Phase III Study With Teriflunomide Versus Placebo in Patients With First Clinical Symptom of Multiple Sclerosis (TOPIC)

• Core Treatment Period: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) [ Time Frame: Up to a maximum of 108 weeks depending on time of enrollment ]
  Conversion to CDMS was defined by the occurrence of a relapse, which was defined as a new neurological abnormality separated by at least 30 days from onset of a preceding clinical event, presented for at least 24 hours and occurred in the absence of fever or known infection. Percent probability of conversion at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.
  
  

• Core Treatment Period: Time to Conversion to Definite Multiple Sclerosis (DMS) [ Time Frame: Up to a maximum of 108 weeks depending on time of enrollment ]
  Conversion to DMS was demonstrated by dissemination of MRI lesions in time (as per McDonald criteria) or a relapse, whichever occurs first. MRI Imaging criteria were detection of Gadolinium (Gd) enhancement at least 3 months after onset of initial clinical event, if not at site corresponding to initial event; detection of new T2 lesion if it appears at any time compared with reference scan (done at time of screening) done at least 30 days after onset of the initial clinical event. Occurrence of relapse was defined as new neurological abnormality separated by at least 30 days from onset of preceding clinical event, present for at least 24 hours and occurring in absence of fever or known infection. New clinical abnormality (neurological sign) that is consistent with participant's symptoms with increase in at least one Functional System (FS) or EDSS score compared to last EDSS assessment. Percent probability of conversion at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.
  
  
• Core Treatment Period: Annualized Relapse Rate (ARR) [ Time Frame: Up to a maximum of 108 weeks depending on time of enrollment ]
  ARR is the total number of confirmed relapses that occurred during the treatment period divided by the total number of patient-years treated. Each episode of relapse (appearance, or worsening of a clinical symptom that was stable for at least 30 days, that persisted for a minimum of 24 hours in the absence of fever) was to be confirmed by an increase in EDSS score or Functional System scores. ARR was assessed using Poisson regression model with robust error variance. To account for the different treatment durations among participants, a Poisson regression model with robust error variance was used (total number of confirmed relapses onset between randomization date and last dose date as the response variable, treatment, region and baseline monofocal/multifocal status as covariates, and log-transformed treatment duration as an offset variable).
  
  
• Core Treatment Period: Brain Magnetic Resonance Imaging (MRI) Assessment: Change From Baseline in Total Lesion Volume at Week 108 [ Time Frame: Baseline, Week 108 ]
  The total lesion volume (burden of disease) is the total volumes of hyperintense on T2 plus hypointense on T1 as measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data with factors for treatment, baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline burden of disease, and baseline-by-visit interaction.
  
  
• Core Treatment Period: Brain MRI Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan (Poisson Regression Estimates) [ Time Frame: Up to a maximum of 108 weeks depending on time of enrollment ]
  Number of Gd-enhancing T1-lesions per scan is the total number of Gd-enhancing T1-lesions that occurred during the treatment period divided by the total number of scans performed during the treatment period. To account for the different numbers of scans performed among the participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable, treatment, baseline monofocal/multifocal status, region and baseline number of Gd-enhancing T1-lesions as covariates, and log-transformed number of scans as an offset variable).
  
  
• Core Treatment Period: Brain MRI Assessment: Volume of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan [ Time Frame: Up to a maximum of 108 weeks depending on time of enrollment ]
  Total volume of Gd-enhancing T1-lesions per scan is the sum of the volumes of Gd-enhancing T1-lesions observed during the treatment period divided by the total number of scans performed during the treatment period. To account for the different numbers of scans performed among the participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable, treatment, baseline monofocal/multifocal status, region and baseline number of Gd-enhancing T1-lesions as covariates, and log-transformed number of scans as an offset variable).
  
