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

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03055338
• Collaborator: (none)
• Enrollment: 224
• Locations: 28
• Arms: 3
• Actual Duration (Months): 10.1
• Patients Per Site: 8
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia, Acute Episode	Drug: MK-8189; Drug: Risperidone; Drug: Placebo matching MK-8189; Drug: Placebo matching risperidone	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 224 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Participants will be randomly assigned to one of three groups in parallel for the duration of the study.Participants will be randomly assigned to one of three groups in parallel for the duration of the study.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: A double-blind/masking technique will be used. MK-8189 and risperidone will be packaged identically relative to their respective matching placebo so that blinding/masking is maintained.
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Mar 8, 2017
• Actual Primary Completion Date: Jan 9, 2018
• Actual Study Completion Date: Jan 9, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MK-8189 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; Oral CR tablets (4 mg) administered QD at the following dose strengths: 4 mg (1 tablet); 8 mg (2 tablets); 12 mg (3 tablets); Drug: Placebo matching risperidone; Oral placebo capsule(s) matching the risperidone capsule, administered QD.
Active Comparator: Risperidone 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; Oral capsules (2 mg) administered QD at the following dose strengths: 2 mg (1 capsule); 4 mg (2 capsules); 6 mg (3 capsules); Drug: Placebo matching MK-8189; Oral placebo tablet(s) matching the MK-8189 tablet, administered QD.
Placebo Comparator: Placebo 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; Oral placebo tablet(s) matching the MK-8189 tablet, administered QD.; Drug: Placebo matching risperidone; Oral placebo capsule(s) matching the risperidone capsule, administered QD.

Outcome Measures

Primary Outcome Measures

1. Least Squares Mean (LSM) Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 4 [Baseline and 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.

2. Percentage of Participants Experiencing an Adverse Event (AE) [Up to 6 weeks]

   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.

3. Percentage of Participants Discontinuing Study Treatment Due to an Adverse Event [Up to 4 weeks]

   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.

Secondary Outcome Measures

1. Least Squares Mean (LSM) Change From Baseline in the Clinical Global Impression-Severity of Illness (CGI-S) Score at Week 4 [Baseline and 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Woodland International Research Group, LLC ( Site 0001)	Little Rock	Arkansas	United States	72211
2	Woodland Research Northwest, LLC ( Site 0014)	Rogers	Arkansas	United States	72758
3	CITRIALS ( Site 0013)	Bellflower	California	United States	90706
4	Comprehensive Clinical Development ( Site 0049)	Cerritos	California	United States	90703
5	Collaborative Neuroscience Network, LLC ( Site 0057)	Garden Grove	California	United States	92845
6	Behavioral Research Specialists, LLC ( Site 0006)	Glendale	California	United States	91206
7	Synergy East ( Site 0003)	Lemon Grove	California	United States	91945
8	NRC Research Institute ( Site 0043)	Orange	California	United States	92868
9	CNRI - Los Angeles, LLC ( Site 0026)	Pico Rivera	California	United States	90660
10	Artemis Institute for Clinical Research ( Site 0027)	San Diego	California	United States	92103
11	Schuster Medical Research Institute ( Site 0032)	Sherman Oaks	California	United States	91403
12	Collaborative Neuroscience Network, LLC ( Site 0046)	Torrance	California	United States	90502
13	Larkin Community Hospital Behavioral Health Services ( Site 0020)	Hollywood	Florida	United States	33021
14	Clinical Research Centers of America, LLC ( Site 0038)	Oakland Park	Florida	United States	33334
15	Aspire Health Partners ( Site 0016)	Orlando	Florida	United States	32810
16	Radiant Research - Atlanta ( Site 0008)	Atlanta	Georgia	United States	30328
17	Atlanta Center For Medical Research ( Site 0056)	Atlanta	Georgia	United States	30331
18	Alexian Center for Psychiatric Research ( Site 0015)	Hoffman Estates	Illinois	United States	60169
19	Lake Charles Clinical Trials, LLC ( Site 0040)	Lake Charles	Louisiana	United States	70629
20	CBH Health, LLC ( Site 0022)	Gaithersburg	Maryland	United States	20877
21	Precise Research Centers ( Site 0018)	Flowood	Mississippi	United States	39232
22	Psych Care Consultants Research ( Site 0025)	Saint Louis	Missouri	United States	63128
23	St. Louis Clinical Trials, LLC ( Site 0012)	Saint Louis	Missouri	United States	63141
24	Altea Research Institute ( Site 0017)	Las Vegas	Nevada	United States	89102
25	Radiant Research -CliniLabs ( Site 0037)	New York	New York	United States	10019
26	Midwest Clinical Research Unit ( Site 0041)	Dayton	Ohio	United States	45417
27	InSite Clinical Research ( Site 0033)	DeSoto	Texas	United States	75115
28	Pillar Clinical Research, LLC ( Site 0004)	Richardson	Texas	United States	75080

