Multiple Sclerosis Relapse
Conditions
Brief summary
The primary objective was to demonstrate the effect of teriflunomide, in comparison to placebo, on frequency of Multiple Sclerosis (MS) relapses in patients with relapsing forms of MS who are treated with Interferon-beta (IFN-beta). The secondary objectives were: * Assess the effect of teriflunomide, in comparison to placebo, when added to IFN-beta on: * Disease activity as measured by brain Magnetic Resonance Imaging (MRI) * Disability progression * Burden of disease and disease progression as measured by brain MRI * Evaluate the safety and tolerability of teriflunomide when added to IFN-beta therapy * Assess the pharmacokinetics of teriflunomide in use in addition to baseline IFN-beta therapy * Assess associations between variations in genes and clinical outcomes (safety and efficacy) * Assess other measures of efficacy of teriflunomide such as fatigue and health-related quality of life * Assess measures of health economics (hospitalization due to relapse, including the length of stay and any admission to intensive care unit)
Detailed description
The study period per patient was expected to be between 56 and 160 weeks depending on when the patient was randomized and this included the following: * a screening period up to 4 weeks, * a treatment period expected to be between 48 and 152 weeks, * 4-week post rapid elimination follow-up period. Patients were to continue on treatment until a fixed common end date which was approximately 48 weeks after randomization of the last patient. For those patients who completed the treatment period, a long term extension study of approximately 1 year (including teriflunomide alone) was initially planned to be proposed.
Interventions
DRUGTeriflunomide
Film-coated tablet Oral administration
Film-coated tablet Oral administration
Any of the IFN-beta which are approved for marketed use in the country where the patient is enrolled. Administration according to the package insert.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
: * Patient with relapsing forms of MS treated with IFN-beta * Stable dose of IFN-beta (approved brand) for at least 6 months prior to randomization * Disease activity in the 12 months prior to randomization and after first 3 months of IFN-beta treatment (defined by at least 1 relapse supported by EDSS or equivalent neurological examination, or, at least 1 brain or spinal cord MRI with at least one T1 gadolinium enhancing lesion)
Exclusion criteria
* McDonald criteria for MS diagnosis not met at time of screening visit * EDSS score greater than (\>) 5.5 at randomization visit * A relapse within 30 days prior randomization * Persistent significant or severe infection * Patients must not have used adrenocorticotrophic hormone or systemic corticosteroids for 2 weeks prior to randomization * Prior or concomitant use of cytokine therapy (except baseline interferons), glatiramer acetate or intravenous immunoglobulins in the 3 months preceding randomization * Liver function impairment or persisting elevations (confirmed by retest) of alanine aminotransferase (ALT), aspartate aminotransferase (AST), or direct bilirubin greater than 2 times the upper limit of normal range (ULN) * Active hepatitis or hepatobiliary disease or known history of severe hepatitis * Pregnant or breast-feeding women or those who were planning to become pregnant during the study * Significantly impaired bone marrow function or significant anemia, leukopenia, or thrombocytopenia * Human Immunodeficiency Virus (HIV) positive * Known history of active tuberculosis not adequately treated * Prior use within 2 years preceding randomization or concomitant use of cladribine and mitoxantrone * Prior use within 6 months preceding randomization or concomitant use of natalizumab, or any other immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate, or fingolimod The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Relapse Rate (ARR) (Poisson Regression Estimates) | 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 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, region of enrollment and IFN-beta dose stratum, and number of relapses in the year prior to randomization as covariates). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Brain Magnetic Resonance Imaging (MRI) Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per Scan (Poisson Regression Estimates) | 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 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, IFN-beta dose stratum and baseline number of Gd-enhancing T1-lesions as covariates). |
| Time to 12-Week Sustained Disability Progression | Up to a maximum of 108 weeks depending on time of enrollment | The 12-week sustained disability progression was defined as an increase from baseline of at least 1-point in EDSS score (at least 0.5-point for participants with baseline EDSS score \>5.5) that persisted for at least 12 weeks. Probability of disability progression was to be estimated using Kaplan-Meier method. |
