Multiple Sclerosis
Conditions
Keywords
Multiple Sclerosis, Relapsing Remitting, Secondary Progressive, Progressive Relapsing
Brief summary
The primary objective was to determine the effect of teriflunomide on the frequency of relapses in patients with relapsing multiple sclerosis (MS). Secondary objectives were: * to evaluate the effect of teriflunomide on the accumulation of disability as measured by Expanded Disability Status Scale \[EDSS\], the burden of disease as measured by Magnetic Resonance Imaging \[MRI\] and patient-reported fatigue; * to evaluate the safety and tolerability of teriflunomide.
Detailed description
The study period per participant was approximatively 128 weeks broken down as follows: * Screening period up to 4 weeks, * 108-week double-blind treatment period (approximatively 2 years)\*, * 16-week post-treatment elimination follow-up period. '\*' Participants successfully completing the week 108 visit were offered the opportunity to enter the optional long-term extension study LTS6050 - NCT00803049.
Interventions
DRUGTeriflunomide
Film-coated tablet Oral administration
Film-coated tablet Oral administration
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
* Multiple sclerosis \[MS\] subject who was ambulatory (EDSS of ≤ 5.5) * Exhibiting a relapsing clinical course, with or without progression (relapsing remitting, secondary progressive or progressive relapsing); * Meeting McDonald's criteria for MS diagnosis; * Experienced at least 1 relapse over the 1 year preceding the trial or at least 2 relapses over the 2 years preceding the trial; * No relapse onset in the preceding 60 days prior to randomization; * Clinically stable during the 30 days prior to randomization, without adrenocorticotrophic hormone \[ACTH\] or systemic steroid treatment.
Exclusion criteria
* Clinically relevant cardiovascular, hepatic, neurological, endocrine or other major systemic disease; * Significantly impaired bone marrow function; * Pregnant or nursing woman; * Alcohol or drug abuse; * Use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporin, methotrexate or mycophenolate before enrollment; * Any known condition or circumstance that would prevent in the investigator's opinion compliance or completion of the study;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Relapse Rate [ARR]: Poisson Regression Estimates | 108 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 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 baseline EDSS stratum as covariates). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | 108 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. Probability of disability progression at 24, 48 and 108 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 (no disability progression observed on treatment) 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. |
| Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | baseline (before randomization) and 108 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. |
| Changes From Baseline in Fatigue Impact Scale [FIS] Total Score | baseline (before randomization) and 108 weeks | FIS is a subject-reported scale that qualifies the impact of fatigue on daily life in patients 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 (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as factors). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) | 108 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, 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, baseline EDSS stratum and baseline number of Gd-enhancing T1-lesions as covariates). |
| Cerebral MRI Assessment: Volume of Gd-enhancing T1-lesions Per Scan | 108 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. |
Countries
Austria, Canada, Chile, Czechia, Denmark, Estonia, Finland, France, Germany, Italy, Netherlands, Norway, Poland, Portugal, Russia, Sweden, Switzerland, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The recruitment initiated in September 2004 was completed in February 2008. A total of 1338 patients were screened at 127 sites in 21 countries.
