Journal of psychiatric research · 2026
A novel, experimental design to assess rapid antidepressant action: Results from a phase 1b randomized trial of NV-5138.
СтатьяРандомизированное исследованиеКлиническое исследование I фазыМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Targum Steven D, Sanacora Gerard, Formella Andrea E, Ceresoli-Borroni Gianpiera, Owen Randall
Аннотация
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 h and included daily centrally rated MADRS assessments and more frequent site-based 6-item Hamilton Depression Rating Scale (HAM-D6) assessments (5 assessments within 24 h following dosing).
RESULTS: Of 93 individuals screened, 47 received placebo run-in, and 32 were randomized. NV-5138-treated participants experienced significant HAM-D6 improvement at 4 and 12 h 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 h. At 12 h, 5 (31 %) participants receiving NV-5138 and none receiving placebo met HAM-D6 response criteria (50 % score reduction; P = .04). At 24 h, 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 other trials evaluating RAADs (ClinicalTrials.gov, NCT03606395).
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 h and included daily centrally rated MADRS assessments and more frequent site-based 6-item Hamilton Depression Rating Scale (HAM-D6) assessments (5 assessments within 24 h following dosing).
RESULTS: Of 93 individuals screened, 47 received placebo run-in, and 32 were randomized. NV-5138-treated participants experienced significant HAM-D6 improvement at 4 and 12 h 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 h. At 12 h, 5 (31 %) participants receiving NV-5138 and none receiving placebo met HAM-D6 response criteria (50 % score reduction; P = .04). At 24 h, 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 other trials evaluating RAADs (ClinicalTrials.gov, NCT03606395).