Pridopidine for the treatment of motor function in patients with Huntington's disease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlled trial

Background: Huntington's disease is a progressive neurodegenerative disorder, characterised by motor, cognitive, and behavioural deficits. Pridopidine belongs to a new class of compounds known as dopaminergic stabilisers, and results from a small phase 2 study in patients with Huntington's disease suggested that this drug might improve voluntary motor function. We aimed to assess further the effects of pridopidine in patients with Huntington's disease.

Methods: We undertook a 6 month, randomised, double-blind, placebo-controlled trial to assess the efficacy of pridopidine in the treatment of motor deficits in patients with Huntington's disease. Our primary endpoint was change in the modified motor score (mMS; derived from the unified Huntington's disease rating scale) at 26 weeks. We recruited patients with Huntington's disease from 32 European centres; patients were aged 30 years or older and had an mMS of 10 points or greater at baseline. Patients were randomly assigned (1:1:1) to receive placebo, 45 mg per day pridopidine, or 90 mg per day pridopidine by use of centralised computer-generated codes. Patients and investigators were masked to treatment assignment. We also assessed the safety and tolerability profile of pridopidine. For our primary analysis, all patients were eligible for inclusion in our full analysis set, in which we used the last observation carried forward method for missing values. We used an analysis of covariance model and the Bonferroni method to adjust for multiple comparisons. We used a prespecified per-protocol population as our sensitivity analysis. The α level was 0·025 for our primary analysis and 0·05 overall. This trial is registered with ClinicalTrials.gov, number NCT00665223.

Findings: At 26 weeks, in our full analysis set the difference in mean mMS was -0·99 points (97·5% CI -2·08 to 0·10, p=0·042) in patients who received 90 mg per day pridopidine (n=145) versus those who received placebo (n=144), and -0·36 points (-1·44 to 0·72, p=0·456) in those who received 45 mg per day pridopidine (n=148) versus those who received placebo. At the 90 mg per day dose, in our per-protocol population (n=114), the reduction in the mMS was of -1·29 points (-2·47 to -0·12; p=0·014) compared with placebo (n=120). We did not identify any changes in non-motor endpoints at either dose. Pridopidine was well tolerated and had an adverse event profile similar to that of placebo.

Interpretation: This study did not provide evidence of efficacy as measured by the mMS, but a potential effect of pridopidine on the motor phenotype of Huntington's disease merits further investigation. Pridopidine up to 90 mg per day was well tolerated in patients with Huntington's disease.

Funding: NeuroSearch A/S.