Multiple Sclerosis
Conditions
Keywords
fingolimod, FTY720, relapsing-remitting multiple sclerosis, MS, RRMS
Brief summary
This study assessed the safety, tolerability and efficacy of two doses of oral fingolimod compared to placebo on efficacy parameters in patients with relapsing-remitting multiple sclerosis (RRMS).
Detailed description
This randomized, multicenter, parallel-group study consisted of 2 phases: a 24-month double-blind, randomized, multicenter, placebo-controlled, parallel-group study and an Extension phase which consisted of a dose-blinded period and an open-label period. In the Core phase, patients were randomized to receive a fixed dose of fingolimod (0.5 mg/day), fingolimod (1.25 mg/day) or placebo for up to 24 months. For the Extension phase, patients who were treated with fingolimod during the Core phase continued treatment at the assigned dose level, while those previously treated with placebo during the Core phase were re-randomized in a 1:1 ratio to receive one of the two doses of fingolimod (1.25 mg or 0.5 mg). All patients in the extension received blinded investigational drug: fingolimod 1.25 mg and 0.5 mg in capsules for oral administration once daily until the decision to discontinue the fingolimod 1.25 mg dose became effective and subsequently all patients were switched to open-label fingolimod 0.5 mg. With the implementation of Amendment 11, the 1.25 mg dose was discontinued and all patients were switched to fingolimod 0.5 mg dose. With the implementation of Amendment 12, all patients treated with Placebo in the fingolimod Core phase were switched to treatment with 0.5 mg fingolimod per day. The Extension phase continued until all patients either discontinued or transferred to Study CFTY720D2399 (NCT01201356; initiated in September 2010).
Interventions
DRUGFingolimod
Fingolimod capsules for oral administration
DRUGPlacebo
Matching placebo capsules for oral administration.
Sponsors
Novartis
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
* Male and female patients between ages 18-55 with a diagnosis of multiple sclerosis * Patients with a relapsing-remitting disease course * Patients with expanded disability status scale (EDSS) score of 0-5.5
Exclusion criteria
* Patients with other chronic disease of the immune system, malignancies, acute pulmonary disease, cardiac failure, etc. * Pregnant or nursing women For inclusion in the extension phase patients should complete the 24 month core study with or without 24 months on study drug. If a patient discontinued study drug during the core study due to an adverse event, serious adverse event, laboratory abnormality etc. they would be excluded from the Extension Phase. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Aggregate Annualized Relapse Rate (ARR) Estimate up to Month 24 | 24 months | ARR is the average number of relapses in a year calculated by negative binomial regression as the sum of confirmed relapses of all patients in the group divided by the sum of the number of days on study of all patients in the group and multiplied by 365.25. A relapse was defined as the appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The abnormality must be present for at least 24 hours and occur in the absence of fever (\<37.5C) or known infection. A relapse must be confirmed by the Independent Evaluating Physician (examining neurologist). ARR estimates were calculated from a negative binomial regression model adjusted for treatment, pooled center, number of relapses in the previous 2 years prior to enrollment, and Baseline expanded disability status scale (EDSS). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Brain Volume | Baseline, Month 24 and end of study (up to approximately 54 months) | Brain volume was measured using magnetic resonance imaging (MRI). Change from Baseline in brain volume is expressed as a percentage of the Baseline brain volume. |
| Number of New or Newly Enlarged T2 Lesions | From Baseline until Month 48 | Inflammatory disease activity was assessed by magnetic resonance imaging (MRI) measurement of the number of new or newly enlarged T2 lesions, by year. |
| Number of Gadolinium-enhanced T1 Lesions | Month 24 and end of study (up to approximately 54 months) | Inflammatory disease activity was assessed by magnetic resonance imaging (MRI) measurement of the number of gadolinium-enhanced T1 lesions. |
| Change From Baseline in Lesion Volume at Month 24 (Core Phase) | Baseline and Month 24 | Change from Baseline in lesion volume was measured by MRI for T2 lesions and for T1 hypointense lesions. |
