PDF: CHAMPS
(2000)Objective
To determine whether weekly intramuscular injections of interferon beta-1a in patients with a first demyelinating event and MRI evidence of prior subclinical demyelination reduces the incidence of clinically definite multiple sclerosis
Study Summary
• Significant MRI benefits: 67% fewer gadolinium-enhancing lesions, fewer new/enlarging T2 lesions (all p<0.001 at 18 months)
• Trial stopped early at preplanned interim analysis due to significant efficacy
Intervention
Interferon beta-1a (Avonex) 30 µg intramuscular weekly; all patients first received IV methylprednisolone 1g/day x 3 days then oral prednisone taper
Inclusion Criteria
Age 18-50, first isolated demyelinating event (optic neuritis, incomplete transverse myelitis, or brain-stem/cerebellar syndrome), ≥2 clinically silent brain lesions ≥3mm on MRI characteristic of MS, symptom onset ≤14 days before IV steroids and ≤27 days before randomization
Study Design
Arms: Interferon beta-1a 30 µg IM weekly (n=193) vs Placebo IM weekly (n=190)
Patients per Arm: 193 (interferon beta-1a), 190 (placebo)
Outcome
• T2 lesion volume increase at 18 months: 1% vs 16% (p<0.001)
• New/enlarging T2 lesions at 18 months: mean 2.1 vs 5.0 (p<0.001)
• Gadolinium-enhancing lesions at 18 months: mean 0.4 vs 1.4 (p<0.001)
Bottom Line
Weekly intramuscular interferon beta-1a initiated at the time of a first demyelinating event (clinically isolated syndrome) significantly reduced the rate of development of clinically definite multiple sclerosis by 44% over three years (35% vs 50%; rate ratio 0.56; p=0.002) in patients with brain lesions on MRI indicating high risk. Treatment also significantly reduced MRI measures of disease activity, including T2 lesion volume, new/enlarging lesions, and gadolinium-enhancing lesions. The trial was stopped early due to significant efficacy at a preplanned interim analysis.
Major Points
- Trial stopped early at preplanned interim analysis after meeting stopping guidelines (P=0.029) demonstrating significant treatment benefit
- Cumulative probability of clinically definite MS at 3 years: 35% interferon beta-1a vs 50% placebo (rate ratio 0.56; 95% CI 0.38-0.81; p=0.002)
- After adjustment for baseline factors, treatment effect was stronger (adjusted rate ratio 0.49; 95% CI 0.33-0.73; p<0.001)
- Treatment effect was consistent across subgroups classified by type of initial event (p=0.49 for interaction) and number of baseline T2 lesions (p=0.88 for interaction)
- At 18 months: median T2 lesion volume increase was 1% (interferon) vs 16% (placebo), p<0.001
- 67% reduction in gadolinium-enhancing lesions at 18 months (mean 0.4 vs 1.4, p<0.001)
- Fewer new or enlarging T2 lesions at 18 months: mean 2.1 vs 5.0 (p<0.001)
- Diagnosis of clinically definite MS was due to a second acute demyelinating event in all but 5 patients
- Corticosteroids prescribed for non-qualifying neurologic events in 9 (5%) interferon patients vs 22 (12%) placebo patients
- This trial established that MRI of the brain should be obtained at time of first demyelinating event to identify high-risk patients for early treatment
Study Design
- Study Type
- Multicenter, randomized, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind. Patients and site personnel were unaware of treatment assignments. Examining neurologist performed structured neurologic examination without knowledge of patient's history during or before the study. Central end-point committee verified all outcomes without knowledge of treatment assignments.
- Sample Size
- 383
- Follow-up
- Up to 3 years (planned); mean 30.9 ± 4.9 months (interferon) and 30.6 ± 5.1 months (placebo) for patients completing trial
- Centers
- 50
- Countries
- USA, Canada
Primary Outcome
Definition: Development of clinically definite multiple sclerosis, defined as (for patients neurologically stable/improving at 1 month): occurrence of new visual or neurologic event (new clinical abnormality lasting >48 hours attributable to different CNS location than initial event), OR progressive neurologic deterioration (≥1.5 point increase in EDSS from month 1). Confirmed by central end-point committee blinded to treatment assignment.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Placebo: 50% cumulative probability at 3 years | Interferon beta-1a: 35% cumulative probability at 3 years | Rate ratio 0.56 (0.38-0.81) | 0.002 |
Limitations & Criticisms
- Trial stopped early at interim analysis, which may overestimate treatment effects
- Patients withdrawn from study upon diagnosis of clinically definite MS - cannot assess long-term effect on disability progression or relapse rates
- MRI follow-up only to 18 months due to expected differential dropout; longer-term MRI effects unknown
- All patients received initial IV methylprednisolone - cannot determine if interferon benefit would be same without steroid pretreatment
- Influenza-like syndrome in 54% of interferon group could have partially unblinded some patients
- No direct assessment of long-term disability outcomes
- Excluded patients without MRI lesions - results may not apply to lower-risk CIS patients
- Study design with withdrawal at diagnosis prevents evaluation of treatment effect on subsequent relapses after CDMS diagnosis
- Higher early withdrawal rate in interferon group for 'other reasons' (27 vs 15 patients)
- Compliance slightly lower in interferon group (93% vs 99.5% took medication ≥80% of time)
Citation
N Engl J Med 2000;343:898-904