Trial Outcomes & Findings for A Study of Ocrelizumab in Participants With Primary Progressive Multiple Sclerosis (NCT NCT01194570)

NCT ID: NCT01194570

Last Updated: 2024-01-10

Results Overview

The time to onset of CDP was defined as time from baseline to first disability progression, which is confirmed at next regularly scheduled visit \>=12 weeks (\>=84 days) after initial disability progression. Baseline for time to onset of CDP is the date of randomization, independent of the first day of dosing. Disability progression is defined as an increase of \>= 1.0 point from baseline expanded disability status scale (EDSS) score, if baseline EDSS value is \<=5.5 points (inclusive), or an increase of \>=0.5 points, if baseline EDSS is \>5.5 points. The total EDSS score ranges from 0 (normal) to 10 (death due to multiple sclerosis). The randomized participants who did not receive any treatment were censored at days 0 in each Arm.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

735 participants

Primary outcome timeframe

Maximal follow up: 216 weeks for Placebo arm and 217 weeks for Ocrelizumab arm

Results posted on

2024-01-10

Participant Flow

A total of 943 participants were screened and 732 were randomized into the study, of which 725 received at least one dose of placebo or ocrelizumab.

Participant milestones

Participant milestones
Measure	Placebo Participants with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.	Ocrelizumab 600 mg Participants with PPMS received ocrelizumab as two IV infusions of 300 mg separated by 14 days at a scheduled interval of every 24 weeks up to at least 120 weeks.
Overall Study STARTED	244	488
Overall Study COMPLETED	89	218
Overall Study NOT COMPLETED	155	270

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.	Ocrelizumab 600 mg Participants with PPMS received ocrelizumab as two IV infusions of 300 mg separated by 14 days at a scheduled interval of every 24 weeks up to at least 120 weeks.
Overall Study Adverse Event	22	40
Overall Study Death	6	20
Overall Study Lack of Efficacy	32	33
Overall Study Lost to Follow-up	4	15
Overall Study Non-Compliance	2	2
Overall Study Non-Compliance With Study Drug	2	2
Overall Study Other	18	47
Overall Study Physician Decision	10	25
Overall Study Protocol Violation	1	2
Overall Study Study Terminated By Sponsor	0	1
Overall Study Withdrawal by Subject	57	82
Overall Study Pregnancy	1	1

Baseline Characteristics

A Study of Ocrelizumab in Participants With Primary Progressive Multiple Sclerosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=244 Participants Participants with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.	Ocrelizumab 600 mg n=488 Participants Participants with PPMS received ocrelizumab as two IV infusions of 300 mg separated by 14 days at a scheduled interval of every 24 weeks up to at least 120 weeks.	Total n=732 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Age, Categorical Between 18 and 65 years	244 Participants n=99 Participants	488 Participants n=107 Participants	732 Participants n=206 Participants
Age, Categorical >=65 years	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Age, Continuous	44.4 years STANDARD_DEVIATION 8.3 • n=99 Participants	44.7 years STANDARD_DEVIATION 7.9 • n=107 Participants	44.6 years STANDARD_DEVIATION 8.0 • n=206 Participants
Sex: Female, Male Female	124 Participants n=99 Participants	237 Participants n=107 Participants	361 Participants n=206 Participants
Sex: Female, Male Male	120 Participants n=99 Participants	251 Participants n=107 Participants	371 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	14 Participants n=99 Participants	32 Participants n=107 Participants	46 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	206 Participants n=99 Participants	385 Participants n=107 Participants	591 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	24 Participants n=99 Participants	71 Participants n=107 Participants	95 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	5 Participants n=107 Participants	5 Participants n=206 Participants
Race (NIH/OMB) Asian	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Black or African American	5 Participants n=99 Participants	9 Participants n=107 Participants	14 Participants n=206 Participants
Race (NIH/OMB) White	235 Participants n=99 Participants	454 Participants n=107 Participants	689 Participants n=206 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=99 Participants	20 Participants n=107 Participants	24 Participants n=206 Participants

PRIMARY outcome

Timeframe: Maximal follow up: 216 weeks for Placebo arm and 217 weeks for Ocrelizumab arm

Population: ITT population included all randomized participants in the study. Number of participants analyzed is the total participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Placebo n=244 Participants Participants with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.	Ocrelizumab 600 mg n=487 Participants Participants with PPMS received ocrelizumab as two IV infusions of 300 mg separated by 14 days at a scheduled interval of every 24 weeks up to at least 120 weeks.	Placebo (Open Label Extension) During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.	Ocrelizumab (Open Label Extension) During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.
Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 12 Weeks During the Double-Blind Treatment Period	NA weeks Interval 0.0 to The median and upper limit of full range for time to onset of CDP has not been reached due to low number of participants with the event at the end of the study.	NA weeks Interval 0.0 to The median and upper limit of full range for time to onset of CDP has not been reached due to low number of participants with the event at the end of the study.	—	—

SECONDARY outcome

Timeframe: Maximal follow up: 216 weeks for Placebo arm and 217 weeks for Ocrelizumab arm

Population: ITT population included all randomized participants in the study. Number of participants analyzed is the total participants who were evaluable for this endpoint.

