Phase II Study of Teriflunomide as Adjunctive Therapy to Glatiramer Acetate in Subjects With Multiple Sclerosis

• Overview of Adverse Events (AE] [ Time Frame: from first study drug intake up to 112 days after last intake or up to the first intake in the extension study LTS6047, whichever occured first (40 weeks max) ] [ Designated as safety issue: Yes ]
  AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
  
  
• Overview of AE With Potential Risk of Occurrence [ Time Frame: from first study drug intake up to 112 days after last intake or up to the first intake in the extension study LTS6047, whichever occured first (40 weeks max) ] [ Designated as safety issue: Yes ]

  AE with potential risk of occurrence were defined as follows:

  • Hepatic disorders;
  • Immune effects, mainly effects on bone marrow and infection;
  • Pancreatic disorders;
  • Malignancy;
  • Skin disorders, mainly hair loss and hair thinning;
  • Pulmonary disorders;
  • Hypertension;
  • Peripheral neuropathy;
  • Psychiatric disorders;
  • Hypersensitivity.
  
  
• 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 or up to the first intake in the extension study LTS6047, whichever occured first (40 weeks max) ] [ Designated as safety issue: Yes ]

  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 Normal Limit [ULN];
  • Aspartate aminotransferase [AST] >3, 5, 10 or 20 ULN;
  • Alkaline Phosphatase >1.5 ULN;
  • Total Bilirubin [TB] >1.5 or 2 ULN;
  • ALT >3 ULN and TB >2 ULN.
  
  

• Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) [ Time Frame: baseline (before randomization) and 24 weeks ] [ Designated as safety issue: No ]

  Total lesion volume is the sum of the total volume of all T2-lesions and the total volume all T1-hypointense post-gadolinium lesions measured through T2/proton density scan analysis and gadolinium-enhanced T1 scan analysis.

  Least-square means were estimated using a Mixed-effect model with repeated measures [MMRM] on cubic root transformed volume data (treatment group, region of enrollment, visit, treatment-by-visit interaction, baseline value (cubic root transformed), and baseline-by-visit interaction as factors).

  
  
• Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

  Number of Gd-enhancing T1-lesions per scan is obtained from the total number of Gd-enhancing T1-lesions observed during the study divided by the total number of scans performed during the study.

  To account for the different number of scans among participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable; log-transformed number of scans as "offset" variable; treatment group, region of enrollment and baseline number of Gd-enhancing T1-lesions as covariates).

  
  
• Cerebral MRI Assessment: Volume of Gd-enhancing T1-lesions Per Scan [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  Total volume of Gd-enhancing T1-lesions per scan is obtained from the sum of the volumes of Gd-enhancing T1-lesions observed during the study divided by the total number of scans performed during the study.
  
  
• Annualized Relapse Rate [ARR]: Poisson Regression Estimates [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

  ARR is obtained from the total number of confirmed relapses that occured during the treatment period divided by the sum of the treatment durations.

  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 Expanded Disability Status Scale [EDSS] score or Functional System scores.

  To account for the different treatment durations among participants, a Poisson regression model with robust error variance was used (total number of confirmed relapses as response variable; log-transformed treatment duration as "offset" variable; treatment group and region of enrollment as covariates).

  
  
• Pharmacokinetic [PK]: Teriflunomide Plasma Concentration [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  Plasma concentrations of teriflunomide were measured using validated liquid chromatography-tandem mass spectrometry methods.
  
  

The duration of the study period for a participant was approximatively 44 weeks broken down as follows:

• Screening period up to 4 weeks,
• 24-week double-blind treatment period*,
• 16-week post-treatment elimination follow-up period.

'*' Participants successfully completing the week 24 visit were offered the opportunity to enter the optional long-term extension study LTS6047 - NCT00811395.