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

Primary Purpose

Relapsing-Remitting Multiple Sclerosis

Status
Terminated
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
natalizumab
fingolimod
Sponsored by
Biogen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Relapsing-Remitting Multiple Sclerosis

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

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Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

natalizumab

fingolimod

Arm Description

Open-label natalizumab 300 mg IV every 4 weeks (Q4W)

Open-label fingolimod 0.5 mg once daily orally

Outcomes

Primary Outcome Measures

Cumulative Number of ≥ 6-Month Confirmed T1-Hypointense Lesions Arising From New On-Treatment T1-Gadolinium-Enhancing (Gd+) Lesions

Secondary Outcome Measures

Cumulative Number of New T1-Gd+ Lesions
Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at 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
As assessed by MRI.
Cumulative Number of New or Enlarging T2 Lesions
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.
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.
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.
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.
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.
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.

Full Information

First Posted
January 15, 2015
Last Updated
May 17, 2017
Sponsor
Biogen
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1. Study Identification

Unique Protocol Identification Number
NCT02342704
Brief Title
Impact of Natalizumab Versus Fingolimod in Relapsing-Remitting Multiple Sclerosis (RRMS) Participants
Acronym
REVEAL
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Terminated
Why Stopped
Business Decision
Study Start Date
November 30, 2014 (Actual)
Primary Completion Date
May 18, 2016 (Actual)
Study Completion Date
May 18, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Biogen

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsing-Remitting Multiple Sclerosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
111 (Actual)

8. Arms, Groups, and Interventions

Arm Title
natalizumab
Arm Type
Experimental
Arm Description
Open-label natalizumab 300 mg IV every 4 weeks (Q4W)
Arm Title
fingolimod
Arm Type
Active Comparator
Arm Description
Open-label fingolimod 0.5 mg once daily orally
Intervention Type
Drug
Intervention Name(s)
natalizumab
Other Intervention Name(s)
BG00002, Tysabri
Intervention Description
Administered as specified in the treatment arm
Intervention Type
Drug
Intervention Name(s)
fingolimod
Other Intervention Name(s)
FTY720, Gilenya
Intervention Description
Administered as specified in the treatment arm
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
Cumulative Number of New T1-Gd+ Lesions
Time Frame
Baseline, Week 4, Week 12, Week 24
Title
Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 24
Description
As assessed by magnetic resonance imaging (MRI).
Time Frame
Baseline, Week 24
Title
Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 52
Description
As assessed by MRI.
Time Frame
Baseline, Week 52
Title
Cumulative Number of New or Enlarging T2 Lesions
Time Frame
Baseline, Week 24
Title
Proportion of Participants With No Evidence of Disease Activity (NEDA)
Description
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 Frame
Up to Week 52
Title
Time to First Relapse
Description
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 Frame
Up to Week 52
Title
Cumulative Risk of Relapse
Description
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 Frame
Up to Week 52
Title
Time to Complete Recovery From First Relapse
Description
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.
Time Frame
Up to Week 52
Title
Change From Baseline in Symbol Digit Modalities Test (SDMT) at Week 24
Description
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.
Time Frame
Baseline, Week 24
Title
Change From Baseline in SDMT at Week 52
Description
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.
Time Frame
Baseline, Week 52

