Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (MS)CombiRx

NCT ID: NCT00211887

Last Updated: 2014-04-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1008 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-01-31
• Study Completion Date: 2013-03-31

Brief Summary

This is for a randomized clinical trial (RCT) to determine if the combined use of interferon beta-1a (IFN) and glatiramer acetate (GA) is a measurably better therapy than either agent used individually in patients with relapsing-remitting (RR) multiple sclerosis (MS).

Detailed Description

This is a multicenter, double blind, randomized trial examining combination therapy versus single agent therapy with three-year follow-up on the last patient randomized. All patients will remain on therapy until the last patient completes the study. All patients will then be transitioned, based on the findings, to open label of combination with continued follow-up or some recommendation about single agent therapy. While the study design benefits from having two arms of single agent therapy to examine the important question of whether there are differences between the single agents, the primary interest is in combination therapy. Therefore, a two-group combination versus single agent concept was used - splitting the population into single agent and combination therapy equally. The single agent arm is divided into two groups, IFN and GA providing for 3 treatment arms: IFN intramuscularly (IM) and GA subcutaneously (SC) (50% of the patients), IFN IM and placebo SC (25% of the patients) and GA SC and placebo IM (25% of the patients).

Conditions

Relapsing Remitting Multiple Sclerosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Interferon beta 1-a

Active Interferon B1a Weekly vs. Placebo Glatiramer Acetate

Interferon b-1a (IFN) intramuscularly weekly

Group Type: ACTIVE_COMPARATOR

Interferon beta 1-a

Intervention Type: DRUG

The single agent arm is divided into two groups, IFN and GA providing for 3 treatment arms: IFN IM and GA SC (50% of the patients), IFN IM and placebo SC (25% of the patients) and GA SC and placebo IM (25% of the patients).

placebo

Intervention Type: OTHER

an inactive substance

glatiramer acetate

Placebo Interferon B1a Weekly vs. Active Glatiramer Acetate

Glatiramer acetate 20mg daily

Group Type: ACTIVE_COMPARATOR

glatiramer acetate

Intervention Type: DRUG

The single agent arm is divided into two groups, IFN and GA providing for 3 treatment arms: IFN IM and GA SC (50% of the patients), IFN IM and placebo SC (25% of the patients) and GA SC and placebo IM (25% of the patients).

placebo

Intervention Type: OTHER

an inactive substance

IFN and GA

Active Interferon B1a Weekly and Active Glatiramer Acetate

Group Type: ACTIVE_COMPARATOR

Interferon beta 1-a

Intervention Type: DRUG

The single agent arm is divided into two groups, IFN and GA providing for 3 treatment arms: IFN IM and GA SC (50% of the patients), IFN IM and placebo SC (25% of the patients) and GA SC and placebo IM (25% of the patients).

glatiramer acetate

Intervention Type: DRUG

The single agent arm is divided into two groups, IFN and GA providing for 3 treatment arms: IFN IM and GA SC (50% of the patients), IFN IM and placebo SC (25% of the patients) and GA SC and placebo IM (25% of the patients).

Interventions

Interferon beta 1-a

The single agent arm is divided into two groups, IFN and GA providing for 3 treatment arms: IFN IM and GA SC (50% of the patients), IFN IM and placebo SC (25% of the patients) and GA SC and placebo IM (25% of the patients).

Intervention Type: DRUG

glatiramer acetate

The single agent arm is divided into two groups, IFN and GA providing for 3 treatment arms: IFN IM and GA SC (50% of the patients), IFN IM and placebo SC (25% of the patients) and GA SC and placebo IM (25% of the patients).

Intervention Type: DRUG

placebo

an inactive substance

Intervention Type: OTHER

Other Intervention Names

IFN; GA

Eligibility Criteria

Inclusion Criteria

• Male and female subjects between the ages of 18 and 60 years, inclusive.
• Diagnosis of relapsing-remitting MS by either the Poser or McDonald criteria.
• Expanded Disability Status Scale (EDSS) score between 0 and 5.5, inclusive.
• At least 2 exacerbations in the prior three years; one exacerbation may utilize the McDonald MRI criteria for dissemination in time (a new gadolinium [Gd]-enhancing lesion demonstrated on a scan done at least 3 months following onset of a clinical attack or a new T2 lesion or Gd-enhancing lesion on a follow-up scan after an additional 3 months).
• Give written informed consent prior to any testing under this protocol, including screening tests and evaluations that are not considered part of the subject's routine care.

