Trial Outcomes & Findings for A 6-Month Efficacy and Safety Study of Org 50081 in Adult Patients With Chronic Primary Insomnia (21106/P05701/MK-8265-002) (NCT NCT00631657)

Results Overview

TST was defined as the time recorded for sleep diary question 6 "How much time did you actually spend sleeping?" as reported by participants using a LogPad (hand-held electronic data capture device). Baseline was defined as the mean TST from the Placebo Run-in Period. Change from Baseline was calculated as the mean of combined data from Weeks 14 through 26, using a last observation carried forward (LOCF) approach.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

460 participants

Primary outcome timeframe

Baseline and the Mean of Weeks 14-26

Results posted on

2018-10-02

Participant Flow

Participant milestones

Participant milestones
Measure	Esmirtazapine 4.5 mg/Esmirtazapine 4.5 mg Participants receive esmirtazapine 4.5 mg tablets, administered once a day (QD) for 6 months, then participants receive esmirtazapine 4.5 mg tablets, administered QD for 7 days	Esmirtazapine 4.5 mg/Placebo Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months, then participants receive placebo tablets, administered QD for 7 days	Placebo/Placebo Participants receive placebo tablets, administered QD for 6 months, then participants receive placebo tablets, administered QD for 7 days
6-Month Treatment Period STARTED	344	0	116
6-Month Treatment Period Treated	342	0	115
6-Month Treatment Period COMPLETED	203	0	66
6-Month Treatment Period NOT COMPLETED	141	0	50
7-Day Discontinuation Period STARTED	67	137	66
7-Day Discontinuation Period Treated	66	136	65
7-Day Discontinuation Period COMPLETED	65	136	65
7-Day Discontinuation Period NOT COMPLETED	2	1	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Esmirtazapine 4.5 mg/Esmirtazapine 4.5 mg Participants receive esmirtazapine 4.5 mg tablets, administered once a day (QD) for 6 months, then participants receive esmirtazapine 4.5 mg tablets, administered QD for 7 days	Esmirtazapine 4.5 mg/Placebo Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months, then participants receive placebo tablets, administered QD for 7 days	Placebo/Placebo Participants receive placebo tablets, administered QD for 6 months, then participants receive placebo tablets, administered QD for 7 days
6-Month Treatment Period Adverse Event	47	0	7
6-Month Treatment Period Withdrawal by Subject	14	0	5
6-Month Treatment Period Lack of Efficacy	34	0	25
6-Month Treatment Period Lost to Follow-up	7	0	2
6-Month Treatment Period Uncooperative Reasons Unrelated to Trial	21	0	6
6-Month Treatment Period Other	16	0	4
6-Month Treatment Period Not Treated	2	0	1
7-Day Discontinuation Period Not Treated	1	1	1
7-Day Discontinuation Period Other	1	0	0

Baseline Characteristics

A 6-Month Efficacy and Safety Study of Org 50081 in Adult Patients With Chronic Primary Insomnia (21106/P05701/MK-8265-002)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Esmirtazapine 4.5 mg n=342 Participants Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months	Placebo n=115 Participants Participants receive placebo tablets, administered QD for 6 months	Total n=457 Participants Total of all reporting groups
Age, Continuous	47.4 years STANDARD_DEVIATION 11.4 • n=5 Participants	49.0 years STANDARD_DEVIATION 11.1 • n=7 Participants	47.8 years STANDARD_DEVIATION 11.3 • n=5 Participants
Sex: Female, Male Female	210 Participants n=5 Participants	71 Participants n=7 Participants	281 Participants n=5 Participants
Sex: Female, Male Male	132 Participants n=5 Participants	44 Participants n=7 Participants	176 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and the Mean of Weeks 14-26

Population: The Intent-To-Treat (ITT) population consisted of all participants who received at least one dose of study drug and had a baseline and at least one postbaseline TST efficacy assessment.

TST was defined as the time recorded for sleep diary question 6 "How much time did you actually spend sleeping?" as reported by participants using a LogPad (hand-held electronic data capture device). Baseline was defined as the mean TST from the Placebo Run-in Period. Change from Baseline was calculated as the mean of combined data from Weeks 14 through 26, using a last observation carried forward (LOCF) approach.

Outcome measures

Outcome measures
Measure	Esmirtazapine 4.5 mg n=342 Participants Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months	Placebo n=115 Participants Participants receive placebo tablets, administered QD for 6 months	Placebo/Placebo Participants receive placebo tablets, administered QD for 6 months during the Treatment Period, followed by placebo tablets, administered QD for 7 days during the Discontinuation Period
Change From Baseline in Total Sleep Time (TST) - 6-Month Treatment Period	65.9 minutes Standard Deviation 71.9	19.3 minutes Standard Deviation 62.1	—

SECONDARY outcome

Timeframe: Up to 31 weeks

Population: The All-Subjects-Treated (AST) population consisted of all participants who received at least one dose of any study drug.

