An Active-Controlled Early Phase Study of MK-8189 in Adults With Schizophrenia (MK-8189-005)

Study Overview
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Brief Summary
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This will be a randomized, placebo-controlled, parallel-group, multi-site, double-blind trial of MK-8189 compared with placebo, using Risperidone as an active control. The participants will be adult subjects experiencing an acute episode of schizophrenia, according to the criteria specified in the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5). This study will be up to 7 weeks in duration, with up to 7 site visits for each participant. The study will consist of a Screening/tapering period (up to one week long), a 4-week treatment period, and a 14-day follow-up period. The primary objective will be to assess symptoms of schizophrenia at 4 weeks, and to assess safety and tolerability during treatment and post-treatment follow-up. The secondary objective will be to assess the severity of schizophrenia at 4 weeks. The primary hypothesis is that MK-8189 is superior to placebo in reducing the overall symptoms of schizophrenia as assessed by the mean change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score after 4 weeks of treatment.

Official Title
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A Phase IIa, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of the Efficacy and Safety of MK-8189 Using Risperidone as an Active Control in Subjects Experiencing an Acute Episode of Schizophrenia

Conditions
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Schizophrenia, Acute Episode

Intervention / Treatment
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* Drug: MK-8189
* Drug: Risperidone
* Drug: Placebo matching MK-8189
* Drug: Placebo matching risperidone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 50 years of age at Screening Male Female not of reproductive potential (e.g., postmenopausal or has had a hysterectomy), or agrees to practice abstinence or use acceptable contraception Meets the diagnostic criteria for schizophrenia according to the DSM-5 criteria, or has a past diagnosis of schizophrenia with the onset of the first episode being >=1 year prior to study entry, and has illness duration of <=20 years Is confirmed to be experiencing an acute episode of schizophrenia Minimum PANSS score >= 80 at Screening Has a score of >=4 in 3 or more of the following items (delusions, conceptual disorganization, hallucinatory behavior, grandiosity, suspiciousness/persecution) in the positive subscale of the PANSS at Screening Has a CGI-S score >= 4 at Screening Is able to taper off psychotropic medications without significant destabilization or increased suicidality Has responded positively to an antipsychotic medication other than clozapine in a prior psychotic episode Has an identified responsible external contact person who has regular contact (no less than once per week) with the participant Exclusion Criteria: Is currently under involuntary commitment because he/she is considered a danger to himself/herself or others Is unwilling to remain hospitalized for the duration of trial treatment Is currently participating in or has participated in an interventional clinical research study <=6 months prior to Screening, or has participated in more than one interventional clinical trial research study within 12 months prior to Screening Is unwilling to allow audio/video taping of the Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders (MINI) and/or PANSS interview at Screening and Baseline Is currently being treated with and benefiting from medications with a moderate or strong inhibiting or inducing effect on Cytochrome P450 (CYP) 3A and/or CYP2C9 and/or sensitive substrates of CYP2B6 Has a history of malignancy <= 5 years except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer Has a body mass index <18.5 or >40 kg/m˄2 Has a history of treatment-resistant schizophrenia Has a prolactin laboratory value of >= 5 times the upper limit of normal at Screening Has a known history or clinical evidence of clinically significant hepatic, cardiovascular, or renal disease, or of untreated narrow-angle glaucoma- Has ever been diagnosed with epilepsy or had any seizure disorder beyond one childhood febrile seizure Has known serological evidence of human immunodeficiency virus (HIV) antibody Has a history of neuroleptic malignant syndrome Has a current diagnosis other than schizophrenia, or a comorbid diagnosis primarily responsible for current symptoms and functional impairment Has a known history of borderline personality disorder, antisocial personality disorder, or bipolar disorder Has a known history of traumatic brain injury, or Alzheimer's disease or another form of dementia Currently meets DSM-5 criteria for substance abuse or alcohol use disorder Is at imminent risk of self-harm or harm to others

