Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS

Abstract

Objective: To examine the safety and tolerability as well as the preliminary efficacy of arimoclomol, a heat shock protein co-inducer that promotes nascent protein folding, in patients with rapidly progressive SOD1 amyotrophic lateral sclerosis (ALS).

Methods: This was a double-blind, placebo-controlled trial in which patients with rapidly progressive SOD1-mutant ALS were randomized 1:1 to receive arimoclomol 200 mg tid or matching placebo for up to 12 months. Study procedures were performed using a mix of in-person and remote assessments. Primary outcome was safety and tolerability. Secondary outcome was efficacy, with survival as the principal measure. Additional efficacy measures were the rates of decline of the Revised ALS Functional Rating Scale (ALSFRS-R) and percent predicted forced expiratory volume in 6 seconds (FEV6), and the Combined Assessment of Function and Survival (CAFS).

Results: Thirty-eight participants were randomized. Thirty-six (19 placebo, 17 arimoclomol) were included in the prespecified intent-to-treat analysis. Apart from respiratory function, groups were generally well-balanced at baseline. Adverse events occurred infrequently, and were usually mild and deemed unlikely or not related to study drug. Adjusting for riluzole and baseline ALSFRS-R, survival favored arimoclomol with a hazard ratio of 0.77 (95% confidence interval [CI] 0.32-1.80). ALSFRS-R and FEV6 declined more slowly in the arimoclomol group, with treatment differences of 0.5 point/month (95% CI -0.63 to 1.63) and 1.24 percent predicted/month (95% CI -2.77 to 5.25), respectively, and the CAFS similarly favored arimoclomol.

Conclusions: This study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. Although not powered for therapeutic effect, the consistency of results across the range of prespecified efficacy outcome measures suggests a possible therapeutic benefit of arimoclomol.

Clinicaltrialsgov identifier: NCT00706147.

Classification of evidence: This study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. The study lacked the precision to conclude, or to exclude, an important therapeutic benefit of arimoclomol.

Figure 1. Consort diagram

There were 2 patients in the arimoclomol group who were excluded from the intent-to-treat (ITT) analysis based on prespecified criteria: 1 patient died before completion of the month 1 visit; the other was found, after randomization, not to have a mutation in the SOD1 gene. The 1 patient in the arimoclomol group who was censored at month 5 had stopped drug at month 2 because of a skin rash thought probably related to study drug, and was then followed until month 5, when the participant enrolled in another clinical trial. PAV = permanent assisted ventilation.

Figure 2. Permanent assisted ventilation (PAV)– and tracheostomy-free survival

(A) All arimoclomol- and placebo-treated participants. At 12 months, 34% of arimoclomol-treated and <21% of placebo-treated participants were alive (and without PAV or tracheostomy). (B) The subgroup of A4V participants. At 12 months, 29% of arimoclomol-treated and 15% of placebo-treated participants were alive (and without PAV or tracheostomy).