An AE is defined as any unfavorable and unintended change in the structure, function or chemistry of the body whether or not considered related to study drug. The number of participants who experienced AEs is combined for the 6-Month Treatment Period and the 7-Day Discontinuation Period.

Outcome measures

Outcome measures
Measure	Esmirtazapine 4.5 mg n=342 Participants Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months	Placebo n=115 Participants Participants receive placebo tablets, administered QD for 6 months	Placebo/Placebo Participants receive placebo tablets, administered QD for 6 months during the Treatment Period, followed by placebo tablets, administered QD for 7 days during the Discontinuation Period
Number of Participants Who Experienced Adverse Events (AEs)	253 participants	75 participants	—

SECONDARY outcome

Timeframe: Up to 27 weeks

Population: The AST population consisted of all participants who received at least one dose of any study drug.

An AE is defined as any unfavorable and unintended change in the structure, function or chemistry of the body whether or not considered related to study drug. The number of participants who discontinued study drug due to an AE is combined for the 6-Month Treatment Period and the 7-Day Discontinuation Period.

Outcome measures

Outcome measures
Measure	Esmirtazapine 4.5 mg n=342 Participants Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months	Placebo n=115 Participants Participants receive placebo tablets, administered QD for 6 months	Placebo/Placebo Participants receive placebo tablets, administered QD for 6 months during the Treatment Period, followed by placebo tablets, administered QD for 7 days during the Discontinuation Period
Number of Participants Who Discontinued Study Drug Due to an AE	47 participants	7 participants	—

SECONDARY outcome

Timeframe: Baseline and the Mean of Weeks 14-26

Population: The ITT population consisted of all participants who received at least one dose of study drug and had a baseline and at least one postbaseline SL efficacy assessment.

SL was defined as the time recorded for sleep diary question 3 "How long did it take you to fall asllep?", as reported by participants using a LogPad. Baseline was defined as the mean SL from the Placebo Run-in Period. Change from Baseline was calculated as the mean of combined data from Weeks 14 through 26, using an LOCF approach.

Outcome measures

Outcome measures
Measure	Esmirtazapine 4.5 mg n=342 Participants Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months	Placebo n=115 Participants Participants receive placebo tablets, administered QD for 6 months	Placebo/Placebo Participants receive placebo tablets, administered QD for 6 months during the Treatment Period, followed by placebo tablets, administered QD for 7 days during the Discontinuation Period
Change From Baseline in Sleep Latency (SL) - 6-Month Treatment Period	-29.7 minutes Standard Deviation 47.3	-26.9 minutes Standard Deviation 46.8	—

SECONDARY outcome

Timeframe: Baseline and the Mean of Weeks 14-26

Population: The ITT population consisted of all participants who received at least one dose of study drug and had a baseline and at least one postbaseline WASO efficacy assessment.

WASO was defined as the time recorded for sleep diary question 5 "How much time were you awake, after falling asleep initially?", as reported by participants using a LogPad. Baseline was defined as the mean WASO from the Placebo Run-in Period. Change from Baseline was calculated as the mean of combined data from Weeks 14 through 26, using an LOCF approach.

Outcome measures

Outcome measures
Measure	Esmirtazapine 4.5 mg n=342 Participants Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months	Placebo n=115 Participants Participants receive placebo tablets, administered QD for 6 months	Placebo/Placebo Participants receive placebo tablets, administered QD for 6 months during the Treatment Period, followed by placebo tablets, administered QD for 7 days during the Discontinuation Period
Change From Baseline in Wake Time After Sleep Onset (WASO) - 6-Month Treatment Period	-46.4 minutes Standard Deviation 57.7	-20.8 minutes Standard Deviation 51.4	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and the Mean of Weeks 14-26

Population: The ITT population consisted of all participants who received at least one dose of study drug and had a baseline and at least one postbaseline NAW efficacy assessment.

NAW was defined as the number of times recorded for sleep diary question 4a "How many times did you wake up during the night?", as reported by participants using a LogPad. Baseline was defined as the mean NAW from the Placebo Run-in Period. Change from Baseline was calculated as the mean of combined data from Weeks 14 through 26, using an LOCF approach.

