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

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

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).

Study Overview

• Status: Terminated
• Conditions: Relapsing-Remitting Multiple Sclerosis
• Intervention / Treatment: Drug: natalizumab; Drug: fingolimod

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: Interventional
• Enrollment (Actual): 111
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Research Site
    • New Lambton Heights, New South Wales, Australia, 2305
      • Research Site
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Research Site
• Czechia
  • Brno, Czechia, 625 00
    • Research Site
  • Brno, Czechia, 656 91
    • Research Site
  • Hradec Kralove, Czechia, 500 05
    • Research Site
  • Jihlava, Czechia, 58633
    • Research Site
  • Ostrava - Poruba, Czechia, 708 52
    • Research Site
  • Pardubice, Czechia, 532 03
    • Research Site
  • Praha 5, Czechia, 150 06
    • Research Site
  • Teplice, Czechia, 415 01
    • Research Site
• France
  • Gard
    • Nimes, Gard, France, 30029
      • Research Site
  • Gironde
    • Libourne Cedex, Gironde, France, 33505
      • Research Site
  • Haute Garonne
    • Toulouse cedex 9, Haute Garonne, France, 31059
      • Research Site
• Germany
  • Baden Wuerttemberg
    • Freiburg, Baden Wuerttemberg, Germany, 79106
      • Research Site
  • Hessen
    • Erbach, Hessen, Germany, 64711
      • Research Site
• Italy
  • Roma, Italy, 00189
    • Research Site
  • Roma
    • Gianicolense, Roma, Italy, 87-00151
      • Research Site
• Spain
  • Barcelona, Spain, 08035
    • Research Site
  • Girona, Spain, 17007
    • Research Site
  • Madrid, Spain, 28006
    • Research Site
  • Sevilla, Spain, E 41009
    • Research Site
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Research Site
  • Málaga
    • Malaga, Málaga, Spain, 29010
      • Research Site
  • Pontevedra
    • Vigo, Pontevedra, Spain, 36204
      • Research Site
  • Tenerife
    • Santa Cruz de Tenerife, Tenerife, Spain, 38010
      • Research Site
• Sweden
  • Göteborg, Sweden, 41345
    • Research Site
  • Stockholm, Sweden, 17176
    • Research Site
• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, SE5 9NU
      • Research Site
  • Strathclyde
    • Glasgow, Strathclyde, United Kingdom, G51 4TF
      • Research Site
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Research Site
    • Colorado Springs, Colorado, United States, 80907
      • Research Site
  • Florida
    • Port Charlotte, Florida, United States, 33952
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30327
      • Research Site
  • Iowa
    • Des Moines, Iowa, United States, 50314
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Research Site
  • Tennessee
    • Knoxville, Tennessee, United States, 37922
      • Research Site
  • Texas
    • Round Rock, Texas, United States, 78681
      • Research Site
    • San Antonio, Texas, United States, 78229
      • Research Site
  • Washington
    • Seattle, Washington, United States, 98122
      • Research Site
    • Tacoma, Washington, United States, 98405
      • Research Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: natalizumab; Open-label natalizumab 300 mg IV every 4 weeks (Q4W)	Drug: natalizumab; Administered as specified in the treatment arm; Other Names: Tysabri; BG00002
Active Comparator: fingolimod; Open-label fingolimod 0.5 mg once daily orally	Drug: fingolimod; Administered as specified in the treatment arm; Other Names: Gilenya; FTY720

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Cumulative Number of ≥ 6-Month Confirmed T1-Hypointense Lesions Arising From New On-Treatment T1-Gadolinium-Enhancing (Gd+) Lesions	Up to Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Number of New T1-Gd+ Lesions		Baseline, Week 4, Week 12, Week 24
Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 24	As assessed by magnetic resonance imaging (MRI).	Baseline, Week 24
Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 52	As assessed by MRI.	Baseline, Week 52
Cumulative Number of New or Enlarging T2 Lesions		Baseline, Week 24
Proportion of Participants With No Evidence of Disease Activity (NEDA)	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.	Up to Week 52
Time to First Relapse	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.	Up to Week 52
Cumulative Risk of Relapse	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.	Up to Week 52
Time to Complete Recovery From First Relapse	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.	Up to Week 52
Change From Baseline in Symbol Digit Modalities Test (SDMT) at 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.	Baseline, Week 24
Change From Baseline in SDMT at 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.	Baseline, Week 52

Collaborators and Investigators

• Sponsor: Biogen

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2014
• Primary Completion (Actual): May 18, 2016
• Study Completion (Actual): May 18, 2016

Study Registration Dates

• First Submitted: January 15, 2015
• First Submitted That Met QC Criteria: January 15, 2015
• First Posted (Estimate): January 21, 2015

Study Record Updates

• Last Update Posted (Actual): June 9, 2017
• Last Update Submitted That Met QC Criteria: May 17, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• 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; Natalizumab; Fingolimod Hydrochloride
• Other Study ID Numbers: 101MS408; 2013-004622-29 (EudraCT Number)