Table 6.
Human safety and efficacy: phase 1 and phase 2 studies with esmethadone
| Author (year) and study title | Study design | Sample size (age group) | Treatment groups and duration | Objective | Results | |
|---|---|---|---|---|---|---|
| Bernstein et al. (2019) Characterization of the safety and pharmacokinetic profile of D-methadone, a novel N-methyl-D-aspartate receptor antagonist in healthy, opioid-naïve subjects | Two phase 1, double-blind, randomized, placebo-controlled single ascending dose (SAD) and multiple ascending dose (MAD) studies | Phase 1 SAD | 42 healthy subjects (18–55 years) | A total of 31 subjects received esmethadone, and a total of 11 subjects received placebo | Safety and tolerability of esmethadone compared to placebo | Single doses of 5 mg, 20 mg, 60 mg, 100 mg, and 150 mg of esmethadone and daily doses up to 75 mg for 10 days were well tolerated, with mostly mild treatment-emergent adverse events and no severe or serious adverse events |
| In each cohort (5 mg, 20 mg, 60 mg, 100 mg, 150 mg), eight subjects were randomly assigned to receive placebo (n = 2) or esmethadone (n = 6), except for 200 mg cohort (placebo n = 1; REL-1017 n = 1) | ||||||
| Single oral dose | ||||||
| Phase 1 MAD | 24 healthy subjects (18–55 years) | A total of 18 subjects received esmethadone, and a total of six subjects received placebo | To determine pharmacokinetic parameters | The maximum tolerated dose was 150 mg due to nausea and vomiting. There were no clinically meaningful opioid or psychotomimetic effects and no QTc-related adverse events | ||
| In each cohort (25 mg, 50 mg, 75 mg), eight subjects were randomly assigned to receive placebo (n = 2) or esmethadone (n = 6) | ||||||
| Daily oral dose for 10 days | ||||||
| Fava et al. (2022) REL-1017 (esmethadone) as adjunctive treatment in patients with major depressive disorder: a phase 2a randomized double-blind trial | Phase 2, double-blind, randomized, placebo-controlled study to assess efficacy and safety of two dosages of esmethadone, 25 mg and 50 mg, in patients with MDD experiencing a major depressive episode (MDE) with inadequate response to one to three courses of antidepressant treatment | 62 adults (18–65 years) with MDD experiencing a current MDE and inadequate response to one to three courses of antidepressant treatment | Twenty-two patients received placebo | Safety, tolerability, and pharmacokinetic (PK) evaluations | No psychotomimetic or opioid effects. No evidence of withdrawal. No adverse events (AEs) related to QTc prolongation | |
| Nineteen patients received 25 mg esmethadone (75 mg loading dose on day 1) | ||||||
| Twenty-one patients received 50 mg esmethadone (100 mg loading dose on day 1) | Efficacy outcomes (changes in MADRS, CGI-I, SDQ scores compared to placebo) | Esmethadone showed efficacy at day 4 that was sustained up to day 14. The effect size ranged from 0.7 to 1.1 | ||||
| Treatment and duration: single daily oral dose for 7 days | ||||||