Outcome measures

Outcome measures
Measure	Esmirtazapine 4.5 mg n=342 Participants Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months	Placebo n=115 Participants Participants receive placebo tablets, administered QD for 6 months	Placebo/Placebo Participants receive placebo tablets, administered QD for 6 months during the Treatment Period, followed by placebo tablets, administered QD for 7 days during the Discontinuation Period
Change From Baseline in Number of Awakenings (NAW) - 6-Month Treatment Period	-0.8 number of awakenings Standard Deviation 1.2	-0.5 number of awakenings Standard Deviation 0.9	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and the Mean of Weeks 14-26

Population: The ITT population consisted of all participants who received at least one dose of study drug and had a baseline and at least one postbaseline Sleep Quality efficacy assessment.

Sleep Quality was assessed using a Visual Analog Scale (VAS) in response to the sleep diary question 7 "Rate the quality of your sleep last night", as reported by participants using a LogPad. Responses could range from 0=Very poor to 100=Excellent, with a higher score indicating greater sleep quality. Baseline was defined as the mean Sleep Quality score from the Placebo Run-in Period. Change from Baseline was calculated as the mean of combined data from Weeks 14 through 26, using an LOCF approach.

Outcome measures

Outcome measures
Measure	Esmirtazapine 4.5 mg n=342 Participants Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months	Placebo n=115 Participants Participants receive placebo tablets, administered QD for 6 months	Placebo/Placebo Participants receive placebo tablets, administered QD for 6 months during the Treatment Period, followed by placebo tablets, administered QD for 7 days during the Discontinuation Period
Change From Baseline in Sleep Quality - 6-Month Treatment Period	16.1 score on a scale Standard Deviation 19.5	5.8 score on a scale Standard Deviation 14.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and the Mean of Weeks 14-26

Population: The ITT population consisted of all participants who received at least one dose of study drug and had a baseline and at least one postbaseline Satisfaction with Sleep Duration efficacy assessment.

Satifaction with Sleep Duration was assessed using a Visual Analog Scale (VAS) in response to the sleep diary question 8 "How satisfied are you about your sleep duration of last night?", as reported by participants using a LogPad. Responses could range from 0=Very unsatisfied to 100=Fully satisfied, with a higher score indicating great satisfaction with sleep duration. Baseline was defined as the mean Satisfaction with Sleep Duration score from the Placebo Run-in Period. Change from Baseline was calculated as the mean of combined data from Weeks 14 through 26, using an LOCF approach.

Outcome measures

Outcome measures
Measure	Esmirtazapine 4.5 mg n=342 Participants Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months	Placebo n=115 Participants Participants receive placebo tablets, administered QD for 6 months	Placebo/Placebo Participants receive placebo tablets, administered QD for 6 months during the Treatment Period, followed by placebo tablets, administered QD for 7 days during the Discontinuation Period
Change From Baseline in Satisfaction With Sleep Duration - 6-Month Treatment Period	18.3 score on a scale Standard Deviation 20.1	7.2 score on a scale Standard Deviation 15.9	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 26

Population: The ITT population consisted of all participants who received at least one dose of study drug and had a baseline and a Week 26 SF-36 efficacy assessment.

SF-36 is a participant-rated questionnaire that consists of 8 scaled scores: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each of the 8 questions carries equal weight. The SF-36 can be divided into 2 aggregate summary measures: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The scores can range from 0 to 100, with a lower score indicating more disability. Baseline was defined as the SF-36 score assessed at randomization.

Outcome measures

Outcome measures
Measure	Esmirtazapine 4.5 mg n=189 Participants Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months	Placebo n=63 Participants Participants receive placebo tablets, administered QD for 6 months	Placebo/Placebo Participants receive placebo tablets, administered QD for 6 months during the Treatment Period, followed by placebo tablets, administered QD for 7 days during the Discontinuation Period
Change From Baseline in Two Aggregate Measures of Short Form 36 (SF-36) Health Survey Score - 6-Month Treatment Period Change from BL at Week 26 - PCS	1.6 score on a scale Standard Deviation 6.8	-0.2 score on a scale Standard Deviation 6.0	—
Change From Baseline in Two Aggregate Measures of Short Form 36 (SF-36) Health Survey Score - 6-Month Treatment Period Change from BL at Week 26 - MCS	4.6 score on a scale Standard Deviation 10.8	4.5 score on a scale Standard Deviation 9.1	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 26

Population: The ITT population consisted of all participants who received at least one dose of study drug and had a baseline and a Week 26 IGR efficacy assessment.

The IGR is a clinician-rated 7-point scale used to assess the severity of illness. Severity is rated on a scale from 1=Normal to 7=Extremely severe. Baseline was defined as the last non-missing value obtained during the Placebo Run-in Period. IGR assessments were done at Baseline of the 6-Month Treatment Period and and at the end of the 6-Month Treatment Period to assess the effects of treatment.