| Aggregate Annualized Relapse Rate (ARR) Estimate up to End of Study | From Baseline until end of study (up to approximately 54 months). | ARR is the average number of relapses in a year calculated by negative binomial regression as the sum of confirmed relapses of all patients in the group divided by the sum of the number of days on study of all patients in the group and multiplied by 365.25. A relapse was defined as the appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The abnormality must be present for at least 24 hours and occur in the absence of fever (\<37.5C) or known infection. A relapse must be confirmed by the Independent Evaluating Physician (examining neurologist). ARR estimates were calculated from a negative binomial regression model adjusted for treatment, pooled center, number of relapses in the previous 2 years prior to enrollment, and Baseline expanded disability status scale (EDSS). |
| Percentage of Participants Free of 6-month Confirmed Disability Progression at Month 24 and End of Study | 24 months and end of study (up to approximately 54 months) | Disability progression was defined using the following criteria: One point increase from baseline in patients with Baseline Expanded Disability Status Scale (EDSS) score from 0 to 5.0; or half a point increase from Baseline in patients with Baseline EDSS score of 5.5 or above. A 6-month confirmed disability progression was defined as a 6-month sustained increase from Baseline in EDSS score. The EDSS quantifies disability in multiple sclerosis in 8 functional systems; the score ranges from 0 (normal) to 10 (death due to MS). Progression curves were generated by the Kaplan-Meier method. |
| Percentage of Participants Relapse-free up to Month 24 | 24 months | Estimates of the percentage of participants relapse-free at 24 months were generated from Kaplan-Meier curves of the time to first relapse. A relapse was defined as the appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The abnormality must be present for at least 24 hours and occur in the absence of fever (\<37.5C) or infection. A relapse was confirmed by an Independent Evaluating Physician. |
| Percentage of Participants Relapse-free up to End of Study | From Baseline until the end of study (up to approximately 54 months) | Estimates of the percentage of participants relapse-free at end of study were generated from Kaplan-Meier curves of the time to first relapse. A relapse was defined as the appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The abnormality must be present for at least 24 hours and occur in the absence of fever (\<37.5C) or infection. A relapse was confirmed by an Independent Evaluating Physician. |
| Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Z-score | Baseline, Month 24 and end of study (up to approximately 54 months) | The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation (Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). The overall MSFC z-score as an average of the three standardized scores derived using baseline data pooled over each treatment arm as reference population. Higher scores reflect better neurological function and a positive change from Baseline indicates improvement. |
| Percentage of Participants Free of 3-month Confirmed Disability Progression at Month 24 and End of Study | 24 months and end of study (up to approximately 54 months) | Disability progression was defined using the following criteria: One point increase from baseline in patients with Baseline Expanded Disability Status Scale (EDSS) score from 0 to 5.0; or half a point increase from Baseline in patients with Baseline EDSS score of 5.5 or above. A 3-month confirmed disability progression was defined as a 3-month sustained increase from Baseline in EDSS score. The EDSS quantifies disability in multiple sclerosis in 8 functional systems; the score ranges from 0 (normal) to 10 (death due to MS). Progression curves were generated by the Kaplan-Meier method. |
Countries
Australia, Austria, Canada, Poland, Romania, Turkey (Türkiye), United Kingdom, United States
Participant flow
Pre-assignment details
Patients were randomized to receive fingolimod 0.5 mg, 1.25 mg or placebo for up to 24 months. Upon entry into the Extension phase, patients treated with fingolimod 0.5 mg or 1.25 mg during the Core phase continued treatment at the same dose, those previously treated with placebo were re-randomized in to receive one of the two doses of fingolimod.
