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

Multiple Sclerosis Clinical Trial

— FREEDOMS II  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00355134
• Other study ID #: CFTY720D2309
• Status: Completed
• Phase: Phase 3
• First received: July 19, 2006
• Last updated: August 2, 2012
• Start date: June 2006
• Est. completion date: August 2011

Study information

• Verified date: August 2012
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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).

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).

Other known NCT identifiers

• NCT00774670

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1083
• Est. completion date: August 2011
• Est. primary completion date: June 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 55 Years

Eligibility

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

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

Intervention

Drug:
• Fingolimod
Fingolimod capsules for oral administration
• Placebo
Matching placebo capsules for oral administration.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Novartis

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Canada,  Poland,  Romania,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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).	24 months	No
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).	From Baseline until end of study (up to approximately 54 months).	No
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.	Baseline, Month 24 and end of study (up to approximately 54 months)	No
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.	From Baseline until Month 48	No
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.	Month 24 and end of study (up to approximately 54 months)	No
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.	Baseline and Month 24	No
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.	24 months and end of study (up to approximately 54 months)	No
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.	24 months and end of study (up to approximately 54 months)	No
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.	24 months	No
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.	From Baseline until the end of study (up to approximately 54 months)	No
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.	Baseline, Month 24 and end of study (up to approximately 54 months)	No

External Links

•   Fingolimod clinical trials information website