Multiple Sclerosis
Conditions
Brief summary
The primary objective was to evaluate the long-term safety and tolerability of teriflunomide when added to treatment with interferon-β \[IFN-β\] or glatiramer Acetate \[GA\] in patients with multiple sclerosis \[MS\] with relapses. Secondary objectives were to evaluate the long-term effect on relapse rate, disability progression and Magnetic Resonance Imaging \[MRI\] parameters. This study is the extension study of the PDY6045 (NCT00489489) and PDY6046 (NCT00475865) studies. Participants who successfully completed the initial study were offered to continue their treatment (same compound, same dose) for 24 additional weeks.
Detailed description
The duration of the extension study per participants was 40 weeks broken down as follows: * 24-week double-blind treatment period, * 16-week post-treatment elimination follow-up period.
Interventions
DRUGTeriflunomide
Film-coated tablet Oral administration
Film-coated tablet Oral administration
DRUGInterferon-β [IFN-β]
Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection
DRUGGlatiramer Acetate [GA]
Solution in prefilled syringe for subcutaneous injection
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* PDY6045 or PDY6046 participant who: * completed the week 24 visit of either study PDY6045 or PDY6046, * was still meeting eligibility criteria for receiving treatment, * had agreed to continue stable dose of Interferon-β \[IFN-β\] or Glatiramer Acetate \[GA\] and consented to continue on treatment.
Exclusion criteria
* Any known condition or circumstance that would have prevented in the investigator's opinion, compliance or completion of the study The above information is not intended to contain all considerations relevant to patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overview of Adverse Events [AE] | from first study drug intake in PDY6045/PDY6046 study up to 112 days after last intake in initial study or in the extension study, whichever occured last (64 weeks max) | 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 Occurence | from first study drug intake in PDY6045/PDY6046 study up to 112 days after last intake in initial study or in the extension study, whichever occured last (64 weeks max) | 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] | from first study drug intake in PDY6045/PDY6046 study up to 112 days after last intake in initial study or in the extension study, whichever occured last (64 weeks max) | 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; |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | baseline (before randomization in PDY6045 or PDY6046) and 48 weeks | 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 two Mixed-effect models with repeated measures \[MMRM\] on cubic root transformed volume data: * Model 1 (IFN-β groups): treatment group, region of enrollment, IFN-β dose level, visit, treatment-by-visit interaction, baseline value (cubic root transformed), and baseline-by-visit interaction as factors; * Model 2 (GA groups): treatment group, region of enrollment, visit, treatment-by-visit interaction, baseline value (cubic root transformed), and baseline-by-visit interaction as factors. |
| Annualized Relapse Rate [ARR]: Poisson Regression Estimates | 48 weeks | 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, two Poisson regression models with robust error variance were used (total number of confirmed relapses as response variable, log-transformed treatment duration as offset variable and: * Model 1 (IFN-β groups): treatment group, region of enrollment and IFN-β dose level as covariates * Model 2 (GA groups): treatment group and region of enrollment as covariates) |
| Cerebral MRI Assessment: Total Volume of Gd-enhancing T1-lesions Per Scan | 48 weeks | 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. |
| Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) | 48 weeks | 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, two Poisson regression models with robust error variance were used (total number of Gd-enhancing T1-lesions as response variable, log-transformed number of scans as offset variable and: * Model 1 (IFN-β groups): Treatment group, region of enrollment, IFN-β dose level and baseline number of Gd-enhancing T1-lesions as covariates * Model 2 (GA groups): Treatment group, region of enrollment and baseline number of Gd-enhancing T1-lesions as covariates) |
| Overview of 12-week Sustained Disability Progression | 48 weeks | 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. If no disability progression was observed on or before last EDSS evaluation before study drug discontinuation, then the participant was considered as free of disability progression. |
| Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | 48 weeks | Probability of disability progression at 24 and 48 weeks was estimated using Kaplan-Meier method on the time to disability progression defined as the time from randomization to first EDSS increase. Participants free of disability progression were censored at the date of the last on-treatment EDSS evaluation. 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. Probability of event at time t is 1 minus the probability of being event-free for the amount of time t. |
Countries
Austria, Canada, Germany, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
107 and 110 participants who successfully completed 24-week visit in, respectively, PDY6045 and PDY6046 studies, were offered to continue their treatment in this extension study. After signature of the informed consent and confirmation of selection criteria, 86 and 96 participants entered the extension study.