Participants by arm
| Arm | Count |
|---|---|
| Fingolimod 1.25 mg Participants received 1.25 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 1.25 mg fingolimod orally. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day. | 370 |
| Fingolimod 0.5 mg Participants received 0.5 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 0.5 mg fingolimod orally once a day. | 358 |
| Placebo (Core) Participants received placebo capsules orally once a day for up to 24 months during the core phase. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day. | 355 |
| Extension: Fingolimod 1.25 mg Participants who had received placebo in the Core phase and then received 1.25 mg fingolimod orally once a day in the Extension phase. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day. | 105 |
| Extension: Fingolimod 0.5 mg Participants who had received placebo in the Core phase and then received 0.5 mg fingolimod orally once a day in the Extension phase. | 107 |
| Total | 1,295 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Core Phase | Abnormal laboratory value(s) | 19 | 14 | 2 | 0 | 0 |
| Core Phase | Abnormal test procedure result(s) | 1 | 2 | 1 | 0 | 0 |
| Core Phase | Administrative problems | 5 | 3 | 5 | 0 | 0 |
| Core Phase | Adverse Event | 28 | 22 | 16 | 0 | 0 |
| Core Phase | Condition no longer requires study drug | 1 | 0 | 1 | 0 | 0 |
| Core Phase | Lost to Follow-up | 17 | 13 | 21 | 0 | 0 |
| Core Phase | Protocol Violation | 3 | 2 | 2 | 0 | 0 |
| Core Phase | Unsatisfactory therapeutic effect | 10 | 6 | 17 | 0 | 0 |
| Core Phase | Withdrawal by Subject | 35 | 24 | 35 | 0 | 0 |
| Extension Phase | Abnormal laboratory value(s) | 4 | 2 | 0 | 2 | 2 |
| Extension Phase | Abnormal test procedure result(s) | 0 | 1 | 0 | 0 | 1 |
| Extension Phase | Administrative problems | 2 | 4 | 0 | 1 | 1 |
| Extension Phase | Adverse Event | 13 | 9 | 0 | 3 | 5 |
| Extension Phase | Lost to Follow-up | 2 | 6 | 0 | 2 | 4 |
| Extension Phase | Protocol Violation | 0 | 0 | 0 | 1 | 0 |
| Extension Phase | Unsatisfactory therapeutic effect | 3 | 4 | 0 | 0 | 1 |
| Extension Phase | Withdrawal by Subject | 7 | 11 | 0 | 7 | 5 |
Baseline characteristics
| Characteristic | Fingolimod 0.5 mg | Placebo (Core) | Extension: Fingolimod 1.25 mg | Extension: Fingolimod 0.5 mg | Total | Fingolimod 1.25 mg |
|---|---|---|---|---|---|---|
| Age Continuous | 40.6 years STANDARD_DEVIATION 8.39 | 40.1 years STANDARD_DEVIATION 8.42 | NA years | NA years | 40.5 years STANDARD_DEVIATION 8.58 | 40.6 years STANDARD_DEVIATION 8.71 |
| Gender Female | 275 participants | 288 participants | 0 participants | 0 participants | 844 participants | 148 participants |
| Gender Male | 57 participants | 0 participants | 17 participants | 22 participants | 239 participants | 55 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 335 / 370 | 320 / 358 | 305 / 355 | 216 / 308 | 223 / 324 |
| serious Total, serious adverse events | 53 / 370 | 53 / 358 | 45 / 355 | 27 / 308 | 21 / 324 |
Outcome results
Primary
Aggregate Annualized Relapse Rate (ARR) Estimate up to Month 24
ARR is the average number of relapses in a year calculated by negative binomial regression as the sum of confirmed relapses of all patients in the group divided by the sum of the number of days on study of all patients in the group and multiplied by 365.25. A relapse was defined as the appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The abnormality must be present for at least 24 hours and occur in the absence of fever (\<37.5C) or known infection. A relapse must be confirmed by the Independent Evaluating Physician (examining neurologist). ARR estimates were calculated from a negative binomial regression model adjusted for treatment, pooled center, number of relapses in the previous 2 years prior to enrollment, and Baseline expanded disability status scale (EDSS).