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 29, 2017

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT03055338
• Other Study ID Numbers: 8189-005; MK-8189-005
• First Posted: Feb 16, 2017
• Last Update Posted: Dec 26, 2018
• Last Verified: Nov 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Merck Sharp & Dohme LLC: Schizophrenia, acute episode; Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders
• Additional relevant MeSH terms: Schizophrenia; Risperidone

Study Results

Participant Flow

Arm/Group Title	MK-8189	Risperidone	Placebo
Arm/Group Description	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 mock 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.	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 mock 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.	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 mock 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.
Period Title: Overall Study
STARTED	90	45	89
COMPLETED	72	34	77
NOT COMPLETED	18	11	12

Baseline Characteristics

Arm/Group Title	MK-8189	Risperidone	Placebo	Total
Arm/Group Description	Participants receive MK-8189 (4 mg CR oral tablet[s]) in combination with placebo matching risperidone (oral capsule[s]) 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 mock 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.	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 mock 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.	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 mock 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.	Total of all reporting groups
Overall Participants	90	45	89	224
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	38.4 (7.4)	37.3 (8.0)	35.6 (7.6)	37.1 (7.7)
Sex: Female, Male (Count of Participants)
Female	23 25.6%	8 17.8%	17 19.1%	48 21.4%
Male	67 74.4%	37 82.2%	72 80.9%	176 78.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 2.2%	0 0%	0 0%	2 0.9%
Asian	2 2.2%	0 0%	2 2.2%	4 1.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	1 1.1%	1 0.4%
Black or African American	65 72.2%	37 82.2%	65 73%	167 74.6%
White	21 23.3%	8 17.8%	20 22.5%	49 21.9%
More than one race	0 0%	0 0%	1 1.1%	1 0.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Positive and Negative Syndrome Scale (PANSS) Total Score (Score on a Scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score on a Scale]	95.1 (10.4)	95.3 (12.4)	96.2 (9.6)	95.6 (10.45)
Clinical Global Impression Severity of Illness (CGI-S) Score (Score on a Scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score on a Scale]	4.9 (0.6)	5.0 (0.7)	5.0 (0.4)	4.9 (0.57)
Duration of Illness (Count of Participants)
<= 10 Years	31 34.4%	18 40%	32 36%	81 36.2%
> 10 Years	59 65.6%	27 60%	57 64%	143 63.8%

Outcome Measures

1. Primary Outcome

Title	Least Squares Mean (LSM) Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 4
Description	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.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Includes all randomized participants who: 1) received ≥1 dose of study treatment; 2) had a baseline PANSS assessment; and 3) had ≥1 post-randomization observation for PANSS score subsequent to ≥1 dose of study treatment.

Arm/Group Title	MK-8189	Risperidone	Placebo
Arm/Group Description	Participants receive MK-8189 (4 mg CR oral tablet[s]) in combination with placebo matching risperidone (oral capsule[s]) 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 mock 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.	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 mock 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.	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 mock 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.
Measure Participants	89	40	89
Least Squares Mean (95% Confidence Interval) [Score on a Scale]	-14.6	-17.2	-10.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MK-8189, Risperidone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.440
	Comments
	Method	Longitudinal ANCOVA
	Comments	Includes terms for treatment, baseline PANSS total score, age, duration of illness, week, and the interaction of week by treatment.
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	2.6
	Confidence Interval	(2-Sided) 95%; -4.0 to 9.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in LSM = MK-8189 - Risperidone

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	MK-8189, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.074
	Comments
	Method	Longitudinal ANCOVA
	Comments	Includes terms for treatment, baseline PANSS total score, age, duration of illness, week, and the interaction of week by treatment.
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	-4.7
	Confidence Interval	(2-Sided) 95%; -9.8 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in LSM = MK-8189 - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Risperidone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.033
	Comments
	Method	Longitudinal ANCOVA
	Comments	Includes terms for treatment, baseline PANSS total score, age, duration of illness, week, and the interaction of week by treatment.
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	-7.3
	Confidence Interval	(2-Sided) 95%; -14.0 to -0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in LSM = Risperidone - Placebo

2. Primary Outcome

Title	Percentage of Participants Experiencing an Adverse Event (AE)
Description	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.
Time Frame	Up to 6 weeks

Outcome Measure Data

Analysis Population Description

Includes all randomized and treated participants.

Arm/Group Title	MK-8189	Risperidone	Placebo
Arm/Group Description	Participants receive MK-8189 (4 mg CR oral tablet[s]) in combination with placebo matching risperidone (oral capsule[s]) 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 mock 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.	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 mock 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.	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 mock 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.
Measure Participants	90	45	89
Number [Percentage of Participants]	71.1 79%	77.8 172.9%	53.9 60.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MK-8189, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in % versus Placebo
	Estimated Value	17.2
	Confidence Interval	(2-Sided) 95%; 3.0 to 30.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in % = MK-8918 - Placebo
Other Statistical Analysis		Based on Miettinen & Nurminen method.

3. Primary Outcome

Title	Percentage of Participants Discontinuing Study Treatment Due to an Adverse Event
Description	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.
Time Frame	Up to 4 weeks

Outcome Measure Data

Analysis Population Description

Includes all randomized and treated participants.

