A novel, experimental design to assess rapid antidepressant action: Results from a phase 1b randomized trial of NV-5138

ABSTRACT BACKGROUND Assessment of rapid-acting antidepressants (RAADs) requires rating scales sensitive to symptomatic changes over short time frames (hours to days). An innovative trial design was employed in an exploratory, first-in-human, phase 1b trial assessing rapid-acting effects of NV-5138 (mefluleucine), an intracellular enhancer of mechanistic target of rapamycin 1 synaptic signaling, for treatment-resistant depression. METHODS This randomized, double-blind, placebo-controlled, multisite inpatient study used centrally rated Montgomery-Åsberg Depression Rating Scale (MADRS) assessments to confirm symptom stability before randomization during a 3-day placebo run-in. Qualifying participants were randomized to single doses of NV-5138 (2400 mg) or matching placebo. Safety and efficacy were assessed over 72 hours and included daily centrally rated MADRS assessments and more frequent site-based 6-item Hamilton Depression Rating Scale (HAM-D 6 ) assessments (5 assessments within 24 hours following dosing). RESULTS Of 93 individuals screened, 47 received placebo run-in, and 32 were randomized. NV-5138-treated participants experienced significant HAM-D 6 improvement at 4 and 12 hours post-dose (both P =.02) versus placebo. Effect sizes for NV-5138–treated participants ranged from −0.5 to −0.8 at all assessments within 24 hours. At 12 hours, 5 (31%) participants receiving NV-5138 and none receiving placebo met HAM-D 6 response criteria (50% score reduction; P =.04). At 24 hours, the MADRS favored NV-5138 but was not statistically different from placebo. NV-5138 was well tolerated, with no psychotomimetic, severe, or serious adverse events reported. CONCLUSIONS The innovative design of this exploratory study facilitated appropriate participant selection and rapid antidepressant response detection. These features may be useful in trials evaluating RAADs. ( ClinicalTrials.gov , NCT03606395)