A landmark study investigating whether combining interferon beta-1a and glatiramer acetate provides better outcomes for relapsing-remitting multiple sclerosis
Imagine having to choose between two medications, both partially effective for your chronic condition, with no clear way to know if taking them together would help more—or simply increase side effects. This was the precise dilemma facing millions living with relapsing-remitting multiple sclerosis (RRMS) in the early 2000s. With approximately 2.5 million people affected worldwide, MS represents one of the most challenging neurological diseases, typically striking in young adulthood and potentially leading to substantial disability over time 1 .
Multiple sclerosis is an autoimmune disease where the immune system attacks the protective sheath (myelin) that covers nerve fibers, causing communication problems between the brain and the rest of the body.
The CombiRx trial emerged as a groundbreaking response to this dilemma, tackling a question that had long puzzled both patients and neurologists: would combining the two most commonly prescribed MS therapies—interferon beta-1a (IFN) and glatiramer acetate (GA)—provide better outcomes than either alone? This ambitious study, funded by the National Institutes of Health, would eventually provide answers that reshaped treatment approaches and revealed unexpected insights about MS management 1 2 .
To understand the significance of CombiRx, we must first explore how these two medications work. Although both are immunomodulatory therapies that calm the overactive immune response in MS, they achieve this through distinct mechanisms of action.
Interferon beta-1a is a synthetic version of a protein naturally produced by the human body. It works by reducing inflammation and preventing immune cells from crossing the protective blood-brain barrier, thereby limiting their attack on the central nervous system. Administered as a weekly intramuscular injection, IFN reduces relapse rates by approximately 32% according to earlier studies 1 4 .
Glatiramer acetate, in contrast, is a synthetic protein resembling myelin—the protective coating around nerves that becomes damaged in MS. Think of it as a decoy target that distracts immune cells from attacking the body's actual myelin. Given as a daily subcutaneous injection, GA reduces relapse rates by about 29% 1 4 .
The compelling theory behind CombiRx was straightforward: if these drugs work through different pathways, perhaps using them together would create complementary benefits, potentially offering patients better disease control without the significant risks associated with newer, more potent medications 1 .
The CombiRx investigators set out to create what would become the gold standard for combination therapy studies in MS. Launched in 2005, this was a 3-arm, randomized, double-blind, placebo-controlled, multi-center Phase III trial—a design that represents the most rigorous approach in clinical research 1 .
Participant Recruitment: The trial enrolled 1,008 participants with RRMS across 68 sites in the United States and Canada.
Partial 2×2 factorial design with a 2:1:1 randomization scheme, meaning twice as many participants were assigned to the combination group compared to either single therapy group.
Participants were followed for a minimum of 3 years, with many continuing in an extension phase for up to 7 years.
The trial enrolled 1,008 participants with RRMS across 68 sites in the United States and Canada between 2005 and 2009. These volunteers represented a typical cross-section of early MS patients: predominantly female (72.4%), with a mean age of 37.7 years, and relatively early in their disease course (median symptom duration of 2 years) 1 2 .
| Characteristic | IFN+GA Group (N=499) | IFN Group (N=250) | GA Group (N=259) | All Participants (N=1008) |
|---|---|---|---|---|
| Female, N (%) | 372 (74.6%) | 173 (69.2%) | 185 (71.4%) | 730 (72.4%) |
| White, N (%) | 440 (88.2%) | 212 (84.8%) | 234 (90.3%) | 886 (87.9%) |
| Mean Age (years) | 37.1 | 37.6 | 39.0 | 37.7 |
| Mean Disease Duration (years) | 1.1 | 1.4 | 1.0 | 1.2 |
| Mean EDSS Score | 1.9 | 2.0 | 1.9 | 2.0 |
| With Enhancing Lesions, N (%) | 189 (37.9%) | 104 (41.6%) | 106 (40.9%) | 399 (39.6%) |
Across United States and Canada
With relapsing-remitting MS
Follow-up duration
When the results were analyzed after all participants had completed the 3-year core study, they held some surprises that would significantly influence MS management.
The primary objective was to determine whether combined treatment reduced the annualized relapse rate more effectively than either agent alone. Surprisingly, the combination therapy did not outperform the better of the single agents 2 .
Even more intriguing was the discovery that both the combination therapy and GA alone were significantly better than IFN in reducing relapse risk. This unexpected finding provided the first high-quality evidence comparing these two foundational therapies, suggesting glatiramer acetate might be more effective than interferon for preventing relapses in some patients 2 .