Pre-assignment details
Randomization was stratified by country and baseline disability (Expanded Disability Status Scale \[EDSS\] score ≤3.5 or \>3.5). Assignment to groups was done centrally using an Interactive Voice Response System (IVRS\] in a 1:1:1 ratio after confirmation of the selection criteria. 1088 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo (for teriflunomide) once daily for 108 weeks | 363 |
| Teriflunomide 7 mg Teriflunomide 7 mg once daily for 108 weeks | 365 |
| Teriflunomide 14 mg Teriflunomide 14 mg once daily for 108 weeks | 358 |
| Total | 1,086 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 29 | 37 | 38 |
| Overall Study | did not wish to continue | 33 | 32 | 26 |
| Overall Study | Lack of Efficacy | 24 | 14 | 17 |
| Overall Study | Lost to Follow-up | 4 | 0 | 2 |
| Overall Study | Not treated due to protocol violation | 0 | 1 | 1 |
| Overall Study | progressive disease | 11 | 4 | 2 |
| Overall Study | Protocol Violation | 3 | 2 | 5 |
| Overall Study | Reason other than above | 0 | 2 | 5 |
Baseline characteristics
| Characteristic | Teriflunomide 7 mg | Placebo | Teriflunomide 14 mg | Total |
|---|---|---|---|---|
| Age Continuous | 37.5 years STANDARD_DEVIATION 9 | 38.4 years STANDARD_DEVIATION 9 | 37.8 years STANDARD_DEVIATION 8.2 | 37.9 years STANDARD_DEVIATION 8.8 |
| Baseline EDSS total score ≤ 3.5 | 280 participants | 281 participants | 276 participants | 837 participants |
| Baseline EDSS total score > 3.5 | 85 participants | 82 participants | 82 participants | 249 participants |
| MS medication in the past 2 years No | 263 participants | 273 participants | 256 participants | 792 participants |
| MS medication in the past 2 years Yes | 102 participants | 90 participants | 102 participants | 294 participants |
| MS subtype Progressive Relapsing | 16 participants | 12 participants | 14 participants | 42 participants |
| MS subtype Relapsing Remitting | 332 participants | 329 participants | 332 participants | 993 participants |
| MS subtype Secondary Progressive | 17 participants | 22 participants | 12 participants | 51 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 | 83 participants | 82 participants | 80 participants | 245 participants |
| Region of enrollment Eastern Europe | 116 participants | 114 participants | 108 participants | 338 participants |
| Region of enrollment Western Europe | 166 participants | 167 participants | 170 participants | 503 participants |
| Sex: Female, Male Female | 254 Participants | 275 Participants | 254 Participants | 783 Participants |
| Sex: Female, Male Male | 111 Participants | 88 Participants | 104 Participants | 303 Participants |
| Time since first diagnosis of multiple sclerosis (MS) | 5.29 Years STANDARD_DEVIATION 5.36 | 5.13 Years STANDARD_DEVIATION 5.59 | 5.59 Years STANDARD_DEVIATION 5.44 | 5.33 Years STANDARD_DEVIATION 5.48 |
| Time since most recent MS relapse onset | 6.29 months STANDARD_DEVIATION 3.29 | 6.28 months STANDARD_DEVIATION 3.62 | 6.50 months STANDARD_DEVIATION 3.71 | 6.35 months STANDARD_DEVIATION 3.54 |
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 | 259 / 360 | 271 / 368 | 265 / 358 |
| serious Total, serious adverse events | 46 / 360 | 52 / 368 | 57 / 358 |
Outcome results
Primary
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 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 baseline EDSS stratum as covariates).
Time frame: 108 weeks
Population: All randomized and treated participants; Participants were included in the treatment group to which they were originally assigned (intent-to-treat analysis).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Annualized Relapse Rate [ARR]: Poisson Regression Estimates | 0.539 relapses per year |
| Teriflunomide 7 mg | Annualized Relapse Rate [ARR]: Poisson Regression Estimates | 0.370 relapses per year |
| Teriflunomide 14 mg | Annualized Relapse Rate [ARR]: Poisson Regression Estimates | 0.369 relapses per year |
Comparison: Null hypothesis:~* H1: No difference between Teriflunomide 14 mg and placebo~* H2: No difference between Teriflunomide 7 mg and placebo~The study was sized to detect a 25% relative risk reduction with teriflunomide in the 2-year relapse rate at a significance level of 0.050 with a power ≥95% anticipating a potential 20% 2-year dropout rate.p-value: 0.0005Regression, Poisson
p-value: 0.0002Regression, Poisson
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.
Time frame: baseline (before randomization) and 108 weeks
Population: All randomized and treated participants; Participants were included in the treatment group to which they were originally assigned (intent-to-treat analysis).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | - Change in T1-hypointense lesion component | 0.533 mililiters (mL) | Standard Deviation 1.063 |
| Placebo | Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | Change in total lesion volume | 2.208 mililiters (mL) | Standard Deviation 7.002 |
| Placebo | Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | - Change in T2-lesion component | 1.674 mililiters (mL) | Standard Deviation 6.473 |
| Teriflunomide 7 mg | Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | - Change in T1-hypointense lesion component | 0.499 mililiters (mL) | Standard Deviation 1.154 |
| Teriflunomide 7 mg | Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | Change in total lesion volume | 1.308 mililiters (mL) | Standard Deviation 6.799 |
| Teriflunomide 7 mg | Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | - Change in T2-lesion component | 0.810 mililiters (mL) | Standard Deviation 6.181 |
| Teriflunomide 14 mg | Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | Change in total lesion volume | 0.723 mililiters (mL) | Standard Deviation 7.591 |
| Teriflunomide 14 mg | Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | - Change in T2-lesion component | 0.392 mililiters (mL) | Standard Deviation 6.901 |
| Teriflunomide 14 mg | Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | - Change in T1-hypointense lesion component | 0.331 mililiters (mL) | Standard Deviation 1.012 |
Comparison: Mixed-effect model with repeated measures \[MMRM\] on cubic root transformed total lesion volume data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value (cubic root transformed) and baseline-by-visit interaction).p-value: 0.0003t-test, 2 sided
Comparison: Mixed-effect model with repeated measures \[MMRM\] on cubic root transformed total lesion volume data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value (cubic root transformed) and baseline-by-visit interaction).p-value: 0.0317t-test, 2 sided
Secondary
Changes From Baseline in Fatigue Impact Scale [FIS] Total Score
FIS is a subject-reported scale that qualifies the impact of fatigue on daily life in patients 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 (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as factors).
