Trial Outcomes & Findings for A Long Term Safety Study of BCX7353 in Hereditary Angioedema (NCT NCT03472040)

NCT ID: NCT03472040

Last Updated: 2023-06-18

Results Overview

The number and percentage of subjects with treatment-emergent adverse events.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

387 participants

Primary outcome timeframe

Up to 96 weeks (US) / 216 weeks (Rest of World (ROW)).

Results posted on

2023-06-18

Participant Flow

Subjects with a clinical diagnosis of HAE Type 1 or 2 who, in the opinion of the investigator, were expected to benefit from an oral treatment for the prevention of angioedema attacks were considered eligible for the study following assessment of data obtained from screening procedures.

Participant milestones

Participant milestones
Measure	110 mg Followed by 150 mg Berotralstat Subjects were initially treated with berotralstat 110 mg per day (QD). Following the results from Part 1 of Study BCX7353-302, all subjects were transitioned to a berotralstat dose of 150 mg QD. Dosing continued for up to 96 weeks (US) / 216 weeks (Rest of World (ROW)).	150 mg Berotralstat Subjects were treated with berotralstat 150 mg QD. Dosing continued for up to 96 weeks (US) / 216 weeks (ROW).
Overall Study STARTED	100	287
Overall Study COMPLETED	0	1
Overall Study NOT COMPLETED	100	286

Reasons for withdrawal

Reasons for withdrawal
Measure	110 mg Followed by 150 mg Berotralstat Subjects were initially treated with berotralstat 110 mg per day (QD). Following the results from Part 1 of Study BCX7353-302, all subjects were transitioned to a berotralstat dose of 150 mg QD. Dosing continued for up to 96 weeks (US) / 216 weeks (Rest of World (ROW)).	150 mg Berotralstat Subjects were treated with berotralstat 150 mg QD. Dosing continued for up to 96 weeks (US) / 216 weeks (ROW).
Overall Study Physician Decision	0	3
Overall Study Withdrawal by Subject	10	23
Overall Study Perceived Lack of Efficacy	29	30
Overall Study Lab Abnormality or Adverse Event (AE)	7	25
Overall Study Intercurrent Illness/Medical Condition	2	3
Overall Study Other - Not Otherwise Specified (NOS)	4	19
Overall Study Subject Non-compliance	2	5
Overall Study Discontinuation due to Rash	0	1
Overall Study Subsequent Ineligibility	0	2
Overall Study Berotralstat Provided by alternative Means (i.e., Early Access Program or Commercially Available)	46	175

Baseline Characteristics

A Long Term Safety Study of BCX7353 in Hereditary Angioedema

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	110 mg Followed by 150 mg Berotralstat n=100 Participants Subjects were initially treated with berotralstat 110 mg QD. Following the results from Part 1 of Study BCX7353-302, all subjects were transitioned to a berotralstat dose of 150 mg QD. Dosing continued for up to 96 weeks (US) / 216weeks (ROW).	150 mg Berotralstat n=287 Participants Subjects were treated with berotralstat 150 mg QD. Dosing continued for up to 96 weeks (US) / 216 weeks (ROW).	Total n=387 Participants Total of all reporting groups
Age, Categorical <=18 years	5 Participants n=5 Participants	23 Participants n=7 Participants	28 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	93 Participants n=5 Participants	253 Participants n=7 Participants	346 Participants n=5 Participants
Age, Categorical >=65 years	2 Participants n=5 Participants	11 Participants n=7 Participants	13 Participants n=5 Participants
Age, Continuous	37.6 years STANDARD_DEVIATION 14.04 • n=5 Participants	40.5 years STANDARD_DEVIATION 15.26 • n=7 Participants	39.8 years STANDARD_DEVIATION 14.99 • n=5 Participants
Sex: Female, Male Female	62 Participants n=5 Participants	180 Participants n=7 Participants	242 Participants n=5 Participants
Sex: Female, Male Male	38 Participants n=5 Participants	107 Participants n=7 Participants	145 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Asian	12 Participants n=5 Participants	11 Participants n=7 Participants	23 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	12 Participants n=7 Participants	12 Participants n=5 Participants
Race (NIH/OMB) White	82 Participants n=5 Participants	256 Participants n=7 Participants	338 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants n=5 Participants	6 Participants n=7 Participants	11 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 96 weeks (US) / 216 weeks (Rest of World (ROW)).

Population: The safety population included all subjects who received at least 1 dose of study drug. This population was used in the assessment and reporting of safety data.

The number and percentage of subjects with treatment-emergent adverse events.

