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 ≥26 for the current MDE at all Screening visits and Baseline (Day 1). - CGI-S score of ≥4 (moderately ill or worse) at all Screening visits and Baseline. - History of inadequate response to ≥2 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, or vortioxetine. - 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 at any visit during the Screening Period. - Clinically significant abnormal laboratory profiles, vital signs, or electrocardiograms (ECGs), per Investigator judgment. - Judged by the Investigator to be at significant risk for suicide, violence, or homicide; or answers 'Yes' to items 4 or 5 on the Suicidal Ideation section of the C-SSRS at Screening or at Baseline; or has attempted suicide within the 6 months prior to Screening. - History of psychotic disorder, including but not limited to schizophrenia, MDD with psychotic features, or bipolar I/II disorder with psychotic features. - History of PTSD, OCD, panic disorder, intellectual disability, autism, acute stress disorder, or Cluster A or B personality disorder (per DSM-5 criteria). - Any condition or procedure that may interfere with the absorption, metabolism, or elimination of the study medication (e.g., cholecystectomy or gastric bypass). - In the Investigator's opinion, is unlikely to comply with the protocol or is unsuitable for any other reason. - History of alcohol and/or substance use disorder within 6 months prior to Screening or is currently using or has positive results at Screening for drugs of abuse or has a positive alcohol result at any Screening or Baseline visit.

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	Either 2 or 4 400 mg oral capsules administered once daily	Drug: NV-5138 NV-5138 is a novel, orally bioavailable, selective, direct activator of mTORC1 cellular signaling Other names: SPN820
Placebo Comparator matched placebo	2 or 4 oral capsules administered once daily	Drug: matched placebo matched placebo oral capsules Other names: placebo PBO

Samuel Schaffer, MD
240-403-5758
samuel.schaffer@premier-research.com

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