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Relapsing Remitting Multiple SclerosisPhase 3NCT00211887

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

A Phase 3 study testing Interferon beta 1-a and glatiramer acetate in people with Relapsing Remitting Multiple Sclerosis, run by Fred Lublin at 71 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 18 to 60 years
Conditions the study is for
Relapsing Remitting Multiple Sclerosis
What is being tested?
Interferon beta 1-a and glatiramer acetate
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
1,008 participants
Where
71 sitesin 2 countries
Study dates
Jan 2005to Mar 2013
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 60 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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.

Who cannot join

  • 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.
Show all 24Show fewer
  • 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).

Trial locations and contacts

71 sites in 2 countries.

71 sites in 2 countries

United States67 sites

  • Neuro Associates of Albany, PC

    Albany, New York, 12208

  • Albany Medical College

    Albany, New York

  • University of New Mexico

    Albuquerque, New Mexico

  • MS Center of Atlanta

    Atlanta, Georgia

  • Shepherd Center

    Atlanta, Georgia

  • Maryland Center for MS

    Baltimore, Maryland

  • Neurological Research Center, Inc.

    Bennington, Vermont

  • Sutter East Bay Medical Group

    Berkeley, California

  • Northern Rockies MS Center

    Billings, Montana

  • University of Alabama - Birmingham

    Birmingham, Alabama

  • Tufts-New England Medical Center

    Boston, Massachusetts

  • University of Massachusetts Memorial Medical Center

    Boston, Massachusetts

  • Alpine Clinical Research Center

    Boulder, Colorado

  • The Jacobs Neurological Institute

    Buffalo, New York

  • Lahey Clinic

    Burlington, Massachusetts

  • Fletcher Allen Health Care

    Burlington, Vermont

  • NeuroCare Center, Inc.

    Canton, Ohio

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

    Charlotte, North Carolina

  • Northwest University

    Chicago, Illinois

  • Cleveland Clinic

    Cleveland, Ohio

  • Patricia Fodor P.C.

    Colorado Springs, Colorado

  • Ohio State University

    Columbus, Ohio

  • Neurology Specialists

    Dayton, Ohio, 45415

  • University of Colorado Health Sciences Center

    Denver, Colorado

  • Ruan Neurology Clinic and Research Center

    Des Moines, Iowa

  • Wayne State University

    Detroit, Michigan

  • Michigan State University

    East Lansing, Michigan

  • Meritcare Neuroscience

    Fargo, North Dakota

  • CentraState Medical Center

    Freehold, New Jersey

  • Minneapolis Clinic - MS Center

    Golden Valley, Minnesota

  • Baylor College of Medicine

    Houston, Texas

  • University of Texas - Houston

    Houston, Texas

  • University of Kansas Medical Center

    Kansas City, Kansas

  • Neurology Center North Orange County

    La Habra, California

  • Dartmouth Medical School

    Lebanon, New Hampshire

  • VA West Los Angeles Healthcare Center

    Los Angeles, California

  • Neurology Associates, PA

    Maitland, Florida

  • Marshfield Clinic

    Marshfield, Wisconsin

  • University of Miami - Neurology

    Miami, Florida, 33124

  • Regional MS Center at St. Luke's Medical Center

    Milwaukee, Wisconsin

  • Winthrop Neurology Faculty Practice

    Mineola, New York

  • Vanderbilt University Medical Center

    Nashville, Tennessee

  • Yale University School of Medicine

    New Haven, Connecticut

  • Icahn School of Medicine at Mount Sinai

    New York, New York, 10029

  • Columbia University Medical Center

    New York, New York, 10032

  • NYU Hospital For Joint Diseases

    New York, New York

  • Consultants in Neurology - Multiple Sclerosis Center

    Northbrook, Illinois

  • South Shore Neurologic Associates Inc.

    Patchogue, New York

  • University of Illinois College of Medicine

    Peoria, Illinois

  • University of Pennsylvania

    Philadelphia, Pennsylvania

  • Barrow Neurology Clinic

    Phoenix, Arizona

  • Allegheny MS Treatment Center

    Pittsburgh, Pennsylvania

  • Neurological Associates, Inc.

    Richmond, Virginia

  • Virginia Commonwealth University

    Richmond, Virginia

  • Mayo Clinic - Rochester

    Rochester, Minnesota

  • University of Rochester

    Rochester, New York

  • University of California - Davis Medical Center

    Sacramento, California, 95817

  • University of Utah

    Salt Lake City, Utah

  • Mayo Clinic - Scottsdale

    Scottsdale, Arizona

  • MS Center at Evergreen

    Seattle, Washington

  • Virginia Mason Medical Center

    Seattle, Washington

  • St. Louis University - St. Louis VA

    St Louis, Missouri

  • Washington University School of Medicine

    St Louis, Missouri

  • SUNY Upstate Medical University

    Syracuse, New York

  • Medical College Of Ohio

    Toledo, Ohio

  • Northwest Neurospecialists PLLC

    Tucson, Arizona, 85741

  • Oak Clinic for Multiple Sclerosis

    Uniontown, Ohio

Other trials in United States

Canada4 sites

  • Foothills Medical Centre

    Calgary, Alberta

  • Capital Health and the University of Alberta

    Edmonton, Alberta

  • Ottawa Hospital

    Ottawa, Ontario

  • St. Michael's Hospital-Multiple Sclerosis Research Center

    Toronto, Ontario

Other trials in Canada

About this study

Official title: A Multi-Center, Double-Blind, Randomized Study Comparing the Combined Use of Interferon Beta-1a and Glatiramer Acetate to Either Agent Alone in Patients With Relapsing-Remitting Multiple Sclerosis (CombiRx)

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).

