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