Time frame: 24 months
Population: Full analysis set, including all patients who were randomized and took at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fingolimod 1.25 mg | Aggregate Annualized Relapse Rate (ARR) Estimate up to Month 24 | 0.203 relapses per year |
| Fingolimod 0.5 mg | Aggregate Annualized Relapse Rate (ARR) Estimate up to Month 24 | 0.208 relapses per year |
| Placebo | Aggregate Annualized Relapse Rate (ARR) Estimate up to Month 24 | 0.403 relapses per year |
Secondary
Aggregate Annualized Relapse Rate (ARR) Estimate up to End of Study
ARR is the average number of relapses in a year calculated by negative binomial regression as the sum of confirmed relapses of all patients in the group divided by the sum of the number of days on study of all patients in the group and multiplied by 365.25. A relapse was defined as the appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The abnormality must be present for at least 24 hours and occur in the absence of fever (\<37.5C) or known infection. A relapse must be confirmed by the Independent Evaluating Physician (examining neurologist). ARR estimates were calculated from a negative binomial regression model adjusted for treatment, pooled center, number of relapses in the previous 2 years prior to enrollment, and Baseline expanded disability status scale (EDSS).
Time frame: From Baseline until end of study (up to approximately 54 months).
Population: Core intent-to-treat (ITT) population: All patients who were randomized in the Core phase and received at least one dose of Core phase drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fingolimod 1.25 mg | Aggregate Annualized Relapse Rate (ARR) Estimate up to End of Study | 0.180 relapses per year |
| Fingolimod 0.5 mg | Aggregate Annualized Relapse Rate (ARR) Estimate up to End of Study | 0.192 relapses per year |
| Placebo | Aggregate Annualized Relapse Rate (ARR) Estimate up to End of Study | 0.363 relapses per year |
Secondary
Change From Baseline in Lesion Volume at Month 24 (Core Phase)
Change from Baseline in lesion volume was measured by MRI for T2 lesions and for T1 hypointense lesions.
Time frame: Baseline and Month 24
Population: Full analysis set for whom data were available. N=the number of patients with non-missing baseline and post-baseline values.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fingolimod 1.25 mg | Change From Baseline in Lesion Volume at Month 24 (Core Phase) | T1 hypointense lesions [N=247, 266, 248] | -99.13 mm^3 | Standard Deviation 391.21 |
| Fingolimod 1.25 mg | Change From Baseline in Lesion Volume at Month 24 (Core Phase) | T2 lesions [N=248, 266, 251] | -436.92 mm^3 | Standard Deviation 1557.82 |
| Fingolimod 0.5 mg | Change From Baseline in Lesion Volume at Month 24 (Core Phase) | T2 lesions [N=248, 266, 251] | -223.27 mm^3 | Standard Deviation 1405.459 |
| Fingolimod 0.5 mg | Change From Baseline in Lesion Volume at Month 24 (Core Phase) | T1 hypointense lesions [N=247, 266, 248] | -111.28 mm^3 | Standard Deviation 530.961 |
| Placebo | Change From Baseline in Lesion Volume at Month 24 (Core Phase) | T2 lesions [N=248, 266, 251] | 541.83 mm^3 | Standard Deviation 2830.868 |
| Placebo | Change From Baseline in Lesion Volume at Month 24 (Core Phase) | T1 hypointense lesions [N=247, 266, 248] | -37.68 mm^3 | Standard Deviation 671.708 |
Secondary
Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Z-score
The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation (Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). The overall MSFC z-score as an average of the three standardized scores derived using baseline data pooled over each treatment arm as reference population. Higher scores reflect better neurological function and a positive change from Baseline indicates improvement.