Exclusion Criteria

• Any prior use of interferon beta or glatiramer acetate.
• Acute exacerbation within 30 days of screening.
• Steroids for acute exacerbations (>100 mg/day) within 30 days of study entrance or chronic systemic steroid use.
• Evidence of progressive MS.
• Use IVIg, azathioprine, methotrexate, cyclosporine, mitoxantrone, cyclophosphamide, mycophenolate (CellCept) or plasma exchange in the twelve weeks prior to study drug dosing.
• Any previous treatment with natalizumab (Tysabri, Antegren), cladribine, T cell vaccine, Campath, daclizumab, rituximab, altered peptide ligand or total lymphoid irradiation.
• Treatment with 4 aminopyridines in the four weeks prior to study drug dosing.
• Prior treatment with any other investigational drug, unless approved by the Clinical Coordinating Center (Dr. Lublin).
• Inability to perform the baseline MSFC (timed 25-foot walk, 9-hole peg test [9HPT], and Paced Auditory Serial Addition Test 3 [PASAT3]).
• Inability to undergo baseline MRI scan.
• History of any significant cardiac, hepatic, pulmonary, or renal disease, immune deficiency, or other medical conditions that would preclude therapy with interferon beta, glatiramer acetate, or participation in this study.
• Known history of sensitivity to gadopentetate dimeglumine or mannitol.
• History of a seizure within the 3 months prior to randomization.
• History of suicidal ideation or an episode of severe depression within the 3 months prior to randomization.
• Abnormal screening blood tests exceeding any of the limits defined below:

• Alanine transaminase (ALT) or aspartate transaminase (AST) greater than two times the upper limit of normal (i.e., >2 × ULN)
• Total white blood cell count <2,300/mm3
• Platelet count <80,000/mm3
• Creatinine >2 × ULN
• Participation in another experimental clinical trial, without formal approval.
• History of alcohol or drug abuse within the 2 years prior to randomization.
• Female subjects who are currently pregnant, breast-feeding, or plan to become pregnant.
• For female subjects, unless postmenopausal or surgically sterile, unwillingness to practice effective contraception, as defined by the investigator, during the study. The rhythm method is not to be used as the sole method of contraception.
• Unwillingness or inability to comply with the requirements of this protocol including the presence of any condition that is likely to affect the subject's returning for scheduled follow-up visits on schedule (any physical, mental, or social condition).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

Fred Lublin

OTHER

Sponsor Role: lead

Responsible Party

Fred Lublin

Principal Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Fred Lublin, MD

Role: PRINCIPAL_INVESTIGATOR

Icahn School of Medicine at Mount Sinai

Locations

University of Alabama - Birmingham

Birmingham, Alabama, United States

Barrow Neurology Clinic

Phoenix, Arizona, United States

Mayo Clinic - Scottsdale

Scottsdale, Arizona, United States

Northwest Neurospecialists PLLC

Tucson, Arizona, United States

Sutter East Bay Medical Group

Berkeley, California, United States

Neurology Center North Orange County

La Habra, California, United States

VA West Los Angeles Healthcare Center

Los Angeles, California, United States

University of California - Davis Medical Center

Sacramento, California, United States

Alpine Clinical Research Center

Boulder, Colorado, United States

Patricia Fodor P.C.

