Trial Outcomes & Findings for Using Patient Reported Outcomes (PROs) to Evaluate Teriflunomide Treatment in Relapsing Multiple Sclerosis (RMS) Patients (NCT NCT01895335)

Last Updated: 2016-12-06

Results Overview

TSQM version 1.4 is a global satisfaction scale used to assess the overall level of participant's satisfaction or dissatisfaction with their medications. It comprises of 14 items assessing the following 4 domains: effectiveness (questions: 1-3), side effects (questions: 4-8), convenience (questions: 9-11), global satisfaction (questions:12-14). Primary outcome was the global satisfaction score. The score of the corresponding item was added based on the algorithm to create a score of 0 to 100. Higher score indicated greater satisfaction in that domain.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

1001 participants

Primary outcome timeframe

Week 48

Results posted on

2016-12-06

Participant Flow

The study was conducted at 169 centers in 14 countries. A total of 1102 participants were screened between June 14, 2013 and November 27, 2014 of whom 101 were screen failures. Screen failures were mainly due to exclusion criteria met.

A total of 1001 participants were included and 1000 participants were treated in the study. Dose of Teriflunomide tablet was given according to local labelling 14 mg or 7 mg (Teriflunomide 14 mg was the recommended dosage worldwide, except in the US \[where both 7 mg and 14 mg were available\]).

Participant milestones

Participant milestones
Measure	Teriflunomide Teriflunomide 14 mg or 7 mg according to local labelling once daily (QD) orally for 48 weeks.
Overall Study STARTED	1001
Overall Study Treated	1000
Overall Study COMPLETED	786
Overall Study NOT COMPLETED	215

Reasons for withdrawal

Reasons for withdrawal
Measure	Teriflunomide Teriflunomide 14 mg or 7 mg according to local labelling once daily (QD) orally for 48 weeks.
Overall Study Adverse Event	106
Overall Study Lack of Efficacy	53
Overall Study Poor Compliance to Protocol	11
Overall Study Included But Not treated	1
Overall Study Other than Specified Above	44

Baseline Characteristics

Using Patient Reported Outcomes (PROs) to Evaluate Teriflunomide Treatment in Relapsing Multiple Sclerosis (RMS) Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Teriflunomide n=1000 Participants Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Age, Continuous	47.1 years STANDARD_DEVIATION 11.0 • n=5 Participants
Sex: Female, Male Female	756 Participants n=5 Participants
Sex: Female, Male Male	244 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 48

Population: Efficacy population that included all treated participants. Number of participants analyzed = participants with available data at specified time point.

Outcome measures

Outcome measures
Measure	Teriflunomide n=889 Participants Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Treatment Satisfaction Questionnaire for Medication (TSQM) Version 1.4 - Assessment of Global Satisfaction Subscale Score With Teriflunomide Treatment at Week 48	68.17 units on a scale Standard Deviation 27.66

SECONDARY outcome

Timeframe: Baseline, Week 4, Week 48

Population: Analysis was performed on Efficacy population. Number of participants analyzed=participants with available data at specified time point. Here, 'n' signifies number of participants with available data for specified category.

TSQM version 1.4 is a global satisfaction scale used to assess the overall level of participant's satisfaction or dissatisfaction with their medications. It comprises of 14 items assessing the following 4 domains: effectiveness (questions: 1-3), side effects (questions: 4-8), convenience (questions: 9-11), global satisfaction (questions: 12-14). For each of the 4 domains the scores of the corresponding items were added based on an algorithm to create a score of 0 to 100. Higher scores indicated greater satisfaction .

