Trial Outcomes & Findings for A Study to Assess the Efficacy and Safety of PT009 Compared to PT005 on COPD Exacerbations Over a 52-Week Period in Subjects With Moderate to Very Severe COPD (Sophos) (NCT NCT02727660)

NCT ID: NCT02727660

Last Updated: 2019-09-26

Results Overview

Morning pre-dose trough FEV1 (Forced Expiratory Volume in one second) at week 12

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1876 participants

Primary outcome timeframe

at Week 12

Results posted on

2019-09-26

Participant Flow

This study screened subjects at 292 study centers in 18 countries and randomized subjects at 259 study centers, from April 2016 to April 2018.

Subjects were randomized in a 1:1:1 ratio to BFF MDI 320/9.6 μg, BFF MDI 160/9.6 μg, and FF MDI 9.6 μg treatment groups

Participant milestones

Participant milestones
Measure	BFF MDI 320/9.6 ug Budesonide Formoterol Fumarate Metered dose inhalation 320/9.6 ug	BFF MDI 160/9.6 ug Budesonide Formoterol Fumarate Metered dose inhalation 160/9.6 ug	FF MDI 9.6 ug Formoterol Fumarate Metered dose inhalation 9.6 ug
Overall Study STARTED	619	617	607
Overall Study COMPLETED	503	501	442
Overall Study NOT COMPLETED	116	116	165

Reasons for withdrawal

Reasons for withdrawal
Measure	BFF MDI 320/9.6 ug Budesonide Formoterol Fumarate Metered dose inhalation 320/9.6 ug	BFF MDI 160/9.6 ug Budesonide Formoterol Fumarate Metered dose inhalation 160/9.6 ug	FF MDI 9.6 ug Formoterol Fumarate Metered dose inhalation 9.6 ug
Overall Study Lack of Efficacy	40	40	70
Overall Study Adverse Event	28	21	32
Overall Study Withdrawal by Subject	26	25	30
Overall Study Physician Decision	3	8	14
Overall Study Lost to Follow-up	5	9	8
Overall Study Protocol Violation	7	5	5
Overall Study Protocol Specified Disc. Criteria	5	5	2
Overall Study Administrative Reasons	2	3	4

Baseline Characteristics

mITT Population

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	BFF MDI 320/9.6 ug n=629 Participants Budesonide Formoterol Fumarate Metered dose inhalation 320/9.6 ug	BFF MDI 160/9.6 ug n=630 Participants Budesonide Formoterol Fumarate Metered dose inhalation 160/9.6 ug	FF MDI 9.6 ug n=617 Participants Formoterol Fumarate Metered dose inhalation 9.6 ug	Total n=1876 Participants Total of all reporting groups
Age, Continuous	65.3 Years STANDARD_DEVIATION 8.1 • n=619 Participants • mITT Population	64.5 Years STANDARD_DEVIATION 8.4 • n=617 Participants • mITT Population	64.8 Years STANDARD_DEVIATION 8.5 • n=607 Participants • mITT Population	64.9 Years STANDARD_DEVIATION 8.3 • n=1843 Participants • mITT Population
Sex: Female, Male Female	252 Participants n=619 Participants • mITT Population	272 Participants n=617 Participants • mITT Population	268 Participants n=607 Participants • mITT Population	792 Participants n=1843 Participants • mITT Population
Sex: Female, Male Male	367 Participants n=619 Participants • mITT Population	345 Participants n=617 Participants • mITT Population	339 Participants n=607 Participants • mITT Population	1051 Participants n=1843 Participants • mITT Population
Ethnicity (NIH/OMB) Hispanic or Latino	190 Participants n=619 Participants • mITT Population	200 Participants n=617 Participants • mITT Population	190 Participants n=607 Participants • mITT Population	580 Participants n=1843 Participants • mITT Population
Ethnicity (NIH/OMB) Not Hispanic or Latino	423 Participants n=619 Participants • mITT Population	414 Participants n=617 Participants • mITT Population	412 Participants n=607 Participants • mITT Population	1249 Participants n=1843 Participants • mITT Population
Ethnicity (NIH/OMB) Unknown or Not Reported	6 Participants n=619 Participants • mITT Population	3 Participants n=617 Participants • mITT Population	5 Participants n=607 Participants • mITT Population	14 Participants n=1843 Participants • mITT Population
Race (NIH/OMB) American Indian or Alaska Native	26 Participants n=619 Participants • mITT Population	18 Participants n=617 Participants • mITT Population	24 Participants n=607 Participants • mITT Population	68 Participants n=1843 Participants • mITT Population
Race (NIH/OMB) Asian	1 Participants n=619 Participants • mITT Population	7 Participants n=617 Participants • mITT Population	4 Participants n=607 Participants • mITT Population	12 Participants n=1843 Participants • mITT Population
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=619 Participants • mITT Population	0 Participants n=617 Participants • mITT Population	0 Participants n=607 Participants • mITT Population	1 Participants n=1843 Participants • mITT Population
Race (NIH/OMB) Black or African American	30 Participants n=619 Participants • mITT Population	22 Participants n=617 Participants • mITT Population	29 Participants n=607 Participants • mITT Population	81 Participants n=1843 Participants • mITT Population
Race (NIH/OMB) White	514 Participants n=619 Participants • mITT Population	516 Participants n=617 Participants • mITT Population	504 Participants n=607 Participants • mITT Population	1534 Participants n=1843 Participants • mITT Population
Race (NIH/OMB) More than one race	0 Participants n=619 Participants • mITT Population	0 Participants n=617 Participants • mITT Population	0 Participants n=607 Participants • mITT Population	0 Participants n=1843 Participants • mITT Population
Race (NIH/OMB) Unknown or Not Reported	47 Participants n=619 Participants • mITT Population	54 Participants n=617 Participants • mITT Population	46 Participants n=607 Participants • mITT Population	147 Participants n=1843 Participants • mITT Population