Outcome measures

Outcome measures
Measure	Placebo n=244 Participants Participants with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.	Ocrelizumab 600 mg n=487 Participants Participants with PPMS received ocrelizumab as two IV infusions of 300 mg separated by 14 days at a scheduled interval of every 24 weeks up to at least 120 weeks.	Placebo (Open Label Extension) During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.	Ocrelizumab (Open Label Extension) During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.
Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 24 Weeks During the Double-Blind Treatment Period	NA weeks Interval 0.0 to The median and upper limit of full range for time to onset of CDP has not been reached due to low number of participants with the event at the end of the study.	NA weeks Interval 0.0 to The median and upper limit of full range for time to onset of CDP has not been reached due to low number of participants with the event at the end of the study.	—	—

SECONDARY outcome

Timeframe: Baseline, Week 120

Population: ITT population included all randomized participants in the study. Here, number of participants analyzed is the total participants who were evaluated for this endpoint. Here, least square mean is indicating adjusted geometric mean.

Outcome measures

Outcome measures
Measure	Placebo n=239 Participants Participants with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.	Ocrelizumab 600 mg n=473 Participants Participants with PPMS received ocrelizumab as two IV infusions of 300 mg separated by 14 days at a scheduled interval of every 24 weeks up to at least 120 weeks.	Placebo (Open Label Extension) During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.	Ocrelizumab (Open Label Extension) During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.
Percent Change From Baseline in Timed 25-Foot Walk (T25-FW) at Week 120	55.097 percent change Interval 39.855 to 71.999	38.933 percent change Interval 29.222 to 49.374	—	—

SECONDARY outcome

Timeframe: From Baseline to Week 120

Population: ITT population included all randomized participants in the study. Here, Number of participants analyzed is the total participants who were evaluated for this endpoint. Here, least square mean is indicating adjusted geometric mean.

Outcome measures

Outcome measures
Measure	Placebo n=234 Participants Participants with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.	Ocrelizumab 600 mg n=464 Participants Participants with PPMS received ocrelizumab as two IV infusions of 300 mg separated by 14 days at a scheduled interval of every 24 weeks up to at least 120 weeks.	Placebo (Open Label Extension) During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.	Ocrelizumab (Open Label Extension) During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.
Percent Change From Baseline in Total Volume of T2 Lesions at Week 120	7.426 percent change Interval 4.967 to 9.942	-3.366 percent change Interval -4.987 to -1.718	—	—

SECONDARY outcome

Timeframe: From Week 24 to Week 120

Population: ITT population included all randomized participants in the study. Number of participants analyzed is the total participants who were evaluable for this endpoint. Here, least square mean is indicating adjusted mean.

Outcome measures

Outcome measures
Measure	Placebo n=203 Participants Participants with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.	Ocrelizumab 600 mg n=407 Participants Participants with PPMS received ocrelizumab as two IV infusions of 300 mg separated by 14 days at a scheduled interval of every 24 weeks up to at least 120 weeks.	Placebo (Open Label Extension) During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.	Ocrelizumab (Open Label Extension) During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.
Percent Change in Total Brain Volume From Week 24 to Week 120	-1.093 percent change Interval -1.236 to -0.951	-0.902 percent change Interval -1.004 to -0.799	—	—

SECONDARY outcome

Timeframe: From Baseline to Week 120

The SF-36v2 is a 36-item, self- reported, generic measure of quality of life that has been widely used in multiple disease areas. It is composed of 8 health domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. The PCS score was derived based on the SF-36 V2 User's Manual. Scoring for PCS involves (a) recoding item response values, (b) summing recoded response values for all items in a given scale to obtain the scale raw score, (c) transforming scale raw score to a 0-100 score. The PCS score was computed by (a) multiplying each health domain z score by a scale-specific physical factor score coefficient, (b) summing the resulting products, (c) converting the product total to T score. The total score ranges from 0-100, higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

Outcome measures

Outcome measures
Measure	Placebo n=128 Participants Participants with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.	Ocrelizumab 600 mg n=292 Participants Participants with PPMS received ocrelizumab as two IV infusions of 300 mg separated by 14 days at a scheduled interval of every 24 weeks up to at least 120 weeks.	Placebo (Open Label Extension) During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.	Ocrelizumab (Open Label Extension) During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.
Change in From Baseline Physical Component Summary Score (PCS) SF- 36 Health Survey (SF-36) at Week 120	-1.108 units on a scale Interval -2.394 to 0.177	-0.731 units on a scale Interval -1.655 to 0.193	—	—

SECONDARY outcome

Timeframe: From baseline to 9 years

Population: The safety population includes all participants who received at least one dose of study drug.