Pre-assignment details
An Interactive Voice Response System was used to allocate kits containing the same treatment as in the initial study. Analysis included all participants randomized in the initial studies and all data collected from randomization according to intent-to-treat principal.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + IFN-β Placebo (for teriflunomide) once daily concomitantly with interferon-β \[IFN-β\] | 41 |
| Teriflunomide 7 mg + IFN-β Teriflunomide 7 mg once daily concomitantly with interferon-β \[IFN-β\] | 37 |
| Teriflunomide 14 mg + IFN-β Teriflunomide 14 mg once daily concomitantly with interferon-β \[IFN-β\] | 38 |
| Placebo + GA Placebo (for teriflunomide) once daily concomitantly with Glatiramer Acetate \[GA\] | 40 |
| Teriflunomide 7 mg + GA Teriflunomide 7 mg once daily concomitantly with Glatiramer Acetate \[GA\] | 42 |
| Teriflunomide 14 mg + GA Teriflunomide 14 mg once daily concomitantly with Glatiramer Acetate \[GA\] | 41 |
| Total | 239 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Extension Treatment | Adverse Event | 1 | 2 | 2 | 2 | 0 | 1 |
| Extension Treatment | Other than above | 0 | 0 | 1 | 0 | 0 | 0 |
| Extension Treatment | Participant did not wish to continue | 0 | 3 | 0 | 1 | 0 | 1 |
| Extension Treatment | Progressive disease | 1 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo + IFN-β | Teriflunomide 7 mg + IFN-β | Teriflunomide 14 mg + IFN-β | Placebo + GA | Teriflunomide 7 mg + GA | Teriflunomide 14 mg + GA | Total |
|---|---|---|---|---|---|---|---|
| Age, Customized <38 years | 17 participants | 9 participants | 15 participants | 11 participants | 12 participants | 13 participants | 77 participants |
| Age, Customized >=38 years | 24 participants | 28 participants | 23 participants | 29 participants | 30 participants | 28 participants | 162 participants |
| Region of Enrollment Europe | 28 participants | 25 participants | 24 participants | 22 participants | 22 participants | 22 participants | 143 participants |
| Region of Enrollment North America | 13 participants | 12 participants | 14 participants | 18 participants | 20 participants | 19 participants | 96 participants |
| Sex: Female, Male Female | 31 Participants | 25 Participants | 25 Participants | 31 Participants | 33 Participants | 33 Participants | 178 Participants |
| Sex: Female, Male Male | 10 Participants | 12 Participants | 13 Participants | 9 Participants | 9 Participants | 8 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 28 / 41 | 33 / 37 | 32 / 38 | 34 / 40 | 30 / 42 | 34 / 41 |
| serious Total, serious adverse events | 2 / 41 | 4 / 37 | 1 / 38 | 6 / 40 | 5 / 42 | 2 / 41 |
Outcome results
Primary
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, 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;
Time frame: from first study drug intake in PDY6045/PDY6046 study up to 112 days after last intake in initial study or in the extension study, whichever occured last (64 weeks max)
Population: All randomized and treated participants; Participants were included in the treatment group according to the drug actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - ALT >10 ULN | 0 participants |
| Placebo + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - ALT >5 ULN | 1 participants |
| Placebo + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | ALT >3 ULN | 2 participants |
| Placebo + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | AST >3 ULN | 1 participants |
| Placebo + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - AST >5 ULN | 1 participants |
| Placebo + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | Alkaline Phosphatase >1.5 ULN | 1 participants |
| Placebo + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | TB >1.5 ULN | 0 participants |
