Efficacy and Safety of Fingolimod (FTY720) in Patients With Relapsing-remitting Multiple Sclerosis

Study Overview
=================
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).

Official Title
-----------------
24-month Double-blind, Randomized, Multicenter, Placebo-controlled, Parallel-group Study Comparing the Efficacy and Safety of 0.5 mg and 1.25 mg Fingolimod (FTY720) Administered Orally Once Daily Versus Placebo in Patients With Relapsing-remitting Multiple Sclerosis With Optional Extension Phase

Conditions
-----------------
Multiple Sclerosis

Intervention / Treatment
-----------------
* Drug: Fingolimod
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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/exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fingolimod 1.25 mg<br>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 once a day. Note: Upon implementation of a protocol amendment all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day. | Drug: Fingolimod<br>* Fingolimod capsules for oral administration<br>* Other names: Gilenya®;|
| Experimental: Fingolimod 0.5 mg<br>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. | Drug: Fingolimod<br>* Fingolimod capsules for oral administration<br>* Other names: Gilenya®;|
| Experimental: Placebo<br>Participants received placebo capsules orally once a day for up to 24 months during the core phase. In the Extension phase participants received either 1.25 or 0.5 mg fingolimod orally once a day. Note: Upon implementation of a protocol amendment all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day. | Drug: Placebo<br>* Matching placebo capsules for oral administration.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | From Baseline until end of study (up to approximately 54 months). | 
| 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. | Baseline, Month 24 and end of study (up to approximately 54 months) | 
| 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. | From Baseline until Month 48 | 
| 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. | Month 24 and end of study (up to approximately 54 months) | 
| 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. | Baseline and Month 24 | 
| 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. | 24 months and end of study (up to approximately 54 months) | 
| 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. | 24 months and end of study (up to approximately 54 months) | 
| 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. | 24 months | 
| 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. | From Baseline until the end of study (up to approximately 54 months) | 
| 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. | Baseline, Month 24 and end of study (up to approximately 54 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
MS, fingolimod, FTY720, relapsing-remitting multiple sclerosis, RRMS