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

Phase 3

Completed

Conditions: Multiple Sclerosis

Interventions: Drug: Fingolimod
Drug: Placebo

Registration Number: NCT00355134

Lead Sponsor: Novartis

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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1083

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fingolimod 1.25 mg	Fingolimod	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.
Placebo	Placebo	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.
Fingolimod 0.5 mg	Fingolimod	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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).
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.
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.
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.

Trial Locations

Locations (101): University of Pennsylvania, Department of Neurology
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Philadelphia, Pennsylvania, United States
Cedars Sinai Medical Center
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Los Angeles, California, United States
Ohio State University
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Columbus, Ohio, United States
University of Pittsburgh - Dept of Neurology
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Pittsburgh, Pennsylvania, United States
Allegheny Neurological Associates
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Pittsburgh, Pennsylvania, United States
University of Miami, Department of Neurology
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Miami, Florida, United States
Northwestern University Medical School - Dept of Neurology
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Chicago, Illinois, United States
University of Texas - Houston Medical School
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Houston, Texas, United States
Seattle Neuroscience Institute at Swedish Medical Center
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Seattle, Washington, United States
Alexian Brothers Neurosciences Research
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Elk Grove Village, Illinois, United States
North Central Neurology Associates, PC
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Cullman, Alabama, United States
Neurological Associates
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Pompano Beach, Florida, United States
Roskamp Institute, Clinical Trials Division
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Sarasota, Florida, United States
University of South Alabama - Dept of Neurology
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Mobile, Alabama, United States
Research and Education Institute of Alta Bates Summit Medical Center
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Berkeley, California, United States
University of California - Irvine, Deptarment of Neurology
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Irvine, California, United States
Neuro-Therapeutics, Inc.
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Pasadena, California, United States
Indiana University Medical Center
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Indianapolis, Indiana, United States
The Neurology Center
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Oceanside, California, United States
Neurology Clinical Research, Inc
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Sunrise, Florida, United States
NYU Hospital for Joint Diseases
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New York, New York, United States
Neurologic Associates, Ltd.
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Palos Heights, Illinois, United States
AMO Corporation
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Tallahassee, Florida, United States
Institute for Neurosciences
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Reno, Nevada, United States
University of Maryland
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Baltimore, Maryland, United States
UMass Memorial Medical Center
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Worchester, Massachusetts, United States
Michigan Neurology Associates, PC
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St. Clair Shores, Michigan, United States
Sunrise Clinical Research, Inc.
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Hollywood, Florida, United States
Alpha Neurology
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Staten Island, New York, United States
Georgetown University Hospital - Dept of Neurology
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Washington, District of Columbia, United States
The MS Center for Innovation in Care
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St. Louis, Missouri, United States
Michigan Medical, P.C.
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Grand Rapids, Michigan, United States
The MS Center of Vero Beach
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Vero Beach, Florida, United States
Springfield Neurology
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Springfield, Massachusetts, United States
Ruan Neurology Clinical Research Center
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Des Moines, Iowa, United States
Mid America Neuroscience Institute
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Lenexa, Kansas, United States
Mount Sinai School of Medicine
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New York, New York, United States
Duke University Medical Center
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Durham, North Carolina, United States
Integra Clinical Research, LLC
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San Antonio, Texas, United States
University of Alabama Birmingham
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Birmingham, Alabama, United States
Barrow Neurology Clinic
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Phoenix, Arizona, United States
Multiple Sclerosis Center at UCSF
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San Francisco, California, United States
University of Colorado
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Denver, Colorado, United States
MS Center of Oklahoma, Mercy Neuroscience Institute
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Oklahoma City, Oklahoma, United States
Advanced Neurosciences Institute
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Nashville, Tennessee, United States
Vanderbilt Stallworth Rehabilitation Hospital
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Nashville, Tennessee, United States
Axiom Clinical Research of Florida
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Tampa, Florida, United States
