Efficacy and Safety of MK-1942 When Added to Stable Antidepressant Therapy in Participants With Treatment-Resistant Depression (TRD) (MK-1942-006)

Study Overview
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Brief Summary
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The main purpose of this study is to assess the efficacy and safety of daily and intermittent dosing of MK-1942 compared to placebo among participants with Treatment-Resistant Depression (TRD) on a stable course of antidepressant therapy. The dual primary hypotheses of the study are that the daily MK-1942 treatment and/or intermittent MK-1942 treatment are superior to placebo in reducing Montgomery-Asberg Depression Rating Scale (MADRS) score.

Official Title
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A Phase 2a, Randomized, Placebo-Controlled Clinical Study to Evaluate the Efficacy and Safety of MK-1942 Added to Stable Antidepressant Therapy in Participants With Treatment-Resistant Depression

Conditions
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Treatment Resistant Depression

Intervention / Treatment
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* Drug: MK-1942
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meets the diagnostic criteria for moderate-to-severe major depressive disorder (MDD) without psychotic features according to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria at Visit 1 (Screening) Is currently experiencing an episode of moderate-to-severe MDD Had an inadequate response to 1 to 4 different courses of antidepressant therapy for the current episode of moderate-to-severe MDD Has been on a stable course of antidepressant therapy for ≥4 weeks before Visit 1 (Screening) Has not initiated psychotherapy for depressive symptoms in the last 3 months before Visit 1 (Screening) and agrees not to initiate a new psychotherapy for depressive symptoms or to modify their current regimen of psychotherapy for depressive symptoms from Visit 1 (Screening) to Visit 9 (Post-dose Follow-up Visit) Male participants are eligible if they agree to the following during the intervention period and for at least 7 days after last dose of study intervention: Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent or agrees to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) A female participant is eligible to participate if she is not a woman of childbearing potential (WOCBP) or a WOCBP who is not pregnant, breastfeeding, or within 3 months from postpartum. WOCBP should use contraceptive methods that are highly effective as per the study specifications or be abstinent from heterosexual intercourse as their preferred and usual lifestyle, have a negative pregnancy test at screening, immediately prior to the first dosing event, and at regular intervals during the study period, and abstain from breastfeeding during the study intervention period and for at least 7 days after last study intervention Has a reliable contact person Exclusion Criteria: Has an ongoing episode of MDD that started more than 2 years before Visit 1 (Screening) Has a current or prior history of one or more of the following: a) diagnosis of a psychotic disorder b) chronic convulsive disorder, except febrile seizures during childhood c) neurodegenerative disorder, traumatic brain injury causing ongoing cognitive difficulties, or any chronic organic disease of the central nervous system d) intellectual disability of a severity that would affect the ability of the participant to participate in the study e) bipolar and related disorders, MDD with psychosis f) MDD with mixed features g) posttraumatic stress disorder if not in remission for at least 5 years before Visit 1 (Screening) h) obsessive-compulsive disorder i) autism spectrum disorder Meets criteria for substance abuse or dependence disorder currently or within the 12 months before Visit 1 (Screening) Has a known allergy or intolerance to the active or inert ingredients in MK-1942 Has a history of malignancy ≤3 years before Visit 1 (Screening) except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer Has a Body Mass Index (BMI) >40 kg/m2 Has HIV or nonstable hypothyroidism, diabetes, cardiovascular disease, or respiratory disease Failed to adequately respond to treatment with ketamine or esketamine for the current or a prior episode of MDD Previously received electroconvulsive therapy within the past 10 years, deep brain stimulation, or vagal nerve stimulation for treatment of depression Is imminent risk for self harm or harm to others Is currently participating in or has previously participated in an interventional clinical study within the 2 months before Visit 1 (Screening), or has participated in >4 interventional clinical studies within the 2 years before Visit 1 (Screening) Has known renal disease or is experiencing renal insufficiency Routinely consumes >3 alcoholic drinks per day. One standard drink is defined as any beverage containing 14 gram (g) of pure alcohol Requires use of a language interpreter to participate in the study Had major surgery or donated or lost >1 unit of blood within the 4 weeks before Visit 1 (Screening) Is pregnant or is currently breastfeeding or plans to breastfeed during the course of the study Is a woman with <12 months of amenorrhea and is receiving hormone replacement therapy (HRT) or an estrogen-based contraceptive Is or has an immediate family member who is investigational site or Sponsor staff directly involved with this study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-1942 Daily Dose Group<br>Participants receive a total daily dose titrated from 5 mg to 20 mg of MK-1942 twice daily (BID), orally, over 4 weeks of treatment duration: 5 mg in Week 1, 10 mg in Week 2, and 20 mg in Weeks 3 and 4. Participants receive MK-1942 and matching placebo packaged in blister cards with an equal number of capsules administered in the morning and evening regardless of treatment assignment. | Drug: MK-1942<br>* MK-1942 (5 mg or 10 mg capsules) titrated from 5 mg to 20 mg dose BID or 10 mg BIW over 4 weeks.<br>Drug: Placebo<br>* Dose matched placebo capsules BID orally over 4 weeks.<br>|