| Brain MRI Assessment: Volume of Gd-enhancing T1-lesions Per MRI Scan | 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. |
| Brain MRI Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) at Week 24 | Baseline, Week 24 | 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, region, IFN-beta dose stratum, visit, treatment-by-visit interaction, cubic root transformed baseline burden of disease, and baseline-by-visit interaction. |
| Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 24 | Baseline, Week 24 | FIS is a participant-reported scale that qualifies the impact of fatigue on daily life in participants with MS. |
| Change From Baseline in Short Form Generic Health Survey - 36 Items, Version 2 (SF-36v2) Summary Scores at Week 24 | Baseline, Week 24 | SF-36 scale is a generic, self-administered, health-related quality-of-life (QOL) instrument. |
| Resource Utilization When Relapse | Up to a maximum of 108 weeks depending on time of enrollment | Resource utilization each time a participant experiences an MS relapse, specifically the number of hospitalizations, the number of over night spent in the hospital and number of intensive care admissions if hospitalized were to be reported. |
| Overview of Adverse Events (AEs) | First study drug intake up to 28 days after last study drug intake, for up to 112 weeks | AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study. |
| Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72 | Up to a maximum of 108 weeks depending on time of enrollment | Probability of no relapse at 24, 48 and 72 weeks was estimated using Kaplan-Meier method on the time to relapse defined as the time from randomization to first EDSS confirmed relapse. Participants free of confirmed relapse (no EDSS confirmed relapse observed on treatment) were censored at the date of the last study drug intake. Kaplan-Meier method consists in computing probabilities of non-occurrence of event at any observed time of event and multiplying successive probabilities for time \<=t by any earlier computed probabilities to estimate the probability of being event-free for the amount of time t. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | First study drug intake up to 28 days after last study drug intake, for up to 112 weeks | 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 or 10 Upper Limit of Normal (ULN); Aspartate Aminotransferase (AST) \>3, 5 or 10 ULN; Alkaline Phosphatase \>1.5 ULN; Total Bilirubin (TB) \>1.5 ULN; and ALT \>3 ULN and TB \>2 ULN. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Colombia, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Italy, Lithuania, Netherlands, Norway, Portugal, Russia, Slovakia, South Korea, Spain, Sweden, Tunisia, United Kingdom, United States
Participant flow
Recruitment details
The recruitment initiated in January 2011, was discontinued in December 2012 following the decision of the Sponsor to discontinue the study, the common treatment end date was defined as February 28th, 2013 (treatment duration between 24 and 108 weeks). A total of 846 participants were screened at 185 sites in 28 countries.
Pre-assignment details
Randomization was stratified by investigational site and Interferon-beta (IFN-beta) dose level (high/low). Assignment to groups was done centrally using an Interactive Voice Response System (IVRS) in a 1:1:1 ratio after confirmation of selection criteria. A total of 534 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + IFN-beta Placebo (for teriflunomide) once daily concomitantly with IFN-beta. | 177 |
| Teriflunomide 7 mg + IFN-beta Teriflunomide 7 mg once daily concomitantly with IFN-beta. | 178 |
| Teriflunomide 14 mg + IFN-beta Teriflunomide 14 mg once daily concomitantly with IFN-beta. | 179 |
| Total | 534 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 9 | 17 | 22 |
| Overall Study | Lack of Efficacy | 6 | 4 | 2 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Other Than Above | 8 | 7 | 7 |
| Overall Study | Poor Compliance to Protocol | 1 | 1 | 1 |
| Overall Study | Progressive Disease | 2 | 0 | 0 |
| Overall Study | Randomized but not Treated | 2 | 0 | 0 |
| Overall Study | Sponsor Early Termination of Study | 149 | 149 | 146 |
Baseline characteristics
| Characteristic | Total | Teriflunomide 7 mg + IFN-beta | Teriflunomide 14 mg + IFN-beta | Placebo + IFN-beta |
|---|---|---|---|---|
| Age, Continuous | 38.2 years STANDARD_DEVIATION 9.2 | 38.7 years STANDARD_DEVIATION 9.5 | 37.7 years STANDARD_DEVIATION 9.2 | 38.3 years STANDARD_DEVIATION 8.9 |
| Baseline Expanded Disability Status Scale (EDSS) Score | 2.65 units on a scale STANDARD_DEVIATION 1.26 | 2.63 units on a scale STANDARD_DEVIATION 1.37 | 2.64 units on a scale STANDARD_DEVIATION 1.18 | 2.67 units on a scale STANDARD_DEVIATION 1.25 |
| Dose Level of Interferon-beta (IFN-beta) Based on IVRS High dose | 368 participants | 128 participants | 120 participants | 120 participants |
