Trial Outcomes & Findings for Efficacy and Safety of BIIB019 (Daclizumab High Yield Process) Versus Interferon β 1a in Participants With Relapsing-Remitting Multiple Sclerosis (NCT NCT01064401)

Last Updated: 2016-07-11

Results Overview

Relapses are defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the examining neurologist. Only relapses confirmed by Independent Neurology Evaluation Committee (INEC) are included in this analysis. Adjusted ARR was estimated from a negative binomial regression model adjusted for the baseline relapse rate, history of prior IFN beta use, baseline Expanded Disability Status Scale score (EDSS; ≤ 2.5 vs \> 2.5) and baseline age (≤ 35 vs \> 35 years). Data after participants switched to alternative MS medications are excluded.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1841 participants

Primary outcome timeframe

Up to 144 weeks

Results posted on

2016-07-11

Participant Flow

Participant milestones

Participant milestones
Measure	Interferon Beta-1a Interferon beta-1a (IFN β-1a) 30 µg intramuscular (IM) injection once weekly plus placebo to daclizumab high yield process (DAC HYP) subcutaneous (SC) once every 4 weeks for 96 to 144 weeks	Daclizumab High Yield Process DAC HYP 150 mg SC injection once every 4 weeks plus placebo to IFN β-1a intramuscular IM injection once weekly for 96 to 144 weeks
Overall Study STARTED	922	919
Overall Study COMPLETED	694	724
Overall Study NOT COMPLETED	228	195

Reasons for withdrawal

Reasons for withdrawal
Measure	Interferon Beta-1a Interferon beta-1a (IFN β-1a) 30 µg intramuscular (IM) injection once weekly plus placebo to daclizumab high yield process (DAC HYP) subcutaneous (SC) once every 4 weeks for 96 to 144 weeks	Daclizumab High Yield Process DAC HYP 150 mg SC injection once every 4 weeks plus placebo to IFN β-1a intramuscular IM injection once weekly for 96 to 144 weeks
Overall Study Adverse Event	47	56
Overall Study Lack of Efficacy	46	23
Overall Study Lost to Follow-up	12	9
Overall Study Consent Withdrawn	98	80
Overall Study Investigator Decision	4	6
Overall Study Death	4	0
Overall Study Pregnancy	4	7
Overall Study Noncompliance	7	8
Overall Study Site Closure	4	5
Overall Study Other	2	1

Baseline Characteristics

Efficacy and Safety of BIIB019 (Daclizumab High Yield Process) Versus Interferon β 1a in Participants With Relapsing-Remitting Multiple Sclerosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Interferon Beta-1a n=922 Participants IFN β-1a 30 µg IM injection once weekly plus placebo to DAC HYP SC once every 4 weeks for 96 to 144 weeks	Daclizumab High Yield Process n=919 Participants DAC HYP 150 mg SC injection once every 4 weeks plus placebo to IFN β-1a IM injection once weekly for 96 to 144 weeks	Total n=1841 Participants Total of all reporting groups
Age, Continuous	36.2 years STANDARD_DEVIATION 9.32 • n=5 Participants	36.4 years STANDARD_DEVIATION 9.36 • n=7 Participants	36.3 years STANDARD_DEVIATION 9.34 • n=5 Participants
Age, Customized 18 to 19 years	25 participants n=5 Participants	14 participants n=7 Participants	39 participants n=5 Participants
Age, Customized 20 to 29 years	227 participants n=5 Participants	236 participants n=7 Participants	463 participants n=5 Participants
Age, Customized 30 to 39 years	327 participants n=5 Participants	322 participants n=7 Participants	649 participants n=5 Participants
Age, Customized 40 to 49 years	256 participants n=5 Participants	250 participants n=7 Participants	506 participants n=5 Participants
Age, Customized 50 to 55 years	86 participants n=5 Participants	96 participants n=7 Participants	182 participants n=5 Participants
Age, Customized > 55 years	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Sex: Female, Male Female	627 Participants n=5 Participants	625 Participants n=7 Participants	1252 Participants n=5 Participants
Sex: Female, Male Male	295 Participants n=5 Participants	294 Participants n=7 Participants	589 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 144 weeks

