Trial Outcomes & Findings for Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 2) (NCT NCT04410991)

Last Updated: 2025-07-02

Results Overview

Multiple sclerosis (MS) relapse was defined as a monophasic, acute or subacute onset of new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination. Symptoms were attributable to MS, lasted for \>=24 hours with or without recovery, present at normal body temperature, and preceded by \>=30 days of clinical stability.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

899 participants

Primary outcome timeframe

Baseline (Day 1) to approximately 48 months

Results posted on

2025-07-02

Participant Flow

This study was conducted at 154 sites in 25 countries. A total of 1093 participants were screened from 11-Jun-2020 to 08-Aug-2022, of which 194 were screen failures. Screen failures were mainly due to not meeting eligibility criteria.

A total of 899 participants were randomized in this study in a 1:1 ratio to either teriflunomide 14 milligrams (mg) or tolebrutinib 60 mg group. This was an event-driven (6-month confirmed disability worsening \[CDW\]) trial with a variable treatment duration (end-of-study \[EOS\] duration: up to approximately 48 months).

Participant milestones

Participant milestones
Measure	Teriflunomide 14 mg Participants received teriflunomide 14 mg tablet orally once daily (QD) along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
Overall Study STARTED	452	447
Overall Study Randomized and Treated	451	447
Overall Study COMPLETED	378	384
Overall Study NOT COMPLETED	74	63

Reasons for withdrawal

Reasons for withdrawal
Measure	Teriflunomide 14 mg Participants received teriflunomide 14 mg tablet orally once daily (QD) along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
Overall Study Poor compliance to protocol	5	4
Overall Study Withdrawal by Subject	59	55
Overall Study Other	10	4

Baseline Characteristics

Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 2)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Teriflunomide 14 mg n=452 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg n=447 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.	Total n=899 Participants Total of all reporting groups
Age, Continuous	36.1 years STANDARD_DEVIATION 9.3 • n=5 Participants	36.6 years STANDARD_DEVIATION 9.3 • n=7 Participants	36.4 years STANDARD_DEVIATION 9.3 • n=5 Participants
Sex: Female, Male Female	293 Participants n=5 Participants	300 Participants n=7 Participants	593 Participants n=5 Participants
Sex: Female, Male Male	159 Participants n=5 Participants	147 Participants n=7 Participants	306 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	19 Participants n=5 Participants	23 Participants n=7 Participants	42 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	11 Participants n=5 Participants	7 Participants n=7 Participants	18 Participants n=5 Participants
Race (NIH/OMB) White	417 Participants n=5 Participants	411 Participants n=7 Participants	828 Participants n=5 Participants
Race (NIH/OMB) More than one race	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Day 1) to approximately 48 months

Population: The intent-to-treat (ITT) population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=452 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg n=447 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
Annualized Relapse Rate (ARR) as Assessed by Confirmed Protocol-defined Adjudicated Relapses	0.109 relapses per participant year Interval 0.088 to 0.134	0.108 relapses per participant year Interval 0.089 to 0.131

SECONDARY outcome

Timeframe: Baseline (Day 1) to approximately 48 months

Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.

The EDSS was a disability scale that assessed the following 7 functional domains: visual, brainstem, pyramidal \[motor\], cerebellar \[coordination\], sensory, cerebral, and bowel/bladder. The total EDSS score ranged from 0 (normal) to 10 (death due to MS), increasing in increments of 0.5 points. Higher scores indicated increased disability. Time to onset of 6-month CDW was defined as the time from randomization to the onset of a confirmed, sustained increase from baseline in EDSS score (of \>=1.5 points when the baseline score was 0, of \>=1.0 point when the baseline score was 0.5 to \<=5.5, of \>=0.5 points when the baseline EDSS score was \>5.5) over at least 6 months that was not attributable to another etiology.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=452 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg n=447 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale	12.14 months Interval 1.4 to 38.9	15.12 months Interval 2.0 to 37.1

SECONDARY outcome

Timeframe: Baseline (Day 1) to approximately 48 months

Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.

The EDSS was a disability scale that assessed the following 7 functional domains: visual, brainstem, pyramidal \[motor\], cerebellar \[coordination\], sensory, cerebral, and bowel/bladder. The total EDSS score ranged from 0 (normal) to 10 (death due to MS), increasing in increments of 0.5 points. Higher scores indicated increased disability. Time to onset of 3-month CDW was defined as the time from randomization to the onset of a confirmed, sustained increase from baseline in EDSS score (of \>=1.5 points when the baseline score was 0, of \>=1.0 point when the baseline score was 0.5 to \<=5.5, of \>=0.5 points when the baseline EDSS score was \>5.5) over at least 3 months that was not attributable to another etiology.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=452 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg n=447 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
Time to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale	12.11 months Interval 1.4 to 39.1	12.11 months Interval 2.0 to 42.1

SECONDARY outcome

Timeframe: Baseline (Day 1) to approximately 48 months

Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.