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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
Interventional Model Description: Participants will be randomly assigned to one of three groups in parallel for the duration of the study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-8189<br>Participants receive MK-8189 (4 mg controlled release [CR] oral tablet[s]) in combination with placebo matching risperidone (oral capsule[s]) once daily (QD) for 4 weeks. Over the initial 7 treatment days, MK-8189 is titrated from 4 mg to 12 mg as follows: 4 mg (1 tablet; Day 1); 8 mg (2 tablets; Day 4); and 12 mg (3 tablets; Day 7). Placebo matching risperidone is also titrated as follows: 1 capsule (Day 1), 2 capsules (Day 4), and 3 capsules (Day 7). After Day 7, MK-8189 is maintained at 12 mg (3 tablets) in combination with placebo matching risperidone (3 capsules), QD for 3 weeks. | Drug: MK-8189<br>* Oral CR tablets (4 mg) administered QD at the following dose strengths: 4 mg (1 tablet); 8 mg (2 tablets); 12 mg (3 tablets)<br>Drug: Placebo matching risperidone<br>* Oral placebo capsule(s) matching the risperidone capsule, administered QD.<br>|
| Active Comparator: Risperidone<br>Participants receive risperidone (2 mg oral capsule[s]) in combination with placebo matching MK-8189 (oral tablet[s]), QD for 4 weeks. Over the initial 7 treatment days, risperidone is titrated from 2 mg to 6 mg as follows: 2 mg (1 capsule; Day 1); 4 mg (2 capsules; Day 4); and 6 mg (3 capsules; Day 7). Placebo matching MK-8189 is also titrated as follows: 1 tablet (Day 1), 2 tablets (Day 4), and 3 tablets (Day 7). After Day 7, risperidone is maintained at 6 mg (3 capsules) in combination with placebo matching MK-8189 (3 tablets), QD for 3 weeks. | Drug: Risperidone<br>* Oral capsules (2 mg) administered QD at the following dose strengths: 2 mg (1 capsule); 4 mg (2 capsules); 6 mg (3 capsules)<br>Drug: Placebo matching MK-8189<br>* Oral placebo tablet(s) matching the MK-8189 tablet, administered QD.<br>|
| Placebo Comparator: Placebo<br>Participants receive both placebo matching MK-8189 (oral tablet[s]) as well as placebo matching Risperidone (oral capsule[s]), QD for 4 weeks. Over the initial 7 treatment days, placebo matching both MK-8189 and risperidone are respectively titrated as follows: 1 tablet/1 capsule (Day 1); 2 tablets/2 capsules (Day 4); and 3 tablets/3 capsules (Day 7). After Day 7, placebo matching both MK-8189 and risperidone are respectively maintained at 3 tablets/3 capsules, QD for 3 weeks. | Drug: Placebo matching MK-8189<br>* Oral placebo tablet(s) matching the MK-8189 tablet, administered QD.<br>Drug: Placebo matching risperidone<br>* Oral placebo capsule(s) matching the risperidone capsule, administered QD.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Least Squares Mean (LSM) Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 4 | The LSM change from baseline at week 4 was assessed for PANSS total score. The PANSS assesses the severity of schizophrenia symptoms through a clinician-rated inventory of 30 items organized in 3 subscales: 1) positive subscale (7 items); 2) negative subscale (7 items); and 3) general psychopathology subscale (16 items). For each item, symptoms are scored from 1 (absent) to 7 (extreme) and sum to a total PANSS score (range: 30-210). Higher scores reflect more severe symptoms of schizophrenia. Further, reduced symptom severity over time is reflected by decreases in score. | Baseline and Week 4 | 
| Percentage of Participants Experiencing an Adverse Event (AE) | The percentage of participants experiencing an AE was assessed. An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. | Up to 6 weeks | 
| Percentage of Participants Discontinuing Study Treatment Due to an Adverse Event | The percentage of participants discontinuing study treatment due to an AE was assessed. An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. | Up to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Least Squares Mean (LSM) Change From Baseline in the Clinical Global Impression-Severity of Illness (CGI-S) Score at Week 4 | The LSM change from baseline at week 4 was assessed for CGI-S score. The CGI-S is a 7-point clinician-rated scale for assessing the global severity of the participant's illness. Possible CGI-S scores range from 1 (participant normal, not ill) to 7 (participant extremely ill). Further, a decrease in CGI-S score indicates reduced severity of the participant's illness. | Baseline and Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia, acute episode, Schizophrenia Spectrum and Other Psychotic Disorders, Mental Disorders