Outcome measures

Outcome measures
Measure	110 mg Followed by 150 mg Berotralstat n=100 Participants Subjects were initially treated with berotralstat 110 mg QD. Following the results from Part 1 of Study BCX7353-302, all subjects were transitioned to a berotralstat dose of 150 mg QD.	150 mg Berotralstat n=287 Participants Subjects were treated with berotralstat 150 mg QD.
Safety & Tolerability TEAE leading to study drug interruption	8 Participants	32 Participants
Safety & Tolerability Drug-related rash	5 Participants	5 Participants
Safety & Tolerability TEAE	94 Participants	240 Participants
Safety & Tolerability Drug-related TEAE	58 Participants	119 Participants
Safety & Tolerability TESAE	23 Participants	20 Participants
Safety & Tolerability Drug-related TESAE	3 Participants	1 Participants
Safety & Tolerability DMID Grade 3 or 4 TEAE	18 Participants	35 Participants
Safety & Tolerability Drug-related DMID Grade 3 or 4 TEAE	7 Participants	11 Participants
Safety & Tolerability TEAE leading to study drug discontinuation	8 Participants	28 Participants
Safety & Tolerability Drug-related rash leading to study drug discontinuation	1 Participants	2 Participants

SECONDARY outcome

Timeframe: Up to 96 weeks (US) / 216 weeks (ROW)

Population: The safety population included all subjects who received at least 1 dose of study drug. This population was used in the assessment and reporting of efficacy data.

Number of 'adjusted' attacks were assessed. Adjusted attacks included at least 1 symptom of swelling, had a response of 'no' to the diary question, 'In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (i.e., allergic reaction, viral cold etc.)?', and were considered unique (attack began \> 24 hours from the end of the prior attack). Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack.

Outcome measures

Outcome measures
Measure	110 mg Followed by 150 mg Berotralstat n=100 Participants Subjects were initially treated with berotralstat 110 mg QD. Following the results from Part 1 of Study BCX7353-302, all subjects were transitioned to a berotralstat dose of 150 mg QD.	150 mg Berotralstat n=287 Participants Subjects were treated with berotralstat 150 mg QD.
Incidence of Acute Attacks of Angioedema in Subjects During Treatment Subjects reporting at least 1 attack	95 Participants	231 Participants
Incidence of Acute Attacks of Angioedema in Subjects During Treatment Subjects reporting at least 1 treated attack	87 Participants	214 Participants
Incidence of Acute Attacks of Angioedema in Subjects During Treatment Subjects reporting at least 1 untreated attack	59 Participants	99 Participants

SECONDARY outcome

Timeframe: Up to 96 weeks (US) / 216 weeks (ROW)

Population: The safety population included all subjects who received at least 1 dose of study drug. This population was used in the assessment and reporting of efficacy data. The reduced number of subjects analysed at each study period reflects the fact that the maximum duration for US subjects was 96 weeks, as well as subject withdrawal prior to study completion, primarily as a result of Berotralstat being provided by alternative means (i.e., early access program or commercially available).

To evaluate if the rate of attacks remains consistent (durable) over time, the monthly attack rate was assessed at 0 to 24 weeks, 24 to 48 weeks, 48 to 96 weeks and 96 weeks until the end of the study. Monthly attack rate was defined as the total number of adjusted HAE attacks experienced during the treatment period adjusted for the length of a month (defined as 28 days) and the number of days the subject was on treatment during that month.

Outcome measures

Outcome measures
Measure	110 mg Followed by 150 mg Berotralstat n=100 Participants Subjects were initially treated with berotralstat 110 mg QD. Following the results from Part 1 of Study BCX7353-302, all subjects were transitioned to a berotralstat dose of 150 mg QD.	150 mg Berotralstat n=287 Participants Subjects were treated with berotralstat 150 mg QD.
The Durability of Response to Treatment 0 - 24 weeks	1.276 HAE attacks per 28 days Standard Deviation 1.2254	1.079 HAE attacks per 28 days Standard Deviation 1.4411
The Durability of Response to Treatment 24 - 48 weeks	1.005 HAE attacks per 28 days Standard Deviation 1.0027	0.694 HAE attacks per 28 days Standard Deviation 1.0072
The Durability of Response to Treatment 48 - 96 weeks	1.121 HAE attacks per 28 days Standard Deviation 1.9573	0.591 HAE attacks per 28 days Standard Deviation 0.8217
The Durability of Response to Treatment 96 weeks - End of Study	0.770 HAE attacks per 28 days Standard Deviation 1.0394	0.725 HAE attacks per 28 days Standard Deviation 0.8395

SECONDARY outcome

Timeframe: Up to 96 weeks (US) / 216 weeks (ROW)

Population: The safety population was used in the assessment \& reporting of efficacy data, \& included subjects receiving at least 1 dose of study drug. The reduced number of subjects analysed at each study period reflects that the maximum duration for US subjects was 96 weeks, variation in the number of subjects completing the AE-QoL questionnaire \& subject withdrawal prior to study completion, primarily as a result of Berotralstat being provided via an early access program or commercially.

