Clinical trial NCT00211887: Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (MS)CombiRx
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Relapsing Remitting Multiple Sclerosis
Keywords: Multiple Sclerosis
Clinical trial
treatment trial
autoimmune disease
Relapsing Remitting
MS Treatment
interferon beta-1a
glatiramer acetate
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2005-09-21
Enrollment: 1008
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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).

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).

Primary outcomes:
measure: ARR - PDEs
timeFrame: Baseline to Month 36
Secondary outcomes:
measure: Confirmed Progression on the Expanded Disability Status Scale
timeFrame: Baseline to Month 36
measure: Change in the Multiple Sclerosis Functional Composite
timeFrame: Baseline to month 36
measure: Change in MRI Composite Score
timeFrame: Baseline to month 36
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama - Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Barrow Neurology Clinic
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic - Scottsdale
state: Arizona
city: Tucson
country: United States
facility: Northwest Neurospecialists PLLC
state: Arizona
city: Berkeley
country: United States
facility: Sutter East Bay Medical Group
state: California
city: La Habra
country: United States
facility: Neurology Center North Orange County
state: California
city: Los Angeles
country: United States
facility: VA West Los Angeles Healthcare Center
state: California
city: Sacramento
country: United States
facility: University of California - Davis Medical Center
state: California
city: Boulder
country: United States
facility: Alpine Clinical Research Center
state: Colorado
city: Colorado Springs
country: United States
facility: Patricia Fodor P.C.
state: Colorado
city: Denver
country: United States
facility: University of Colorado Health Sciences Center
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Maitland
country: United States
facility: Neurology Associates, PA
state: Florida
city: Miami
country: United States
facility: University of Miami - Neurology
state: Florida
city: Atlanta
country: United States
facility: MS Center of Atlanta
state: Georgia
city: Atlanta
country: United States
facility: Shepherd Center
state: Georgia
city: Chicago
country: United States
facility: Northwest University
state: Illinois
city: Northbrook
country: United States
facility: Consultants in Neurology - Multiple Sclerosis Center
state: Illinois
city: Peoria
country: United States
facility: University of Illinois College of Medicine
state: Illinois
city: Des Moines
country: United States
facility: Ruan Neurology Clinic and Research Center
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: Maryland Center for MS
state: Maryland
city: Boston
country: United States
facility: Tufts-New England Medical Center
state: Massachusetts
city: Boston
country: United States
facility: University of Massachusetts Memorial Medical Center
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Clinic
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: East Lansing
country: United States
facility: Michigan State University
state: Michigan
city: Golden Valley
country: United States
facility: Minneapolis Clinic - MS Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: St. Louis
country: United States
facility: St. Louis University - St. Louis VA
state: Missouri
city: St. Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Billings
country: United States
facility: Northern Rockies MS Center
state: Montana
city: Lebanon
country: United States
facility: Dartmouth Medical School
state: New Hampshire
city: Freehold
country: United States
facility: CentraState Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Albany
country: United States
facility: Neuro Associates of Albany, PC
state: New York
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Buffalo
country: United States
facility: The Jacobs Neurological Institute
state: New York
city: Mineola
country: United States
facility: Winthrop Neurology Faculty Practice
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: NYU Hospital For Joint Diseases
state: New York
city: Patchogue
country: United States
facility: South Shore Neurologic Associates Inc.
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Charlotte
country: United States
facility: CMC-Neuroscience & Spine Institute, Division of Neurology, MS Center
state: North Carolina
city: Fargo
country: United States
facility: Meritcare Neuroscience
state: North Dakota
city: Canton
country: United States
facility: NeuroCare Center, Inc.
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Dayton
country: United States
facility: Neurology Specialists
state: Ohio
city: Toledo
country: United States
facility: Medical College Of Ohio
state: Ohio
city: Uniontown
country: United States
facility: Oak Clinic for Multiple Sclerosis
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny MS Treatment Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: University of Texas - Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Bennington
country: United States
facility: Neurological Research Center, Inc.
state: Vermont
city: Burlington
country: United States
facility: Fletcher Allen Health Care
state: Vermont
city: Richmond
country: United States
facility: Neurological Associates, Inc.
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: MS Center at Evergreen
state: Washington
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Marshfield
country: United States
facility: Marshfield Clinic
state: Wisconsin
city: Milwaukee
country: United States
facility: Regional MS Center at St. Luke's Medical Center
state: Wisconsin
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Edmonton
country: Canada
facility: Capital Health and the University of Alberta
state: Alberta
city: Ottawa
country: Canada
facility: Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital-Multiple Sclerosis Research Center
state: Ontario
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: Fred Lublin, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.