| Placebo + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | ALT >3 ULN and TB >2 ULN | 0 participants |
| Teriflunomide 7 mg + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | AST >3 ULN | 0 participants |
| Teriflunomide 7 mg + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | ALT >3 ULN and TB >2 ULN | 0 participants |
| Teriflunomide 7 mg + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | ALT >3 ULN | 1 participants |
| Teriflunomide 7 mg + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | TB >1.5 ULN | 0 participants |
| Teriflunomide 7 mg + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | Alkaline Phosphatase >1.5 ULN | 0 participants |
| Teriflunomide 7 mg + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - ALT >10 ULN | 0 participants |
| Teriflunomide 7 mg + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - ALT >5 ULN | 0 participants |
| Teriflunomide 7 mg + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - AST >5 ULN | 0 participants |
| Teriflunomide 14 mg + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - ALT >5 ULN | 1 participants |
| Teriflunomide 14 mg + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - ALT >10 ULN | 0 participants |
| Teriflunomide 14 mg + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | AST >3 ULN | 1 participants |
| Teriflunomide 14 mg + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | ALT >3 ULN and TB >2 ULN | 0 participants |
| Teriflunomide 14 mg + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - AST >5 ULN | 0 participants |
| Teriflunomide 14 mg + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | Alkaline Phosphatase >1.5 ULN | 0 participants |
| Teriflunomide 14 mg + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | TB >1.5 ULN | 0 participants |
| Teriflunomide 14 mg + IFN-β | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | ALT >3 ULN | 3 participants |
| Placebo + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | TB >1.5 ULN | 0 participants |
| Placebo + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | Alkaline Phosphatase >1.5 ULN | 0 participants |
| Placebo + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - AST >5 ULN | 0 participants |
| Placebo + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | ALT >3 ULN | 1 participants |
| Placebo + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - ALT >10 ULN | 1 participants |
| Placebo + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | AST >3 ULN | 1 participants |
| Placebo + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | ALT >3 ULN and TB >2 ULN | 0 participants |
| Placebo + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - ALT >5 ULN | 1 participants |
| Teriflunomide 7 mg + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | ALT >3 ULN and TB >2 ULN | 0 participants |
| Teriflunomide 7 mg + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | ALT >3 ULN | 0 participants |
| Teriflunomide 7 mg + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - AST >5 ULN | 0 participants |
| Teriflunomide 7 mg + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | Alkaline Phosphatase >1.5 ULN | 0 participants |
| Teriflunomide 7 mg + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | TB >1.5 ULN | 0 participants |
| Teriflunomide 7 mg + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - ALT >5 ULN | 0 participants |
| Teriflunomide 7 mg + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - ALT >10 ULN | 0 participants |
| Teriflunomide 7 mg + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | AST >3 ULN | 0 participants |
| Teriflunomide 14 mg + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | ALT >3 ULN and TB >2 ULN | 0 participants |