Quality of Life (QoL) specific to hereditary angioedema (HAE) was assessed at baseline and at each study visit until the end of the study. The questionnaire (i.e. AE-QoL) consisted of 17 questions spanning 4 domains (functioning, fatigue/mood, fear/shame, and nutrition). Each AE-QoL question had 5 answer options (scored 1-5), with lower and higher scores indicting less and more adverse impact, respectively. Per-subject scores for each domain were computed using the appropriate scoring algorithm applied to the question response scores for each domain. Per-subject total scores (including all 4 domains) were similarly computed using the question response scores for all 17 questions. The outputs from the scoring algorithm were normalized on a scale ranging from 0 (less adverse impact) to 100 (most adverse impact). The Mean change from baseline (CFB) in AE-QoL total score over time is presented below.

Outcome measures

SECONDARY outcome

Timeframe: Up to 96 weeks (US) / 216 weeks (ROW)

Population: The safety population was used in the assessment \& reporting of efficacy data, \& included subjects receiving at least 1 dose of study drug. The reduced number of subjects analysed at each study period reflects that the maximum duration for US subjects was 96 weeks, variation in the number of subjects completing the TSQM questionnaire \& subject withdrawal prior to study completion, primarily as a result of Berotralstat being provided via an early access program or commercially.

The Treatment Satisfaction Questionnaire for Medication (TSQM) was completed by subjects at baseline and at each study visit until the end of the study. TSQM scores consisted of 14 items of which 13 items were made up of 3 specific scales (Effectiveness, Side Effects, and Convenience) and 1 global satisfaction scale (Global Satisfaction). At baseline, TSQM questionnaires were completed based on subject's satisfaction with usual medications. At all other time points for collection of TSQM, subjects were asked about their level of satisfaction or dissatisfaction with the study drug. Scale scores were calculated for each scale and were transformed into scores ranging from 0 to 100, with higher scores indicating higher satisfaction. TSQM score and corresponding change from baseline values were calculated at each visit. Note: Subjects in Hong Kong did not complete the TSQM.

