A phase 2a randomised, double-blind, placebo-controlled, parallel-group, add-on clinical trial of ebselen (SPI-1005) as a novel treatment for mania or hypomania

Abstract

Rationale: Lithium is an effective prophylactic and anti-manic treatment in bipolar disorder; however, its use is declining through perceived poor tolerance and toxicity. Lithium inhibits inositol monophosphatase (IMPase), a probable key therapeutic mechanism. The anti-inflammatory drug, ebselen, also inhibits IMPase and appears well-tolerated and safe. Objectives: To assess the efficacy of adjunctive ebselen in mania using the Young Mania Rating Scale (YMRS) (primary outcome) and the Altman Self-Rating Mania (ASRM) Scale and Clinical Global Impression-Severity Scale (CGI-S) among the secondary outcomes. Methods: Randomised, double-blind, placebo-controlled, parallel-group trial conducted between October 2017 and June 2019, at Oxford Health NHS Foundation Trust. Pharmacy-controlled randomisation was computer-generated, with full allocation concealment. In/outpatients (n = 68) aged 18–70, experiencing mania or hypomania, were assigned to 3 weeks ebselen (600 mg bd) (n = 33) or placebo (n = 35). Participants received usual clinical care and psychotropic medication. Results: Ebselen was numerically, but not statistically, superior to placebo in lowering scores on the YMRS (adjusted mean difference and 95% confidence interval, − 1.71 (− 5.34 to 1.91), p = 0.35) and ASRM (− 1.36 (− 3.75 to 1.17), p = 0.29). However, scores on the CGI-S were significantly lower at week 3 in ebselen-treated participants (adjusted mean difference, − 0.58 (− 1.14 to − 0.03), p = 0.04). A post hoc analysis excluding patients taking concomitant valproate treatment magnified the difference between ebselen and placebo on the YMRS. Adverse events were comparable between groups, and mild. Conclusions: Ebselen merits further investigation where concomitant psychotropic medication is better controlled and participants taking valproate are excluded. If effective, ebselen’s superior tolerance and safety could make it a useful alternative to lithium. Trial registration: Trial Registry: www.clinicaltrials.gov, Identifier: NCT03013400.