Population: participants with a relapse

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=643 Relapses IFN β-1a 30 µg IM injection once weekly plus placebo to DAC HYP SC once every 4 weeks for 96 to 144 weeks	Daclizumab High Yield Process n=402 Relapses DAC HYP 150 mg subcutaneous (SC) injection once every 4 weeks plus placebo to IFN β-1a intramuscular (IM) injection once weekly for 96 to 144 weeks
Adjusted Annualized Relapse Rate (ARR)	0.393 relapses per person-years Interval 0.353 to 0.438	0.216 relapses per person-years Interval 0.191 to 0.244

SECONDARY outcome

Timeframe: up to 96 weeks

Population: participants with baseline and at least one post-baseline MRI measurement

The quantity of lesions is assessed by brain magnetic resonance imaging (MRI). The adjusted mean number is estimated from a negative binomial regression model, adjusted for baseline volume of T2 from a negative binomial regression model, adjusted for baseline volume of T2 hyperintense lesions, history of prior IFN beta use and baseline age (≤ 35 vs \> 35 years). To account for the timing of the MRI measurement, the logarithmic transformation of the scan number of the MRI assessment is included in the model as the 'offset' parameter. Observed data after participants switched to alternative MS medications are excluded. Missing data are not imputed. Only observed new or newly enlarging T2 lesions at the last visit of the participant up to Week 96 visit are used in this analysis.

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=841 Participants IFN β-1a 30 µg IM injection once weekly plus placebo to DAC HYP SC once every 4 weeks for 96 to 144 weeks	Daclizumab High Yield Process n=864 Participants DAC HYP 150 mg subcutaneous (SC) injection once every 4 weeks plus placebo to IFN β-1a intramuscular (IM) injection once weekly for 96 to 144 weeks
Adjusted Mean Number of New or Newly Enlarging T2 Hyperintense Lesions up to Week 96	9.44 lesions Interval 8.46 to 10.54	4.31 lesions Interval 3.85 to 4.81

SECONDARY outcome

Timeframe: Baseline through 144 weeks

Sustained disability progression is defined as: at least a 1.0-point increase on the EDSS from Baseline EDSS ≥ 1.0 that is sustained for 12 weeks, or at least a 1.5-point increase on the EDSS from baseline EDSS = 0 that is sustained for 12 weeks. The EDSS measures the disability status of people with MS on a scale that ranges from 0 to 10, with higher scores indicating more disability. Estimated proportion of participants with progression is based on the Kaplan-Meier product limit method. Participants were censored at the time of withdrawal/switch if they withdrew from study or switched to alternative MS medication without a progression. Participants with a tentative progression at the End of Treatment Period Visit (or the last EDSS assessment prior to alternative MS start date) and no confirmation assessment were censored at their last EDSS assessment.

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=922 Participants IFN β-1a 30 µg IM injection once weekly plus placebo to DAC HYP SC once every 4 weeks for 96 to 144 weeks	Daclizumab High Yield Process n=919 Participants DAC HYP 150 mg subcutaneous (SC) injection once every 4 weeks plus placebo to IFN β-1a intramuscular (IM) injection once weekly for 96 to 144 weeks
Proportion of Participants With Sustained Disability Progression at 144 Weeks	0.203 proportion of participants	0.162 proportion of participants

SECONDARY outcome

Timeframe: 144 weeks

Relapses are defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the examining neurologist. Only relapses confirmed by INEC are included in this analysis. Data after participants switched to alternative MS medications are excluded. The estimated proportion of subjects relapse-free at Week 144 is based on the Kaplan-Meier product limit method.

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=922 Participants IFN β-1a 30 µg IM injection once weekly plus placebo to DAC HYP SC once every 4 weeks for 96 to 144 weeks	Daclizumab High Yield Process n=919 Participants DAC HYP 150 mg subcutaneous (SC) injection once every 4 weeks plus placebo to IFN β-1a intramuscular (IM) injection once weekly for 96 to 144 weeks
Proportion of Participants Relapse-free at Week 144	0.508 proportion of participants	0.673 proportion of participants

SECONDARY outcome

Timeframe: Baseline and 96 weeks

Population: participants with a baseline and Week 96 assessment

The MSIS-29 is a 29-item disease-specific patient-reported outcome measure that has been developed and validated to examine the physical and psychological impact of MS from a patient's perspective; it measures physical and psychological items. Worsening in the MSIS-29 physical score is defined as an increase of ≥ 7.5 points in the MSIS-29 physical score at 96 weeks compared to baseline. If a participant was missing data for less than 10 of the 20 items that make up the physical score, then the mean of the non-missing items were used for the missing items. If a participant was missing 10 or more of the 20 items that make up the physical score, or missing the questionnaire entirely, or if the questionnaire was completed after the participant switched to alternative MS medication, a random effects model was used to estimate the MSIS-29 physical score.

