CHAMPS
Intramuscular Interferon Beta-1a Therapy Initiated During a First Demyelinating Event in Multiple Sclerosis (Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study)
Clinical Question
Does initiating treatment with interferon beta-1a at the time of a first clinical demyelinating event reduce the incidence of clinically definite multiple sclerosis in patients who have MRI evidence of prior subclinical demyelination in the brain?
Study Overview
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
- Interferon beta-1a reduced the rate of clinically definite MS during 3-year follow-up (cumulative probability 35% vs 50%; rate ratio 0.56, 95% CI 0.38-0.81; p=0.002)
- Significant MRI benefits at 18 months: 67% fewer gadolinium-enhancing lesions, fewer new/enlarging T2 lesions, and less T2 lesion-volume increase (all p<0.001)
- 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
Patients per Arm
193 (interferon beta-1a), 190 (placebo)
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 over three years (cumulative probability 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
Design
Study Type: Multicenter, randomized, double-blind, placebo-controlled trial
Randomization: 1
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.
Enrollment Period: April 1996 to April 1998
Follow-up Duration: 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
Sample Size: 383
Analysis: Intention-to-treat. Kaplan-Meier product-limit method for cumulative probability of clinically definite MS. Mantel log-rank test for between-group comparison. Proportional-hazards model for rate ratios. Mann-Whitney rank-sum test for MRI outcomes. Sample size: 380 patients for 80% power to detect 33% relative treatment effect at α=0.05 (two-tailed), assuming 50% 3-year MS rate in placebo group and 15% withdrawal. Single preplanned interim analysis led to early termination.
Inclusion Criteria
- Age 18 to 50 years
- First isolated, well-defined neurologic event consistent with demyelination involving optic nerve (unilateral optic neuritis), spinal cord (incomplete transverse myelitis), or brain stem/cerebellum
- Event confirmed on ophthalmologic or neurologic examination
- Two or more clinically silent brain lesions ≥3 mm in diameter on MRI characteristic of multiple sclerosis
- At least one lesion periventricular or ovoid
- Onset of symptoms no more than 14 days before IV corticosteroid therapy started
- Onset no more than 27 days before randomization
Exclusion Criteria
- Prior neurologic or visual event consistent with demyelination that lasted longer than 48 hours
- Any prior episode suggesting previous demyelinating event
Arms
| Field | Control | Interferon beta-1a (Avonex) |
|---|---|---|
| Intervention | All patients first received intravenous methylprednisolone 1 g/day for 3 days, followed by oral prednisone 1 mg/kg/day for 11 days, then taper (20 mg day 1, 10 mg day 2, 0 mg day 3, 10 mg day 4). Matching placebo by weekly intramuscular injection for up to 3 years. Acetaminophen 650 mg before each injection and every 6 hours for 24 hours during first 6 months. | All patients first received intravenous methylprednisolone 1 g/day for 3 days, followed by oral prednisone 1 mg/kg/day for 11 days, then taper (20 mg day 1, 10 mg day 2, 0 mg day 3, 10 mg day 4). Interferon beta-1a (Avonex) 30 µg by weekly intramuscular injection for up to 3 years. Treatment began while still receiving oral prednisone. Acetaminophen 650 mg before each injection and every 6 hours for 24 hours during first 6 months to minimize influenza-like syndrome. |
| Duration | Up to 3 years | Up to 3 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Development of clinically definite multiple sclerosis. For patients neurologically stable or improving at month 1: reached if new visual/neurologic event (new clinical abnormality lasting >48 hours attributable to a different CNS location than the initial event) OR progressive neurologic deterioration (≥1.5-point increase in EDSS from month 1). For patients whose initial demyelinating event was clinically worse at month 1: reached if further worsening was documented at month 2 OR the patient withdrew before completing 2 months of treatment. All end points confirmed by a central end-point committee blinded to treatment assignment. | Primary | Placebo: 50% cumulative probability at 3 years | Interferon beta-1a: 35% cumulative probability at 3 years | Rate ratio 0.56 | 0.002 |
| Change in T2 lesion volume at 6 months (mm³), median (25th, 75th) | Secondary | 40 (-175, 624) [n=145] | -123 (-653, 254) [n=145] | <0.001 | |
| Change in T2 lesion volume at 12 months (mm³), median (25th, 75th) | Secondary | 214 (-45, 1238) [n=120] | 102 (-375, 573) [n=134] | 0.004 | |
| Change in T2 lesion volume at 18 months (mm³), median (25th, 75th) | Secondary | 313 (5, 1140) [n=109]; 16% median increase | 28 (-576, 397) [n=119]; 1% median increase | <0.001 | |
| New or enlarging T2 lesions at 6 months, mean ± SD | Secondary | 2.8 ± 4.3 [n=152] | 1.5 ± 2.7 [n=165] | 0.01 | |
| New or enlarging T2 lesions at 12 months, mean ± SD | Secondary | 4.0 ± 5.0 [n=126] | 2.1 ± 3.3 [n=149] | <0.001 | |
| New or enlarging T2 lesions at 18 months, mean ± SD | Secondary | 5.0 ± 7.7 [n=119] | 2.1 ± 3.2 [n=132] | <0.001 | |
| Gadolinium-enhancing lesions at 6 months, mean ± SD | Secondary | 1.5 ± 3.1 [n=152] | 0.9 ± 2.3 [n=165] | 42% fewer in interferon group | 0.03 |
| Gadolinium-enhancing lesions at 12 months, mean ± SD | Secondary | 1.6 ± 3.8 [n=124] | 0.7 ± 2.0 [n=147] | 55% fewer in interferon group | 0.02 |
| Gadolinium-enhancing lesions at 18 months, mean ± SD | Secondary | 1.4 ± 3.6 [n=114] | 0.4 ± 1.5 [n=134] | 67% fewer in interferon group | <0.001 |
| Patients with 0 gadolinium-enhancing lesions at 18 months | Secondary | 66 (58%) [n=114] | 109 (81%) [n=134] | <0.001 | |
| Corticosteroids prescribed for non-qualifying neurologic event | Secondary | 22 (12%); 7 later developed CDMS | 9 (5%); 3 later developed CDMS | ||
| Influenza-like syndrome (first 6 months) | Adverse | 26% | 54% | <0.001 | |
| Depression (first 6 months) | Adverse | 13% | 20% | 0.05 | |
| Serious adverse events | Adverse | 19 patients | 12 patients | ||
| Treatment discontinuation due to adverse event | Adverse | 7 (4%) | 1 (<1%) | ||
| Neutralizing antibodies (≥1:20) at 12 and 18 months | Adverse | N/A | <1% | ||
| Neutralizing antibodies (≥1:20) at 24 and 30 months | Adverse | N/A | 2% | ||
| Abnormal laboratory values requiring treatment discontinuation | Adverse | 0 | 0 |
Subgroup Analysis
Treatment effect was consistent across subgroups. No significant interaction by type of initial event (p=0.49): optic neuritis, spinal cord syndrome, and brain-stem/cerebellar syndrome all showed similar benefit. No significant interaction by number of baseline T2 lesions (p=0.88): patients with 2, 3-4, 5-7, and ≥8 lesions all showed similar benefit. This suggests treatment is beneficial across the range of patients meeting inclusion criteria.
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)
Funding
Biogen
Based on: CHAMPS (The New England Journal of Medicine, 2000)
Authors: Lawrence D. Jacobs, Roy W. Beck, Jack H. Simon, ..., and the CHAMPS Study Group
Citation: N Engl J Med 2000;343:898-904
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