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

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

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).

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: Placebo; Drug: Fingolimod

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).

• Study Type: Interventional
• Enrollment (Actual): 1083
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • North Gosford, New South Wales, Australia
      • Novartis Investigative Site
• Austria
  • Vienna, Austria
    • Novartis Investigative Site
• Canada
  • Ontario
    • Ottawa, Ontario, Canada
      • Novartis Investigative Site
  • Quebec
    • Greenfield Park, Quebec, Canada
      • Novartis Investigative Site
• Poland
  • Bialystok, Poland
    • Novartis Investigative Site
  • Warsaw, Poland
    • Novartis Investigative Site
  • Warszawa, Poland
    • Novartis Investigative Site
• Romania
  • Bucharest, Romania
    • Novartis Investigative Site
  • Targu Mures, Romania
    • Novartis Investigative Site
• Turkey
  • Istanbul, Turkey
    • Novartis Investigative Site
  • Izmir, Turkey
    • Novartis Investigative Site
  • Yenisehir/Izmir, Turkey
    • Novartis Investigative Site
• United Kingdom
  • Bristol, United Kingdom
    • Novartis Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama Birmingham
    • Cullman, Alabama, United States, 35058
      • North Central Neurology Associates, PC
    • Mobile, Alabama, United States, 36693
      • University of South Alabama - Dept of Neurology
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurology Clinic
  • California
    • Berkeley, California, United States, 94705
      • Research and Education Institute of Alta Bates Summit Medical Center
    • Irvine, California, United States, 92697
      • University of California - Irvine, Deptarment of Neurology
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
    • Oceanside, California, United States, 92056
      • The Neurology Center
    • Pasadena, California, United States, 91105
      • Neuro-Therapeutics, Inc.
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
    • San Francisco, California, United States, 94117
      • Multiple Sclerosis Center at UCSF
  • Colorado
    • Denver, Colorado, United States, 80262
      • University of Colorado
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Associated Neurologists, PC
    • Fairfield, Connecticut, United States, 06824
      • Associated Neurologists of Southern CT, P.C.
    • New Haven, Connecticut, United States, 06510
      • Yale University - Yale Multiple Sclerosis Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Hospital - Dept of Neurology
  • Florida
    • Hollywood, Florida, United States, 33021
      • Sunrise Clinical Research, Inc.
    • Jacksonville, Florida, United States, 32209
      • University of Florida Health Sciences Center/Shands Jacksonville
    • Maitland, Florida, United States, 32751
      • Neurology Associates, PA
    • Miami, Florida, United States, 33136
      • University of Miami, Department of Neurology
    • Pompano Beach, Florida, United States, 33060
      • Neurological Associates
    • Sarasota, Florida, United States, 34243
      • Roskamp Institute, Clinical Trials Division
    • Sunrise, Florida, United States, 33351
      • Neurology Clinical Research, Inc
    • Tallahassee, Florida, United States, 32308
      • AMO Corporation
    • Tampa, Florida, United States, 33609
      • Axiom Clinical Research of Florida
    • Vero Beach, Florida, United States, 32960
      • The MS Center of Vero Beach
  • Georgia
    • Atlanta, Georgia, United States, 30327
      • MS Center of Atlanta
    • Augusta, Georgia, United States, 30912
      • Medical College of Georgia
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center Department of Neurological Sciences
    • Chicago, Illinois, United States, 60611
      • Northwestern University Medical School - Dept of Neurology
    • Chicago, Illinois, United States, 60637
      • University of Chicago - Dept of Neurology
    • Elk Grove Village, Illinois, United States, 60007
      • Alexian Brothers Neurosciences Research
    • Flossmoor, Illinois, United States, 60402
      • South Suburban Neurology
    • Palos Heights, Illinois, United States, 60453
      • Neurologic Associates, Ltd.
  • Indiana
    • Fort Wayne, Indiana, United States, 46805
      • Fort Wayne Neurological Center
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Medical Center
  • Iowa
    • Des Moines, Iowa, United States, 50314
      • Ruan Neurology Clinical Research Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
    • Lenexa, Kansas, United States, 66214
      • Mid America Neuroscience Institute
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kentucky Research Associates
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins MS Center
  • Massachusetts
    • Brighton, Massachusetts, United States, 02135
      • Caritas St. Elizabeth's Medical Center
    • Newton, Massachusetts, United States, 02462
      • Newton Wesley Hospital
    • Springfield, Massachusetts, United States, 01104
      • Springfield Neurology