AEs included infusion related reactions (IRRs) and serious multiple sclerosis (MS) relapses, but excluded non-serious MS relapses.

Outcome measures

Outcome measures
Measure	Placebo n=239 Participants Participants with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.	Ocrelizumab 600 mg n=486 Participants Participants with PPMS received ocrelizumab as two IV infusions of 300 mg separated by 14 days at a scheduled interval of every 24 weeks up to at least 120 weeks.	Placebo (Open Label Extension) n=158 Participants During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.	Ocrelizumab (Open Label Extension) n=369 Participants During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.
Number of Participants With at Least One Adverse Event (AE) Serious Adverse Events	53 Participants	99 Participants	59 Participants	167 Participants
Number of Participants With at Least One Adverse Event (AE) Adverse Events	215 Participants	462 Participants	148 Participants	354 Participants

Adverse Events

DB PLACEBO

Serious events: 58 serious events

Other events: 175 other events

Deaths: 3 deaths

DB OCRELIZUMAB

Serious events: 104 serious events

Other events: 400 other events

Deaths: 3 deaths

OLE PLACEBO

Serious events: 59 serious events

Other events: 134 other events

Deaths: 4 deaths

OLE OCRELIZUMAB

Serious events: 167 serious events

Other events: 318 other events

Deaths: 19 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	DB PLACEBO n=239 participants at risk	DB OCRELIZUMAB n=486 participants at risk	OLE PLACEBO n=158 participants at risk	OLE OCRELIZUMAB n=369 participants at risk
Gastrointestinal disorders DIARRHOEA	5.0% 12/239 • Number of events 15 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	5.6% 27/486 • Number of events 43 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	7.0% 11/158 • Number of events 15 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	11.4% 42/369 • Number of events 54 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
General disorders FATIGUE	10.0% 24/239 • Number of events 32 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	6.2% 30/486 • Number of events 33 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	7.6% 12/158 • Number of events 14 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	6.5% 24/369 • Number of events 30 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Infections and infestations BRONCHITIS	6.3% 15/239 • Number of events 21 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	6.2% 30/486 • Number of events 40 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	7.0% 11/158 • Number of events 15 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	8.7% 32/369 • Number of events 52 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Infections and infestations INFLUENZA	8.8% 21/239 • Number of events 25 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	11.7% 57/486 • Number of events 76 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	10.1% 16/158 • Number of events 21 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	10.6% 39/369 • Number of events 59 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Infections and infestations NASOPHARYNGITIS	26.4% 63/239 • Number of events 125 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	24.1% 117/486 • Number of events 206 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	30.4% 48/158 • Number of events 95 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	27.1% 100/369 • Number of events 190 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	5.9% 14/239 • Number of events 21 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	12.3% 60/486 • Number of events 87 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	8.9% 14/158 • Number of events 17 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	15.2% 56/369 • Number of events 110 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Infections and infestations URINARY TRACT INFECTION	23.8% 57/239 • Number of events 117 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	21.2% 103/486 • Number of events 255 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	27.8% 44/158 • Number of events 120 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	34.4% 127/369 • Number of events 488 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Injury, poisoning and procedural complications CONTUSION	7.9% 19/239 • Number of events 22 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	2.9% 14/486 • Number of events 19 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	5.7% 9/158 • Number of events 13 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	6.2% 23/369 • Number of events 35 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Injury, poisoning and procedural complications INFUSION RELATED REACTION	25.5% 61/239 • Number of events 154 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	39.9% 194/486 • Number of events 496 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	25.3% 40/158 • Number of events 98 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	15.2% 56/369 • Number of events 178 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Musculoskeletal and connective tissue disorders ARTHRALGIA	12.6% 30/239 • Number of events 39 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	11.5% 56/486 • Number of events 66 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	14.6% 23/158 • Number of events 36 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	15.4% 57/369 • Number of events 73 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Musculoskeletal and connective tissue disorders BACK PAIN	15.9% 38/239 • Number of events 54 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	12.1% 59/486 • Number of events 71 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	14.6% 23/158 • Number of events 30 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	14.6% 54/369 • Number of events 70 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Gastrointestinal disorders CONSTIPATION	5.0% 12/239 • Number of events 14 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	5.1% 25/486 • Number of events 28 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	5.1% 8/158 • Number of events 8 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	6.2% 23/369 • Number of events 23 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Musculoskeletal and connective tissue disorders PAIN IN EXTREMITY	10.5% 25/239 • Number of events 31 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	7.2% 35/486 • Number of events 38 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	11.4% 18/158 • Number of events 23 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	8.9% 33/369 • Number of events 38 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Nervous system disorders DIZZINESS	4.2% 10/239 • Number of events 12 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	5.6% 27/486 • Number of events 33 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	6.3% 10/158 • Number of events 13 