| Teriflunomide 14 mg + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - AST >5 ULN | 0 participants |
| Teriflunomide 14 mg + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - ALT >10 ULN | 0 participants |
| Teriflunomide 14 mg + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | AST >3 ULN | 0 participants |
| Teriflunomide 14 mg + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | Alkaline Phosphatase >1.5 ULN | 0 participants |
| Teriflunomide 14 mg + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | - ALT >5 ULN | 1 participants |
| Teriflunomide 14 mg + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | TB >1.5 ULN | 0 participants |
| Teriflunomide 14 mg + GA | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] | ALT >3 ULN | 1 participants |
Primary
Overview of Adverse Events [AE]
AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
Time frame: from first study drug intake in PDY6045/PDY6046 study up to 112 days after last intake in initial study or in the extension study, whichever occured last (64 weeks max)
Population: All randomized and treated participants; Participants were included in the treatment group according to the drug actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + IFN-β | Overview of Adverse Events [AE] | - AE leading to death | 0 participants |
| Placebo + IFN-β | Overview of Adverse Events [AE] | - serious AE | 2 participants |
| Placebo + IFN-β | Overview of Adverse Events [AE] | - AE leading to study drug discontinuation | 2 participants |
| Placebo + IFN-β | Overview of Adverse Events [AE] | Any AE | 35 participants |
| Teriflunomide 7 mg + IFN-β | Overview of Adverse Events [AE] | - AE leading to death | 0 participants |
| Teriflunomide 7 mg + IFN-β | Overview of Adverse Events [AE] | Any AE | 35 participants |
| Teriflunomide 7 mg + IFN-β | Overview of Adverse Events [AE] | - serious AE | 4 participants |
| Teriflunomide 7 mg + IFN-β | Overview of Adverse Events [AE] | - AE leading to study drug discontinuation | 3 participants |
| Teriflunomide 14 mg + IFN-β | Overview of Adverse Events [AE] | - serious AE | 1 participants |
| Teriflunomide 14 mg + IFN-β | Overview of Adverse Events [AE] | - AE leading to death | 0 participants |
| Teriflunomide 14 mg + IFN-β | Overview of Adverse Events [AE] | - AE leading to study drug discontinuation | 3 participants |
| Teriflunomide 14 mg + IFN-β | Overview of Adverse Events [AE] | Any AE | 33 participants |
| Placebo + GA | Overview of Adverse Events [AE] | - serious AE | 6 participants |
| Placebo + GA | Overview of Adverse Events [AE] | Any AE | 39 participants |
| Placebo + GA | Overview of Adverse Events [AE] | - AE leading to death | 0 participants |
| Placebo + GA | Overview of Adverse Events [AE] | - AE leading to study drug discontinuation | 2 participants |
| Teriflunomide 7 mg + GA | Overview of Adverse Events [AE] | - AE leading to death | 0 participants |
| Teriflunomide 7 mg + GA | Overview of Adverse Events [AE] | Any AE | 40 participants |
| Teriflunomide 7 mg + GA | Overview of Adverse Events [AE] | - serious AE | 5 participants |
| Teriflunomide 7 mg + GA | Overview of Adverse Events [AE] | - AE leading to study drug discontinuation | 3 participants |
| Teriflunomide 14 mg + GA | Overview of Adverse Events [AE] | - AE leading to study drug discontinuation | 5 participants |
| Teriflunomide 14 mg + GA | Overview of Adverse Events [AE] | Any AE | 38 participants |
| Teriflunomide 14 mg + GA | Overview of Adverse Events [AE] | - AE leading to death | 0 participants |
| Teriflunomide 14 mg + GA | Overview of Adverse Events [AE] | - serious AE | 2 participants |
Primary
Overview of AE With Potential Risk of Occurence
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.
