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Impact of Natalizumab Versus Fingolimod in Relapsing-Remitting Multiple Sclerosis (RRMS) Participants (REVEAL)

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ClinicalTrials.gov Identifier: NCT02342704
Recruitment Status : Terminated (Business Decision)
First Posted : January 21, 2015
Results First Posted : June 9, 2017
Last Update Posted : June 9, 2017
Sponsor:
Information provided by (Responsible Party):
Biogen

Tracking Information
First Submitted Date  ICMJE January 15, 2015
First Posted Date  ICMJE January 21, 2015
Results First Submitted Date  ICMJE May 17, 2017
Results First Posted Date  ICMJE June 9, 2017
Last Update Posted Date June 9, 2017
Actual Study Start Date  ICMJE November 30, 2014
Actual Primary Completion Date May 18, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 17, 2017)
Cumulative Number of ≥ 6-Month Confirmed T1-Hypointense Lesions Arising From New On-Treatment T1-Gadolinium-Enhancing (Gd+) Lesions [ Time Frame: Up to Week 52 ]
Original Primary Outcome Measures  ICMJE
 (submitted: January 15, 2015)
Cumulative number of ≥6-month confirmed T1-hypointense lesions arising from new on-treatment T1-gadolinium-enhancing (Gd+) [ Time Frame: Week 52 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 17, 2017)
  • Cumulative Number of New T1-Gd+ Lesions [ Time Frame: Baseline, Week 4, Week 12, Week 24 ]
  • Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 24 [ Time Frame: Baseline, Week 24 ]
    As assessed by magnetic resonance imaging (MRI).
  • Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 52 [ Time Frame: Baseline, Week 52 ]
    As assessed by MRI.
  • Cumulative Number of New or Enlarging T2 Lesions [ Time Frame: Baseline, Week 24 ]
  • Proportion of Participants With No Evidence of Disease Activity (NEDA) [ Time Frame: Up to Week 52 ]
    NEDA was defined as all of the following: no relapses; no 12-week confirmed disability progression based on Expanded Disability Status Scale (EDSS; defined as an increase of 1.0 or more on the EDSS from baseline of 1.0 or more, or an increase of 1.5 or more from a baseline score of 0) that was sustained for 12 weeks; no new T1-Gd+ lesions on brain MRI. No new or enlarging T2-hyperintense lesions.
  • Time to First Relapse [ Time Frame: Up to Week 52 ]
    A clinical relapse was defined as new or recurrent neurological symptoms, not associated with fever, lasting for at least 24 hours, and followed by a period of 30 days of stability or improvement.
  • Cumulative Risk of Relapse [ Time Frame: Up to Week 52 ]
    A clinical relapse was defined as new or recurrent neurological symptoms, not associated with fever, lasting for at least 24 hours, and followed by a period of 30 days of stability or improvement.
  • Time to Complete Recovery From First Relapse [ Time Frame: Up to Week 52 ]
    12-week confirmed complete EDSS recovery from first on-treatment relapse is defined as an EDSS score that is equal to or lower than the last pre-relapse EDSS score and sustained for at least 12 weeks.
  • Change From Baseline in Symbol Digit Modalities Test (SDMT) at Week 24 [ Time Frame: Baseline, Week 24 ]
    The SDMT measures the time to pair abstract symbols with specific numbers. The test requires elements of attention, visuoperceptual processing, working memory, and psychomotor speed. The score is the number of correctly coded items from 0-110 in 90 seconds. The total score provides a measure of the speed and accuracy of symbol-digit substitution.
  • Change From Baseline in SDMT at Week 52 [ Time Frame: Baseline, Week 52 ]
    The SDMT measures the time to pair abstract symbols with specific numbers. The test requires elements of attention, visuoperceptual processing, working memory, and psychomotor speed. The score is the number of correctly coded items from 0-110 in 90 seconds. The total score provides a measure of the speed and accuracy of symbol-digit substitution.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 15, 2015)
  • Cumulative Number of New T1-Gd+ Lesions [ Time Frame: Up to 52 Weeks ]
  • Change in total T1-hypointense and total T2-hyperintense lesion volumes [ Time Frame: Up to 52 Weeks ]
  • Cumulative Number of New or Enlarging T2 Lesions [ Time Frame: Up to 52 Weeks ]