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	3.8% 14/369 • Number of events 17 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Nervous system disorders HEADACHE	13.0% 31/239 • Number of events 48 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	14.0% 68/486 • Number of events 98 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	9.5% 15/158 • Number of events 19 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	11.1% 41/369 • Number of events 73 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Psychiatric disorders DEPRESSION	13.0% 31/239 • Number of events 35 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	7.0% 34/486 • Number of events 35 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	5.7% 9/158 • Number of events 9 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	6.2% 23/369 • Number of events 24 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Psychiatric disorders INSOMNIA	6.3% 15/239 • Number of events 15 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	5.8% 28/486 • Number of events 31 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	6.3% 10/158 • Number of events 10 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	3.3% 12/369 • Number of events 13 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Respiratory, thoracic and mediastinal disorders COUGH	3.3% 8/239 • Number of events 8 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	7.2% 35/486 • Number of events 44 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	7.6% 12/158 • Number of events 13 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	10.3% 38/369 • Number of events 45 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
General disorders ASTHENIA	0.00% 0/239 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	0.00% 0/486 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	6.3% 10/158 • Number of events 11 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	5.7% 21/369 • Number of events 26 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
General disorders INFLUENZA LIKE ILLNESS	0.00% 0/239 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	0.00% 0/486 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	6.3% 10/158 • Number of events 13 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	6.8% 25/369 • Number of events 36 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
General disorders OEDEMA PERIPHERAL	0.00% 0/239 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	0.00% 0/486 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	7.0% 11/158 • Number of events 12 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	6.0% 22/369 • Number of events 25 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
General disorders PYREXIA	0.00% 0/239 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	0.00% 0/486 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	8.9% 14/158 • Number of events 23 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	6.2% 23/369 • Number of events 39 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Infections and infestations COVID-19	0.00% 0/239 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	0.00% 0/486 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	13.3% 21/158 • Number of events 22 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	20.6% 76/369 • Number of events 87 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Infections and infestations PNEUMONIA	0.00% 0/239 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	0.00% 0/486 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	13.3% 21/158 • Number of events 22 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	20.6% 76/369 • Number of events 87 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Infections and infestations SINUSITIS	0.00% 0/239 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	0.00% 0/486 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	3.8% 6/158 • Number of events 10 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	5.4% 20/369 • Number of events 26 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Infections and infestations TOOTH INFECTION	0.00% 0/239 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	0.00% 0/486 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	1.3% 2/158 • Number of events 2 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	5.4% 20/369 • Number of events 38 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Injury, poisoning and procedural complications FALL	0.00% 0/239 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	0.00% 0/486 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	10.1% 16/158 • Number of events 28 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	10.8% 40/369 • Number of events 75 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Injury, poisoning and procedural complications SKIN LACERATION	0.00% 0/239 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	0.00% 0/486 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	5.1% 8/158 • Number of events 8 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	3.3% 12/369 • Number of events 14 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Musculoskeletal and connective tissue disorders MUSCLE SPASMS	0.00% 0/239 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	0.00% 0/486 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	3.8% 6/158 • Number of events 6 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	5.1% 19/369 • Number of events 21 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Nervous system disorders TRIGEMINAL NEURALGIA	0.00% 0/239 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	0.00% 0/486 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	5.7% 9/158 • Number of events 14 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	2.2% 8/369 • Number of events 18 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Skin and subcutaneous tissue disorders ECZEMA	0.00% 0/239 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	0.00% 0/486 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	5.1% 8/158 • Number of events 8 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	3.8% 14/369 • Number of events 17 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Skin and subcutaneous tissue disorders RASH	0.00% 0/239 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	0.00% 0/486 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	3.2% 5/158 • Number of events 6 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	6.2% 23/369 • Number of events 24 • Baseline up to 615 weeks The safety population included all participants who received any study drug.
Vascular disorders HYPERTENSION	0.00% 0/239 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	0.00% 0/486 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	7.6% 12/158 • Number of events 12 • Baseline up to 615 weeks The safety population included all participants who received any study drug.	7.6% 28/369 • Number of events 33 • Baseline up to 615 weeks The safety population included all participants who received any study drug.