| Dose Level of Interferon-beta (IFN-beta) Based on IVRS Low dose | 166 participants | 50 participants | 59 participants | 57 participants |
| MS Subtype Progressive Relapsing | 3 participants | 2 participants | 0 participants | 1 participants |
| MS Subtype Relapsing Remitting | 522 participants | 173 participants | 175 participants | 174 participants |
| MS Subtype Secondary Progressive | 9 participants | 3 participants | 4 participants | 2 participants |
| Number of MS Relapses Within the past 2 years | 2 MS relapses | 2 MS relapses | 2 MS relapses | 2 MS relapses |
| Number of MS Relapses Within the past year | 1 MS relapses | 1 MS relapses | 1 MS relapses | 1 MS relapses |
| Region of Enrollment America | 100 participants | 30 participants | 37 participants | 33 participants |
| Region of Enrollment Asia, Africa and Australia | 25 participants | 11 participants | 7 participants | 7 participants |
| Region of Enrollment Eastern Europe | 158 participants | 51 participants | 56 participants | 51 participants |
| Region of Enrollment Western Europe | 251 participants | 86 participants | 79 participants | 86 participants |
| Sex: Female, Male Female | 352 Participants | 125 Participants | 114 Participants | 113 Participants |
| Sex: Female, Male Male | 182 Participants | 53 Participants | 65 Participants | 64 Participants |
| Time Since First Diagnosis of Multiple Sclerosis (MS) | 6.8 years STANDARD_DEVIATION 5.7 | 6.6 years STANDARD_DEVIATION 5.6 | 6.8 years STANDARD_DEVIATION 5.9 | 7.0 years STANDARD_DEVIATION 5.6 |
| Time Since Most Recent MS Relapse Onset | 5.0 months FULL_RANGE 10.47 | 5.0 months FULL_RANGE 4.83 | 4.0 months FULL_RANGE 15.36 | 5.0 months FULL_RANGE 8.29 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 85 / 175 | 94 / 179 | 104 / 178 |
| serious Total, serious adverse events | 8 / 175 | 13 / 179 | 14 / 178 |
Outcome results
Primary
Annualized Relapse Rate (ARR) (Poisson Regression Estimates)
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 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, region of enrollment and IFN-beta dose stratum, and number of relapses in the year prior to randomization as covariates).
Time frame: Up to a maximum of 108 weeks depending on time of enrollment
Population: Intent-to-treat (ITT) population: all randomized and treated participants. Participants were considered in the treatment group to which they were randomized regardless of the drug they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + IFN-beta | Annualized Relapse Rate (ARR) (Poisson Regression Estimates) | 0.298 relapses per patient-year |
| Teriflunomide 7 mg + IFN-beta | Annualized Relapse Rate (ARR) (Poisson Regression Estimates) | 0.242 relapses per patient-year |
| Teriflunomide 14 mg + IFN-beta | Annualized Relapse Rate (ARR) (Poisson Regression Estimates) | 0.238 relapses per patient-year |
Secondary
Brain Magnetic Resonance Imaging (MRI) Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per Scan (Poisson Regression Estimates)
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 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, IFN-beta dose stratum and baseline number of Gd-enhancing T1-lesions as covariates).
Time frame: Up to a maximum of 108 weeks depending on time of enrollment
Population: ITT population as previously defined but including only participants who had post-baseline data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + IFN-beta | Brain Magnetic Resonance Imaging (MRI) Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per Scan (Poisson Regression Estimates) | 0.542 lesions per scan |
| Teriflunomide 7 mg + IFN-beta | Brain Magnetic Resonance Imaging (MRI) Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per Scan (Poisson Regression Estimates) | 0.257 lesions per scan |
| Teriflunomide 14 mg + IFN-beta | Brain Magnetic Resonance Imaging (MRI) Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per Scan (Poisson Regression Estimates) | 0.158 lesions per scan |
Secondary
Brain MRI Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) at Week 24
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, region, IFN-beta dose stratum, visit, treatment-by-visit interaction, cubic root transformed baseline burden of disease, and baseline-by-visit interaction.
Time frame: Baseline, Week 24
Population: ITT population as previously defined but including only participants who had post-baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + IFN-beta | Brain MRI Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) at Week 24 | -0.008 milliliter | Standard Error 0.021 |
| Teriflunomide 7 mg + IFN-beta | Brain MRI Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) at Week 24 | -0.011 milliliter | Standard Error 0.021 |
| Teriflunomide 14 mg + IFN-beta | Brain MRI Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) at Week 24 | -0.044 milliliter | Standard Error 0.02 |
Secondary
Brain MRI Assessment: Volume of Gd-enhancing T1-lesions Per MRI Scan
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.