Outcome measures

Adverse Events

110 mg Followed by 150 mg Berotralstat

Serious events: 23 serious events

Other events: 94 other events

Deaths: 0 deaths

150 mg Berotralstat

Serious events: 20 serious events

Other events: 240 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

BioCryst Pharmaceuticals Inc

Phone: +1 919-859-1302

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	110 mg Followed by 150 mg Berotralstat n=81 Participants Subjects were initially treated with berotralstat 110 mg QD. Following the results from Part 1 of Study BCX7353-302, all subjects were transitioned to a berotralstat dose of 150 mg QD.	150 mg Berotralstat n=272 Participants Subjects were treated with berotralstat 150 mg QD.
Patient Reported Quality of Life (QoL) During Treatment Week 4	-8.85 AE-QoL score - change from baseline Standard Deviation 18.986	-10.38 AE-QoL score - change from baseline Standard Deviation 17.845
Patient Reported Quality of Life (QoL) During Treatment Week 8	-11.20 AE-QoL score - change from baseline Standard Deviation 19.386	-10.39 AE-QoL score - change from baseline Standard Deviation 19.690
Patient Reported Quality of Life (QoL) During Treatment Week 12	-11.92 AE-QoL score - change from baseline Standard Deviation 18.484	-11.47 AE-QoL score - change from baseline Standard Deviation 18.561
Patient Reported Quality of Life (QoL) During Treatment Week 24	-11.58 AE-QoL score - change from baseline Standard Deviation 17.630	-11.98 AE-QoL score - change from baseline Standard Deviation 18.724
Patient Reported Quality of Life (QoL) During Treatment Week 36	-11.79 AE-QoL score - change from baseline Standard Deviation 17.377	-13.53 AE-QoL score - change from baseline Standard Deviation 18.556
Patient Reported Quality of Life (QoL) During Treatment Week 48	-13.60 AE-QoL score - change from baseline Standard Deviation 17.339	-14.08 AE-QoL score - change from baseline Standard Deviation 19.351
Patient Reported Quality of Life (QoL) During Treatment Week 60	-12.81 AE-QoL score - change from baseline Standard Deviation 15.888	-16.42 AE-QoL score - change from baseline Standard Deviation 18.568
Patient Reported Quality of Life (QoL) During Treatment Week 72	-13.14 AE-QoL score - change from baseline Standard Deviation 16.774	-14.93 AE-QoL score - change from baseline Standard Deviation 18.991
Patient Reported Quality of Life (QoL) During Treatment Week 84	-15.25 AE-QoL score - change from baseline Standard Deviation 16.776	-14.70 AE-QoL score - change from baseline Standard Deviation 17.710
Patient Reported Quality of Life (QoL) During Treatment Week 96	-14.72 AE-QoL score - change from baseline Standard Deviation 15.342	-17.44 AE-QoL score - change from baseline Standard Deviation 19.701
Patient Reported Quality of Life (QoL) During Treatment Week 108	-14.85 AE-QoL score - change from baseline Standard Deviation 15.077	-17.06 AE-QoL score - change from baseline Standard Deviation 18.963
Patient Reported Quality of Life (QoL) During Treatment Week 120	-14.21 AE-QoL score - change from baseline Standard Deviation 16.140	-18.20 AE-QoL score - change from baseline Standard Deviation 18.705
Patient Reported Quality of Life (QoL) During Treatment Week 132	-14.58 AE-QoL score - change from baseline Standard Deviation 15.765	-16.57 AE-QoL score - change from baseline Standard Deviation 16.151
Patient Reported Quality of Life (QoL) During Treatment Week 144	-13.05 AE-QoL score - change from baseline Standard Deviation 19.678	-18.40 AE-QoL score - change from baseline Standard Deviation 18.081
Patient Reported Quality of Life (QoL) During Treatment Week 156	-15.53 AE-QoL score - change from baseline Standard Deviation 15.823	-21.29 AE-QoL score - change from baseline Standard Deviation 20.015
Patient Reported Quality of Life (QoL) During Treatment Week 168	-16.70 AE-QoL score - change from baseline Standard Deviation 13.690	-22.06 AE-QoL score - change from baseline Standard Deviation 18.281
Patient Reported Quality of Life (QoL) During Treatment Week 180	-21.69 AE-QoL score - change from baseline Standard Deviation 23.014	-21.94 AE-QoL score - change from baseline Standard Deviation 17.652
Patient Reported Quality of Life (QoL) During Treatment Week 192	-10.29 AE-QoL score - change from baseline Standard Deviation 0	-18.53 AE-QoL score - change from baseline Standard Deviation 8.860
Patient Reported Quality of Life (QoL) During Treatment Week 204	—	-13.24 AE-QoL score - change from baseline Standard Deviation 11.672
Patient Reported Quality of Life (QoL) During Treatment Week 216	—	-17.65 AE-QoL score - change from baseline Standard Deviation 14.558