Outcome measures

Outcome measures
Measure	Esmirtazapine 4.5 mg n=200 Participants Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months	Placebo n=65 Participants Participants receive placebo tablets, administered QD for 6 months	Placebo/Placebo Participants receive placebo tablets, administered QD for 6 months during the Treatment Period, followed by placebo tablets, administered QD for 7 days during the Discontinuation Period
Change From Baseline in Investigator Global Rating (IGR) - 6-Month Treatment Period	-2.1 score on a scale Standard Deviation 1.4	-1.4 score on a scale Standard Deviation 1.4	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and End of 7-day Discontinuation Period

Population: The ITT population consisted of all participants who received at least one dose of study drug and had a baseline and a 7-Day Discontinuation Period IGR efficacy assessment.

The IGR is a clinician-rated 7-point scale used to assess the severity of illness. Severity is rated on a scale from 1=Normal to 7=Extremely severe. Baseline was defined as the last non-missing value obtained during the Placebo Run-in Period. IGR assessments were done at Baseline of the 6-Month Treatment Period and and at the end of the 7-day Discontinuation Period to assess the effects of discontinuing treatment.

Outcome measures

Outcome measures
Measure	Esmirtazapine 4.5 mg n=59 Participants Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months	Placebo n=128 Participants Participants receive placebo tablets, administered QD for 6 months	Placebo/Placebo n=60 Participants Participants receive placebo tablets, administered QD for 6 months during the Treatment Period, followed by placebo tablets, administered QD for 7 days during the Discontinuation Period
Change From Baseline in Investigator Global Rating (IGR) - 7-Day Discontinuation Period	0.3 score on a scale Standard Deviation 0.7	0.5 score on a scale Standard Deviation 1.0	0.0 score on a scale Standard Deviation 0.7

Adverse Events

Esmirtazapine 4.5 mg

Serious events: 8 serious events

Other events: 183 other events

Deaths: 0 deaths

Placebo

Serious events: 2 serious events

Other events: 40 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Esmirtazapine 4.5 mg n=342 participants at risk Participants receive esmirtazapine 4.5 mg tablets, administered QD	Placebo n=115 participants at risk Participants receive placebo tablets, administered QD
Gastrointestinal disorders Dry mouth	5.8% 20/342 • Number of events 21 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	4.3% 5/115 • Number of events 5 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
General disorders Fatigue	5.3% 18/342 • Number of events 20 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	6.1% 7/115 • Number of events 7 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Infections and infestations Nasopharyngitis	10.2% 35/342 • Number of events 42 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	12.2% 14/115 • Number of events 17 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Investigations Weight increased	17.0% 58/342 • Number of events 63 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	3.5% 4/115 • Number of events 4 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Metabolism and nutrition disorders Increased appetite	9.9% 34/342 • Number of events 37 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.87% 1/115 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Nervous system disorders Dizziness	7.9% 27/342 • Number of events 29 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	3.5% 4/115 • Number of events 4 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Nervous system disorders Headache	8.8% 30/342 • Number of events 35 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	12.2% 14/115 • Number of events 21 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Nervous system disorders Somnolence	14.9% 51/342 • Number of events 56 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	3.5% 4/115 • Number of events 4 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Esmirtazapine 4.5 mg n=342 participants at risk Participants receive esmirtazapine 4.5 mg tablets, administered QD	Placebo n=115 participants at risk Participants receive placebo tablets, administered QD
Cardiac disorders Coronary artery disease	0.29% 1/342 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.00% 0/115 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Eye disorders Retinal vein occlusion	0.29% 1/342 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.00% 0/115 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Eye disorders Sudden visual loss	0.29% 1/342 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.00% 0/115 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Gastrointestinal disorders Pancreatitis	0.29% 1/342 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.00% 0/115 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Infections and infestations Infectious mononucleosis	0.29% 1/342 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.00% 0/115 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Injury, poisoning and procedural complications Cartilage injury	0.00% 0/342 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.87% 1/115 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Injury, poisoning and procedural complications Concussion	0.29% 1/342 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.00% 0/115 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Injury, poisoning and procedural complications Facial bones fracture	0.29% 1/342 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.00% 0/115 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Injury, poisoning and procedural complications Fall	0.00% 0/342 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.87% 1/115 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Injury, poisoning and procedural complications Limb injury	0.00% 0/342 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.87% 1/115 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Injury, poisoning and procedural complications Road traffic accident	0.29% 1/342 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.00% 0/115 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Injury, poisoning and procedural complications Synovial rupture	0.29% 1/342 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.00% 0/115 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.29% 1/342 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.00% 0/115 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.29% 1/342 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.00% 0/115 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Nervous system disorders Nerve compression	0.29% 1/342 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.00% 0/115 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
Surgical and medical procedures Bunion operation	0.29% 1/342 • Number of events 1 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.	0.00% 0/115 • Up to 30 days after last dose of study drug (up to 31 weeks) AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.