PRIMARY outcome

Timeframe: at Week 12

Population: mITT Population Only subjects who had morning pre-dose trough FEV1 measured at the week 12 visit are included in the "at Week 12" timepoint

Morning pre-dose trough FEV1 (Forced Expiratory Volume in one second) at week 12

Outcome measures

Outcome measures
Measure	BFF MDI 320/9.6 ug n=542 Participants Budesonide Formoterol Fumarate Metered dose inhalation 320/9.6 ug	BFF MDI 160/9.6 ug n=540 Participants Budesonide Formoterol Fumarate Metered dose inhalation 160/9.6 ug	FF MDI 9.6 ug n=501 Participants Formoterol Fumarate Metered dose inhalation 9.6 ug
Morning Pre-dose Trough FEV1	0.072 Liter Interval 0.053 to 0.09	0.069 Liter Interval 0.051 to 0.087	0.037 Liter Interval 0.018 to 0.056

SECONDARY outcome

Timeframe: over 52 weeks

Population: mITT Population

Time to first moderate or severe COPD (Chronic Obstructive Pulmonary Disease) exacerbation over 52 weeks

Outcome measures

Outcome measures
Measure	BFF MDI 320/9.6 ug n=619 Participants Budesonide Formoterol Fumarate Metered dose inhalation 320/9.6 ug	BFF MDI 160/9.6 ug n=617 Participants Budesonide Formoterol Fumarate Metered dose inhalation 160/9.6 ug	FF MDI 9.6 ug n=607 Participants Formoterol Fumarate Metered dose inhalation 9.6 ug
Time to First Moderate or Severe COPD Exacerbation Percent of Subjects Exacerbated within 24 Weeks	31.2 Percentage of Subjects with Exacerbation Interval 27.5 to 35.4	32.9 Percentage of Subjects with Exacerbation Interval 29.1 to 37.1	35.1 Percentage of Subjects with Exacerbation Interval 31.3 to 39.4
Time to First Moderate or Severe COPD Exacerbation Percent of Subjects Exacerbated within 12 Weeks	19.2 Percentage of Subjects with Exacerbation Interval 16.2 to 22.6	19.3 Percentage of Subjects with Exacerbation Interval 16.3 to 22.7	24.8 Percentage of Subjects with Exacerbation Interval 21.5 to 28.6
Time to First Moderate or Severe COPD Exacerbation Percent of Subjects Exacerbated within 36 Weeks	41.0 Percentage of Subjects with Exacerbation Interval 36.5 to 45.9	41.3 Percentage of Subjects with Exacerbation Interval 36.9 to 46.0	46.2 Percentage of Subjects with Exacerbation Interval 41.5 to 51.2
Time to First Moderate or Severe COPD Exacerbation Percent of Subjects Exacerbated within 52 Weeks	50.1 Percentage of Subjects with Exacerbation Interval 44.4 to 56.0	48.6 Percentage of Subjects with Exacerbation Interval 43.1 to 54.4	54.8 Percentage of Subjects with Exacerbation Interval 49.0 to 60.7