Time frame: Baseline, Month 24 and end of study (up to approximately 54 months)
Population: Core intent-to-treat (ITT) population: All patients who were randomized in the Core phase and received at least one dose of Core phase drug. N indicates the number of participants with non-missing data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fingolimod 1.25 mg | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Z-score | Month 24 [N=250; 271; 258] | -0.08 units on a scale | Standard Deviation 0.916 |
| Fingolimod 1.25 mg | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Z-score | End of Study [N=174; 187; 184] | 0.011 units on a scale | Standard Deviation 0.3499 |
| Fingolimod 0.5 mg | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Z-score | Month 24 [N=250; 271; 258] | 0.00 units on a scale | Standard Deviation 0.6 |
| Fingolimod 0.5 mg | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Z-score | End of Study [N=174; 187; 184] | -0.091 units on a scale | Standard Deviation 0.877 |
| Placebo | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Z-score | Month 24 [N=250; 271; 258] | -0.07 units on a scale | Standard Deviation 0.54 |
| Placebo | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Z-score | End of Study [N=174; 187; 184] | 0.019 units on a scale | Standard Deviation 0.6304 |
Secondary
Number of Gadolinium-enhanced T1 Lesions
Inflammatory disease activity was assessed by magnetic resonance imaging (MRI) measurement of the number of gadolinium-enhanced T1 lesions.
Time frame: Month 24 and end of study (up to approximately 54 months)
Population: Core intent-to-treat (ITT) population: All patients who were randomized in the Core phase and received at least one dose of Core phase drug. N indicates the number of participants with evaluable MRI data for the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fingolimod 1.25 mg | Number of Gadolinium-enhanced T1 Lesions | Core Phase (Month 24) [N=251; 269; 256] | 0.24 lesions | Standard Deviation 2.395 |
| Fingolimod 1.25 mg | Number of Gadolinium-enhanced T1 Lesions | End of Extension study [N=184; 194; 184] | 0.46 lesions | Standard Deviation 2.381 |
| Fingolimod 0.5 mg | Number of Gadolinium-enhanced T1 Lesions | Core Phase (Month 24) [N=251; 269; 256] | 0.37 lesions | Standard Deviation 1.841 |
| Fingolimod 0.5 mg | Number of Gadolinium-enhanced T1 Lesions | End of Extension study [N=184; 194; 184] | 0.09 lesions | Standard Deviation 0.308 |
| Placebo | Number of Gadolinium-enhanced T1 Lesions | Core Phase (Month 24) [N=251; 269; 256] | 1.22 lesions | Standard Deviation 2.967 |
| Placebo | Number of Gadolinium-enhanced T1 Lesions | End of Extension study [N=184; 194; 184] | 0.45 lesions | Standard Deviation 3.618 |
Secondary
Number of New or Newly Enlarged T2 Lesions
Inflammatory disease activity was assessed by magnetic resonance imaging (MRI) measurement of the number of new or newly enlarged T2 lesions, by year.