  
• Core Treatment Period: Brain MRI Assessment: Change From Baseline in Volume of Hypointense Post-Gadolinium T1 Lesion Component [ Time Frame: Baseline, Week 108 ]
  Volume of hypointense post-gadolinium T1 lesion component was measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline value, and baseline-by-visit interaction
  
  
• Core Treatment Period: Brain MRI Assessment: Change From Baseline in Volume of T2 Lesion Component [ Time Frame: Baseline, Week 108 ]
  Volume of T2 lesion component was measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline value, and baseline-by-visit interaction.
  
  
• Core Treatment Period: Brain MRI Assessment: Percent Change From Baseline in Atrophy [ Time Frame: Baseline, Week 108 ]
  Atrophy was measured by MRI scan.
  
  
• Core Treatment Period: Time to 12-Week Sustained Disability Progression [ Time Frame: Up to a maximum of 108 weeks depending on time of enrollment ]
  The 12-week sustained disability progression was defined as increase from baseline of at least 1-point in EDSS score (at least 0.5-point for participants with baseline EDSS score of greater than [>] 5.5) that persisted for at least 12 weeks. Percent probability of participants free of 12-week sustained disability progression at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.
  
  
• Core Treatment Period: Change From Baseline in EDSS at Week 108 [ Time Frame: Baseline, Week 108 ]
  EDSS is an ordinal scale in half-point increments that qualifies disability in participants with MS. It consists of 8 ordinal rating scales assessing seven functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS). Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, baseline value and baseline-by-visit interaction
  
  
• Core Treatment Period: Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 108 [ Time Frame: Baseline, Week 108 ]
  FIS is a participant-reported scale that qualifies the impact of fatigue on daily life in participants with MS. It consists of 40 statements that measure fatigue in three areas; physical, cognitive, and social. FIS total score ranges from 0 (no problem) to 160 (extreme problem). Least-square means were estimated using a Mixed-effect model with repeated measures [MMRM] on FIS total score data adjusted for or baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, baseline value and baseline-by-visit interaction.
  
  
• Core Treatment Period: Overview of Adverse Events (AEs) [ Time Frame: From first study drug intake up to 112 days after last intake in the placebo-controlled period or up to first intake in the extension treatment period, whichever occurred first ]
  AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
  
  
• Extension Treatment Period: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) [ Time Frame: From randomization in the core period up to 390 Weeks (Extension treatment period [maximum exposure: 283 Weeks]) ]
  Conversion to CDMS was defined by the occurrence of a relapse, which was defined as a new neurological abnormality separated by at least 30 days from onset of a preceding clinical event, presented for at least 24 hours and occurred in the absence of fever or known infection. Percent probability of conversion was estimated using Kaplan-Meier method.
  
  
• Extension Treatment Period: Overview of Adverse Events (AEs) [ Time Frame: From re-randomization up to 283 Weeks ]
  AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study. Safety population included all randomized population who actually received at least 1 dose of the IMP in extension and analyzed according to the treatment actually received in core study followed by treatment actually received in the extension treatment period.
  
  

• Core Treatment Period: Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) [ Time Frame: From first study drug intake up to 112 days after last intake in the placebo-controlled period or up to first intake in the extension treatment period, whichever occurred first ]

  PCSA values are abnormal values considered medically important by the Sponsor according to predefined criteria based on literature review.

  Hepatic parameters thresholds were defined as follows:

  • Alanine Aminotransferase (ALT) >3, 5, 10 or 20 upper limit of normal(ULN);
  • Aspartate aminotransferase (AST) >3, 5, 10 or 20 ULN;
  • Alkaline Phosphatase >1.5 ULN;
  • Total Bilirubin (TB) >1.5, 2, or 3 ULN;
  • ALT >3 ULN and TB >2 ULN.
  
  

The study consisted of 4 periods:

• Screening period: up to 4 weeks,
• Placebo-controlled treatment period: up to 108 weeks (at least 24 weeks for participants who experienced conversion to CDMS),
• Extension treatment period (without placebo-control): the extension period continued until teriflunomide was commercially available in participant's country of residence.
• Post-treatment washout period: 4 weeks after last treatment intake.

The maximal duration of the study period per participant was expected to be 116 weeks if he/she did not continue in the extension treatment period.