| Experimental: MK-1942 Intermittent Dose Group<br>Participants receive a total daily dose of 10 mg of MK-1942 twice weekly (BIW), orally, for Weeks 1-4. Participants receive MK-1942 and matching placebo packaged in blister cards with an equal number of capsules administered in the morning and evening regardless of treatment assignment. | Drug: MK-1942<br>* MK-1942 (5 mg or 10 mg capsules) titrated from 5 mg to 20 mg dose BID or 10 mg BIW over 4 weeks.<br>Drug: Placebo<br>* Dose matched placebo capsules BID orally over 4 weeks.<br>|
| Placebo Comparator: Placebo<br>Participants receive a dose-matched placebo BID, orally, for 4 weeks. Participants receive matching placebo packaged in blister cards with an equal number of capsules administered in the morning and evening regardless of treatment assignment. | Drug: Placebo<br>* Dose matched placebo capsules BID orally over 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score to Week 3 | The 10-item MADRS scale will be used to evaluate the severity of depressive symptoms. Participants receiving daily dose of MK-1942 will be rated on 10 items, rated on a scale from 0 (normal, no symptom) to 6 (symptoms of maximum severity) with total scores ranging from 0 (normal/no symptom) to 60 (severe depression). Higher scores correspond to greater symptom severity. A negative change score indicates improvement. The longitudinal analysis of covariance (ANCOVA) model will be used to report the mean change from baseline in the MADRS total score to Week 3. | Baseline, Week 3 | 
| Change From Baseline in MADRS Total Score to Week 1 | The 10-item MADRS scale will be used to evaluate the severity of depressive symptoms. Participants receiving intermittent dose of MK-1942 will be rated on 10 items, rated on a scale from 0 (normal, no symptom) to 6 (symptoms of maximum severity) with total scores ranging from 0 (normal/no symptom) to 60 (severe depression). Higher scores correspond to greater symptom severity. A negative change score indicates improvement. The longitudinal analysis of covariance (ANCOVA) model will be used to report the mean change from baseline in the MADRS total score to Week 1. | Baseline, Week 1 | 
| Number of Participants Who Experienced An Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to approximately 6 Weeks | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to approximately 4 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Hamilton Depression Rating Scale (HAM-D17) Total Score to Week 3 | The 17 item HAM-D17 scale will be used to evaluate the depressive symptoms experienced over the past week among participants who received daily dose of MK-1942. Participants will be rated using 17 individual items. Each item is rated on a scale from 0 to 2 or 0 to 4 reflective of severity (0 being absence of symptom and higher scores being more severe), with total scores ranging from 0 (no apparent symptoms) to 52 (most severe symptoms). Higher scores correspond to greater symptom. A negative change score indicates improvement. The longitudinal ANCOVA model will be used to report the mean change from baseline in HAM-D17 total score to Week 3. | Baseline, Week 3 | 
| Change From Baseline in the HAM-D17 Scale Total Score to Week 1 | The 17 item HAM-D17 scale will be used to evaluate the depressive symptoms experienced over the past week among participants who received intermittent dose of MK-1942. Participants will be rated using 17 individual items. Each item is rated on a scale from 0 to 2 or 0 to 4 reflective of severity (0 being absence of symptom and higher scores being more severe), with total scores ranging from 0 (no apparent symptoms) to 52 (most severe symptoms). Higher scores correspond to greater symptom severity. A negative change score indicates improvement. The longitudinal ANCOVA model will be used to report the mean change from baseline in HAM-D17 total score to Week 1. | Baseline, Week 1 | 
| Change From Baseline in the Clinician Global Impression-Severity (CGI-S) Total Score to Week 3 | A single-item CGI-S scale will be used to assess the severity of depression among participants who received daily dose of MK-1942. The CGI-S is rated on a 7-point scale using a range of responses from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). Higher score corresponds to greater symptom severity. A negative change score indicates improvement. The longitudinal ANCOVA model will be used to report the mean change from baseline in CGI-S score to Week 3. | Baseline, Week 3 | 
| Change From Baseline in the CGI-S Total Score to Week 1 | A single-item CGI-S scale will be used to assess the severity of depression among participants who received intermittent dose of MK-1942. The CGI-S is rated on a 7-point scale using a range of responses from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). Higher score corresponds to greater symptom severity. A negative change score indicates improvement. The longitudinal ANCOVA model will be used to report the mean change from baseline in CGI-S score to Week 1. | Baseline, Week 1 | 
| Mean Plasma Concentration of MK-1942 plasma concentration | Blood samples will be collected at predetermined predose and postdose specified timepoints to report the mean plasma concentration of MK-1942 at prespecified timepoints. | Week 0 (Day 1): Predose and 1-hour postdose and Weeks 1, 2, 3 & 4: Predose |