SECONDARY outcome

Timeframe: over 12 weeks

Population: mITT Population Only subjects who had rescue Ventolin HFA doses recorded over the 12 week period are included in the "over 12 Weeks" timepoint

Change from baseline in average daily rescue Ventolin HFA use over 12 weeks

Outcome measures

Outcome measures
Measure	BFF MDI 320/9.6 ug n=612 Participants Budesonide Formoterol Fumarate Metered dose inhalation 320/9.6 ug	BFF MDI 160/9.6 ug n=610 Participants Budesonide Formoterol Fumarate Metered dose inhalation 160/9.6 ug	FF MDI 9.6 ug n=599 Participants Formoterol Fumarate Metered dose inhalation 9.6 ug
Change From Baseline in Average Daily Rescue Ventolin HFA Use	-0.9 Puffs per day Interval -1.1 to -0.7	-0.9 Puffs per day Interval -1.1 to -0.7	-0.6 Puffs per day Interval -0.8 to -0.4

SECONDARY outcome

Timeframe: at Week 12

Population: mITT Population

The SGRQ (St. George's Respiratory Questionnaire) is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of BFF MDI on health-related quality of life as compared to FF MDI in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. A decrease from baseline in SGRQ total score of 4 units or more is considered a clinically meaningful improvement in quality of life.

Outcome measures

Outcome measures
Measure	BFF MDI 320/9.6 ug n=619 Participants Budesonide Formoterol Fumarate Metered dose inhalation 320/9.6 ug	BFF MDI 160/9.6 ug n=617 Participants Budesonide Formoterol Fumarate Metered dose inhalation 160/9.6 ug	FF MDI 9.6 ug n=607 Participants Formoterol Fumarate Metered dose inhalation 9.6 ug
Percentage of Subjects Achieving an MCID (Minimal Clinically Important Difference) of 4 Units or More in Saint George's Respiratory Questionnaire (SGRQ) Total Score	52 Percentage of Subjects	54 Percentage of Subjects	44 Percentage of Subjects

Adverse Events

BFF MDI 320/9.6 ug

Serious events: 60 serious events

Other events: 266 other events

Deaths: 3 deaths

BFF MDI 160/9.6 ug

Serious events: 78 serious events

Other events: 279 other events

Deaths: 4 deaths

FF MDI 9.6 ug

Serious events: 83 serious events

Other events: 268 other events

Deaths: 8 deaths

Serious adverse events

Other adverse events

Additional Information

Paul M. Dorinsky, MD

Pearl Therapeutics, a Member of the AstraZeneca Group

Phone: 650-305-2600

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Drafts of any and all publications or presentations of this study must be submitted at least 30 days prior to submission for publication or presentation to Pearl Therapeutics for review, approval, and to ensure consistency. Pearl Therapeutics has the right to request appropriate modification to correct facts and to represent it's opinions, or the opinions of the publication committee, if these differ with the proposed publication.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	BFF MDI 320/9.6 ug n=619 participants at risk Budesonide Formoterol Fumarate Metered dose inhalation 320/9.6 ug	BFF MDI 160/9.6 ug n=617 participants at risk Budesonide Formoterol Fumarate Metered dose inhalation 160/9.6 ug	FF MDI 9.6 ug n=607 participants at risk Formoterol Fumarate Metered dose inhalation 9.6 ug
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	4.4% 27/619 • Number of events 32 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	4.9% 30/617 • Number of events 33 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	8.2% 50/607 • Number of events 65 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.32% 2/619 • Number of events 2 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.32% 2/617 • Number of events 2 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.99% 6/607 • Number of events 6 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.16% 1/619 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/617 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 4 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.32% 2/617 • Number of events 2 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.32% 2/617 • Number of events 2 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Respiratory, thoracic and mediastinal disorders Hypercapnia	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Respiratory, thoracic and mediastinal disorders Hypoxia	0.16% 1/619 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/607 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.16% 1/619 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/607 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Respiratory, thoracic and mediastinal disorders Pulmonary alveolar haemorrhage	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Pneumonia	0.97% 6/619 • Number of events 6 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	1.9% 12/617 • Number of events 12 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	1.5% 9/607 • Number of events 9 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Bronchitis	0.16% 1/619 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/617 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Influenza	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.32% 2/617 • Number of events 2 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Sepsis	0.16% 1/619 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.33% 2/607 • Number of events 2 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Urinary tract infection	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.32% 2/617 • Number of events 4 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/607 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Gastroenteritis	0.16% 1/619 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Diverticulitis	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 2 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Abscess intestinal	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Appendicitis perforated	0.16% 1/619 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/607 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Clostridial infection	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Clostridium difficile colitis	0.16% 1/619 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/607 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Clostridium difficile infection	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/617 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/607 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Hydrocele male infected	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/617 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/607 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Osteomyelitis	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Pneumonia bacterial	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Pnuemonia mycoplasmal	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Pneumonia streptococcal	0.16% 1/619 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/607 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Post procedural infection	0.16% 1/619 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/607 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Pyelonephritis	0.16% 1/619 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/607 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Septic shock	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/617 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/607 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Cardiac disorders Acute myocardial infarction	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.66% 4/607 • Number of events 4 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Cardiac disorders Cardiac failure congestive	0.16% 1/619 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.32% 2/617 • Number of events 2 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Cardiac disorders Atrial fibrilation	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.49% 3/617 • Number of events 3 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/607 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Cardiac disorders Myocardial infarction	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.32% 2/617 • Number of events 2 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Cardiac disorders Cardiac arrest	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.33% 2/607 • Number of events 2 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Cardiac disorders Cardiac failure	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/617 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/607 • Number of events 2 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Cardiac disorders Angina unstable	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/617 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/607 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Cardiac disorders Atrial flutter	0.00% 0/619 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.16% 1/617 • Number of events 1 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.00% 0/607 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).