Colorado Springs, Colorado, United States

University of Colorado Health Sciences Center

Denver, Colorado, United States

Yale University School of Medicine

New Haven, Connecticut, United States

Neurology Associates, PA

Maitland, Florida, United States

University of Miami - Neurology

Miami, Florida, United States

MS Center of Atlanta

Atlanta, Georgia, United States

Shepherd Center

Atlanta, Georgia, United States

Northwest University

Chicago, Illinois, United States

Consultants in Neurology - Multiple Sclerosis Center

Northbrook, Illinois, United States

University of Illinois College of Medicine

Peoria, Illinois, United States

Ruan Neurology Clinic and Research Center

Des Moines, Iowa, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

Maryland Center for MS

Baltimore, Maryland, United States

Tufts-New England Medical Center

Boston, Massachusetts, United States

University of Massachusetts Memorial Medical Center

Boston, Massachusetts, United States

Lahey Clinic

Burlington, Massachusetts, United States

Wayne State University

Detroit, Michigan, United States

Michigan State University

East Lansing, Michigan, United States

Minneapolis Clinic - MS Center

Golden Valley, Minnesota, United States

Mayo Clinic - Rochester

Rochester, Minnesota, United States

St. Louis University - St. Louis VA

St Louis, Missouri, United States

Washington University School of Medicine

St Louis, Missouri, United States

Northern Rockies MS Center

Billings, Montana, United States

Dartmouth Medical School

Lebanon, New Hampshire, United States

CentraState Medical Center

Freehold, New Jersey, United States

University of New Mexico

Albuquerque, New Mexico, United States

Neuro Associates of Albany, PC

Albany, New York, United States

Albany Medical College

Albany, New York, United States

The Jacobs Neurological Institute

Buffalo, New York, United States

Winthrop Neurology Faculty Practice

Mineola, New York, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Columbia University Medical Center

New York, New York, United States

NYU Hospital For Joint Diseases

New York, New York, United States

South Shore Neurologic Associates Inc.

Patchogue, New York, United States

University of Rochester

Rochester, New York, United States

SUNY Upstate Medical University

Syracuse, New York, United States

CMC-Neuroscience & Spine Institute, Division of Neurology, MS Center

Charlotte, North Carolina, United States

Meritcare Neuroscience

Fargo, North Dakota, United States

NeuroCare Center, Inc.

Canton, Ohio, United States

Cleveland Clinic

Cleveland, Ohio, United States

Ohio State University

Columbus, Ohio, United States

Neurology Specialists

Dayton, Ohio, United States

Medical College Of Ohio

Toledo, Ohio, United States

Oak Clinic for Multiple Sclerosis

Uniontown, Ohio, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Allegheny MS Treatment Center

Pittsburgh, Pennsylvania, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Baylor College of Medicine

Houston, Texas, United States

University of Texas - Houston

Houston, Texas, United States

University of Utah

Salt Lake City, Utah, United States

Neurological Research Center, Inc.

Bennington, Vermont, United States

Fletcher Allen Health Care

Burlington, Vermont, United States

Neurological Associates, Inc.

Richmond, Virginia, United States

Virginia Commonwealth University

Richmond, Virginia, United States

MS Center at Evergreen

Seattle, Washington, United States

Virginia Mason Medical Center

Seattle, Washington, United States

Marshfield Clinic

Marshfield, Wisconsin, United States

Regional MS Center at St. Luke's Medical Center

Milwaukee, Wisconsin, United States

Foothills Medical Centre

Calgary, Alberta, Canada

Capital Health and the University of Alberta

Edmonton, Alberta, Canada

Ottawa Hospital

Ottawa, Ontario, Canada

St. Michael's Hospital-Multiple Sclerosis Research Center

Toronto, Ontario, Canada

Countries

United States; Canada

References

Lublin FD, Cofield SS, Cutter GR, Conwit R, Narayana PA, Nelson F, Salter AR, Gustafson T, Wolinsky JS; CombiRx Investigators. Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol. 2013 Mar;73(3):327-40. doi: 10.1002/ana.23863. Epub 2013 Mar 11.

Reference Type: RESULT

PMID: 23424159 (View on PubMed)

Koch MW, Moral E, Brieva L, Mostert J, Strijbis EM, Comtois J, Repovic P, Bowen JD, Wolinsky JS, Lublin FD, Cutter G. Relapse recovery in relapsing-remitting multiple sclerosis: An analysis of the CombiRx dataset. Mult Scler. 2023 Dec;29(14):1776-1785. doi: 10.1177/13524585231202320. Epub 2023 Oct 13.

Reference Type: DERIVED

PMID: 37830451 (View on PubMed)

Satyanarayan S, Cutter G, Krieger S, Cofield S, Wolinsky JS, Lublin F. The impact of relapse definition and measures of durability on MS clinical trial outcomes. Mult Scler. 2023 Apr;29(4-5):568-575. doi: 10.1177/13524585231157211.

