Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials

Abstract

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal motor neuron disease. We carried out two randomized, double-blind, placebo-controlled, multi-centre, multi-national studies with xaliproden (a drug with neurotrophic effect) to assess drug efficacy and safety at two doses. Patients with clinically probable or definite ALS of more than 6 months and less than 5 years duration were randomly assigned to placebo, 1 mg or 2 mg xaliproden orally once daily as monotherapy in Study 1 (n=867); or to the same regimen with addition of riluzole 50 mg bid background therapy in Study 2 (n=1210 patients). The two primary endpoints were defined as: 1. Time to death, tracheostomy, or permanent assisted ventilation (DTP), and 2. Time to vital capacity (VC)<50% or DTP before (log-rank test) and after adjustment using a Cox proportional hazard model for prespecified prognostic factors. Secondary endpoints were rates of change of various functional measures. In Study 1, primary outcome measures did not reach statistical significance. For the 2 mg group, for time to VC<50% analysis (without DTP) a significant 30% RRR was obtained (95% confidence interval [CI]: 8.46, P=0.009). In Study 2, no significant results were obtained. However, there was a trend in favour of add-on 1 mg dose xaliproden vs. placebo (RRR 15% [-6.31, ns] for time to VC<50%; RRR 12% [CI: -6.27, ns] for time to VC<50% or DTP). Adjusted RR ratios were consistently more favourable for the xaliproden groups. Tolerability was good, and dose-dependent side effects were largely associated with the serotonergic properties of xaliproden. An effect of xaliproden on functional parameters, especially VC, was noted. Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS.

Being PRO-ACTive: What can a Clinical Trial Database Reveal About ALS?

“…Of the 27 trials, the data of 17 (63%) trials were donated, representing a mix of sources (industry, academic, and government-sponsored trials, including the Riluzole trials [13,14], lithium carbonate [15], creatine [16], celecoxib [17], topiramate [18], TCH-346 [19], brain-derived neurotrophic factor [20], ciliary neurotrophic factor [21], xaliproden [22], talampanel [23], arimoclomol [24], and gabapentin [25]). A full list of trials is available by referring to Attasi et al [26].…”

Amyotrophic Lateral Sclerosis: An Introduction to Treatment and Trials

“…AVP-923 was tested in two phase III trials in ALS patients with pseudobulbar affect (PBA), which is characterized by emotional dysregulation, such as uncontrollable outbursts of laughing or crying that are inappropriate to the emotions being experienced (Garnock-Jones, 2011;Olney & Rosen, 2010). The study showed that AVP-923 ameliorates symptoms of PBA in ALS patients and improved quality of life and quality of relationships (Brooks et al, 2004).…”

“…It has been evaluated in phase II/III trials, which showed modest effects on vital capacity, but not on survival of ALS patients Meininger et al, 2004).…”

Practice Parameter update: The care of the patient with amyotrophic lateral sclerosis: Drug, nutritional, and respiratory therapies (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology

“…The number needed to treat to delay 1 death until after 12 months was 11. However, 5 studies using large databases spanning 5 to 10 years have suggested that treatment with riluzole might be associated with a prolonged survival of 6 months (Class II), 7 10 months (Class III), 8 12 months (Class III), 9 14 months (Class III), 10 or even 21 months (Class III). 11 These cohort studies had longer-term follow-up than the clinical trials, but are subject to greater bias.…”