Time frame: From Baseline until Month 48
Population: Core intent-to-treat (ITT) population: All patients who were randomized in the Core phase and received at least one dose of Core phase drug. Patients were grouped according to the assigned treatment. N indicates the number of participants with MRI data available for the specified time period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fingolimod 1.25 mg | Number of New or Newly Enlarged T2 Lesions | Month 24 to 36 [N=103; 111; 102] | 0.63 lesions | Standard Deviation 2.856 |
| Fingolimod 1.25 mg | Number of New or Newly Enlarged T2 Lesions | Core Phase (Month 0 to 24) [N=245; 264; 251] | 1.6 lesions | Standard Deviation 5.41 |
| Fingolimod 1.25 mg | Number of New or Newly Enlarged T2 Lesions | Month 36 to 48 [N=24; 15; 15] | 0.13 lesions | Standard Deviation 0.448 |
| Fingolimod 0.5 mg | Number of New or Newly Enlarged T2 Lesions | Month 24 to 36 [N=103; 111; 102] | 0.45 lesions | Standard Deviation 1.36 |
| Fingolimod 0.5 mg | Number of New or Newly Enlarged T2 Lesions | Core Phase (Month 0 to 24) [N=245; 264; 251] | 2.3 lesions | Standard Deviation 7.26 |
| Fingolimod 0.5 mg | Number of New or Newly Enlarged T2 Lesions | Month 36 to 48 [N=24; 15; 15] | 0.07 lesions | Standard Deviation 0.258 |
| Placebo | Number of New or Newly Enlarged T2 Lesions | Core Phase (Month 0 to 24) [N=245; 264; 251] | 8.9 lesions | Standard Deviation 13.86 |
| Placebo | Number of New or Newly Enlarged T2 Lesions | Month 36 to 48 [N=24; 15; 15] | 2.53 lesions | Standard Deviation 8.741 |
| Placebo | Number of New or Newly Enlarged T2 Lesions | Month 24 to 36 [N=103; 111; 102] | 0.63 lesions | Standard Deviation 1.455 |
Secondary
Percentage of Participants Free of 3-month Confirmed Disability Progression at Month 24 and End of Study
Disability progression was defined using the following criteria: One point increase from baseline in patients with Baseline Expanded Disability Status Scale (EDSS) score from 0 to 5.0; or half a point increase from Baseline in patients with Baseline EDSS score of 5.5 or above. A 3-month confirmed disability progression was defined as a 3-month sustained increase from Baseline in EDSS score. The EDSS quantifies disability in multiple sclerosis in 8 functional systems; the score ranges from 0 (normal) to 10 (death due to MS). Progression curves were generated by the Kaplan-Meier method.
Time frame: 24 months and end of study (up to approximately 54 months)
Population: Core intent-to-treat (ITT) population: All patients who were randomized in the Core phase and received at least one dose of Core phase drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fingolimod 1.25 mg | Percentage of Participants Free of 3-month Confirmed Disability Progression at Month 24 and End of Study | At month 24 | 78.3 percentage of participants |
| Fingolimod 1.25 mg | Percentage of Participants Free of 3-month Confirmed Disability Progression at Month 24 and End of Study | At end of study | 66.64 percentage of participants |
| Fingolimod 0.5 mg | Percentage of Participants Free of 3-month Confirmed Disability Progression at Month 24 and End of Study | At month 24 | 74.7 percentage of participants |
| Fingolimod 0.5 mg | Percentage of Participants Free of 3-month Confirmed Disability Progression at Month 24 and End of Study | At end of study | 58.89 percentage of participants |
| Placebo | Percentage of Participants Free of 3-month Confirmed Disability Progression at Month 24 and End of Study | At month 24 | 71.0 percentage of participants |
| Placebo | Percentage of Participants Free of 3-month Confirmed Disability Progression at Month 24 and End of Study | At end of study | 63.51 percentage of participants |
Secondary
Percentage of Participants Free of 6-month Confirmed Disability Progression at Month 24 and End of Study
Disability progression was defined using the following criteria: One point increase from baseline in patients with Baseline Expanded Disability Status Scale (EDSS) score from 0 to 5.0; or half a point increase from Baseline in patients with Baseline EDSS score of 5.5 or above. A 6-month confirmed disability progression was defined as a 6-month sustained increase from Baseline in EDSS score. The EDSS quantifies disability in multiple sclerosis in 8 functional systems; the score ranges from 0 (normal) to 10 (death due to MS). Progression curves were generated by the Kaplan-Meier method.
