Randomized Placebo-Controlled Phase 2 Study of Extended-Release Ketamine Tablets (R-107) for Treatment-Resistant Depression – the BEDROC Study

Abstract

Abstract Ketamine has rapid-onset antidepressant activity in patients with treatment-resistant major depression (TRD). The safety and tolerability of racemic ketamine may be improved if given orally, as an extended release tablet (R-107), compared with other routes of administration. In this phase 2 multicentre clinical trial, adult patients with TRD and Montgomery-Asberg Depression Rating Scale (MADRS) scores >20 received open label R-107 tablets 120mg/day for 5 days and were assessed on Day 8 (enrichment phase). On Day 8, responders (MADRS scores <12 and reduction >50%) were randomized on a 1:1:1:1:1 basis to receive double-blind R-107 doses of 30, 60, 120, or 180mg, or placebo, twice weekly for a further 12 weeks. Non-responders on Day 8 exited the study. The primary endpoint was least square mean change in MADRS for each active treatment compared with placebo at 13 weeks, starting with the 180mg dose, using a fixed sequence step-down closed test procedure. Between August 2016 and April 2020, 329 individuals were screened for eligibility, 231 entered the open label enrichment phase (Days 1-8), and 168 responders were randomized to double-blind treatment. The primary objective was met; the least square mean difference of MADRS score for the 180mg tablet group and placebo was -6.1 (95% CI 1.0-11.16, p=0·019) at 13 weeks. Relapse rates during double-blind treatment showed a dose-response, from 70.6% for placebo, to 42.9% for 180mg. Tolerability was excellent, with no changes in blood pressure, minimal reports of sedation, and minimal dissociation. The most common adverse events were headache, dizziness and anxiety. During the randomised phase of the study most patient dosing occurred at home. R-107 tablets were effective, safe and well-tolerated in a patient population with TRD, enriched for initial response to R-107 tablets. Clinical Trial Registration ACTRN12618001042235.