Outcome measures

Outcome measures
Measure	Teriflunomide n=594 Participants Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Change From Baseline in TSQM Scores in Participants Switching From Another Disease Modifying Therapy (DMT) at Week 4 and Week 48 Global Satisfaction Score Change at Week 4 (n=482)	21.35 units on a scale Standard Deviation 27.51
Change From Baseline in TSQM Scores in Participants Switching From Another Disease Modifying Therapy (DMT) at Week 4 and Week 48 Global Satisfaction Score Change at Week 48(n=457)	16.55 units on a scale Standard Deviation 34.29
Change From Baseline in TSQM Scores in Participants Switching From Another Disease Modifying Therapy (DMT) at Week 4 and Week 48 Effectiveness Score Change at Week 4 (n=477)	12.02 units on a scale Standard Deviation 25.53
Change From Baseline in TSQM Scores in Participants Switching From Another Disease Modifying Therapy (DMT) at Week 4 and Week 48 Effectiveness Score Change at Week 48 (n=453)	10.19 units on a scale Standard Deviation 28.90
Change From Baseline in TSQM Scores in Participants Switching From Another Disease Modifying Therapy (DMT) at Week 4 and Week 48 Side effects Score Change at Week 4 (n=479)	24.31 units on a scale Standard Deviation 35.47
Change From Baseline in TSQM Scores in Participants Switching From Another Disease Modifying Therapy (DMT) at Week 4 and Week 48 Side effects Score Change at Week 48 (n=456)	19.95 units on a scale Standard Deviation 39.00
Change From Baseline in TSQM Scores in Participants Switching From Another Disease Modifying Therapy (DMT) at Week 4 and Week 48 Convenience Score Change at Week 4 (n=487)	34.64 units on a scale Standard Deviation 26.37
Change From Baseline in TSQM Scores in Participants Switching From Another Disease Modifying Therapy (DMT) at Week 4 and Week 48 Convenience Score Change at Week 48 (n=461)	32.21 units on a scale Standard Deviation 27.01

SECONDARY outcome

Timeframe: Week 4, Week 48

TSQM version 1.4 is a global satisfaction scale used to assess the overall level of participant's satisfaction or dissatisfaction with their medications. It comprises of 14 items assessing the following 4 domains: effectiveness (questions: 1-3), side effects (questions: 4-8), convenience (questions: 9-11), global satisfaction (questions: 12-14). For each of the 4 domains the scores of the corresponding items were added based on an algorithm to create a score of 0 to 100. Higher scores indicated greater satisfaction.

Outcome measures

Outcome measures
Measure	Teriflunomide n=285 Participants Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Change From Week 4 in TSQM Scores in Naïve Participants to Week 48 Change in Global Satisfaction Score (n=234)	-1.34 units on a scale Standard Deviation 23.59
Change From Week 4 in TSQM Scores in Naïve Participants to Week 48 Change in Effectiveness Score (n=231)	1.76 units on a scale Standard Deviation 27.48
Change From Week 4 in TSQM Scores in Naïve Participants to Week 48 Change in Side effects Score (n=234)	-5.44 units on a scale Standard Deviation 25.11
Change From Week 4 in TSQM Scores in Naïve Participants to Week 48 Change in Convenience Score (n=235)	0.33 units on a scale Standard Deviation 12.96

SECONDARY outcome

Timeframe: Baseline, Week 48

Population: Analysis was performed on Efficacy population. Number of participants analyzed=participants with available data at specified time point.

PDDS scale developed to assess the disability in Multiple Sclerosis (MS) participants and in assessing disease progression that focuses mainly on how participants walk. PDDS scale consists of 0 = normal; 1 = mild disability; 2 = moderate disability; 3 = gait disability; 4 = early cane; 5 = late cane; 6 = bilateral support; 7 = wheelchair/scooter and 8 = bedridden. A higher score represented higher level of disability.

Outcome measures

Outcome measures
Measure	Teriflunomide n=860 Participants Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Change From Baseline in Disease Progression Using Patient Determined Disease Steps (PDDS) Score at Week 48	-0.01 units on a scale Standard Deviation 1.05

SECONDARY outcome

Timeframe: Baseline, Week 24, Week 48

Population: Analysis was performed on Efficacy population. Here, 'n' signifies number of participants with available data at specified time points.

MSPS was a self-reported measure for MS associated disability in which participants were asked to indicate the category that best described their condition during the past month on the following 8 subscales: mobility, hand function, vision, fatigue, cognitive symptoms, bladder/bowel, sensory symptoms and spasticity symptoms. MSPS used a single question to assess each of 8 subscales. All of the subscales ranged from 0= normal to 5= total disability, except mobility subscale which ranged from 0= normal to 6=total disability. Total MSPS score ranged from 0 =normal to 41=greater disability, where higher score reflected greater disability.

Outcome measures

Outcome measures
Measure	Teriflunomide n=1000 Participants Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Change From Baseline in Multiple Sclerosis Performance Scale (MSPS) Score at Week 24 and Week 48 Change at Week 24 (n=854)	-0.61 units on a scale Standard Deviation 3.89
Change From Baseline in Multiple Sclerosis Performance Scale (MSPS) Score at Week 24 and Week 48 Change at Week 48 (n=875)	-0.06 units on a scale Standard Deviation 4.33

SECONDARY outcome

Timeframe: Baseline up to end of treatment (up to Week 48)

Population: Analysis was performed on Efficacy population.