Arm/Group Title	MK-8189	Risperidone	Placebo
Arm/Group Description	Participants receive MK-8189 (4 mg CR oral tablet[s]) in combination with placebo matching risperidone (oral capsule[s]) 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 mock 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.	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 mock 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.	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 mock 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.
Measure Participants	90	45	89
Number [Percentage of Participants]	6.7 7.4%	8.9 19.8%	7.9 8.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MK-8189, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in % versus Placebo
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95%; -9.6 to 7.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in % = MK-8918 - Placebo
Other Statistical Analysis		Based on Miettinen & Nurminen method.

4. Secondary Outcome

Title	Least Squares Mean (LSM) Change From Baseline in the Clinical Global Impression-Severity of Illness (CGI-S) Score at Week 4
Description	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.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Includes all randomized participants who: 1) received ≥1 dose of study treatment; 2) had a baseline CGI-S assessment; and 3) had ≥1 post-randomization observation for CGI-S score subsequent to ≥1 dose of study treatment.

Arm/Group Title	MK-8189	Risperidone	Placebo
Arm/Group Description	Participants receive MK-8189 (4 mg CR oral tablet[s]) in combination with placebo matching risperidone (oral capsule[s]) 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 mock 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.	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 mock 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.	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 mock 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.
Measure Participants	89	40	89
Least Squares Mean (95% Confidence Interval) [Score on a Scale]	-0.9	-1.0	-0.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MK-8189, Risperidone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in LSM = MK-8189 - Risperidone

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	MK-8189, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in LSM = MK-8189 - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Risperidone, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.8 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in LSM = Risperidone - Placebo

Adverse Events

Time Frame	Up to 6 weeks
Adverse Event Reporting Description	The analysis population includes all randomized and treated participants.
Arm/Group Title	MK-8189		Risperidone		Placebo
Arm/Group Description	Participants receive MK-8189 (4 mg CR oral tablet[s]) in combination with placebo matching risperidone (oral capsule[s]) 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 mock 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.		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 mock 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.		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 mock 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.
All Cause Mortality
	MK-8189		Risperidone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/90 (0%)		0/45 (0%)		0/89 (0%)
Serious Adverse Events
	MK-8189		Risperidone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/90 (0%)		3/45 (6.7%)		3/89 (3.4%)
Infections and infestations
Otitis externa	0/90 (0%)	0	0/45 (0%)	0	1/89 (1.1%)	1
Injury, poisoning and procedural complications
Alcohol poisoning	0/90 (0%)	0	1/45 (2.2%)	1	0/89 (0%)	0
Psychiatric disorders
Psychotic disorder	0/90 (0%)	0	0/45 (0%)	0	2/89 (2.2%)	2
Schizophrenia	0/90 (0%)	0	2/45 (4.4%)	2	0/89 (0%)	0
Other (Not Including Serious) Adverse Events
	MK-8189		Risperidone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/90 (58.9%)		27/45 (60%)		31/89 (34.8%)
Gastrointestinal disorders
Diarrhoea	7/90 (7.8%)	9	0/45 (0%)	0	3/89 (3.4%)	3
Dyspepsia	5/90 (5.6%)	5	3/45 (6.7%)	3	5/89 (5.6%)	6
Nausea	14/90 (15.6%)	15	4/45 (8.9%)	4	5/89 (5.6%)	5
Vomiting	7/90 (7.8%)	7	1/45 (2.2%)	1	1/89 (1.1%)	1
General disorders
Fatigue	2/90 (2.2%)	2	3/45 (6.7%)	4	2/89 (2.2%)	2
Investigations
Weight increased	2/90 (2.2%)	2	8/45 (17.8%)	8	4/89 (4.5%)	4
Metabolism and nutrition disorders
Decreased appetite	6/90 (6.7%)	6	1/45 (2.2%)	1	2/89 (2.2%)	2
Nervous system disorders
Akathisia	16/90 (17.8%)	16	4/45 (8.9%)	4	3/89 (3.4%)	3
Dizziness	3/90 (3.3%)	4	4/45 (8.9%)	4	1/89 (1.1%)	1
Dystonia	8/90 (8.9%)	10	0/45 (0%)	0	0/89 (0%)	0
Headache	14/90 (15.6%)	18	5/45 (11.1%)	6	12/89 (13.5%)	17
Lethargy	1/90 (1.1%)	1	3/45 (6.7%)	6	1/89 (1.1%)	1
Sedation	7/90 (7.8%)	7	6/45 (13.3%)	6	2/89 (2.2%)	2
Somnolence	6/90 (6.7%)	6	2/45 (4.4%)	2	3/89 (3.4%)	3
Psychiatric disorders
Agitation	1/90 (1.1%)	1	3/45 (6.7%)	3	3/89 (3.4%)	3
Anxiety	7/90 (7.8%)	7	1/45 (2.2%)	1	3/89 (3.4%)	3
Insomnia	6/90 (6.7%)	6	0/45 (0%)	0	1/89 (1.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.