Anxiety & Depression Association of America

Phase 2 Study of NV-5138 in Adults With Treatment Resistant Depression

This study will evaluate the efficacy and safety of NV-5138 in adults with TRD

Male or female, aged 18 to 70 years at Screening. - Diagnosis of Major Depressive Disorder (MDD) according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) for either recurrent or single episode MDD without psychotic features that is confirmed by the Mini International Neuropsychiatric Interview (MINI). - Montgomery-Asberg Depression Rating Scale (MADRS) Total Score of ≥24 for the current MDE at all Screening visits and Baseline (Day 1). - CGI-S score of ≥4 (moderately ill or worse) at the Screening visits and Baseline. - History of inadequate response to ≥1 but ≤4 prior ADT therapies (including the current ADT for the current MDE) ≥ 2 weeks at Screening and ≥ 8 weeks at Baseline. - Stable therapeutic dose of one of the following ADTs for the current MDE for ≥2 weeks prior to Screening and maintain the therapeutic dose throughout the study: citalopram, escitalopram, paroxetine, fluoxetine, sertraline, duloxetine, venlafaxine (IR or XR), desvenlafaxine, vilazodone, levomilnacipran, vortioxetine, bupropion or dextromethorphan//bupropion. - Detectable blood level of the approved ADT at Visits 1 and 2 of the Screening Period.

MADRS Total Score improvement of ≥25% from the highest to the lowest score during the Screening Period and Baseline. - Clinically significant abnormal laboratory profiles, vital signs, or electrocardiograms (ECGs), per Investigator judgment. - Judged by the Investigator to be at significant risk for suicide or answers 'Yes' to items 4 or 5 on the Suicidal Ideation section of the C-SSRS in the 1 year before Screening; a history of suicide attempt in the last 2 years; or more than 2 lifetime suicide attempts. - History of psychotic disorder, including but not limited to schizophrenia, MDD with psychotic features, or bipolar I/II disorder with and without psychotic features. - Diagnosis within 12 months before Screening or current diagnosis of PTSD, OCD, panic disorder, intellectual disability, autism, acute stress disorder, or Cluster A or B personality disorder (per DSM-5 criteria). - History of substance use disorder within 6 months prior to Screening or currently using or had positive results (UDS) at Screening or Baseline for drugs of abuse. - History of alcohol and cannabis use disorder within 6 months prior to Screening and had a positive alcohol test at Baseline or a positive UDS for cannabis at Screening.

Phase: Phase 2
Study Type: Interventional
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: randomized, double-blind, placebo-controlled
Primary Purpose: Treatment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: matched placebo

Arm	Description	Assigned Intervention
Experimental NV-5138 400 mg oral capsules	Participants received either 800 or 1600 mg NV-5138 (2 or 4, 400 mg capsules) once daily for 4 weeks. During the first week of the Treatment Period, all participants took 1600 mg once a day. Participants who experienced an intolerable adverse effect at 1600 mg at Week 2, could have their dose reduced to 800 mg. Participants who had an inadequate response to 800 mg might have their dose increased again to 1600 mg per Investigator judgment to maximize their treatment response; however, no dose adjustments were allowed after Week 3. The dose at Week 4 was the same as stable dose at Week 3. After completion of the 4-week treatment, all participants received placebo in a double-blinded fashion and continued the treatment for one week.	Drug: NV-5138 NV-5138 is a novel, orally bioavailable, selective, direct enhancer of mTORC1 cellular signaling Other names: SPN820
Placebo Comparator matched placebo	Participants received either 2 or 4 capsules of placebo once daily for 5 weeks.	Drug: matched placebo matched placebo oral capsules Other names: placebo PBO

The is a multicenter, randomized, double-blind, flexible- dose, placebo-controlled, parallel design of adjunctive NV-5138 in adults with TRD.