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=912 Participants IFN β-1a 30 µg IM injection once weekly plus placebo to DAC HYP SC once every 4 weeks for 96 to 144 weeks	Daclizumab High Yield Process n=906 Participants DAC HYP 150 mg subcutaneous (SC) injection once every 4 weeks plus placebo to IFN β-1a intramuscular (IM) injection once weekly for 96 to 144 weeks
Percentage of Participants With a ≥ 7.5 Point Worsening From Baseline in the Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score at 96 Weeks	23 percentage of participants	19 percentage of participants

Adverse Events

IFN Beta-1a 30 mcg

Serious events: 194 serious events

Other events: 783 other events

Deaths: 0 deaths

DAC HYP 150 mg

Serious events: 221 serious events

Other events: 731 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Biogen Study Medical Director

Biogen

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	IFN Beta-1a 30 mcg n=922 participants at risk IFN β-1a 30 µg IM injection once weekly plus placebo to DAC HYP SC once every 4 weeks for 96 to 144 weeks	DAC HYP 150 mg n=919 participants at risk DAC HYP 150 mg subcutaneous (SC) injection once every 4 weeks plus placebo to IFN β-1a intramuscular (IM) injection once weekly for 96 to 144 weeks
Blood and lymphatic system disorders Lymphadenopathy	0.76% 7/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	5.0% 46/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Gastrointestinal disorders Diarrhoea	6.0% 55/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	7.3% 67/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Gastrointestinal disorders Nausea	5.0% 46/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	5.0% 46/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
General disorders Asthenia	6.0% 55/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	4.0% 37/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
General disorders Fatigue	8.2% 76/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	7.5% 69/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
General disorders Influenza like illness	37.4% 345/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	9.6% 88/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
General disorders Injection site erythema	5.1% 47/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	4.4% 40/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
General disorders Injection site pain	11.1% 102/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	10.4% 96/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
General disorders Pyrexia	14.5% 134/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	11.3% 104/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Infections and infestations Bronchitis	4.7% 43/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	6.6% 61/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Infections and infestations Influenza	6.1% 56/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	8.9% 82/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Infections and infestations Nasopharyngitis	21.4% 197/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	24.6% 226/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Infections and infestations Oral herpes	4.8% 44/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	6.2% 57/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Infections and infestations Pharyngitis	7.5% 69/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	8.4% 77/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Infections and infestations Upper respiratory tract infection	13.4% 124/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	16.1% 148/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Infections and infestations Urinary tract infection	10.4% 96/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	10.0% 92/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Investigations Alanine aminotransferase increased	7.2% 66/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	7.5% 69/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Investigations Aspartate aminotransferase increased	4.8% 44/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	5.2% 48/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Musculoskeletal and connective tissue disorders Arthralgia	6.7% 62/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	7.7% 71/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Musculoskeletal and connective tissue disorders Back pain	7.6% 70/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	9.4% 86/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Musculoskeletal and connective tissue disorders Myalgia	5.3% 49/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	4.6% 42/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Musculoskeletal and connective tissue disorders Pain in extremity	6.3% 58/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	6.0% 55/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Nervous system disorders Dizziness	4.0% 37/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	5.2% 48/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Nervous system disorders Headache	19.0% 175/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	17.3% 159/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Nervous system disorders Hypoaesthesia	5.9% 54/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	5.9% 54/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Nervous system disorders Multiple sclerosis relapse	46.4% 428/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	31.9% 293/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Nervous system disorders Paraesthesia	6.2% 57/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	4.6% 42/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Psychiatric disorders Depression	6.1% 56/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	7.8% 72/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Psychiatric disorders Insomnia	5.9% 54/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	4.6% 42/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Respiratory, thoracic and mediastinal disorders Cough	5.0% 46/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	5.8% 53/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	4.4% 41/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	7.5% 69/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
Skin and subcutaneous tissue disorders Rash	2.8% 26/922 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.	7.0% 64/919 • All events were collected from Baseline through Week 164 (end of Post-dosing period). Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.