Annualized treated relapse rate was defined as the total number of treated relapses during the study treatment period divided by the total number participants-years of treatment. Only events occurred during the treatment period (first drug administration to last drug administration) were considered for analysis.

Outcome measures

Outcome measures
Measure	Teriflunomide n=1000 Participants Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Annualized Treated Relapse Rate	0.200 relapses per patient-year

SECONDARY outcome

Timeframe: Baseline up to end of treatment (up to Week 48)

Population: Analysis was performed on Efficacy population.

A treated relapse was defined as a relapse treated by a systemic corticosteroid treatment or by another DMT. If a participant had no treated relapse before treatment discontinuation/completion, then the participant was considered as free of treated relapse until the date of treatment discontinuation/completion. Only treated relapse occurred during the treatment period (first drug administration to last drug administration) were considered for analysis. Kaplan-Meier method was used to estimate the probability of treated MS relapse at 4, 24 and 48 weeks.

Outcome measures

Outcome measures
Measure	Teriflunomide n=1000 Participants Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Time to Relapse: Kaplan-Meier Estimates of the Probability of Treated Relapse at Week 4, Week 24 and Week 48 Percent Probability of Treated Relapse at Week 4	1.8 percent probability of treated relapse Interval 1.0 to 2.6
Time to Relapse: Kaplan-Meier Estimates of the Probability of Treated Relapse at Week 4, Week 24 and Week 48 Percent Probability of Treated Relapse at Week 24	9.4 percent probability of treated relapse Interval 7.5 to 11.2
Time to Relapse: Kaplan-Meier Estimates of the Probability of Treated Relapse at Week 4, Week 24 and Week 48 Percent Probability of Treated Relapse at Week 48	15.5 percent probability of treated relapse Interval 13.2 to 17.9

SECONDARY outcome

Timeframe: Baseline, Week 48

Population: Analysis was performed on Efficacy population. Number of participants analyzed=participants with available data at specified time point.

SDMT measures the time to pair abstract symbols with specific numbers. It is a simple substitution task that gives the examinee 90 seconds to pair specific numbers with given geometric figures as a measure for screening cognitive impairment. The score is computed as a ratio of number of correct responses divided by the total number of responses. The test score range from 0 (worst outcome) to 1 (best outcome). Higher scores are indicative of better cognition function.

Outcome measures

Outcome measures
Measure	Teriflunomide n=854 Participants Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Change From Baseline in Cognition Measured by Symbol Digit Modalities Test (SDMT) Score at Week 48	0.00 units on a scale Standard Deviation 0.06

SECONDARY outcome

Timeframe: From first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants with AEP

Population: Safety Population that included all treated participants who received at least 1 dose or part of a dose of IMP.

Any untoward medical occurrence in a participant who received investigational medicinal product (IMP) was considered an AE without regard to possibility of causal relationship with this treatment. Treatment-emergent adverse events (TEAEs) were defined as AEs that developed or worsened or became serious during from first study drug intake up to 112 days after last intake for participant with no accelerated elimination procedure (AEP) or to last AEP follow up visit for participants with AEP. A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included participants with both serious and non-serious AEs.

Outcome measures

Outcome measures
Measure	Teriflunomide n=1000 Participants Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Overview of Adverse Events (AEs) Any TEAE	82.3 percentage of participants
Overview of Adverse Events (AEs) Any treatment emergent SAE	12.7 percentage of participants
Overview of Adverse Events (AEs) Any TEAE leading to death	0.4 percentage of participants
Overview of Adverse Events (AEs) Any TEAE leading to permanent discontinuation	10.9 percentage of participants

SECONDARY outcome

Timeframe: Baseline up to end of treatment (up to Week 48)

Population: Analysis was performed on Safety population.

Percentage of compliance for a participant was defined as the number of days that the participant was compliant (1 tablet/day) divided by the exposure duration in days (from the first dose administration to the last dose administration) times 100.

Outcome measures

Outcome measures
Measure	Teriflunomide n=1000 Participants Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Percentage of Participants With Treatment Compliance of ≥80% During the Study Treatment Period	98.2 percentage of participants

SECONDARY outcome

Timeframe: Baseline up to end of treatment (up to Week 48)

Population: Analysis was performed on Safety population.

Duration of exposure was defined as last dose date - first dose date + 1 day, regardless of unplanned intermittent discontinuations and regardless of dosage administered (14 mg or 7 mg).

Outcome measures

Outcome measures
Measure	Teriflunomide n=1000 Participants Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Duration of Teriflunomide Treatment Exposure	301.6 Days Standard Deviation 89.1

SECONDARY outcome

Timeframe: Baseline, Week 48

Population: Analysis was performed on Efficacy population. Number of participants analyzed=participants with available data at specified time point.