Magnetic resonance imaging (MRI) of the brain was performed to identify number of new and/or enlarging T2-hyperintense lesions defined as the sum of the individual number of new and/or enlarging T2 lesions starting from baseline up to and including the EOS visit.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=452 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg n=447 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
Mean Number of New and/or Enlarging T2-Hyperintense Lesions Per Year	4.369 number of new and/or enlarging T2lesions Interval 3.587 to 5.322	5.092 number of new and/or enlarging T2lesions Interval 4.34 to 5.975

SECONDARY outcome

Timeframe: Baseline (Day 1) to approximately 48 months

Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.

MRI of the brain was performed to identify number of new Gd-enhancing T1-hyperintense lesions defined as the sum of the individual number of new Gd- enhancing T1-hyperintense lesions starting from baseline up to and including the EOS visit.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=452 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg n=447 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
Mean Number of New Gadolinium-Enhancing T1-Hyperintense Lesions Per Scan	0.217 number of new Gd-enhancing T1 lesions Interval 0.169 to 0.28	0.460 number of new Gd-enhancing T1 lesions Interval 0.365 to 0.581

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 48 months)

Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received. Only participants with data collected at specified timepoints are reported.

The SDMT was used to assess processing speed, divided attention, visual scanning, tracking and motor speed. It involved a simple substitution task using a reference key. The number of correct substitutions and number of items completed within a 90 second interval (maximum 110 seconds) were recorded. A decrease of 4 points from baseline on the SDMT was considered meaningful worsening. The score was the number of correctly coded items from 0-110 in 90 seconds; higher scores indicating a better outcome. Baseline was defined as the last available value prior to the first dose of study intervention.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=359 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg n=366 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
Change From Baseline in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT) at EOS	0.428 score on a scale Standard Error 0.0373	0.374 score on a scale Standard Error 0.0370

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 48 months)

The CVLT-II was a verbal learning and memory test consisting of recall and recognition of a list of 16 words. For each assessment, 5 trials were completed. Total Correct Recall Trials 1-5 was scaled to a normalized T-score metric, which had a mean of 50 and standard deviation of 10, the maximum possible score was 80 and a minimum was 0. Higher values indicated improved cognitive function. Baseline was defined as the last available value prior to the first dose of study intervention.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=347 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg n=357 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test Second Edition (CVLT-II) at EOS	16.431 T-score Standard Error 0.6825	15.819 T-score Standard Error 0.6740

SECONDARY outcome

Timeframe: Baseline (Day 1) to approximately 48 months

Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=452 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg n=447 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
Time to Onset of 6-Month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale	12.05 months Interval 2.8 to 30.6	9.04 months Interval 2.6 to 33.5

SECONDARY outcome

Timeframe: Month 6 to EOS (up to approximately 48 months)

MRI of the brain was performed at the specified timepoints to detect the changes in brain volume loss.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=307 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg n=317 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
Percent Change in Brain Volume Loss at EOS Compared to Month 6	-0.740 percent change Standard Error 0.0394	-0.696 percent change Standard Error 0.0387

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 48 months)

MSQoL-54 was standardized instrument comprising generic and MS-specific items. This 54-item instrument generated 12 subscales and 2 single-item measures (satisfaction with sexual function \[1 item\]; change in health \[1 item\]). 12 subscales were: a: physical health (10 items), b: health perceptions (5 items), c: energy (5 items), d: role limit physical (4 items), e: sexual function (4 items), f: pain (3 items), g: social function (3 items), h: health distress (4 items), i: overall quality of life (2 items), j: emotional well-being (5 items), k: role limitations emotional (3 items) and l: cognitive function (4 items). Physical and mental health composite score were calculated as weighted sum of 'a to h' and 'i to l' subscales respectively. Each composite score was transformed linearly to common 0 (worst) to 100 (best) score range; higher score indicated improved quality of life. Baseline was defined as last available value prior to first dose of study intervention.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=357 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg n=370 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS Physical health composite score	-1.040 score on a scale Standard Error 0.7404	-1.199 score on a scale Standard Error 0.7304
Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS Mental health composite score	-1.657 score on a scale Standard Error 0.8709	-1.390 score on a scale Standard Error 0.8581

SECONDARY outcome

Timeframe: From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months

An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. An AESI was an AE (serious or nonserious) of scientific and medical concern specific to the Sponsor's product or program for which ongoing monitoring and immediate notification by the Investigator to the Sponsor was required. TEAEs were defined as AEs that developed, worsened or became serious during the treatment period.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=451 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg n=447 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Adverse Events of Special Interest (AESIs) TEAEs	387 Participants	385 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Adverse Events of Special Interest (AESIs) TESAEs	37 Participants	49 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Adverse Events of Special Interest (AESIs) TEAEs leading to permanent study intervention discontinuation	17 Participants	19 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Adverse Events of Special Interest (AESIs) TEAESIs	40 Participants	46 Participants

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 48 months)

Population: The safety population included all randomized participants exposed to the study intervention, regardless of the amount of exposure, analyzed according to the intervention actually received. Only participants with data collected at specified timepoints for the specified categories are reported.