Other adverse events
Measure	BFF MDI 320/9.6 ug n=619 participants at risk Budesonide Formoterol Fumarate Metered dose inhalation 320/9.6 ug	BFF MDI 160/9.6 ug n=617 participants at risk Budesonide Formoterol Fumarate Metered dose inhalation 160/9.6 ug	FF MDI 9.6 ug n=607 participants at risk Formoterol Fumarate Metered dose inhalation 9.6 ug
Infections and infestations Nasopharyngitis	6.6% 41/619 • Number of events 53 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	8.6% 53/617 • Number of events 61 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	5.9% 36/607 • Number of events 43 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Upper respiratory tract infection	4.5% 28/619 • Number of events 29 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	2.3% 14/617 • Number of events 18 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	4.0% 24/607 • Number of events 28 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Pneumonia	2.3% 14/619 • Number of events 14 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	3.1% 19/617 • Number of events 20 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	2.5% 15/607 • Number of events 15 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Influenza	2.4% 15/619 • Number of events 15 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	3.1% 19/617 • Number of events 20 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	1.6% 10/607 • Number of events 10 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Bronchitis	1.8% 11/619 • Number of events 11 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	2.1% 13/617 • Number of events 15 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	1.6% 10/607 • Number of events 14 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Sinusitis	1.5% 9/619 • Number of events 9 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	1.5% 9/617 • Number of events 11 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	2.1% 13/607 • Number of events 13 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Acute sinusitis	0.32% 2/619 • Number of events 2 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.97% 6/617 • Number of events 10 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	2.0% 12/607 • Number of events 17 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	4.4% 27/619 • Number of events 32 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	4.9% 30/617 • Number of events 33 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	8.2% 50/607 • Number of events 65 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.7% 23/619 • Number of events 23 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	2.6% 16/617 • Number of events 19 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	2.6% 16/607 • Number of events 18 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Gastrointestinal disorders Diarrhoea	2.1% 13/619 • Number of events 14 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	1.6% 10/617 • Number of events 11 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	1.6% 10/607 • Number of events 11 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Nervous system disorders Headache	2.6% 16/619 • Number of events 24 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	3.1% 19/617 • Number of events 24 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	3.0% 18/607 • Number of events 20 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Vascular disorders Hypertension	2.4% 15/619 • Number of events 15 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	2.4% 15/617 • Number of events 15 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	2.3% 14/607 • Number of events 14 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Musculoskeletal and connective tissue disorders Back pain	2.4% 15/619 • Number of events 21 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	2.8% 17/617 • Number of events 17 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	1.8% 11/607 • Number of events 13 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Respiratory, thoracic and mediastinal disorders Cough	2.3% 14/619 • Number of events 15 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	2.4% 15/617 • Number of events 17 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	1.5% 9/607 • Number of events 9 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Oral candidiasis	2.1% 13/619 • Number of events 16 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	0.97% 6/617 • Number of events 7 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	1.2% 7/607 • Number of events 8 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).
Infections and infestations Urinary tract infection	1.6% 10/619 • Number of events 12 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	2.9% 18/617 • Number of events 20 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).	2.1% 13/607 • Number of events 15 • Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug. Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 52 weeks, which includes screening and follow up (14 days after last dose of study drug).