Time frame: 24 months and end of study (up to approximately 54 months)
Population: Core intent-to-treat (ITT) population: All patients who were randomized in the Core phase and received at least one dose of Core phase drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fingolimod 1.25 mg | Percentage of Participants Free of 6-month Confirmed Disability Progression at Month 24 and End of Study | At Month 24 | 86.9 percentage of participants |
| Fingolimod 1.25 mg | Percentage of Participants Free of 6-month Confirmed Disability Progression at Month 24 and End of Study | At end of study | 79.92 percentage of participants |
| Fingolimod 0.5 mg | Percentage of Participants Free of 6-month Confirmed Disability Progression at Month 24 and End of Study | At Month 24 | 86.2 percentage of participants |
| Fingolimod 0.5 mg | Percentage of Participants Free of 6-month Confirmed Disability Progression at Month 24 and End of Study | At end of study | 74.89 percentage of participants |
| Placebo | Percentage of Participants Free of 6-month Confirmed Disability Progression at Month 24 and End of Study | At Month 24 | 82.2 percentage of participants |
| Placebo | Percentage of Participants Free of 6-month Confirmed Disability Progression at Month 24 and End of Study | At end of study | 75.03 percentage of participants |
Secondary
Percentage of Participants Relapse-free up to End of Study
Estimates of the percentage of participants relapse-free at end of study were generated from Kaplan-Meier curves of the time to first relapse. A relapse was defined as the appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The abnormality must be present for at least 24 hours and occur in the absence of fever (\<37.5C) or infection. A relapse was confirmed by an Independent Evaluating Physician.
Time frame: From Baseline until the end of study (up to approximately 54 months)
Population: Core intent-to-treat (ITT) population: All patients who were randomized in the Core phase and received at least one dose of Core phase drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fingolimod 1.25 mg | Percentage of Participants Relapse-free up to End of Study | 63.88 percentage of participants |
| Fingolimod 0.5 mg | Percentage of Participants Relapse-free up to End of Study | 66.57 percentage of participants |
| Placebo | Percentage of Participants Relapse-free up to End of Study | 49.12 percentage of participants |
Secondary
Percentage of Participants Relapse-free up to Month 24
Estimates of the percentage of participants relapse-free at 24 months were generated from Kaplan-Meier curves of the time to first relapse. A relapse was defined as the appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The abnormality must be present for at least 24 hours and occur in the absence of fever (\<37.5C) or infection. A relapse was confirmed by an Independent Evaluating Physician.
Time frame: 24 months
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fingolimod 1.25 mg | Percentage of Participants Relapse-free up to Month 24 | 73.2 percentage of participants |
| Fingolimod 0.5 mg | Percentage of Participants Relapse-free up to Month 24 | 71.5 percentage of participants |
| Placebo | Percentage of Participants Relapse-free up to Month 24 | 52.7 percentage of participants |
Secondary
Percent Change From Baseline in Brain Volume
Brain volume was measured using magnetic resonance imaging (MRI). Change from Baseline in brain volume is expressed as a percentage of the Baseline brain volume.
Time frame: Baseline, Month 24 and end of study (up to approximately 54 months)
Population: Core intent-to-treat (ITT) population: All patients who were randomized in the Core phase and received at least one dose of Core phase drug. Patients were grouped according to the assigned treatment. N indicates the number of participants with data available for the specified time period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fingolimod 1.25 mg | Percent Change From Baseline in Brain Volume | Month 24 [N=247; 266; 249] | -0.595 percent change | Standard Deviation 1.3897 |
| Fingolimod 1.25 mg | Percent Change From Baseline in Brain Volume | End of study [N=178; 187; 182] | -1.130 percent change | Standard Deviation 1.638 |
| Fingolimod 0.5 mg | Percent Change From Baseline in Brain Volume | Month 24 [N=247; 266; 249] | -0.858 percent change | Standard Deviation 1.2215 |
| Fingolimod 0.5 mg | Percent Change From Baseline in Brain Volume | End of study [N=178; 187; 182] | -1.266 percent change | Standard Deviation 1.6941 |
| Placebo | Percent Change From Baseline in Brain Volume | Month 24 [N=247; 266; 249] | -1.279 percent change | Standard Deviation 1.5028 |
| Placebo | Percent Change From Baseline in Brain Volume | End of study [N=178; 187; 182] | -1.694 percent change | Standard Deviation 1.9567 |