Elsevier

The Lancet Neurology

Volume 12, Issue 11, November 2013, Pages 1059-1067
The Lancet Neurology

Articles
Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial

https://doi.org/10.1016/S1474-4422(13)70221-7Get rights and content

Summary

Background

In a phase 2 study, dexpramipexole (25–150 mg twice daily) was well tolerated for up to 9 months and showed a significant benefit at the high dose in a combined assessment of function and mortality in patients with amyotrophic lateral sclerosis. We aimed to assess efficacy and safety of dexpramipexole in a phase 3 trial of patients with familial or sporadic disease.

Methods

In our randomised, double-blind, placebo-controlled phase 3 trial (EMPOWER), we enrolled participants aged 18–80 years (with first amyotrophic lateral sclerosis symptom onset 24 months or less before baseline) at 81 academic medical centres in 11 countries. We randomly allocated eligible participants (1:1) with a centralised voice–interactive online system to twice-daily dexpramipexole 150 mg or matched placebo for 12–18 months, stratified by trial site, area of disease onset (bulbar vs other areas), and previous use of riluzole. The primary endpoint was the combined assessment of function and survival (CAFS) score, based on changes in amyotrophic lateral sclerosis functional rating scale–revised (ALSFRS-R) total scores and time to death up to 12 months. We assessed the primary endpoint in all participants who received at least one dose and had at least one post-dose ALSFRS-R measurement or died. We monitored adverse events in all participants. This study is registered with ClinicalTrials.gov, number NCT01281189.

Findings

Between March 28, 2011, and Sept 30, 2011, we enrolled 943 participants (474 randomly allocated dexpramipexole, 468 randomly allocated placebo, and one withdrew). Least-square mean CAFS scores at 12 months did not differ between participants in the dexpramipexole group (score 441·76, 95% CI 415·43–468·08) and those in the placebo group (438·84, 412·81–464·88; p=0·86). At 12 months, we noted no differences in mean change from baseline in ALSFRS-R total score (–13·34 in the dexpramipexole group vs −13·42 in the placebo group; p=0·90) or time to death (74 [16%] vs 79 [17%]; hazard ratio 1·03 [0·75–1·43]; p=0·84). 37 (8%) participants in the dexpramipexole group developed neutropenia compared with eight (2%) participants in the placebo group, and incidence of other adverse events was similar between groups.

Interpretation

Dexpramipexole was generally well tolerated but did not differ from placebo on any prespecified efficacy endpoint measurement. Our trial can inform the design of future clinical research strategies in amyotrophic lateral sclerosis.

Funding

Biogen Idec.

Introduction

Amyotrophic lateral sclerosis is a rapidly progressive disease that leads to debilitating upper and lower motor neuron dysfunction and death.1, 2 No cure exists for the disease at present. Only one approved therapy, riluzole, provides a modest effect on survival but no proven effect on muscle strength.3, 4, 5, 6, 7, 8

Although progress has been made in understanding the complex pathophysiology of amyotrophic lateral sclerosis, no unifying model of disease pathogenesis exists. Therefore, identification of therapeutic targets is a substantial challenge. Mitochondria are key energy producers for neurons and are implicated in several neurodegenerative diseases, including amyotrophic lateral sclerosis; thus, drugs that target mitochondria might be useful for treatment.9, 10, 11, 12, 13, 14

Dexpramipexole is thought to enhance mitochondrial function, is active in in-vitro assays of neuroprotection, and leads to increased rates of survival and retention of motor function in in-vivo models of amyotrophic lateral sclerosis.15, 16, 17 Dexpramipexole was assessed in a two-part phase 2 study in amyotrophic lateral sclerosis.18 In part 1 of the study (which provided participants 12 weeks of treatment), non-significant dose-dependent trends were noted toward a decrease in the slope of decline in amyotrophic lateral sclerosis functional rating scale–revised (ALSFRS-R) total score.18 In part 2 of the study (which provided participants 24 weeks of treatment at two doses, compared with three doses in part 1), a significant difference was reported (p=0·046) in a prespecified sensitivity analysis comparing a twice-daily regimen of dexpramipexole 150 mg and 25 mg using the combined assessment of function and survival (CAFS;18, 19 a joint-rank test based on mortality and change from baseline in ALSFRS-R total score).20 This study met the primary endpoint, which was safety, and dexpramipexole was generally well tolerated. The results from preclinical studies and favourable phase 2 results provided the rationale for further assessment of dexpramipexole in amyotrophic lateral sclerosis.

We aimed to assess efficacy and safety of twice-daily oral dexpramipexole 150 mg in participants with amyotrophic lateral sclerosis, with a null hypothesis that dexpramipexole was no better than placebo on the primary endpoint, the CAFS.

Section snippets

Study design and participants

In our double-blind, randomised, phase 3 study (EMPOWER), we enrolled adults aged 18–80 years with a diagnosis of possible, laboratory-supported probable, probable, or definite amyotrophic lateral sclerosis (familial or sporadic) in accordance with the revised El Escorial criteria.21 Participants were enrolled at 81 academic medical centres in Australia, Belgium, Canada, France, Germany, Ireland, the Netherlands, Spain, Sweden, the UK, and the USA. Eligible participants had onset of first

Results

We enrolled 943 participants between March 28, 2011, and Sept 30, 2011 (figure 1). Table 1 shows baseline charcteristics. Enrolment rates varied between participating study sites (0·25–6·45 participants per centre per month). The mean time from screening to baseline visit was 14·87 (range 1–28) days. Of 942 participants randomly allocated treatment and who received at least one dose of allocated drug, 632 (67%) completed the study treatment (figure 1). Most discontinuations from treatment in

Discussion

EMPOWER was a large phase 3 international study that assessed a novel outcome measure (the CAFS) to investigate the efficacy and safety of dexpramipexole in amyotrophic lateral sclerosis (panel). Although rare events of neutropenia and severe neutropenia were more common in dexpramipexole-treated participants, dexpramipexole was generally well tolerated but it was not efficacious compared with placebo on the primary endpoint or key secondary endpoints.

With the negative efficacy results of this

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