Oral Prolonged-Release Ketamine for Treatment-Resistant Depression: Two Randomized Clinical Trials.

Abstract

Ketamine exerts rapid antidepressant effects. However, currently available ketamine-based treatments are associated with dissociative and cardiovascular adverse effects. To evaluate the antidepressant efficacy and tolerability of KET01, a novel, oral, prolonged-release racemic ketamine tablet formulation. KET01-03 was an active-comparator, double-blind, double-dummy, crossover phase 1 randomized clinical trial (RCT) conducted among healthy adult male volunteers (aged ≥18 years) between July and August 2023 at a single trial site in Germany. KET01-02 was a placebo-controlled, double-blind phase 2 RCT conducted between May 2022 and May 2023 among adult outpatients (aged ≥18 years) with treatment-resistant depression across 29 trial sites in the Czech Republic, Germany, and Poland. KET01-02 data were analyzed from May to October 2023 and KET01-03 data from August to October 2024. KET01-03 investigated a single dose of KET01 (240 mg) vs intranasal esketamine (84 mg), and KET01-02 evaluated KET01 dosages of 120 or 240 mg/d (adjunctive to ongoing standard therapy) against placebo for 3 weeks. The primary end points were the difference in mean maximum change in Clinician-Administered Dissociative States Scale (CADSS) score between KET01 and intranasal esketamine within the first 24 hours in KET01-03 and the least squares (LS) mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 21 for 240 mg/d of KET01 vs placebo in KET01-02. KET01-03 randomized 26 males (median age, 32 years [range, 21-45 years]), and KET01-02 randomized 122 outpatients with treatment-resistant depression (72 [59.0%] female; median age, 41 years [range, 19-65 years]). In KET01-03, intranasal esketamine but not KET01 induced significant dissociation within 24 hours after dosing (mean [SD] maximum change in CADSS score, 29.6 [12.5] points vs 0.7 [1.7] points; P < .001). The maximum plasma concentration was lower for KET01 (39.1 ng/mL) than esketamine (104.1 ng/mL); conversely, exposure to metabolites was higher for KET01 (eg, area under the curve [AUC] from baseline to last measurement for norketamine was 3.5 µg × h/mL) than esketamine (AUC for [S]-norketamine, 1.4 µg × h/mL). Pulse and blood pressure did not change markedly in the KET01 group in both trials, in contrast to rapid increases after intranasal esketamine in KET01-03. In KET01-02, the primary efficacy end point at day 21 was not met: LS mean MADRS score difference for 240 mg/d of KET01 vs placebo was -1.82 points (95% CI, -6.21 to 2.57 points; P = .41). However, a reduction in MADRS scores was observed 7 hours after administering the first 240 mg dose of KET01, with an LS mean difference vs placebo at day 4 (-3.66 [95% CI, -6.74 to -0.59] points; nominal P = .02) and day 7 (-3.95 [95% CI, -7.75 to -0.15] points; nominal P = .04). During follow-up, the LS mean MADRS point difference vs placebo at 4 weeks was -3.35 (95% CI, -7.62 to 0.93; nominal P = .13). The antidepressant properties and tolerability profile of KET01 in these RCTs, including minimal dissociation and cardiovascular effects, support further development of oral KET01 formulation for at-home administration. EU Clinical Trials Register Identifiers: 2023-503971-45-00 and 2021-004927-34.