Read the 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).

Being tested
Interferon beta 1-a, glatiramer acetate, placebo
Keywords
Multiple Sclerosis, Clinical trial, treatment trial, autoimmune disease, Relapsing Remitting, MS Treatment, interferon beta-1a, glatiramer acetate
Medical subject headings
Multiple Sclerosis, Relapsing-Remitting, Multiple Sclerosis, Autoimmune Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Interferon beta 1-aDrug

    Also called IFN

    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 acetateDrug

    Also called GA

    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).

  • placeboOther

    an inactive substance

Study groups in NCT00211887
Study groupRoleWhat they receive
Interferon beta 1-aActive comparatorActive Interferon B1a Weekly vs. Placebo Glatiramer Acetate Interferon b-1a (IFN) intramuscularly weekly
Receives: Drug: Interferon beta 1-a; Other: placebo
glatiramer acetateActive comparatorPlacebo Interferon B1a Weekly vs. Active Glatiramer Acetate Glatiramer acetate 20mg daily
Receives: Drug: glatiramer acetate; Other: placebo
IFN and GAActive comparatorActive Interferon B1a Weekly and Active Glatiramer Acetate
Receives: Drug: Interferon beta 1-a; Drug: glatiramer acetate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. ARR - PDEs

    Annualized relapse rate of protocol-defined exacerbations Protocol defined relapse - an relapse seen within 7 days of onset, verified by the treating physician and independently observed as a change in EDSS by the examining physician. This relapse is defined as: the appearance of a new symptom or worsening of an old symptom, attributable to MS; accompanied by a change in the neurologic examination (defined as a 0.5 or greater increase in the EDSS over the last scheduled or unscheduled visit or a 2 point change in one functional system or a 1 point change in two functional systems, except bladder and cognitive changes); lasting at least 24 hours in the absence of fever; and preceded by stability or improvement for at least 30 days.

    Measured: Baseline to Month 36

Secondary outcomes (3)

  1. Confirmed Progression on the Expanded Disability Status Scale

    % with EDSS progression

    Confirmed progression in a participant was defined as a 1.0 increase in the EDSS from baseline, when baseline <=5.0; or an increase of 0.5 from baseline, when baseline >=5.5, sustained for 6 months (2 successive quarterly visits), as assessed by the blinded EDSS examiner and confirmed centrally.

    Measured: Baseline to Month 36

  2. Change in the Multiple Sclerosis Functional Composite

    positive indicates improvement

    The Multiple Sclerosis Functional Composite (MSFC) is a scale measuring pyramidal functions, sensory functions, cerebellar functions, bowel \& bladder functions,brain stem functions, mental functions, and visual functions from 0 to 6.

    0= normal 6= severe loss

    Measured: Baseline to month 36

  3. Change in MRI Composite Score

    MRI composite score (Z4 score) - the unweighted sum of the individual Z scores for enhanced tissue volume, T2 lesion burden, equivalence of the T1 hypointense lesion burden, normalized CSF (an inverse measure of atrophy with the appropriate sign so that all scores are directionally compatible - larger is worse) MRI enhancement status at baseline (0, 1-4, and 5 or more enhancing lesions)

    Measured: Baseline to month 36

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Sep 2005 (estimated)
  2. Study startJan 2005
  3. Primary completionApr 2012
  4. Study completionMar 2013

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Factorial
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
1,008 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00211887
Sponsor's protocol ID
GCO 02-0526
Other IDs
02-0526, CRC, U01NS045719
Status last verified
Mar 2014
First submitted
13 Sep 2005
Last updated
3 Apr 2014
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 23424159

  • 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.

    PubMed 37830451

  • 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.

    PubMed 37119208

  • 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.

    PubMed 36382118

  • 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.

    PubMed 34927308

  • 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.

    PubMed 34759712

  • 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.

    PubMed 34695274

  • 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.

    PubMed 34433679

  • 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.

    PubMed 34376508

  • 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.

    PubMed 32554770

  • 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.

    PubMed 31289819

  • Bhanushali MJ, Gustafson T, Powell S, Conwit RA, Wolinsky JS, Cutter GR, Lublin FD, Cofield SS. Recruitment of participants to a multiple sclerosis trial: the CombiRx experience. Clin Trials. 2014 Apr;11(2):159-66. doi: 10.1177/1740774513517184.

    PubMed 24686106

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Interferon beta 1-a and glatiramer acetate in people with Relapsing Remitting Multiple Sclerosis, run by Fred Lublin at 71 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 Apr 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 71 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 3 Apr 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

ARR - PDEs (time frame: Baseline to Month 36). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00211887, which also lists 12 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Apr 2014.

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