Wayne State University MS Clinic
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Detroit, Michigan, United States
Henry Ford Hospital, Department of Neurology
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Detroit, Michigan, United States
River Hills Health Care
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Cincinnati, Ohio, United States
Gimbel Multiple Sclerosis Center at Holy Name Hospital
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Teaneck, New Jersey, United States
MS Center of Atlanta
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Atlanta, Georgia, United States
University of Florida Health Sciences Center/Shands Jacksonville
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Jacksonville, Florida, United States
Neurology Associates, PA
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Maitland, Florida, United States
Associated Neurologists, PC
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Danbury, Connecticut, United States
University of Chicago - Dept of Neurology
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Chicago, Illinois, United States
Medical College of Georgia
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Augusta, Georgia, United States
Associated Neurologists of Southern CT, P.C.
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Fairfield, Connecticut, United States
Rush University Medical Center Department of Neurological Sciences
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Chicago, Illinois, United States
South Suburban Neurology
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Flossmoor, Illinois, United States
Fort Wayne Neurological Center
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Fort Wayne, Indiana, United States
Johns Hopkins MS Center
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Baltimore, Maryland, United States
Caritas St. Elizabeth's Medical Center
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Brighton, Massachusetts, United States
Newton Wesley Hospital
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Newton, Massachusetts, United States
Michigan State University MS Clinic
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East Lansing, Michigan, United States
Multiple Sclerosis Center
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Lebanon, New Hampshire, United States
Cornell University - NY Presbyterian Hospital
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New York, New York, United States
Raleigh Neurology Associates
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Raleigh, North Carolina, United States
Empire Neurology, PC
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Latham, New York, United States
SUNY Stony Brook
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Stony Brook, New York, United States
University of Rochester Medical Center
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Rochester, New York, United States
Island Neurological Associates, PC
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Plainview, New York, United States
SUNY Upstate Medical University
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Syracuse, New York, United States
Neurology & Neuroscience Associates, Inc.
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Akron, Ohio, United States
Northern Ohio Neuroscience, LLC.
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Bellevue, Ohio, United States
NeuroCare Center, Inc
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Canton, Ohio, United States
University of Toledo Health Science Campus
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Toledo, Ohio, United States
Oak Clinic
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Uniontown, Ohio, United States
Neurologial Associates of Tulsa
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Tulsa, Oklahoma, United States
Thomas Jefferson University Hospital, Department of Neurology
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Philadelphia, Pennsylvania, United States
Absher Neurology
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Greenville, South Carolina, United States
Oregon Neurology
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Tualatin, Oregon, United States
Mountain Empire Neurological Associates, PC
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Bristol, Tennessee, United States
Investigational Site - Private Practice
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Lubbock, Texas, United States
Neurology Health Care Service - Fletcher Allen Hospital
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Burlington, Vermont, United States
University of Virginia - Fontaine Adult Neurology
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Charlottesville, Virginia, United States
University Health Associates - West Virgina University
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Morgantown, West Virginia, United States
Novartis Investigative Site
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Bristol, United Kingdom
Dean Foundation
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Madison, Wisconsin, United States
Virginia Mason Multiple Sclerosis Center
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Seattle, Washington, United States
University of Wisconsin Medical School
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Madison, Wisconsin, United States
St. Luke's Medical Center
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Milwaukee, Wisconsin, United States
UC Davis Medical Center
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Sacramento, California, United States
Yale University - Yale Multiple Sclerosis Center
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New Haven, Connecticut, United States
Kentucky Research Associates
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Louisville, Kentucky, United States
UNC - Chapel Hill Neuroscience Hospital
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Chapel Hill, North Carolina, United States
University of Michigan Mulitiple Sclerosis Clinic
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Ann Arbor, Michigan, United States
St. Luke's Hospital - Mid-America Brain and Stroke Institute
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Kansas City, Missouri, United States
Wake Forest University Baptist Medical Center
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Winston-Salem, North Carolina, United States
University of New Mexico Health Science Center
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Albuquerque, New Mexico, United States
University of Kansas Medical Center
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Kansas City, Kansas, United States