The MusiQoL is a quality of life questionnaire that consists of 31 questions, divided into 9 dimensions: activities of daily living, physiological well-being, symptoms, relationship with friends, relationship with family, sentimental and sexual life, coping, rejection and relationship with healthcare system. All the 9 dimension scores and the global scores are linearly transformed and standardized on 0 (worst outcome) -100 (best outcome) scale. Higher scores represents higher quality of life.

Outcome measures

Outcome measures
Measure	Teriflunomide n=826 Participants Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Change From Baseline in Multiple Sclerosis International Quality of Life (MusiQoL) Score at Week 48	0.99 units on a scale Standard Deviation 10.82

SECONDARY outcome

Timeframe: Baseline, Week 48

Population: Analysis was performed on Efficacy population. Number of participants analyzed=participants with available data at specified time point.

The Stern Leisure Activity Scale is a self-reported scale that consists of 13 questions assessing the participant's participation in leisure activities during the preceding month. One point is given for participation in each of the 13 activities and an aggregate score (range from 0 to 13) is obtained. ≤ 6 score is considered as low leisure activity and \> 6 score as high leisure activity.

Outcome measures

Outcome measures
Measure	Teriflunomide n=845 Participants Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Change From Baseline in Stern Leisure Activity Scale at Week 48	0.07 units on a scale Standard Deviation 1.93

SECONDARY outcome

Timeframe: Baseline, Week 48

EDSS is a method of quantifying disability in MS participants and monitoring changes in the level of disability over time. EDSS quantifies disability in 8 functional systems: pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral, and other. EDSS scale ranges from 0 to 10 in 0.5 unit increments that represents higher levels of disability. EDSS score 1.0 to 4.5 refers to people with MS who are fully ambulatory; EDSS score 5.0 to 9.5 refers to impairment to ambulation; EDSS score 10 refers to death due to MS.

Outcome measures

Outcome measures
Measure	Teriflunomide n=1000 Participants Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Expanded Disability Status Scale (EDSS) Score at Baseline and Week 48 Baseline (n=981)	3.05 units on a scale Standard Deviation 1.94
Expanded Disability Status Scale (EDSS) Score at Baseline and Week 48 Week 48 (n=886)	3.05 units on a scale Standard Deviation 1.98

