atrial fibrillation	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Cardiac disorders Cardiac failure	0.23% 1/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Cardiac disorders Cardiopulmonary failure	0.23% 1/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Ear and labyrinth disorders Vertigo	0.23% 1/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Gastrointestinal disorders Abdominal mass	0.23% 1/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Gastrointestinal disorders Colitis ulcerative	0.23% 1/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Gastrointestinal disorders Femoral hernia incarcerated	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Infections and infestations Pneumonia	0.45% 2/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Infections and infestations Infective exacerbation of chronic obstructive airways disease	0.23% 1/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Infections and infestations Acute sinusitis	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Infections and infestations Appendicitis	0.23% 1/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Infections and infestations Bronchopneumonia	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Infections and infestations Respiratory tract infection	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Infections and infestations Upper respiratory tract infection	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Injury, poisoning and procedural complications Lower limb fracture	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Metabolism and nutrition disorders Gout	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Musculoskeletal and connective tissue disorders Spinal osteoarthritis	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Transitional cell carcinoma	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Nervous system disorders Sciatica	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Nervous system disorders Syncope	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Nervous system disorders Transient ischaemic attack	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Psychiatric disorders Anxiety	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	1.8% 8/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.0% 13/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	1.6% 7/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.7% 1/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.68% 3/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.68% 3/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Respiratory, thoracic and mediastinal disorders Pneumothorax spontaneous	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.23% 1/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Vascular disorders Hypertension	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Vascular disorders Hypertensive crisis	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Vascular disorders Vasculitis	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.23% 1/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.

Other adverse events

Other adverse events
Measure	Roflumilast 250 μg OD Then 500 μg OD_Main Treatment Period n=441 participants at risk Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD Then 500 μg OD_Main Treatment Period n=437 participants at risk Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD_Main Treatment Period n=443 participants at risk Roflumilast 500 μg tablets, orally, once daily for 12 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 250 μg OD Then 500 μg OD_Down Titration Period n=27 participants at risk Participants in the roflumilast 250 μg once daily (OD) then 500 μg OD who were not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg EOD_Down-Titration Period n=39 participants at risk Participants in the roflumilast 500 μg, every other day (EOD) treatment arm who were not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.	Roflumilast 500 μg OD_Down Titration Period n=38 participants at risk Participants in the roflumilast 500 μg once daily (OD) treatment arm who were not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Gastrointestinal disorders Abdominal pain upper	4.3% 19/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.4% 15/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	6.1% 27/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	7.7% 3/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	7.9% 3/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Gastrointestinal disorders Diarrhoea	24.3% 107/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	25.9% 113/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	30.2% 134/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	11.1% 3/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	15.4% 6/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	28.9% 11/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Gastrointestinal disorders Nausea	19.7% 87/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	21.1% 92/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	24.8% 110/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.7% 1/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	12.8% 5/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	21.1% 8/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Gastrointestinal disorders Abdominal pain	15.6% 69/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	13.3% 58/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	14.4% 64/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	15.4% 6/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	13.2% 5/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
General disorders Fatigue	0.91% 4/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.3% 10/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	1.1% 5/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.6% 1/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Infections and infestations Nasopharyngitis	1.6% 7/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.5% 11/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.7% 12/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	7.9% 3/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Investigations Weight decreased	2.3% 10/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.1% 9/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.8% 17/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	5.3% 2/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Metabolism and nutrition disorders Decreased appetite	22.7% 100/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	24.0% 105/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	29.1% 129/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	11.1% 3/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	20.5% 8/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	23.7% 9/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Musculoskeletal and connective tissue disorders Pain in extremity	4.5% 20/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	4.8% 21/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	4.5% 20/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Musculoskeletal and connective tissue disorders Arthralgia	1.8% 8/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	1.6% 7/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.0% 9/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Nervous system disorders Headache	24.3% 107/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	26.3% 115/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	26.0% 115/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	7.4% 2/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	17.9% 7/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	26.3% 10/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Nervous system disorders Dizziness	3.6% 16/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	4.6% 20/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.2% 14/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Psychiatric disorders Insomnia	22.0% 97/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	22.9% 100/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	23.9% 106/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	7.4% 2/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	25.6% 10/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	15.8% 6/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	7.7% 34/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	8.9% 39/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	8.6% 38/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	11.1% 3/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	7.7% 3/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.6% 1/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.4% 15/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.0% 13/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.5% 11/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.7% 1/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Blood and lymphatic system disorders Anaemia	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.6% 1/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Eye disorders Chalazion	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.6% 1/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Gastrointestinal disorders Bowel movement irregularity	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.6% 1/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Gastrointestinal disorders Duodenitis	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.6% 1/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Gastrointestinal disorders Dyspepsia	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.7% 1/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
General disorders Feeling hot	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.7% 1/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
General disorders Malaise	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.7% 1/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Infections and infestations Pharyngitis	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.7% 1/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	5.3% 2/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Infections and infestations Candida infection	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.7% 1/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Infections and infestations Rhinitis	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.7% 1/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Infections and infestations Viral pharyngitis	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.6% 1/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Injury, poisoning and procedural complications Procedural dizziness	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.7% 1/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Injury, poisoning and procedural complications Skin abrasion	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.7% 1/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Investigations Blood glucose increased	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.6% 1/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.6% 1/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Nervous system disorders Tremor	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	7.4% 2/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.6% 1/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Nervous system disorders Amnesia	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	3.7% 1/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Reproductive system and breast disorders Postmenopausal haemorrhage	0.00% 0/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.6% 1/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
Infections and infestations Bronchitis	1.4% 6/441 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.92% 4/437 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	2.0% 9/443 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/27 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/39 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.	0.00% 0/38 • Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days). Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.

Additional Information

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AstraZeneca

Phone: 1-877-240-9479

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Publication restrictions are in place

Restriction type: OTHER