Time frame: from first study drug intake in PDY6045/PDY6046 study up to 112 days after last intake in initial study or in the extension study, whichever occured last (64 weeks max)
Population: All randomized and treated participants; Participants were included in the treatment group according to the drug actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + IFN-β | Overview of AE With Potential Risk of Occurence | - Pulmonary disorder AE | 0 participants |
| Placebo + IFN-β | Overview of AE With Potential Risk of Occurence | - Malignancy AE | 0 participants |
| Placebo + IFN-β | Overview of AE With Potential Risk of Occurence | - Hypersensitivity AE | 6 participants |
| Placebo + IFN-β | Overview of AE With Potential Risk of Occurence | - Peripheral neuropathy AE | 5 participants |
| Placebo + IFN-β | Overview of AE With Potential Risk of Occurence | - Hair loss / hair thinning AE | 1 participants |
| Placebo + IFN-β | Overview of AE With Potential Risk of Occurence | - Hepatic disorder AE | 7 participants |
| Placebo + IFN-β | Overview of AE With Potential Risk of Occurence | Any AE with potential risk of occurence | 28 participants |
| Placebo + IFN-β | Overview of AE With Potential Risk of Occurence | - Immune effects related AE | 16 participants |
| Placebo + IFN-β | Overview of AE With Potential Risk of Occurence | - Pancreatic disorder AE | 8 participants |
| Placebo + IFN-β | Overview of AE With Potential Risk of Occurence | - Hypertension-related AE | 1 participants |
| Placebo + IFN-β | Overview of AE With Potential Risk of Occurence | - Psychiatric disorder AE | 1 participants |
| Teriflunomide 7 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Psychiatric disorder AE | 1 participants |
| Teriflunomide 7 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Pulmonary disorder AE | 0 participants |
| Teriflunomide 7 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Pancreatic disorder AE | 5 participants |
| Teriflunomide 7 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Malignancy AE | 0 participants |
| Teriflunomide 7 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Immune effects related AE | 21 participants |
| Teriflunomide 7 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Hypersensitivity AE | 4 participants |
| Teriflunomide 7 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Peripheral neuropathy AE | 3 participants |
| Teriflunomide 7 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Hypertension-related AE | 4 participants |
| Teriflunomide 7 mg + IFN-β | Overview of AE With Potential Risk of Occurence | Any AE with potential risk of occurence | 30 participants |
| Teriflunomide 7 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Hair loss / hair thinning AE | 3 participants |
| Teriflunomide 7 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Hepatic disorder AE | 11 participants |
| Teriflunomide 14 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Hair loss / hair thinning AE | 4 participants |
| Teriflunomide 14 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Hypertension-related AE | 6 participants |
| Teriflunomide 14 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Pulmonary disorder AE | 0 participants |
| Teriflunomide 14 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Hepatic disorder AE | 13 participants |
| Teriflunomide 14 mg + IFN-β | Overview of AE With Potential Risk of Occurence | Any AE with potential risk of occurence | 30 participants |
| Teriflunomide 14 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Immune effects related AE | 20 participants |
| Teriflunomide 14 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Psychiatric disorder AE | 2 participants |
| Teriflunomide 14 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Pancreatic disorder AE | 11 participants |
| Teriflunomide 14 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Hypersensitivity AE | 4 participants |
| Teriflunomide 14 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Peripheral neuropathy AE | 4 participants |
| Teriflunomide 14 mg + IFN-β | Overview of AE With Potential Risk of Occurence | - Malignancy AE | 0 participants |
| Placebo + GA | Overview of AE With Potential Risk of Occurence | - Psychiatric disorder AE | 3 participants |
| Placebo + GA | Overview of AE With Potential Risk of Occurence | Any AE with potential risk of occurence | 34 participants |
| Placebo + GA | Overview of AE With Potential Risk of Occurence | - Hepatic disorder AE | 5 participants |
| Placebo + GA | Overview of AE With Potential Risk of Occurence | - Immune effects related AE | 27 participants |
| Placebo + GA | Overview of AE With Potential Risk of Occurence | - Pancreatic disorder AE | 6 participants |
| Placebo + GA | Overview of AE With Potential Risk of Occurence | - Malignancy AE | 0 participants |
| Placebo + GA | Overview of AE With Potential Risk of Occurence | - Hair loss / hair thinning AE | 1 participants |
| Placebo + GA | Overview of AE With Potential Risk of Occurence | - Pulmonary disorder AE | 0 participants |