Adverse Events

Teriflunomide

Serious events: 127 serious events

Other events: 498 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Teriflunomide n=1000 participants at risk Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Blood and lymphatic system disorders Neutropenia	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Cardiac disorders Acute Myocardial Infarction	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Cardiac disorders Coronary Artery Disease	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Cardiac disorders Myocardial Infarction	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Cardiac disorders Myocarditis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Ear and labyrinth disorders Vertigo	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Eye disorders Blindness Unilateral	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Eye disorders Retinal Artery Thrombosis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Gastrointestinal disorders Abdominal Hernia Obstructive	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Gastrointestinal disorders Colitis Microscopic	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Gastrointestinal disorders Diarrhoea	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Gastrointestinal disorders Dysphagia	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Gastrointestinal disorders Gastritis	0.20% 2/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Gastrointestinal disorders Gastrooesophageal Reflux Disease	0.20% 2/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Gastrointestinal disorders Hiatus Hernia	0.20% 2/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Gastrointestinal disorders Volvulus	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
General disorders Asthenia	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
General disorders Chest Pain	0.30% 3/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
General disorders Non-Cardiac Chest Pain	0.30% 3/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
General disorders Oedema Peripheral	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Hepatobiliary disorders Bile Duct Stone	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Hepatobiliary disorders Biliary Colic	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Hepatobiliary disorders Cholecystitis	0.20% 2/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Hepatobiliary disorders Cholelithiasis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Immune system disorders Hypersensitivity	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Appendicitis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Cellulitis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Clostridium Difficile Colitis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Clostridium Difficile Infection	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Diverticulitis	0.20% 2/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Gastroenteritis	0.20% 2/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Myelitis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Oesophageal Candidiasis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Osteomyelitis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Pelvic Abscess	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Perichondritis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Pneumonia	0.40% 4/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Pyelonephritis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Sepsis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Urinary Tract Infection	0.50% 5/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Viral Infection	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Viral Upper Respiratory Tract Infection	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Injury, poisoning and procedural complications Accidental Overdose	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Injury, poisoning and procedural complications Facial Bones Fracture	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Injury, poisoning and procedural complications Intentional Overdose	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Investigations Alanine Aminotransferase Increased	0.60% 6/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Investigations Blood Pressure Increased	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Investigations Clostridium Test Positive	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Investigations Fibrin D Dimer Increased	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Investigations Transaminases Increased	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Investigations Weight Decreased	0.20% 2/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Metabolism and nutrition disorders Diabetic Ketoacidosis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Metabolism and nutrition disorders Hypokalaemia	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Metabolism and nutrition disorders Metabolic Acidosis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Musculoskeletal and connective tissue disorders Back Pain	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Musculoskeletal and connective tissue disorders Cervical Spinal Stenosis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Musculoskeletal and connective tissue disorders Intervertebral Disc Disorder	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Musculoskeletal and connective tissue disorders Intervertebral Disc Protrusion	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Musculoskeletal and connective tissue disorders Musculoskeletal Pain	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Musculoskeletal and connective tissue disorders Periarthritis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Musculoskeletal and connective tissue disorders Rhabdomyolysis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal Cell Carcinoma	0.20% 2/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast Cancer	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Fibroma	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Invasive Ductal Breast Carcinoma	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant Melanoma	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-Small Cell Lung Cancer Stage Iv	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal Cancer	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine Leiomyoma	0.20% 2/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Carpal Tunnel Syndrome	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Cerebral Sarcoidosis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Cerebrovascular Accident	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Cervicobrachial Syndrome	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Encephalopathy	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Epilepsy	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Headache	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Hemiparesis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Hypoaesthesia	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Medication Overuse Headache	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Multiple Sclerosis	0.20% 2/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Multiple Sclerosis Relapse	2.1% 21/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Neuromyelitis Optica	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Paraesthesia	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Seizure	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Syncope	0.40% 4/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Toxic Encephalopathy	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Transient Ischaemic Attack	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Trigeminal Neuralgia	0.20% 2/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Uhthoff's Phenomenon	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Pregnancy, puerperium and perinatal conditions Pregnancy	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Psychiatric disorders Acute Psychosis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Psychiatric disorders Adjustment Disorder With Depressed Mood	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Psychiatric disorders Depression	0.20% 2/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Psychiatric disorders Suicidal Ideation	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Psychiatric disorders Suicide Attempt	0.20% 2/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Renal and urinary disorders Acute Kidney Injury	0.20% 2/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Renal and urinary disorders Haematuria	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Renal and urinary disorders Hypertonic Bladder	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Renal and urinary disorders Nephrolithiasis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Reproductive system and breast disorders Female Genital Tract Fistula	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Reproductive system and breast disorders Menorrhagia	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Reproductive system and breast disorders Ovarian Cyst	0.20% 2/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Acute Interstitial Pneumonitis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Acute Respiratory Failure	0.20% 2/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Asthmatic Crisis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Atelectasis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Chronic Obstructive Pulmonary Disease	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Lung Cyst	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Pneumonia Aspiration	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Pulmonary Embolism	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Skin and subcutaneous tissue disorders Alopecia	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Skin and subcutaneous tissue disorders Eczema	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Skin and subcutaneous tissue disorders Psoriasis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Skin and subcutaneous tissue disorders Rash	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Surgical and medical procedures Abdominoplasty	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Vascular disorders Deep Vein Thrombosis	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Vascular disorders Essential Hypertension	0.10% 1/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Vascular disorders Hypertension	0.60% 6/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.

Other adverse events

Other adverse events
Measure	Teriflunomide n=1000 participants at risk Teriflunomide 14 mg or 7 mg according to local labelling QD orally for 48 weeks.
Gastrointestinal disorders Diarrhoea	17.2% 172/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Gastrointestinal disorders Nausea	8.2% 82/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
General disorders Fatigue	5.2% 52/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Nasopharyngitis	5.4% 54/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Infections and infestations Urinary Tract Infection	6.2% 62/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Investigations Alanine Aminotransferase Increased	5.7% 57/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Nervous system disorders Headache	6.8% 68/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.
Skin and subcutaneous tissue disorders Alopecia	22.9% 229/1000 • All AEs were collected from signature of the informed consent form up to the last visit (Week 52) regardless of seriousness or relationship to investigational product. Reported AEs are TEAEs that is AEs that developed/worsened from first study drug intake up to 112 days after last intake for participant with no AEP or to last AEP follow up visit for participants in AEP. Analysis was performed on safety population.

Additional Information

Trial Transparency Team

Sanofi

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.
Publication restrictions are in place

Restriction type: OTHER