High-dose ubiquinol supplementation in multiple-system atrophy: a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial

Abstract

Background: Functionally impaired variants of COQ2, encoding an enzyme in biosynthesis of coenzyme Q10 (CoQ10), were found in familial multiple system atrophy (MSA) and V393A in COQ2 is associated with sporadic MSA. Furthermore, reduced levels of CoQ10 have been demonstrated in MSA patients.

Methods: This study was a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. Patients with MSA were randomly assigned (1:1) to either ubiquinol (1500 mg/day) or placebo. The primary efficacy outcome was the change in the unified multiple system atrophy rating scale (UMSARS) part 2 at 48 weeks. Efficacy was assessed in all patients who completed at least one efficacy assessment (full analysis set). Safety analyses included patients who completed at least one dose of investigational drug. This trial is registered with UMIN-CTR (UMIN000031771), where the drug name of MSA-01 was used to designate ubiquinol.

Findings: Between June 26, 2018, and May 27, 2019, 139 patients were enrolled and randomly assigned to the ubiquinol group (n = 69) or the placebo group (n = 70). A total of 131 patients were included in the full analysis set (63 in the ubiquinol group; 68 in the placebo group). This study met the primary efficacy outcome (least square mean difference in UMSARS part 2 score (-1.7 [95% CI, -3.2 to -0.2]; P = 0.023)). The ubiquinol group also showed better secondary efficacy outcomes (Barthel index, Scale for the Assessment and Rating of Ataxia, and time required to walk 10 m). Rates of adverse events potentially related to the investigational drug were comparable between ubiquinol (n = 15 [23.8%]) and placebo (n = 21 [30.9%]).

Interpretation: High-dose ubiquinol was well-tolerated and led to a significantly smaller decline of UMSARS part 2 score compared with placebo.

Funding: Japan Agency for Medical Research and Development.

Keywords: COQ2; Clinical trial; Disease-modifying therapy; Multiple system atrophy; Ubiquinol.

Fig. 1

Clinical trial flow chart. Eight patients underwent randomisation but discontinued the trial before receiving medication: six withdrew their consent and two did not meet the inclusion criteria of the primary endpoint of no more than a 3-point change in UMSARS part 2 score during the screening-observation period as defined in the second inclusion criteria before the administration of the investigational drug after the screening-observation period. Two patients underwent randomisation but withdrew their consent before the first efficacy assessment and were not included in the full analysis set. No patients were lost to follow-up in the full analysis set. The per protocol set (PPS) is defined as a population, where any of the following cases were excluded from the FAS: 1. Cases that did not meet the inclusion criteria, 2. Cases that met the exclusion criteria, 3. Cases that used prohibited concomitant drugs, 4. Cases with less than 80% medication compliance during the trial period, 5. Cases that had major protocol deviations, 6. Cases that did not start 1500 mg/day by Week 12, and 7. Cases in which plasma ubiquinol levels exceeded 1.98 μg/mL at Week 0.

Fig. 2

Primary and subgroup analyses. Panel A shows the results for the primary efficacy outcome, the least squares mean changes from the baseline to 48 weeks in the score on the unified multiple-system atrophy rating scale part 2 (UMSARS part 2; range, 0–56, with higher scores indicating more severe symptoms) in the ubiquinol and placebo groups, analyzed with a restricted maximum likelihood (REML)-based repeated measures (MMRM) approach in combination with the Newton–Raphson algorithm. The difference between the ubiquinol and placebo groups in the primary outcome was −1.9 (95% confidence interval, −3.1 to −0.6; P = 0.003). Bars represent 95% confidence intervals. The number of participants evaluated is indicated below the figure. Panel B shows the results for secondary efficacy outcome, the least squares mean changes from the baseline at 48 weeks in the scores of the Barthel index (scores range from 0 to 18, with higher scores indicating greater impairment) in the ubiquinol and placebo groups, analyzed with a REML-based MMRM approach in combination with the Newton–Raphson algorithm. Bars represent standard errors. The number of participants evaluated is indicated below the figure. P-value in the Barthel index is not corrected for multiple comparison. Panel C shows forest plots of the difference in the change of UMSARS part 2 score from the baseline at 48 weeks between the ubiquinol and placebo groups in the full analysis set, stratified by disease subtype (MSA-C or MSA-P), presence or absence of the V393A variant in COQ2, above or below the median of the baseline UMSARS part 2 score, gender (male or female), above or below the median of age, and above or below the median of duration of disease. For each subgroup, the MMRM model used in the primary efficacy outcome analysis was added to the treatment group × each subgroup to calculate the P-value of the interaction.