Measure	110 mg Followed by 150 mg Berotralstat n=91 Participants Subjects were initially treated with berotralstat 110 mg QD. Following the results from Part 1 of Study BCX7353-302, all subjects were transitioned to a berotralstat dose of 150 mg QD.	150 mg Berotralstat n=277 Participants Subjects were treated with berotralstat 150 mg QD.
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 4	-4.1 TSQM score - change from baseline Standard Deviation 35.51	-1.3 TSQM score - change from baseline Standard Deviation 30.48
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 8	-0.6 TSQM score - change from baseline Standard Deviation 36.29	-3.6 TSQM score - change from baseline Standard Deviation 30.38
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 12	1.5 TSQM score - change from baseline Standard Deviation 34.35	-0.1 TSQM score - change from baseline Standard Deviation 31.37
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 24	5.4 TSQM score - change from baseline Standard Deviation 34.46	1.7 TSQM score - change from baseline Standard Deviation 31.77
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 36	5.8 TSQM score - change from baseline Standard Deviation 32.00	-4.4 TSQM score - change from baseline Standard Deviation 27.41
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 48	5.5 TSQM score - change from baseline Standard Deviation 31.79	4.1 TSQM score - change from baseline Standard Deviation 27.78
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 60	8.0 TSQM score - change from baseline Standard Deviation 30.13	3.1 TSQM score - change from baseline Standard Deviation 25.89
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 72	9.3 TSQM score - change from baseline Standard Deviation 33.33	4.5 TSQM score - change from baseline Standard Deviation 27.32
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 84	4.2 TSQM score - change from baseline Standard Deviation 32.32	1.3 TSQM score - change from baseline Standard Deviation 20.76
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 96	6.2 TSQM score - change from baseline Standard Deviation 35.64	5.5 TSQM score - change from baseline Standard Deviation 23.44
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 108	-7.1 TSQM score - change from baseline Standard Deviation 44.61	-21.4 TSQM score - change from baseline Standard Deviation 10.10
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 120	16.3 TSQM score - change from baseline Standard Deviation 33.06	6.8 TSQM score - change from baseline Standard Deviation 22.68
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 132	5.4 TSQM score - change from baseline Standard Deviation 41.80	-5.7 TSQM score - change from baseline Standard Deviation 40.85
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 144	18.2 TSQM score - change from baseline Standard Deviation 30.85	2.2 TSQM score - change from baseline Standard Deviation 26.82
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 156	43.7 TSQM score - change from baseline Standard Deviation 32.23	-30.2 TSQM score - change from baseline Standard Deviation 32.10
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 168	-1.4 TSQM score - change from baseline Standard Deviation 22.46	6.1 TSQM score - change from baseline Standard Deviation 30.24
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 180	-7.1 TSQM score - change from baseline Standard Deviation 0	11.9 TSQM score - change from baseline Standard Deviation 21.98
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 192	0 TSQM score - change from baseline Standard Deviation 0	14.3 TSQM score - change from baseline Standard Deviation 8.75
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 204	—	14.3 TSQM score - change from baseline Standard Deviation 0
Patient's Satisfaction With Medication During Long Term Administration of Berotralstat Week 216	—	10.7 TSQM score - change from baseline Standard Deviation 15.15

Measure	110 mg Followed by 150 mg Berotralstat n=100 participants at risk Subjects were initially treated with berotralstat 110 mg QD. Following the results from Part 1 of Study BCX7353-302, all subjects were transitioned to a berotralstat dose of 150 mg QD. Dosing continued for up to 96 weeks (US) / 216 weeks (ROW).	150 mg Berotralstat n=287 participants at risk Subjects were treated with berotralstat 150 mg QD. Dosing continued for up to 96 weeks (US) / 216 weeks (ROW).
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	10.0% 10/100 • Number of events 19 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	4.2% 12/287 • Number of events 20 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.
Nervous system disorders Headache	23.0% 23/100 • Number of events 44 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	11.8% 34/287 • Number of events 49 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.
Gastrointestinal disorders Diarrhoea	14.0% 14/100 • Number of events 17 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	14.6% 42/287 • Number of events 51 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.
Gastrointestinal disorders Abdominal pain	14.0% 14/100 • Number of events 40 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	10.1% 29/287 • Number of events 37 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.
Gastrointestinal disorders Gastrooesophageal reflux disease	8.0% 8/100 • Number of events 8 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	4.9% 14/287 • Number of events 16 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.
Gastrointestinal disorders Vomiting	3.0% 3/100 • Number of events 3 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	5.9% 17/287 • Number of events 17 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.
Gastrointestinal disorders Nausea	9.0% 9/100 • Number of events 10 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	9.8% 28/287 • Number of events 32 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.
Gastrointestinal disorders Abdominal pain upper	10.0% 10/100 • Number of events 13 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	6.3% 18/287 • Number of events 25 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.
Gastrointestinal disorders Dyspepsia	5.0% 5/100 • Number of events 5 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	6.6% 19/287 • Number of events 21 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.
Gastrointestinal disorders Abdominal discomfort	6.0% 6/100 • Number of events 7 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	5.9% 17/287 • Number of events 25 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.
Infections and infestations Nasopharyngitis	33.0% 33/100 • Number of events 84 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	20.6% 59/287 • Number of events 140 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.
Infections and infestations Upper respiratory tract infection	14.0% 14/100 • Number of events 31 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	12.5% 36/287 • Number of events 47 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.
Infections and infestations COVID-19	10.0% 10/100 • Number of events 10 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	7.0% 20/287 • Number of events 20 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.
Infections and infestations Influenza	8.0% 8/100 • Number of events 8 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	7.0% 20/287 • Number of events 25 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.
Infections and infestations Urinary tract infection	7.0% 7/100 • Number of events 10 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	7.3% 21/287 • Number of events 33 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.
Infections and infestations Sinusitis	10.0% 10/100 • Number of events 20 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	5.2% 15/287 • Number of events 19 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.
Infections and infestations Gastroenteritis	10.0% 10/100 • Number of events 11 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.	4.2% 12/287 • Number of events 17 • Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.