Time frame: Up to a maximum of 108 weeks depending on time of enrollment
Population: ITT population as previously defined but including only participants who had post-baseline data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + IFN-beta | Brain MRI Assessment: Volume of Gd-enhancing T1-lesions Per MRI Scan | 0.045 milliliters per scan |
| Teriflunomide 7 mg + IFN-beta | Brain MRI Assessment: Volume of Gd-enhancing T1-lesions Per MRI Scan | 0.009 milliliters per scan |
| Teriflunomide 14 mg + IFN-beta | Brain MRI Assessment: Volume of Gd-enhancing T1-lesions Per MRI Scan | 0.01 milliliters per scan |
Secondary
Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 24
FIS is a participant-reported scale that qualifies the impact of fatigue on daily life in participants with MS.
Time frame: Baseline, Week 24
Population: Data for this outcome was not analyzed because of insufficient data after early study termination.
Secondary
Change From Baseline in Short Form Generic Health Survey - 36 Items, Version 2 (SF-36v2) Summary Scores at Week 24
SF-36 scale is a generic, self-administered, health-related quality-of-life (QOL) instrument.
Time frame: Baseline, Week 24
Population: Data for this outcome was not analyzed because of insufficient data after early study termination.
Secondary
Overview of Adverse Events (AEs)
AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
Time frame: First study drug intake up to 28 days after last study drug intake, for up to 112 weeks
Population: Safety population: all randomized and treated participants. Participants were included in the treatment group according to the drug actually received.The participant randomized to Teriflunomide 14 mg group who received Teriflunomide 7 mg was analyzed in the Teriflunomide 7 mg group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + IFN-beta | Overview of Adverse Events (AEs) | Any AE | 119 participants |
| Placebo + IFN-beta | Overview of Adverse Events (AEs) | Any AE Leading to Study Drug Discontinuation | 9 participants |
| Placebo + IFN-beta | Overview of Adverse Events (AEs) | Any Serious AE | 8 participants |
| Placebo + IFN-beta | Overview of Adverse Events (AEs) | Any AE Leading to Death | 0 participants |
| Teriflunomide 7 mg + IFN-beta | Overview of Adverse Events (AEs) | Any AE Leading to Study Drug Discontinuation | 16 participants |
| Teriflunomide 7 mg + IFN-beta | Overview of Adverse Events (AEs) | Any AE Leading to Death | 0 participants |
| Teriflunomide 7 mg + IFN-beta | Overview of Adverse Events (AEs) | Any Serious AE | 13 participants |
| Teriflunomide 7 mg + IFN-beta | Overview of Adverse Events (AEs) | Any AE | 140 participants |
| Teriflunomide 14 mg + IFN-beta | Overview of Adverse Events (AEs) | Any AE Leading to Study Drug Discontinuation | 22 participants |
| Teriflunomide 14 mg + IFN-beta | Overview of Adverse Events (AEs) | Any AE | 140 participants |
| Teriflunomide 14 mg + IFN-beta | Overview of Adverse Events (AEs) | Any Serious AE | 14 participants |
| Teriflunomide 14 mg + IFN-beta | Overview of Adverse Events (AEs) | Any AE Leading to Death | 0 participants |
Secondary
Resource Utilization When Relapse
Resource utilization each time a participant experiences an MS relapse, specifically the number of hospitalizations, the number of over night spent in the hospital and number of intensive care admissions if hospitalized were to be reported.
Time frame: Up to a maximum of 108 weeks depending on time of enrollment
Population: Data for this outcome was not analyzed because of insufficient data after early study termination.
Secondary
Time to 12-Week Sustained Disability Progression
The 12-week sustained disability progression was defined as an increase from baseline of at least 1-point in EDSS score (at least 0.5-point for participants with baseline EDSS score \>5.5) that persisted for at least 12 weeks. Probability of disability progression was to be estimated using Kaplan-Meier method.
Time frame: Up to a maximum of 108 weeks depending on time of enrollment
Population: Data for this outcome was not analyzed because of insufficient data after early study termination.