| Placebo + GA | Overview of AE With Potential Risk of Occurence | - Hypertension-related AE | 0 participants |
| Placebo + GA | Overview of AE With Potential Risk of Occurence | - Peripheral neuropathy AE | 4 participants |
| Placebo + GA | Overview of AE With Potential Risk of Occurence | - Hypersensitivity AE | 4 participants |
| Teriflunomide 7 mg + GA | Overview of AE With Potential Risk of Occurence | - Hypersensitivity AE | 6 participants |
| Teriflunomide 7 mg + GA | Overview of AE With Potential Risk of Occurence | - Immune effects related AE | 22 participants |
| Teriflunomide 7 mg + GA | Overview of AE With Potential Risk of Occurence | - Hypertension-related AE | 2 participants |
| Teriflunomide 7 mg + GA | Overview of AE With Potential Risk of Occurence | - Psychiatric disorder AE | 3 participants |
| Teriflunomide 7 mg + GA | Overview of AE With Potential Risk of Occurence | - Peripheral neuropathy AE | 5 participants |
| Teriflunomide 7 mg + GA | Overview of AE With Potential Risk of Occurence | - Hepatic disorder AE | 4 participants |
| Teriflunomide 7 mg + GA | Overview of AE With Potential Risk of Occurence | - Malignancy AE | 0 participants |
| Teriflunomide 7 mg + GA | Overview of AE With Potential Risk of Occurence | Any AE with potential risk of occurence | 33 participants |
| Teriflunomide 7 mg + GA | Overview of AE With Potential Risk of Occurence | - Pancreatic disorder AE | 6 participants |
| Teriflunomide 7 mg + GA | Overview of AE With Potential Risk of Occurence | - Pulmonary disorder AE | 1 participants |
| Teriflunomide 7 mg + GA | Overview of AE With Potential Risk of Occurence | - Hair loss / hair thinning AE | 5 participants |
| Teriflunomide 14 mg + GA | Overview of AE With Potential Risk of Occurence | - Hair loss / hair thinning AE | 7 participants |
| Teriflunomide 14 mg + GA | Overview of AE With Potential Risk of Occurence | - Hypertension-related AE | 2 participants |
| Teriflunomide 14 mg + GA | Overview of AE With Potential Risk of Occurence | - Malignancy AE | 0 participants |
| Teriflunomide 14 mg + GA | Overview of AE With Potential Risk of Occurence | - Pancreatic disorder AE | 11 participants |
| Teriflunomide 14 mg + GA | Overview of AE With Potential Risk of Occurence | - Hypersensitivity AE | 10 participants |
| Teriflunomide 14 mg + GA | Overview of AE With Potential Risk of Occurence | - Peripheral neuropathy AE | 10 participants |
| Teriflunomide 14 mg + GA | Overview of AE With Potential Risk of Occurence | - Immune effects related AE | 21 participants |
| Teriflunomide 14 mg + GA | Overview of AE With Potential Risk of Occurence | - Hepatic disorder AE | 5 participants |
| Teriflunomide 14 mg + GA | Overview of AE With Potential Risk of Occurence | - Psychiatric disorder AE | 1 participants |
| Teriflunomide 14 mg + GA | Overview of AE With Potential Risk of Occurence | Any AE with potential risk of occurence | 32 participants |
| Teriflunomide 14 mg + GA | Overview of AE With Potential Risk of Occurence | - Pulmonary disorder AE | 0 participants |
Secondary
Annualized Relapse Rate [ARR]: Poisson Regression Estimates
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, two Poisson regression models with robust error variance were used (total number of confirmed relapses as response variable, log-transformed treatment duration as offset variable and: * Model 1 (IFN-β groups): treatment group, region of enrollment and IFN-β dose level as covariates * Model 2 (GA groups): treatment group and region of enrollment as covariates)
Time frame: 48 weeks
Population: All randomized and treated participants; Participants were included in the treatment group according to the drug actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + IFN-β | Annualized Relapse Rate [ARR]: Poisson Regression Estimates | 0.343 relapses per year |
| Teriflunomide 7 mg + IFN-β | Annualized Relapse Rate [ARR]: Poisson Regression Estimates | 0.231 relapses per year |
| Teriflunomide 14 mg + IFN-β | Annualized Relapse Rate [ARR]: Poisson Regression Estimates | 0.144 relapses per year |
| Placebo + GA | Annualized Relapse Rate [ARR]: Poisson Regression Estimates | 0.420 relapses per year |
| Teriflunomide 7 mg + GA | Annualized Relapse Rate [ARR]: Poisson Regression Estimates | 0.262 relapses per year |
| Teriflunomide 14 mg + GA | Annualized Relapse Rate [ARR]: Poisson Regression Estimates | 0.497 relapses per year |
Secondary
Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease)
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 two Mixed-effect models with repeated measures \[MMRM\] on cubic root transformed volume data: * Model 1 (IFN-β groups): treatment group, region of enrollment, IFN-β dose level, visit, treatment-by-visit interaction, baseline value (cubic root transformed), and baseline-by-visit interaction as factors; * Model 2 (GA groups): treatment group, region of enrollment, visit, treatment-by-visit interaction, baseline value (cubic root transformed), and baseline-by-visit interaction as factors.