Blood samples were collected at specified timepoints to assess change from baseline in NfL and Chi3L1. Baseline was defined as the last available value prior to the first dose of study intervention.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=311 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg n=319 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 Like Protein-1 (Chi3L1) Levels at EOS Chi3L1	-281.100 picogram/milliliter Interval -6148.4 to 5647.0	1462.500 picogram/milliliter Interval -4578.6 to 7002.7
Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 Like Protein-1 (Chi3L1) Levels at EOS NfL	-0.900 picogram/milliliter Interval -4.39 to 0.77	-0.150 picogram/milliliter Interval -3.56 to 2.75

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 48 months)

Blood samples were collected at specified timepoints to assess change from baseline in IgG and IgM levels. Baseline was defined as the last available value prior to the first dose of study intervention.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=281 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg n=287 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS IgG	-0.590 gram per liter Interval -1.33 to 0.23	0.140 gram per liter Interval -0.72 to 1.06
Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS IgM	-0.160 gram per liter Interval -0.32 to -0.02	-0.320 gram per liter Interval -0.53 to -0.15

Adverse Events

Teriflunomide 14 mg

Serious events: 37 serious events

Other events: 313 other events

Deaths: 2 deaths

Tolebrutinib 60 mg

Serious events: 49 serious events

Other events: 279 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Trial Transparency Team

Sanofi aventis recherche & développement

Phone: 800-633-1610

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.
Publication restrictions are in place

Restriction type: OTHER

Measure	Teriflunomide 14 mg n=451 participants at risk Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.	Tolebrutinib 60 mg n=447 participants at risk Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
Infections and infestations Covid-19	25.5% 115/451 • Number of events 131 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	23.7% 106/447 • Number of events 126 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)
Infections and infestations Influenza	5.5% 25/451 • Number of events 35 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	6.0% 27/447 • Number of events 33 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)
Infections and infestations Nasopharyngitis	14.2% 64/451 • Number of events 97 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	13.4% 60/447 • Number of events 102 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)
Infections and infestations Upper Respiratory Tract Infection	8.0% 36/451 • Number of events 49 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	6.9% 31/447 • Number of events 43 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)
Infections and infestations Urinary Tract Infection	6.7% 30/451 • Number of events 43 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	5.6% 25/447 • Number of events 35 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)
Infections and infestations Viral Upper Respiratory Tract Infection	5.3% 24/451 • Number of events 26 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	4.3% 19/447 • Number of events 28 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)
Blood and lymphatic system disorders Neutropenia	7.5% 34/451 • Number of events 72 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	2.2% 10/447 • Number of events 14 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)
Psychiatric disorders Anxiety	6.2% 28/451 • Number of events 33 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	5.4% 24/447 • Number of events 25 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)
Nervous system disorders Headache	12.0% 54/451 • Number of events 64 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	13.6% 61/447 • Number of events 82 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)
Nervous system disorders Paraesthesia	5.5% 25/451 • Number of events 30 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	3.6% 16/447 • Number of events 16 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)
Vascular disorders Hypertension	7.5% 34/451 • Number of events 35 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	2.9% 13/447 • Number of events 14 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)
Gastrointestinal disorders Diarrhoea	10.9% 49/451 • Number of events 57 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	4.9% 22/447 • Number of events 25 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)
Skin and subcutaneous tissue disorders Alopecia	16.2% 73/451 • Number of events 74 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	8.3% 37/447 • Number of events 39 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)
Musculoskeletal and connective tissue disorders Arthralgia	3.8% 17/451 • Number of events 21 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	5.1% 23/447 • Number of events 35 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)
Musculoskeletal and connective tissue disorders Back Pain	5.5% 25/451 • Number of events 39 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	6.0% 27/447 • Number of events 33 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)
General disorders Fatigue	4.7% 21/451 • Number of events 22 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	6.7% 30/447 • Number of events 30 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)
Investigations Alanine Aminotransferase Increased	5.1% 23/451 • Number of events 28 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)	4.5% 20/447 • Number of events 23 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months)