ASCEND
(2018)Objective
To assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses
Study Summary
• Natalizumab significantly reduced upper-limb disability progression on 9HPT (15% vs 23%, OR 0.56, p=0.001)
• No effect on EDSS or T25FW (ambulatory) components
Intervention
Natalizumab 300 mg IV every 4 weeks vs placebo for 2 years
Inclusion Criteria
Age 18-58 years, natalizumab-naive, SPMS for ≥2 years, EDSS 3.0-6.5, MS Severity Score ≥4, disability progression unrelated to relapses in prior year, no relapse within 3 months of randomization
Study Design
Arms: Natalizumab 300 mg IV every 4 weeks, Placebo
Patients per Arm: 439 natalizumab, 448 placebo (ITT population)
Outcome
• 9HPT progression: 15% vs 23% (OR 0.56, 95% CI 0.40-0.80, p=0.001)
• EDSS progression: 16% vs 15% (OR 1.06, p=0.753); T25FW: 35% vs 35% (OR 0.98, p=0.914)
Bottom Line
Natalizumab did not reduce overall disability progression on the primary multicomponent endpoint in secondary progressive MS over 2 years. However, it significantly reduced upper-limb disability progression as measured by the 9-Hole Peg Test, suggesting potential domain-specific benefits that may require longer treatment duration to manifest in ambulatory measures.
Major Points
- Primary endpoint NOT met: No significant reduction in multicomponent disability progression (44% vs 48%, OR 0.86, p=0.287)
- Natalizumab significantly reduced 9HPT (upper-limb) progression by 44% (15% vs 23%, OR 0.56, p=0.001)
- No treatment effect on EDSS (OR 1.06, p=0.753) or T25FW (OR 0.98, p=0.914) ambulatory components
- Enrolled predominantly non-relapsing SPMS patients: 84% relapse-free in year before baseline, 71% relapse-free in 2 years before baseline
- Majority had advanced disability: 63% had EDSS 6.0-6.5 (requiring walking aid)
- Effect on upper-limb function occurred regardless of baseline Gd+ lesions or recent relapses
- Open-label extension (part 2) showed nominally significant benefit on multicomponent endpoint with longer treatment
- No progressive multifocal leukoencephalopathy (PML) occurred
- Two deaths in part 1, neither related to study treatment
Study Design
- Study Type
- Phase 3, randomized, double-blind, placebo-controlled trial with open-label extension
- Randomization
- Yes
- Blinding
- Double-blind in part 1; patients and study staff masked to treatment assignments; only pharmacists preparing infusion were unmasked; masking maintained through open-label extension regarding original allocation
- Sample Size
- 887
- Follow-up
- 96 weeks (part 1); median 157-160 weeks total including open-label extension
- Centers
- 163
- Countries
- Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Ireland, Israel, Italy, Netherlands, Poland, Russia, Spain, Sweden, UK, USA
Primary Outcome
Definition: Proportion of patients with confirmed disability progression on multicomponent endpoint (≥1.0 point increase on EDSS from baseline ≤5.5 or ≥0.5 point from baseline ≥6.0; OR ≥20% increase on T25FW; OR ≥20% increase on 9HPT either hand), confirmed at ≥6 months and at week 96
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 214/448 (48%) | 195/439 (44%) | 0.86 (0.66-1.13) | 0.287 |
Limitations & Criticisms
- Primary endpoint NOT met - trial considered negative for its primary objective
- Part 2 results are limited by open-label design and nominal significance only (no multiplicity adjustment)
- Early termination of part 2 before planned 2 years due to negative part 1 results
- Higher than expected dropout rate (28% vs predicted 20%)
- Enrolled population had advanced disability (63% EDSS 6.0-6.5), limiting sensitivity to detect ambulatory changes
- Two of three multicomponent endpoint measures focus on lower-limb/ambulatory function
- EDSS has poor responsiveness to disease progression in patients with high baseline scores
- Selection bias possible for part 2 participants, though baseline characteristics were similar
- Potential pseudoatrophy affecting brain volume measures in patients initiating natalizumab in part 2
- Benefits restricted to upper-limb function may not be sufficient for regulatory approval
Citation
Lancet Neurol 2018;17:405-415