Time frame: baseline (before randomization in PDY6045 or PDY6046) and 48 weeks
Population: All randomized and treated participants; Participants were included in the treatment group according to the drug actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + IFN-β | Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | -0.017 mililiters (mL) | Standard Error 0.028 |
| Teriflunomide 7 mg + IFN-β | Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | -0.011 mililiters (mL) | Standard Error 0.03 |
| Teriflunomide 14 mg + IFN-β | Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | -0.012 mililiters (mL) | Standard Error 0.029 |
| Placebo + GA | Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | 0.016 mililiters (mL) | Standard Error 0.036 |
| Teriflunomide 7 mg + GA | Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | -0.010 mililiters (mL) | Standard Error 0.037 |
| Teriflunomide 14 mg + GA | Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | -0.063 mililiters (mL) | Standard Error 0.039 |
Secondary
Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates)
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, two Poisson regression models with robust error variance were used (total number of Gd-enhancing T1-lesions as response variable, log-transformed number of scans as offset variable and: * Model 1 (IFN-β groups): Treatment group, region of enrollment, IFN-β dose level and baseline number of Gd-enhancing T1-lesions as covariates * Model 2 (GA groups): Treatment group, region of enrollment and baseline number of Gd-enhancing T1-lesions as covariates)
Time frame: 48 weeks
Population: All randomized and treated participants; Participants were included in the treatment group according to the drug actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + IFN-β | Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) | 0.521 lesions per scan |
| Teriflunomide 7 mg + IFN-β | Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) | 0.080 lesions per scan |
| Teriflunomide 14 mg + IFN-β | Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) | 0.090 lesions per scan |
| Placebo + GA | Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) | 0.333 lesions per scan |
| Teriflunomide 7 mg + GA | Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) | 0.120 lesions per scan |
| Teriflunomide 14 mg + GA | Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) | 0.178 lesions per scan |
Secondary
Cerebral MRI Assessment: Total Volume of Gd-enhancing T1-lesions Per Scan
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.
Time frame: 48 weeks
Population: All randomized and treated participants; Participants were included in the treatment group according to the drug actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + IFN-β | Cerebral MRI Assessment: Total Volume of Gd-enhancing T1-lesions Per Scan | 0.068 mililiters per scan |
| Teriflunomide 7 mg + IFN-β | Cerebral MRI Assessment: Total Volume of Gd-enhancing T1-lesions Per Scan | 0.019 mililiters per scan |
| Teriflunomide 14 mg + IFN-β | Cerebral MRI Assessment: Total Volume of Gd-enhancing T1-lesions Per Scan | 0.020 mililiters per scan |
| Placebo + GA | Cerebral MRI Assessment: Total Volume of Gd-enhancing T1-lesions Per Scan | 0.052 mililiters per scan |
| Teriflunomide 7 mg + GA | Cerebral MRI Assessment: Total Volume of Gd-enhancing T1-lesions Per Scan | 0.031 mililiters per scan |
| Teriflunomide 14 mg + GA | Cerebral MRI Assessment: Total Volume of Gd-enhancing T1-lesions Per Scan | 0.014 mililiters per scan |
Secondary
Overview of 12-week Sustained Disability Progression
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. If no disability progression was observed on or before last EDSS evaluation before study drug discontinuation, then the participant was considered as free of disability progression.