Time frame: baseline (before randomization) and 108 weeks
Population: All randomized and treated participants; Participants were included in the treatment group to which they were originally assigned (intent-to-treat analysis).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes From Baseline in Fatigue Impact Scale [FIS] Total Score | 4.300 units on a scale | Standard Error 1.67 |
| Teriflunomide 7 mg | Changes From Baseline in Fatigue Impact Scale [FIS] Total Score | 2.343 units on a scale | Standard Error 1.641 |
| Teriflunomide 14 mg | Changes From Baseline in Fatigue Impact Scale [FIS] Total Score | 3.804 units on a scale | Standard Error 1.67 |
p-value: 0.8271t-test, 2 sided
p-value: 0.3861t-test, 2 sided
Secondary
Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints
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 at 24, 48 and 108 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 (no disability progression observed on treatment) 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: 108 weeks
Population: All randomized and treated participants; Participants were included in the treatment group to which they were originally assigned (intent-to-treat analysis).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | 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 | 16.0 percent probability |
| Placebo | 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 | 8.6 percent probability |
| Placebo | Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | Probability of disability progression at 108 weeks | 27.3 percent probability |
| Teriflunomide 7 mg | 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 | 13.1 percent probability |
| Teriflunomide 7 mg | 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 | 5.8 percent probability |
| Teriflunomide 7 mg | Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | Probability of disability progression at 108 weeks | 21.7 percent probability |
| Teriflunomide 14 mg | 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 | 6.2 percent probability |
| Teriflunomide 14 mg | Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | Probability of disability progression at 108 weeks | 20.2 percent probability |
| Teriflunomide 14 mg | 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 | 11.3 percent probability |
Comparison: Null hypothesis:~* H1: No difference between Teriflunomide 14 mg and placebo~* H2: No difference between Teriflunomide 7 mg and placebo~The study was also sized to detect a 37% hazard rate reduction of an assumed disability progression hazard rate of 0.1783 in the placebo group and 0.1116 in the teriflunomide group by the end of 2 years with a power of 80% anticipating a potential 20% 2-year dropout rate.p-value: 0.0279Log Rank
p-value: 0.0835Log Rank
Other Pre-specified
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, 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, baseline EDSS stratum and baseline number of Gd-enhancing T1-lesions as covariates).
Time frame: 108 weeks
Population: All randomized and treated participants; Participants were included in the treatment group to which they were originally assigned (intent-to-treat analysis).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) | 1.331 lesions per scan |
| Teriflunomide 7 mg | Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) | 0.570 lesions per scan |
| Teriflunomide 14 mg | Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) | 0.261 lesions per scan |
Other Pre-specified
Cerebral MRI Assessment: 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: 108 weeks
Population: All randomized and treated participants; Participants were included in the treatment group to which they were originally assigned (intent-to-treat analysis).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cerebral MRI Assessment: Volume of Gd-enhancing T1-lesions Per Scan | 0.102 mililiters (mL) | Standard Deviation 0.329 |
| Teriflunomide 7 mg | Cerebral MRI Assessment: Volume of Gd-enhancing T1-lesions Per Scan | 0.059 mililiters (mL) | Standard Deviation 0.247 |
| Teriflunomide 14 mg | Cerebral MRI Assessment: Volume of Gd-enhancing T1-lesions Per Scan | 0.025 mililiters (mL) | Standard Deviation 0.079 |