The CombiRx investigators also examined whether the treatments could slow confirmed disability progression, an important measure of long-term function. Again, the combination offered no advantage over either single therapy in preventing disability progression or improving scores on the Multiple Sclerosis Functional Composite, a test assessing walking, hand function, and cognitive processing speed 2 .
| Outcome Measure | IFN+GA Group | IFN Group | GA Group | Statistical Significance |
|---|---|---|---|---|
| Reduction in Relapse Risk | Significant vs. IFN | Reference | Significant vs. IFN | Combination not superior to GA |
| Disability Progression | No significant benefit | No significant benefit | No significant benefit | No difference between groups |
| MSFC Change | No significant benefit | No significant benefit | No significant benefit | No difference between groups |
| Disease Activity Free Status | Higher proportion | Lower proportion | Lower proportion | Combination superior to both |
One of the most fascinating aspects of the CombiRx results was the disconnect between MRI findings and clinical outcomes. While the combination failed to demonstrate clinical superiority, it significantly outperformed both single therapies on several important MRI measures 2 .
The combination therapy was superior to either agent alone in reducing new lesion formation and accumulation of total lesion volumes. This was measured using a sophisticated composite Z-score (Z4) that combined four different MRI parameters: enhancing lesion volume, T2 lesion volume, T1 hypointense lesion volume, and normalized CSF 1 2 .
This radiologic-clinical paradox prompted important questions about the relationship between inflammatory brain lesions observed on MRI and the clinical manifestations experienced by patients. The findings suggested that while combination therapy more effectively suppressed inflammatory activity, this didn't necessarily translate to measurable clinical benefits over the 3-year study period 2 .
| MRI Parameter | IFN+GA Group | IFN Group | GA Group | Statistical Significance |
|---|---|---|---|---|
| New Lesion Activity | Largest reduction | Intermediate reduction | Least reduction | Combination superior to both |
| Total Lesion Volume Accumulation | Smallest increase | Intermediate increase | Largest increase | Combination superior to both |
| Gadolinium-Enhancing Lesions | Lowest proportion | Intermediate proportion | Highest proportion | Combination superior to both |
Conducting a trial of CombiRx's scale and duration required sophisticated infrastructure and carefully standardized materials. The investigators established three specialized centers to manage different aspects of the study 1 .
| Component | Function in the Trial | Significance |
|---|---|---|
| Clinical Coordinating Center | Overall study management including regulatory and financial aspects | Ensured consistent protocol implementation across all sites |
| Statistical and Data Management Center | Design of case report forms, data entry system, collection and analysis | Guaranteed statistical rigor and data integrity |
| MRI Analysis Center | Standardized processing and analysis of all MRI scans using specialized software | Enabled objective, consistent measurement of radiological outcomes |
| Matched Placebos | Visually identical preparations without active medication | Maintained blinding essential for trial validity |
| Z4 Composite Score | Combined four different MRI measures into a single standardized value | Provided comprehensive assessment of radiological disease activity |
Although the CombiRx trial demonstrated that routine combination of interferon and glatiramer acetate wasn't clinically warranted, its contributions extended far beyond this conclusion. The extensive dataset and carefully collected biological samples continued to generate insights years after the main results were published 2 .
Perhaps one of the most impactful legacies of CombiRx has been its role in advancing personalized medicine for MS. In 2020, researchers used data from the trial to develop a Treatment Response Score that helps identify which patients are most likely to benefit from glatiramer acetate versus interferon based on their individual characteristics 5 .
This scoring system incorporates age, sex, recent relapses, disease duration, and disability level to calculate which medication might work better for a specific individual. For example, a 25-year-old with recent relapses and minimal disability showed a 42% greater reduction in relapse risk with glatiramer acetate compared to interferon. This approach represents the future of MS treatment—moving beyond one-size-fits-all recommendations to tailored therapeutic strategies 5 .
The CombiRx extension phase continued to follow participants for up to 7 years, addressing whether the MRI differences observed might eventually translate to clinical benefits over a longer timeframe. Additionally, the trial's comprehensive dataset has enabled investigations into how comorbidities affect MS progression and treatment response, acknowledging that most patients have other health conditions that may influence their disease course .
The CombiRx trial stands as a testament to the importance of asking straightforward clinical questions with methodological rigor. While the combination of interferon and glatiramer acetate didn't prove to be the breakthrough many had hoped for, the trial provided definitive answers that saved countless patients from unnecessary treatment complexity and potential side effects.
More significantly, CombiRx generated a wealth of data that continues to fuel discoveries in MS research. Its findings have helped refine our understanding of how to evaluate MS treatments, highlighted the complex relationship between radiological and clinical outcomes, and advanced the goal of personalized medicine for people living with multiple sclerosis.
As MS treatment continues to evolve with an expanding arsenal of therapeutic options, the rigorous methodology and collaborative spirit embodied by CombiRx will remain essential guides in the ongoing quest to optimize outcomes for every person with MS.
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