Reference Type: DERIVED

PMID: 37119208 (View on PubMed)

Zhang Y, Cofield S, Cutter G, Krieger S, Wolinsky JS, Lublin F. Predictors of Disease Activity and Worsening in Relapsing-Remitting Multiple Sclerosis. Neurol Clin Pract. 2022 Aug;12(4):e58-e65. doi: 10.1212/CPJ.0000000000001177.

Reference Type: DERIVED

PMID: 36382118 (View on PubMed)

Koch MW, Mostert J, Repovic P, Bowen JD, Wolinsky JS, Lublin FD, Strijbis E, Cutter G. Early first-line treatment response and subsequent disability worsening in relapsing-remitting multiple sclerosis. Eur J Neurol. 2022 Apr;29(4):1106-1116. doi: 10.1111/ene.15220. Epub 2021 Dec 26.

Reference Type: DERIVED

PMID: 34927308 (View on PubMed)

Ben-Zacharia AB, Janal MN, Brody AA, Wolinsky J, Lublin F, Cutter G. The Effect of Body Mass Index on Brain Volume and Cognitive Function in Relapsing-Remitting Multiple sclerosis: A CombiRx Secondary Analysis. J Cent Nerv Syst Dis. 2021 Nov 6;13:11795735211042173. doi: 10.1177/11795735211042173. eCollection 2021.

Reference Type: DERIVED

PMID: 34759712 (View on PubMed)

Petracca M, Cutter G, Cocozza S, Freeman L, Kangarlu J, Margoni M, Moro M, Krieger S, El Mendili MM, Droby A, Wolinsky JS, Lublin F, Inglese M. Cerebellar pathology and disability worsening in relapsing-remitting multiple sclerosis: A retrospective analysis from the CombiRx trial. Eur J Neurol. 2022 Feb;29(2):515-521. doi: 10.1111/ene.15157. Epub 2021 Nov 17.

Reference Type: DERIVED

PMID: 34695274 (View on PubMed)

Koch MW, Mostert JP, Wolinsky JS, Lublin FD, Uitdehaag B, Cutter GR. Comparison of the EDSS, Timed 25-Foot Walk, and the 9-Hole Peg Test as Clinical Trial Outcomes in Relapsing-Remitting Multiple Sclerosis. Neurology. 2021 Oct 19;97(16):e1560-e1570. doi: 10.1212/WNL.0000000000012690. Epub 2021 Aug 25.

Reference Type: DERIVED

PMID: 34433679 (View on PubMed)

Koch MW, Mostert J, Zhang Y, Wolinsky JS, Lublin FD, Strijbis E, Cutter G. Association of Age With Contrast-Enhancing Lesions Across the Multiple Sclerosis Disease Spectrum. Neurology. 2021 Sep 28;97(13):e1334-e1342. doi: 10.1212/WNL.0000000000012603. Epub 2021 Aug 10.

Reference Type: DERIVED

PMID: 34376508 (View on PubMed)

Salter A, Kowalec K, Fitzgerald KC, Cutter G, Marrie RA. Comorbidity is associated with disease activity in MS: Findings from the CombiRx trial. Neurology. 2020 Aug 4;95(5):e446-e456. doi: 10.1212/WNL.0000000000010024. Epub 2020 Jun 17.

Reference Type: DERIVED

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Fitzgerald KC, Kim K, Smith MD, Aston SA, Fioravante N, Rothman AM, Krieger S, Cofield SS, Kimbrough DJ, Bhargava P, Saidha S, Whartenby KA, Green AJ, Mowry EM, Cutter GR, Lublin FD, Baranzini SE, De Jager PL, Calabresi PA. Early complement genes are associated with visual system degeneration in multiple sclerosis. Brain. 2019 Sep 1;142(9):2722-2736. doi: 10.1093/brain/awz188.

Reference Type: DERIVED

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Other Identifiers

02-0526

Identifier Type: -

Identifier Source: secondary_id

CRC

Identifier Type: -

Identifier Source: secondary_id

U01NS045719

Identifier Type: NIH

Identifier Source: secondary_id

View Link

GCO 02-0526

Identifier Type: -

Identifier Source: org_study_id