  • Proportion of participants with No Evidence of Disease Activity (NEDA) [ Time Frame: Week 52 ]
    No Evidence of Disease Activity is defined as: No relapses; No 12-week confirmed disability progression based on Expanded Disability Status Scale (EDSS) (defined as an increase of 1.0 or more on the EDSS from baseline of 1.0 or more, or an increase of 1.5 or more from a baseline score of 0) that was sustained for 12 weeks; No new T1-Gd+ lesions on brain MRI. No new or enlarging T2-hyperintense lesions.
  • Time to First Relapse [ Time Frame: 52 weeks ]
    A clinical relapse is defined as new or recurrent neurological symptoms, not associated with fever, lasting for at least 24 hours, and followed by a period of 30 days of stability or improvement.
  • Cumulative Risk of Relapse [ Time Frame: 52 weeks ]
  • Time to Complete Recovery From First Relapse [ Time Frame: 52 weeks ]
    12-week confirmed complete Expanded Disability Status Scale (EDSS) recovery from first on-treatment relapse is defined as an EDSS score that is equal to or lower than the last pre-relapse EDSS score and sustained for at least 12 weeks.
  • Change in information processing speed as measured by the Symbol Digit Modalities Test (SDMT) [ Time Frame: Up to 52 Weeks ]
    The SDMT examines sustained attention and concentration by primarily assessing complex visual scanning and tracking. The participant examines a series of 9 meaningless geometric symbols, which are labeled 1 to 9. For 90 seconds, the participant substitutes symbols in a row by the corresponding numbers and responds verbally. The score is the number of correct answers in 90 seconds.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Impact of Natalizumab Versus Fingolimod in Relapsing-Remitting Multiple Sclerosis (RRMS) Participants
Official Title  ICMJE A Multicenter, Randomized, Open-Label Study to Assess the Impact of Natalizumab Versus Fingolimod on Central Nervous System Tissue Damage and Recovery in Active Relapsing-Remitting Multiple Sclerosis Subjects
Brief Summary The primary objective of this study is to assess the effect of natalizumab compared to fingolimod on the evolution of new on-treatment T1-gadolinium-enhancing (Gd+) lesions to persistent black holes (PBH) over 52 weeks. The secondary objectives of this study in this study population are to assess the effect of natalizumab compared to fingolimod on: magnetic resonance imaging (MRI) measures of central nervous system (CNS) tissue destruction as measured by the number of new T1-Gd+ lesions; various other MRI measures of disease activity; No Evidence of Disease Activity (NEDA); Relapse on treatment over 52 weeks; The change in information processing speed as measured by the Symbol Digit Modalities Test (SDMT).
Detailed Description This study also includes a Diffusion Tensor Imaging (DTI) sub-study that includes healthy volunteers. Healthy volunteers will not receive any study medication.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Relapsing-Remitting Multiple Sclerosis
Intervention  ICMJE
  • Drug: natalizumab
    Administered as specified in the treatment arm
    Other Names:
    • BG00002
    • Tysabri
  • Drug: fingolimod
    Administered as specified in the treatment arm
    Other Names:
    • FTY720
    • Gilenya
Study Arms  ICMJE
  • Experimental: natalizumab
    Open-label natalizumab 300 mg IV every 4 weeks (Q4W)
    Intervention: Drug: natalizumab
  • Active Comparator: fingolimod
    Open-label fingolimod 0.5 mg once daily orally
    Intervention: Drug: fingolimod
Publications * Butzkueven H, Licata S, Jeffery D, Arnold DL, Filippi M, Geurts JJ, Santra S, Campbell N, Ho PR; REVEAL Investigators. Natalizumab versus fingolimod for patients with active relapsing-remitting multiple sclerosis: results from REVEAL, a prospective, randomised head-to-head study. BMJ Open. 2020 Oct 20;10(10):e038861. doi: 10.1136/bmjopen-2020-038861.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 17, 2017)
111
Original Estimated Enrollment  ICMJE
 (submitted: January 15, 2015)
540
Actual Study Completion Date  ICMJE May 18, 2016
Actual Primary Completion Date May 18, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria for MS Patients:

