CombiRx
(2013)Objective
To determine whether combination therapy with interferon beta-1a and glatiramer acetate is superior to either drug alone for relapsing-remitting MS
Study Summary
• Combination NOT superior to GA alone for relapse rate (primary endpoint): ARR 0.22 (combo) vs 0.25 (GA) vs 0.33 (IFN) -- combo vs GA p=0.27; combo significantly better than IFN alone (p=0.03)
• GA alone was superior to IFN alone for relapse rate; MRI outcomes mixed; combination had most AEs; landmark negative trial ending the combination therapy question
Intervention
IFN beta-1a 30 mcg IM weekly + GA 20 mg SC daily vs IFN beta-1a alone vs GA alone
Inclusion Criteria
Age 18-60, RRMS by McDonald criteria, EDSS 0-5.5, >=2 relapses in prior 3 years or >=1 in prior 13 months
Study Design
Arms: IFN + GA Combination vs IFN beta-1a Alone vs GA Alone
Patients per Arm: Combination: 499, IFN: 250, GA: 259
Outcome
• GA alone superior to IFN alone (p=0.03); MRI: combo had fewer new T2 lesions than IFN but not GA
• Combination had highest AE burden without added efficacy over GA monotherapy
Bottom Line
Combination therapy with IFN beta-1a and GA was NOT superior to GA monotherapy for reducing relapse rate in RRMS (ARR 0.22 vs 0.25, p=0.27). Unexpectedly, GA alone was significantly better than IFN alone (p=0.03). The combination did show MRI benefits over IFN alone but not over GA alone, while causing more adverse events. This landmark negative trial ended the longstanding question of whether combining these two first-line therapies would produce synergistic benefit.
Major Points
- Primary endpoint negative: combination ARR 0.22 not significantly different from GA alone ARR 0.25 (p=0.27)
- GA alone was significantly superior to IFN alone for relapse rate (0.25 vs 0.33, p=0.03) -- unexpected finding favoring GA
- Combination was superior to IFN alone (0.22 vs 0.33, p=0.03) but this benefit was entirely attributable to the GA component
- MRI: combination reduced new/enlarging T2 lesions vs IFN alone but not vs GA alone
- No significant differences in disability progression (EDSS) among the three arms
- Combination had highest adverse event burden without added efficacy over GA monotherapy
- Largest NIH-funded MS treatment trial; definitively answered the combination therapy question
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, double-dummy, parallel-group trial
- Randomization
- Yes
- Blinding
- Double-blind, double-dummy (all patients received both IM injection and SC injection, one active and one placebo)
- Sample Size
- 1008
- Follow-up
- 3 years
- Centers
- 70
- Countries
- United States
Primary Outcome
Definition: Exacerbation (relapse) rate over 3 years
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| GA alone: ARR 0.25; IFN alone: ARR 0.33 | Combination: ARR 0.22 | - | Combo vs GA: p=0.27 (NS); Combo vs IFN: p=0.03; GA vs IFN: p=0.03 |
Limitations & Criticisms
- 2:1:1 randomization (499 combo vs 250 IFN vs 259 GA) gives more statistical power for combo comparisons but less for head-to-head IFN vs GA
- IFN beta-1a 30 mcg IM weekly (Avonex dose) is the lowest IFN dose; higher-dose IFN formulations (44 mcg SC) might have performed differently
- 3-year duration may be insufficient to detect differences in disability progression
- Double-dummy design required patients to receive both IM and SC injections, increasing placebo-related injection-site reactions
- No dose optimization period: fixed IFN dose from start may increase early dropout due to flu-like symptoms
- Trial did not include high-efficacy comparators (natalizumab, fingolimod) that were available by completion
Citation
Lublin FD et al. Ann Neurol. 2013;73(3):327-340. DOI: 10.1002/ana.23863