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Biogen
Official's Role
Study Director
Facility Information:
Facility Name
Research Site
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Research Site
City
Colorado Springs
State/Province
Colorado
ZIP/Postal Code
80907
Country
United States
Facility Name
Research Site
City
Port Charlotte
State/Province
Florida
ZIP/Postal Code
33952
Country
United States
Facility Name
Research Site
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30327
Country
United States
Facility Name
Research Site
City
Des Moines
State/Province
Iowa
ZIP/Postal Code
50314
Country
United States
Facility Name
Research Site
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Research Site
City
Knoxville
State/Province
Tennessee
ZIP/Postal Code
37922
Country
United States
Facility Name
Research Site
City
Round Rock
State/Province
Texas
ZIP/Postal Code
78681
Country
United States
Facility Name
Research Site
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
Research Site
City
Seattle
State/Province
Washington
ZIP/Postal Code
98122
Country
United States
Facility Name
Research Site
City
Tacoma
State/Province
Washington
ZIP/Postal Code
98405
Country
United States
Facility Name
Research Site
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53215
Country
United States
Facility Name
Research Site
City
Camperdown
State/Province
New South Wales
ZIP/Postal Code
2050
Country
Australia
Facility Name
Research Site
City
New Lambton Heights
State/Province
New South Wales
ZIP/Postal Code
2305
Country
Australia
Facility Name
Research Site
City
Heidelberg
State/Province
Victoria
ZIP/Postal Code
3084
Country
Australia
Facility Name
Research Site
City
Brno
ZIP/Postal Code
625 00
Country
Czechia
Facility Name
Research Site
City
Brno
ZIP/Postal Code
656 91
Country
Czechia
Facility Name
Research Site
City
Hradec Kralove
ZIP/Postal Code
500 05
Country
Czechia
Facility Name
Research Site
City
Jihlava
ZIP/Postal Code
58633
Country
Czechia
Facility Name
Research Site
City
Ostrava - Poruba
ZIP/Postal Code
708 52
Country
Czechia
Facility Name
Research Site
City
Pardubice
ZIP/Postal Code
532 03
Country
Czechia
Facility Name
Research Site
City
Praha 5
ZIP/Postal Code
150 06
Country
Czechia
Facility Name
Research Site
City
Teplice
ZIP/Postal Code
415 01
Country
Czechia
Facility Name
Research Site
City
Nimes
State/Province
Gard
ZIP/Postal Code
30029
Country
France
Facility Name
Research Site
City
Libourne Cedex
State/Province
Gironde
ZIP/Postal Code
33505
Country
France
Facility Name
Research Site
City
Toulouse cedex 9
State/Province
Haute Garonne
ZIP/Postal Code
31059
Country
France
Facility Name
Research Site
City
Freiburg
State/Province
Baden Wuerttemberg
ZIP/Postal Code
79106
Country
Germany
Facility Name
Research Site
City
Erbach
State/Province
Hessen
ZIP/Postal Code
64711
Country
Germany
Facility Name
Research Site
City
Gianicolense
State/Province
Roma
ZIP/Postal Code
87-00151
Country
Italy
Facility Name
Research Site
City
Roma
ZIP/Postal Code
00189
Country
Italy
Facility Name
Research Site
City
El Palmar
State/Province
Murcia
ZIP/Postal Code
30120
Country
Spain
Facility Name
Research Site
City
Malaga
State/Province
Málaga
ZIP/Postal Code
29010
Country
Spain
Facility Name
Research Site
City
Vigo
State/Province
Pontevedra
ZIP/Postal Code
36204
Country
Spain
Facility Name
Research Site
City
Santa Cruz de Tenerife
State/Province
Tenerife
ZIP/Postal Code
38010
Country
Spain
Facility Name
Research Site
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Research Site
City
Girona
ZIP/Postal Code
17007
Country
Spain
Facility Name
Research Site
City
Madrid
ZIP/Postal Code
28006
Country
Spain
Facility Name
Research Site
City
Sevilla
ZIP/Postal Code
E 41009
Country
Spain
Facility Name
Research Site
City
Göteborg
ZIP/Postal Code
41345
Country
Sweden
Facility Name
Research Site
City
Stockholm
ZIP/Postal Code
17176
Country
Sweden
Facility Name
Research Site
City
London
State/Province
Greater London
ZIP/Postal Code
SE5 9NU
Country
United Kingdom
Facility Name
Research Site
City
Glasgow
State/Province
Strathclyde
ZIP/Postal Code
G51 4TF
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
33082194
Citation
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.
Results Reference
derived

Learn more about this trial

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

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