    • Worchester, Massachusetts, United States, 01605
      • UMASS Memorial Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Mulitiple Sclerosis Clinic
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital, Department of Neurology
    • Detroit, Michigan, United States, 48201
      • Wayne State University MS Clinic
    • East Lansing, Michigan, United States, 48824
      • Michigan State University MS Clinic
    • Grand Rapids, Michigan, United States, 49525
      • Michigan Medical, P.C.
    • St. Clair Shores, Michigan, United States, 48080
      • Michigan Neurology Associates, PC
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • St. Luke's Hospital - Mid-America Brain and Stroke Institute
    • St. Louis, Missouri, United States, 63110
      • The MS Center for Innovation in Care
  • Nevada
    • Reno, Nevada, United States, 85902
      • Institute for Neurosciences
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Multiple Sclerosis Center
  • New Jersey
    • Teaneck, New Jersey, United States, 07666
      • Gimbel Multiple Sclerosis Center at Holy Name Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico Health Science Center
  • New York
    • Latham, New York, United States, 12110
      • Empire Neurology, PC
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
    • New York, New York, United States, 10003
      • NYU Hospital for Joint Diseases
    • New York, New York, United States, 10021
      • Cornell University - NY Presbyterian Hospital
    • Plainview, New York, United States, 11803
      • Island Neurological Associates, PC
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
    • Staten Island, New York, United States, 10306
      • Alpha Neurology
    • Stony Brook, New York, United States, 11794
      • SUNY Stony Brook
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC - Chapel Hill Neuroscience Hospital
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
    • Raleigh, North Carolina, United States, 27607
      • Raleigh Neurology Associates
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Baptist Medical Center
  • Ohio
    • Akron, Ohio, United States, 44302
      • Neurology & Neuroscience Associates, Inc.
    • Bellevue, Ohio, United States, 44811
      • Northern Ohio Neuroscience, LLC.
    • Canton, Ohio, United States, 44718
      • NeuroCare Center, Inc
    • Cincinnati, Ohio, United States, 45219
      • River Hills Health Care
    • Columbus, Ohio, United States, 48221
      • Ohio State University
    • Toledo, Ohio, United States, 43614
      • University of Toledo Health Science Campus
    • Uniontown, Ohio, United States, 44685
      • Oak Clinic
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73120
      • MS Center of Oklahoma, Mercy Neuroscience Institute
    • Tulsa, Oklahoma, United States, 74137
      • Neurologial Associates of Tulsa
  • Oregon
    • Tualatin, Oregon, United States, 97062
      • Oregon Neurology
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania, Department of Neurology
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital, Department of Neurology
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny Neurological Associates
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh - Dept of Neurology
  • South Carolina
    • Greenville, South Carolina, United States, 29615
      • Absher Neurology
  • Tennessee
    • Bristol, Tennessee, United States, 37620
      • Mountain Empire Neurological Associates, PC
    • Nashville, Tennessee, United States, 37205
      • Advanced Neurosciences Institute
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt Stallworth Rehabilitation Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas - Houston Medical School
    • Lubbock, Texas, United States, 79410
      • Investigational Site - Private Practice
    • San Antonio, Texas, United States, 78231
      • Integra Clinical Research, Llc
  • Vermont
    • Burlington, Vermont, United States, 05401
      • Neurology Health Care Service - Fletcher Allen Hospital
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia - Fontaine Adult Neurology
  • Washington
    • Seattle, Washington, United States, 98111
      • Virginia Mason Multiple Sclerosis Center
    • Seattle, Washington, United States, 98122
      • Seattle Neuroscience Institute at Swedish Medical Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • University Health Associates - West Virgina University
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Medical School
    • Madison, Wisconsin, United States, 53715
      • Dean Foundation
    • Milwaukee, Wisconsin, United States, 53215
      • St. Luke's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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 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; Fingolimod capsules for oral administration; Other Names: FTY720; Gilenya®
Experimental: 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.	Drug: Fingolimod; Fingolimod capsules for oral administration; Other Names: FTY720; Gilenya®
Experimental: 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.	Drug: Placebo; Matching placebo capsules for oral administration.

