MS Study Evaluating Safety and Efficacy of Two Doses of Fingolimod Versus Copaxone

Study Overview
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Brief Summary
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The purpose of this study was to demonstrate that at least one dose (0.5 mg followed by 0.25 mg) of fingolimod is superior to glatiramer acetate 20 mg SC in reducing the ARR up to 12 months in patients with relapsing-remitting MS

Detailed Description
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This was a multicenter, randomized, rater- and dose-blinded, study to compare the efficacy and safety of 0.25 mg and 0.5 mg of fingolimod with glatimer acetate 20 mg s.c. in patients with RRMS. This study consisted of 3 periods: Screening Period: up to 45 days for all patients Treatment Period: 12 months of glatiramer acetate 20 mg, fingolimod 0.25 mg, or fingolimod 0.5 mg Follow-up occurred 3 months (12 weeks) after the last dose of study drug for all patients The informed consent form was signed prior to any study related activities at the screening visit. Randomization to either treatment group was preformed at visit 1 after a diligent check of applicable in- and exclusion criteria in a 1:1:1 ratio (changed to 5:3:2 after implementation of Amendment 2 in 2015). Treatment groups: fingolimod 0.5 mg/day orally for up to 12 months fingolimod 0.25 mg/day orally for up to 12 months glatiramer acetate 20 mg/day subcutaneously for up to 12 months

Official Title
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A 12-month, Randomized, Rater- and Dose-blinded Study to Compare the Efficacy and Safety of Fingolimod 0.25 mg and 0.5 mg Administered Orally Once Daily With Glatiramer Acetate 20 mg Administered Subcutaneously Once Daily in Patients With Relapsing-remitting Multiple Sclerosis

Conditions
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Relapsing-remitting Multiple Sclerosis (RRMS)

Intervention / Treatment
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* Drug: fingolimod
* Drug: glatiramer acetate


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Written informed consent must be obtained before any assessment is performed Male and female patients 18 to 65 years of age, inclusive. Patients with RRMS, as defined by 2010 revised McDonald criteria. Patients must be neurologically stable with no onset of relapse within 30 days of randomization Patients with at least 1 documented relapse during the previous year or 2 documented relapses during the previous 2 years before randomization. Patients with an EDSS score of 0 to 6, inclusive, at Screening. A score of 6.0 indicates unilateral assistance (cane or crutch) required to walk at least 100 meters with or without resting. Exclusion criteria: Patients with a history of malignancy of any organ system (other than cutaneous basal cell carcinoma) in the last 5 years that do not have confirmation of absence of a malignancy prior to randomization Patients with an active chronic disease (or stable but treated with immune therapy) of the immune system other than MS (e.g., rheumatoid arthritis, scleroderma, Sjogren's syndrome, Crohn's disease, ulcerative colitis) or with a known immunodeficiency syndrome (HIV-antibody positive, AIDS, hereditary immune deficiency, drug-induced immune deficiency). Patients who have been treated with: High-dose intravenous (IV) immunoglobulin (Ig) within 4 weeks before randomization Immunosuppressive/chemotherapeutic medications (e.g., azathioprine, cyclophosphamide, methotrexate) within 6 months before randomization Natalizumab within 2 months before randomization Previous treatment with lymphocyte-depleting therapies (e.g., rituximab, alemtuzumab, ofatumumab, ocrelizumab, or cladribine) within 1 year before randomization Previous treatment with mitoxantrone within 6 months before randomization Use of teriflunomide within 3.5 months prior to randomization, except if active washout (with either cholestyramine or activated charcoal) was done. In that case, plasma levels are required to be measured and be below 0.02 mg/L before randomization. No washout period is necessary for patients treated with dimethyl fumarate, interferon (IFN) beta, or glatiramer acetate. Patients being treated with dimethyl fumarate, glatiramer acetate, or IFN beta at the Screening visit can continue drug intake up to the day before Day 1 of this study (i.e., there is no need for a washout period). Patients who have been treated with systemic corticosteroids or adrenocorticotropic hormones in the past 30 days prior to the screening magnetic resonance imaging (MRI) procedure. Patients with uncontrolled diabetes mellitus (glycosylated hemoglobin >9%) or with diabetic neuropathy. Patients with a diagnosis of macular edema during Screening (patients with a history of macular edema will be allowed to enter the study provided that they do not have macular edema at Screening). Patients with severe active bacterial, viral, or fungal infections. Patients without acceptable evidence of immunity to varicella zoster virus (VZV) at randomization. Patients who have received any live or live-attenuated vaccines (including VZV, herpes simplex, or measles) within 1 month before randomization. Patients who have received total lymphoid irradiation or bone marrow transplantation. Patients with any unstable medical/psychiatric condition, as assessed by the primary treating physician at each site. Patients who in the last 6 months experienced any of the following cardiovascular conditions or findings in the screening electrocardiogram (ECG): myocardial infarction, unstable angina, stroke, transient ischemic attack or decompensated heart failure requiring hospitalization or Class III/IV heart failure.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: fingolimod 0.5 mg<br>orally once daily | Drug: fingolimod<br>* capsule<br>* Other names: Gilenya;|
| Experimental: fingolimod 0.25mg<br>orally once daily | Drug: fingolimod<br>* capsule<br>* Other names: Gilenya;|
| Active Comparator: glatiramer acetate 20 mg<br>subcutaneous once daily | Drug: glatiramer acetate<br>* subcutaneous injection<br>* Other names: Copaxone, Glatopa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Annualized Relapse Rate | Annualized relapse rate (ARR) was defined as the average number of confirmed relapses per year (i.e., the total number of confirmed relapses divided by the total days in the study multiplied by 365.25). The number of relapses included all the confirmed relapses experienced during the study from first dose to end of study. | up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| New or Newly Enlarging T2 Lesions | Inflammatory activity based on MRI measurement of new/newly enlarged T2 lesion count. | At 12 months/end of study | 
| Number of Participants Free of New/Newly Enlarged T2 Lesions | Inflammatory activity based on MRI measurement of new/newly enlarged T2 lesion count. | At 12 months/end of study | 
| Change From Baseline in T2 Lesion Volume | Inflammatory activity based on MRI measurement of new/newly enlarged T2 lesion volume | Baseline, 12 months/end of study | 
| Gd Enhancing T1 Lesion Count | Inflammatory activity based on MRI measurement of Gd enhancing T1 lesion count | At 12 months/end of study | 
| Gd Enhancing T1 Lesion Volume | Inflammatory activity based on MRI measurement of Gd enhancing T1 lesion count | Baseline, 12 months/end of study | 
| Percentage of Patients Free of New T1 Hypointense Lesions | Based on MRI measures of new T1 hypointense lesions | 12 months | 
| Change From Baseline in TSQM Scales | Treatment Satisfaction Questionnaire for Medication (TSQM) was developed and validated as a general measure for treatment satisfaction. Each scale score was calculated by summing individual items and then transformed to a 0-100 scale. Higher summary scores indicate better satisfaction with study drug. | 6 months, 12 months/end of study | 
| Percent Brain Volume Change From Baseline | Using a Central MRI vendor to ensure calibrated MRI scanning equipment across all sites, MRI scans were performed on subjects following the established parameters and transferred to the central vendor for review of quality and assessment/evaluation. | Baseline, 12 months, end of study |