Secondary
Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72
Probability of no relapse at 24, 48 and 72 weeks was estimated using Kaplan-Meier method on the time to relapse defined as the time from randomization to first EDSS confirmed relapse. Participants free of confirmed relapse (no EDSS confirmed relapse observed on treatment) were censored at the date of the last study drug intake. Kaplan-Meier method consists in computing probabilities of non-occurrence of event at any observed time of event and multiplying successive probabilities for time \<=t by any earlier computed probabilities to estimate the probability of being event-free for the amount of time t.
Time frame: Up to a maximum of 108 weeks depending on time of enrollment
Population: ITT population as previously defined.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + IFN-beta | Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72 | Percent probability of no relapse at Week 48 | 67.3 percent probability of no relapse |
| Placebo + IFN-beta | Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72 | Percent probability of no relapse at Week 24 | 81.9 percent probability of no relapse |
| Placebo + IFN-beta | Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72 | Percent probability of no relapse at Week 72 | 58.3 percent probability of no relapse |
| Teriflunomide 7 mg + IFN-beta | Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72 | Percent probability of no relapse at Week 48 | 80.6 percent probability of no relapse |
| Teriflunomide 7 mg + IFN-beta | Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72 | Percent probability of no relapse at Week 24 | 86.8 percent probability of no relapse |
| Teriflunomide 7 mg + IFN-beta | Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72 | Percent probability of no relapse at Week 72 | 78.2 percent probability of no relapse |
| Teriflunomide 14 mg + IFN-beta | Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72 | Percent probability of no relapse at Week 24 | 87.1 percent probability of no relapse |
| Teriflunomide 14 mg + IFN-beta | Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72 | Percent probability of no relapse at Week 72 | 73.1 percent probability of no relapse |
| Teriflunomide 14 mg + IFN-beta | Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72 | Percent probability of no relapse at Week 48 | 80.8 percent probability of no relapse |
Other Pre-specified
Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA)
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 or 10 Upper Limit of Normal (ULN); Aspartate Aminotransferase (AST) \>3, 5 or 10 ULN; Alkaline Phosphatase \>1.5 ULN; Total Bilirubin (TB) \>1.5 ULN; and ALT \>3 ULN and TB \>2 ULN.
Time frame: First study drug intake up to 28 days after last study drug intake, for up to 112 weeks
Population: Safety population as previously defined but including only participants who had post-baseline values.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | AST >3 ULN | 3 participants |
| Placebo + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | ALT >3 ULN | 6 participants |
| Placebo + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | ALT >5 ULN | 1 participants |
| Placebo + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | ALT >10 ULN | 1 participants |
| Placebo + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | AST >5 ULN | 2 participants |
| Placebo + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | AST >10 ULN | 1 participants |
| Placebo + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | Alkaline Phosphatase >1.5 ULN | 0 participants |
| Placebo + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | TB >1.5 ULN | 2 participants |
| Placebo + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | ALT >3 ULN and TB >2 ULN | 0 participants |
| Teriflunomide 7 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | ALT >10 ULN | 3 participants |
| Teriflunomide 7 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | AST >3 ULN | 4 participants |
| Teriflunomide 7 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | TB >1.5 ULN | 0 participants |
| Teriflunomide 7 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | AST >5 ULN | 3 participants |
| Teriflunomide 7 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | AST >10 ULN | 2 participants |
| Teriflunomide 7 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | Alkaline Phosphatase >1.5 ULN | 2 participants |
| Teriflunomide 7 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | ALT >3 ULN | 9 participants |
| Teriflunomide 7 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | ALT >5 ULN | 6 participants |
| Teriflunomide 7 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | ALT >3 ULN and TB >2 ULN | 0 participants |
| Teriflunomide 14 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | AST >10 ULN | 0 participants |
| Teriflunomide 14 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | ALT >10 ULN | 2 participants |
| Teriflunomide 14 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | Alkaline Phosphatase >1.5 ULN | 0 participants |
| Teriflunomide 14 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | AST >3 ULN | 4 participants |
| Teriflunomide 14 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | ALT >3 ULN | 9 participants |
| Teriflunomide 14 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | ALT >3 ULN and TB >2 ULN | 0 participants |
| Teriflunomide 14 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | AST >5 ULN | 3 participants |
| Teriflunomide 14 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | TB >1.5 ULN | 2 participants |
| Teriflunomide 14 mg + IFN-beta | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | ALT >5 ULN | 5 participants |