EPIDYS
Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS)
Clinical Question
Does givinostat slow disease progression in ambulant boys with DMD on corticosteroids?
Study Overview
Objective
To evaluate the safety and efficacy of givinostat in ambulant boys with Duchenne muscular dystrophy on corticosteroids
Study Summary
- Primary analysis in 120 boys (Group A) showed significant reduction in disease progression on four-stair climb test (ratio 0.86, p=0.035)
- Givinostat is the first HDAC inhibitor to demonstrate efficacy in a Phase 3 DMD trial
Intervention
Givinostat oral twice daily (weight-based dosing) vs placebo
Patients per Arm
118 givinostat, 61 placebo; Group A: 81 givinostat, 39 placebo
Bottom Line
Givinostat significantly slowed disease progression on four-stair climb test over 72 weeks (ratio 0.86, p=0.035) in boys with intermediate vastus lateralis fat fraction (Group A). First HDAC inhibitor to show efficacy in a Phase 3 DMD trial.
Major Points
- Phase 3, multicenter, double-blind, placebo-controlled RCT of givinostat (an HDAC inhibitor) in ambulant boys with genetically confirmed DMD on corticosteroids; 179 randomized 2:1 (118 givinostat, 61 placebo) across 41 sites in 11 countries.
- Primary endpoint was change in the four-stair climb assessment from baseline to 72 weeks, analyzed in the intention-to-treat Group A population (baseline vastus lateralis fat fraction >5% but ≤30%; n=120: 81 givinostat, 39 placebo).
- Four-stair climb time worsened in both arms but the decline was significantly smaller with givinostat: geometric LSM ratio 1.27 (95% CI 1.17-1.37) vs placebo 1.48 (1.32-1.66); ratio 0.86 (95% CI 0.745-0.989; p=0.035).
- Most common adverse events with givinostat were diarrhea (43/118, 36% vs 11/61, 18%) and vomiting (34/118, 29% vs 8/61, 13%); no treatment-related deaths occurred.
- Starting dose of givinostat was reduced following a protocol amendment after an interim safety analysis; no new safety signals were reported.
- Sample size was adaptively re-estimated using masked four-stair climb data after the first 50 Group A boys completed 12 months of treatment.
- First HDAC inhibitor to demonstrate slowing of motor decline in a Phase 3 DMD trial; an extension study is ongoing for long-term safety and efficacy.
- Registered as NCT02851797; funded by Italfarmaco.
Design
Study Type: Phase 3 randomized controlled trial
Randomization: 1
Blinding: Double-blind
Enrollment Period: June 2017 to February 2022
Follow-up Duration: 72 weeks
Centers: 41
Countries: Multiple (11 countries)
Sample Size: 179
Analysis: Intention-to-treat, Group A population (primary)
Inclusion Criteria
- Ambulant males >=6 years
- Genetically confirmed DMD
- Four-stair climb <=8 seconds
- Time-to-rise >=3 and <10 seconds
- Corticosteroids >=6 months
Arms
| Field | Givinostat | Control |
|---|---|---|
| Intervention | Givinostat oral twice daily, weight-based dosing | Matching placebo oral twice daily |
| Duration | 72 weeks | 72 weeks |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Change in four-stair climb from baseline to 72 weeks (Group A) | Primary | Geometric LSM ratio 1.48 (95% CI 1.32-1.66) | Geometric LSM ratio 1.27 (95% CI 1.17-1.37) | 0.035 | |
| Diarrhea | Adverse | 11/61 (18%) | 43/118 (36%) | ||
| Vomiting | Adverse | 8/61 (13%) | 34/118 (29%) |
Subgroup Analysis
Primary analysis limited to Group A (vastus lateralis fat fraction >5% and ≤30%)
Criticisms
- Primary analysis on subgroup (Group A) rather than full ITT
- Protocol amendment reduced dose mid-trial
- GI side effects may have unblinded some participants
- 359 screened to analyze only 120 patients
Funding
Italfarmaco
Based on: EPIDYS (Lancet Neurology, 2024)
Authors: Mercuri E, Vilchez JJ, Boespflug-Tanguy O, ..., McDonald CM; EPIDYS Study Group
Citation: Mercuri E et al. Lancet Neurol. 2024 Apr;23(4):393-403. DOI: 10.1016/S1474-4422(24)00036-X. PMID: 38508835. NCT02851797
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