Time frame: 48 weeks
Population: All randomized and treated participants; Participants were included in the treatment group according to the drug actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + IFN-β | Overview of 12-week Sustained Disability Progression | Disability progression | 0 participants |
| Placebo + IFN-β | Overview of 12-week Sustained Disability Progression | Free of disability progression | 40 participants |
| Teriflunomide 7 mg + IFN-β | Overview of 12-week Sustained Disability Progression | Disability progression | 3 participants |
| Teriflunomide 7 mg + IFN-β | Overview of 12-week Sustained Disability Progression | Free of disability progression | 33 participants |
| Teriflunomide 14 mg + IFN-β | Overview of 12-week Sustained Disability Progression | Disability progression | 2 participants |
| Teriflunomide 14 mg + IFN-β | Overview of 12-week Sustained Disability Progression | Free of disability progression | 36 participants |
| Placebo + GA | Overview of 12-week Sustained Disability Progression | Disability progression | 4 participants |
| Placebo + GA | Overview of 12-week Sustained Disability Progression | Free of disability progression | 37 participants |
| Teriflunomide 7 mg + GA | Overview of 12-week Sustained Disability Progression | Disability progression | 1 participants |
| Teriflunomide 7 mg + GA | Overview of 12-week Sustained Disability Progression | Free of disability progression | 41 participants |
| Teriflunomide 14 mg + GA | Overview of 12-week Sustained Disability Progression | Disability progression | 4 participants |
| Teriflunomide 14 mg + GA | Overview of 12-week Sustained Disability Progression | Free of disability progression | 36 participants |
Secondary
Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints
Probability of disability progression at 24 and 48 weeks was estimated using Kaplan-Meier method on the time to disability progression defined as the time from randomization to first EDSS increase. Participants free of disability progression were censored at the date of the last on-treatment EDSS evaluation. 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. Probability of event at time t is 1 minus the probability of being event-free for the amount of time t.
Time frame: 48 weeks
Population: All randomized and treated participants; Participants were included in the treatment group according to the drug actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + IFN-β | Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | Probability of disability progression at 24 weeks | 0.0 percent probability |
| Placebo + IFN-β | Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | Probability of disability progression at 48 weeks | 0.0 percent probability |
| Teriflunomide 7 mg + IFN-β | Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | Probability of disability progression at 24 weeks | 3.0 percent probability |
| Teriflunomide 7 mg + IFN-β | Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | Probability of disability progression at 48 weeks | 11.1 percent probability |
| Teriflunomide 14 mg + IFN-β | Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | Probability of disability progression at 24 weeks | 2.7 percent probability |
| Teriflunomide 14 mg + IFN-β | Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | Probability of disability progression at 48 weeks | 6.4 percent probability |
| Placebo + GA | Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | Probability of disability progression at 24 weeks | 2.5 percent probability |
| Placebo + GA | Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | Probability of disability progression at 48 weeks | 10.6 percent probability |
| Teriflunomide 7 mg + GA | Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | Probability of disability progression at 24 weeks | 0.0 percent probability |
| Teriflunomide 7 mg + GA | Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | Probability of disability progression at 48 weeks | 3.3 percent probability |
| Teriflunomide 14 mg + GA | Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | Probability of disability progression at 24 weeks | 5.6 percent probability |
| Teriflunomide 14 mg + GA | Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | Probability of disability progression at 48 weeks | 12.8 percent probability |