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)

Collaborators and Investigators

• Sponsor: Novartis

Publications and helpful links

General Publications

• Fox RJ, Chan A, Zhang A, Xiao J, Levison D, Lewin JB, Edwards MR, Marantz JL. Comparative effectiveness using a matching-adjusted indirect comparison between delayed-release dimethyl fumarate and fingolimod for the treatment of multiple sclerosis. Curr Med Res Opin. 2017 Feb;33(2):175-183. doi: 10.1080/03007995.2016.1248380. Epub 2016 Nov 10.
• Derfuss T, Bergvall NK, Sfikas N, Tomic DL. Efficacy of fingolimod in patients with highly active relapsing-remitting multiple sclerosis. Curr Med Res Opin. 2015;31(9):1687-91. doi: 10.1185/03007995.2015.1067191. Epub 2015 Aug 20.
• Chinea Martinez AR, Correale J, Coyle PK, Meng X, Tenenbaum N. Efficacy and safety of fingolimod in Hispanic patients with multiple sclerosis: pooled clinical trial analyses. Adv Ther. 2014 Oct;31(10):1072-81. doi: 10.1007/s12325-014-0154-4. Epub 2014 Sep 23.
• Wang L, Tan H, Yu J, ZhangBao J, Huang W, Chang X, Zhou L, Lu C, Xiao Y, Lu J, Zhao C, Wang M, Wu X, Wu M, Dong Q, Ngew KY, Quan C. Baseline retinal nerve fiber layer thickness as a predictor of multiple sclerosis progression: New insights from the FREEDOMS II study. Eur J Neurol. 2023 Feb;30(2):443-452. doi: 10.1111/ene.15612. Epub 2022 Nov 15.
• Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, Li B, Cappiello L, von Rosenstiel P, Lublin FD. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Jun;13(6):545-56. doi: 10.1016/S1474-4422(14)70049-3. Epub 2014 Mar 28. Erratum In: Lancet Neurol. 2013 Jun;13(6):536.
• Winges KM, Werner JS, Harvey DJ, Cello KE, Durbin MK, Balcer LJ, Calabresi PA, Keltner JL. Baseline retinal nerve fiber layer thickness and macular volume quantified by OCT in the North American phase 3 fingolimod trial for relapsing-remitting multiple sclerosis. J Neuroophthalmol. 2013 Dec;33(4):322-9. doi: 10.1097/WNO.0b013e31829c51f7.

Helpful Links

• Fingolimod clinical trials information website

Study record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: July 19, 2006
• First Submitted That Met QC Criteria: July 19, 2006
• First Posted (Estimate): July 21, 2006

Study Record Updates

• Last Update Posted (Estimate): August 7, 2012
• Last Update Submitted That Met QC Criteria: August 2, 2012
• Last Verified: August 1, 2012

More Information

Terms related to this study

• Keywords: RRMS; MS; FTY720; relapsing-remitting multiple sclerosis; fingolimod
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Sphingosine 1 Phosphate Receptor Modulators; Fingolimod Hydrochloride
• Other Study ID Numbers: CFTY720D2309