  • Must have a documented diagnosis of relapsing MS (McDonald 2010 Criteria) at study screening with EDSS score from 0.0 to 5.5.
  • If the subject is on Betaseron, Rebif, Avonex, Copaxone, Extavia, Tecfidera, and Aubagio (BRACE-TA) at study screening:
  • He/she must have been on therapy for at least 6 months (unless experiencing highly active disease), have at least 9 T2-hyperintense lesions on a brain MRI scan, and have experienced ≥1 relapse within the last 6 months prior to study screening with ≥1 new T1-Gd+ lesion on a brain MRI scan performed ≤6 months prior to study screening or ≥2 new T2 lesions on a brain MRI scan performed ≤6 months prior to study screening, with comparison made to a T2 MRI scan performed up to 18 months before study screening
  • If the subject has highly active disease, regardless of whether they are disease-modifying therapy (DMT)-naïve or had previous exposure to Betaseron, Rebif, Avonex, Copaxone, Extavia, Tecfidera, and Aubagio (BRACE-TA), they must have had ≥2 disabling relapses in the 12 months prior to study screening and either ≥1 new T1-Gd+ lesion on a brain MRI scan performed ≤6 months prior to study screening or ≥2 new T2 lesions on a brain MRI scan performed ≤6 months prior to study screening, with comparison made to a T2 MRI scan performed up to 18 months before study screening

Key Exclusion Criteria for MS Patients:

  • Diagnosis of Primary Progressive Multiple Sclerosis and/or Secondary Progressive Multiple Sclerosis.
  • History or positive test result at study screening for human immunodeficiency virus (HIV), hepatitis C virus (HCV) antibody or current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]).
  • Prior treatment with natalizumab or fingolimod.
  • History of or known active malignant disease, including solid tumors and hematologic malignancies (subjects with cutaneous basal and squamous cell carcinoma that has been completely excised and considered cured prior to study screening remain eligible).
  • History of opportunistic infections or any clinically significant major disease, as determined by the Investigator.
  • A clinically significant infectious illness (e.g., pneumonia, septicemia) within the 1 month prior to study screening.
  • History of drug or alcohol abuse (as defined by the Investigator) within 1 year prior to study screening.
  • Prior history of immunosuppressant use (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate, cladribine, rituximab), or exposure to intravenous immunoglobulin (IGIV), monoclonal antibodies, cytokines, growth factors, soluble receptors, other recombinant products, or fusion proteins in the last 12 months prior to study screening.
  • History of myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure in last 6 months.
  • Treatment with Class Ia (e.g., procainamide, quinidine, ajmaline, disopyramide) or Class III (amiodarone, bretylium, dofelitide, sotalol, ibulitide, azilimide) anti-arrhythmic drugs.
  • Concurrent therapy with drugs that slow heart rate (e.g., beta-blockers, heart-rate lowering calcium channel blockers such as diltiazem or verapamil, or digoxin).
  • Hypertension not controlled with prescribed medications.
  • History of severe respiratory disease, pulmonary fibrosis or class III or IV chronic obstructive pulmonary disease.
  • The use of live or live attenuated vaccination within 8 weeks of study screening.

Key Inclusion Criteria for Healthy Volunteers:

  • Subjects who are generally healthy as demonstrated by physical examination and by medical history, with no history or evidence of major illnesses, diseases, or disorders.
  • Subjects of childbearing potential must practice effective contraception and be willing and able to continue contraception for duration of the study.
  • No history of drug or alcohol abuse (as defined by the Investigator) within 1 year prior to study screening.

Key Exclusion Criteria for Healthy Volunteers:

  • Claustrophobia sufficient to interfere with generating reliable MRI scans.
  • History of other major illness including neurological disorders as determined by the Investigator.
  • Presence of a metal device affected by MRI (e.g., any type of electronic, mechanical or magnetic implant, cardiac pacemaker, aneurysm clips, implanted cardiac defibrillator) or potential ferromagnetic foreign body (metal slivers, metal shavings, other metal objects), which would be a contraindication for MRI.
  • Women who are currently pregnant or breastfeeding, or who have a positive pregnancy test result at screening.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Czechia,   France,   Germany,   Italy,   Spain,   Sweden,   United Kingdom,   United States
Removed Location Countries Czech Republic,   Denmark
 
Administrative Information
NCT Number  ICMJE NCT02342704
Other Study ID Numbers  ICMJE 101MS408
2013-004622-29 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Biogen
Study Sponsor  ICMJE Biogen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Biogen
PRS Account Biogen
Verification Date May 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP