Conditions: Schizophrenia, Acute Episode
Keywords: Schizophrenia, acute episode Schizophrenia Spectrum and Other Psychotic Disorders Mental Disorders
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 224
Healthy volunteers: no

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.

Detailed description:

Arms:
arm 1: 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. arm 2: 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. arm 3: 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.

Interventions: intervention 1: MK-8189 intervention 2: Risperidone intervention 3: Placebo matching MK-8189 intervention 4: Placebo matching risperidone
Intervention descriptions: intervention 1: Oral CR tablets (4 mg) administered QD at the following dose strengths: 4 mg (1 tablet); 8 mg (2 tablets); 12 mg (3 tablets) intervention 2: Oral capsules (2 mg) administered QD at the following dose strengths: 2 mg (1 capsule); 4 mg (2 capsules); 6 mg (3 capsules) intervention 3: Oral placebo tablet(s) matching the MK-8189 tablet, administered QD. intervention 4: Oral placebo capsule(s) matching the risperidone capsule, administered QD.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03055338 
Document Date: 
29-Mar-2017
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


Product:  MK-8189 
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Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
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  
IND NUMBER:  118,986
EudraCT NUMBER:  Not Applicable
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 13
2.0
TRIAL DESIGN........................................................................................................ 13
Trial Design ........................................................................................................... 13
2.1
Trial Diagram........................................................................................................ 15
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 15
Primary Objective(s) & Hypothesis(es) .............................................................. 15
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 16
3.2
Other Objectives (e.g., Tertiary, Exploratory, etc.)........................................... 16
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 17
Background ........................................................................................................... 17
4.1
Pharmaceutical and Therapeutic Background .................................................... 17
4.1.1
Information on Other Trial-Related Therapy...................................................... 17
4.1.2
Rationale................................................................................................................ 17
4.2
Rationale for the Trial and Selected Subject Population .................................... 17
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 18
4.2.2
4.2.2.1
Rationale for the Use of Comparator/Placebo ............................................. 19
Rationale for Endpoints ...................................................................................... 19
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 19
4.2.3.2
Safety Endpoints .......................................................................................... 20
4.2.3.3
Pharmacokinetic Endpoints ......................................................................... 20
4.2.3.4
Pharmacodynamic Endpoints....................................................................... 21
4.2.3.5
Planned Exploratory Biomarker Research................................................... 21
4.2.3.6
Future Biomedical Research........................................................................ 21
Benefit/Risk ........................................................................................................... 22
4.3
5.0
METHODOLOGY ................................................................................................... 22
Entry Criteria........................................................................................................ 22
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 22
5.1.1
 
 
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Subject Inclusion Criteria.................................................................................... 22
5.1.2
Subject Exclusion Criteria .................................................................................. 25
5.1.3
Trial Treatment(s) ................................................................................................ 28
5.2
Dose Selection/Modification .............................................................................. 29
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 29
5.2.1.2
Dose Modification (Escalation/Titration/Other).......................................... 29
Timing of Dose Administration .......................................................................... 30
5.2.2
Trial Blinding/Masking....................................................................................... 30
5.2.3
Randomization or Treatment Allocation............................................................ 30
5.3
Stratification.......................................................................................................... 31
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 31
5.5
Rescue Medications & Supportive Care............................................................. 33
5.6
Diet/Activity/Other Considerations..................................................................... 34
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 34
5.8
Discontinuation of Treatment ............................................................................. 34
5.8.1
Withdrawal from the Trial .................................................................................. 35
5.8.2
Subject Replacement Strategy............................................................................. 36
5.9
Beginning and End of the Trial ........................................................................... 36
5.10
Clinical Criteria for Early Trial Termination ................................................... 36
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 37
7.0
TRIAL PROCEDURES ........................................................................................... 40
Trial Procedures ................................................................................................... 40
7.1
Administrative Procedures.................................................................................. 40
7.1.1
7.1.1.1
Informed Consent......................................................................................... 40
7.1.1.1.1
General Informed Consent.................................................................... 40
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 41
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 41
7.1.1.3
Subject Identification Card .......................................................................... 41
7.1.1.4
Medical History ........................................................................................... 41
7.1.1.4.1
Substance/Alcohol/Smoking History/ Social History........................... 41
7.1.1.5
Psychiatric History....................................................................................... 41
 
 
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7.1.1.5.1
Psychiatric Intake Evaluation and MINI .............................................. 42
7.1.1.6
Identify External Contact Person ................................................................. 43
7.1.1.7
Prior and Concomitant Medications Review ............................................... 43
7.1.1.7.1
Prior Medications.................................................................................. 43
7.1.1.7.2
Concomitant Medications..................................................................... 43
7.1.1.8
Assignment of Screening Number............................................................... 43
7.1.1.9
Assignment of Treatment/Randomization Number ..................................... 44
7.1.1.10 Interactive Voice Response System/Integrated Web Response System ...... 44
7.1.1.11 Trial Medication Dispensing........................................................................ 44
7.1.1.12 Trial Compliance (Medication/Diet/Activity/Other) ................................... 44
Clinical Procedures/Assessments........................................................................ 45
7.1.2
7.1.2.1
Physical Assessments/Examinations ........................................................... 45
7.1.2.1.1
Physical Examination/Neurological Examination ................................ 45
7.1.2.1.2
Body Height/Weight/Waist Circumference.......................................... 46
7.1.2.1.3
12-Lead Electrocardiogram .................................................................. 46
7.1.2.1.4
Vital Signs............................................................................................. 46
7.1.2.2
Clinical Assessment..................................................................................... 46
7.1.2.2.1
Positive and Negative Symptom Scale (PANSS) ................................. 47
7.1.2.2.2
Clinical Global Impression Scale-Severity (CGI-S)............................. 47
7.1.2.2.3
C-SSRS................................................................................................. 47
7.1.2.2.4
Monitoring of Extrapyramidal Symptoms ............................................ 48
Laboratory Procedures/Assessments .................................................................. 49
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 49
7.1.3.2
Pregnancy Testing........................................................................................ 51
7.1.3.3
Urine Alcohol Drug Screen ......................................................................... 51
7.1.3.4
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 52
7.1.3.4.1
Blood Collection for Plasma MK-8189................................................ 52
7.1.3.5
Planned Genetic Analysis Sample Collection.............................................. 52
7.1.3.6
Future Biomedical Research........................................................................ 52
Other Procedures................................................................................................. 52
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 52
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 52
 
 
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7.1.4.2
Blinding/Unblinding .................................................................................... 53
7.1.4.3
Domiciling ................................................................................................... 53
7.1.4.4
Calibration of Critical Equipment................................................................ 53
7.1.4.5
Administer Trial Medication........................................................................ 54
Visit Requirements.............................................................................................. 54
7.1.5
7.1.5.1
Screening...................................................................................................... 54
7.1.5.1.1
Hospitalization During the Trial ........................................................... 55
7.1.5.2
Treatment Period Visit 2 through Visit 6..................................................... 56
7.1.5.3
Telephone Contact Procedures .................................................................... 57
7.1.5.4
Post-Treatment Contact (phone and visit) ................................................... 57
Assessing and Recording Adverse Events .......................................................... 57
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 58
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 59
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 59
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 59
7.2.3.2
Events of Clinical Interest............................................................................ 60
Evaluating Adverse Events ................................................................................. 61
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 64
7.2.5
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 64
7.3
Scientific Advisory Committee........................................................................... 64
7.3.1
Executive Oversight Committee ......................................................................... 64
7.3.2
Data Monitoring Committee ............................................................................... 64
7.3.3
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 64
Statistical Analysis Plan Summary ..................................................................... 65
8.1
Responsibility for Analyses/In-House Blinding ................................................. 66
8.2
Hypotheses/Estimation ......................................................................................... 66
8.3
Analysis Endpoints ............................................................................................... 67
8.4
Efficacy Endpoints.............................................................................................. 67
8.4.1
Safety Endpoints ................................................................................................. 67
8.4.2
Analysis Populations............................................................................................. 67
8.5
Efficacy Analysis Populations ............................................................................ 67
8.5.1
 
 
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Safety Analysis Populations ............................................................................... 68
8.5.2
Statistical Methods................................................................................................ 68
8.6
Statistical Methods for Efficacy Analyses .......................................................... 68
8.6.1
Statistical Methods for Safety Analyses ............................................................. 69
8.6.2
Demographic and Baseline Characteristics ........................................................ 71
8.6.3
Interim Analyses ................................................................................................... 71
8.7
Futility of Primary Outcome............................................................................... 72
8.7.1
Multiplicity ............................................................................................................ 73
8.8
Sample Size and Power Calculations .................................................................. 73
8.9
Subgroup Analyses and Effect of Baseline Factors ........................................... 75
8.10
Compliance (Medication Adherence).................................................................. 75
8.11
Extent of Exposure................................................................................................ 76
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 76
Investigational Product ........................................................................................ 76
9.1
Packaging and Labeling Information ................................................................. 77
9.2
Clinical Supplies Disclosure................................................................................. 77
9.3
Storage and Handling Requirements.................................................................. 77
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 77
9.5
Standard Policies................................................................................................... 78
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 78
Confidentiality....................................................................................................... 78
10.1
Confidentiality of Data ....................................................................................... 78
10.1.1
Confidentiality of Subject Records ..................................................................... 78
10.1.2
Confidentiality of Investigator Information........................................................ 78
10.1.3
Confidentiality of IRB/IEC Information............................................................. 79
10.1.4
Compliance with Financial Disclosure Requirements....................................... 79
10.2
Compliance with Law, Audit and Debarment ................................................... 79
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 81
10.4
Quality Management System............................................................................... 82
10.5
Data Management................................................................................................. 82
10.6
Publications ........................................................................................................... 82
10.7
 
 
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11.0
LIST OF REFERENCES......................................................................................... 83
12.0
APPENDICES........................................................................................................... 85
Merck Code of Conduct for Clinical Trials........................................................ 85
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 87
Pharmacogenetics 
Informational 
Brochure 
for 
IRBs/IECs 
& 
12.3
Investigational Site Staff ...................................................................................... 93
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.4
by Sample Types ................................................................................................. 112
Abbreviations ...................................................................................................... 113
12.5
Risperidone Label............................................................................................... 117
12.6
Mapping Between the 11 Categories of Suicidal Ideation and Behavior 
12.7
and the C-SSRS and CDR for Programming Standard Tables ..................... 124
13.0
SIGNATURES......................................................................................................... 125
Sponsor's Representative ................................................................................... 125
13.1
Investigator.......................................................................................................... 125
13.2
 
 
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LIST OF TABLES
    
Table 1
Trial Treatment ................................................................................................... 28
Table 2
Prohibited Medications during the Treatment Period......................................... 32
Table 3
Medications and Procedures Permitted during the Treatment Period................. 33
Table 4
Laboratory Tests ................................................................................................. 50
Table 5
Evaluating Adverse Events................................................................................. 62
Table 6
Analysis Strategy for Key Efficacy Variables.................................................... 69
Table 7
Analysis Strategy for Safety Parameters............................................................. 71
Table 8
Operating Characteristics of the Futility Analysis†............................................ 73
Table 9
Power† (%) Under Various Assumptions With 215 Subjects 
Randomized if Futility Analysis is Not Performed............................................ 74
Table 10
Power† (%) Under Various Assumptions With 215 Subjects 
Randomized if Futility Analysis is Performed................................................... 75
Table 11
Product Descriptions........................................................................................... 76
 
 
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LIST OF FIGURES
          
Figure 1
Diagram of PN-005 Study Structure................................................................... 15
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.5
Concomitant 
Medications/Vaccinations 
(Allowed & Prohibited), 
Table 2
Prohibited medications added
These changes were made to 
enhance the usefulness of the 
table.
5.5
Concomitant 
Medications/Vaccinations 
(Allowed & Prohibited), 
Table 3
Dosage of lorazepam or 
lorazepam equivalents 
decreased. Added text 
instructing sites to avoid using 
“PRN” when entering dosage 
in the CRF
These changes were made to 
reduce the dosage of 
benzodiazepine permitted 
during the clinical trial, and to 
promote reporting of daily 
dosage administered.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.1.2 
Subject Inclusion Criterion 8
Minor wording change 
Clarification
5.1.2 
Subject Inclusion Criterion 10
Deleted sentence
Text did not apply to this 
protocol
5.1.3
Subject Exclusion Criterion 5
“Or” changed to “and”
Clarification
5.1.3
Subject Exclusion Criterion 19
“Known” inserted before 
“serological evidence”
Clarification
5.8.1
Discontinuation of Treatment
Delete “confirmed” from text 
“the subject has a confirmed 
positive serum pregnancy test.”
Clarification
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
6.0
Trial Flow chart assessments, 
footnotes
Changes in assessments and 
some assessment wording. 
Revisions better encapsulate 
actions needed at these 
assessments; footnotes revised 
for clarity 
7.1.1.5.1 
Psychiatric Intake Evaluation 
and MINI
Delete “vendor” from phrase
external vendor’s SDME
To make consistent with the 
rest of the protocol. 
7.1.3.1
Laboratory Tests (Table 4)
Addition of creatinine 
phosphokinase total analyte, 
and other clarifications
Clarification
7.1.3.2
Pregnancy Testing
Section revised to provide 
clarity on use of urine 
pregnancy tests and results 
confirmation through serum 
pregnancy testing
Consistent with rest of protocol
7.1.3.3 
Urine Alcohol Drug Screen
Added text to align with other 
protocol sections
Consistency
7.1.4.4 
Calibration of Critical 
Equipment
Added text regarding ECG 
equipment calibration
documentation.
Minor correction
7.1.5.1
Screening
Added sentence regarding 
re-screens
Clarification 
7.1.5.1.1 
Hospitalization During the 
Trial
Added text regarding in-patient 
period
Clarification
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
12.4  
Approximate Blood/Tissue 
Volumes Drawn/Collected by 
Trial Visit and by Sample 
Types
Deleted Visit 4 prolactin 
collection. 
Consistency with Trial Flow 
Chart
12.4
Approximate Blood/Tissue 
Volumes Drawn/Collected by 
Trial Visit and by Sample 
Types
“At the discretion of the 
investigator” added to HIV/ 
hepatitis screen.
Clarification, alignment with 
flow chart update
12.5 
Abbreviations
Expanded one abbreviation, 
added another. 
Global
Minor spelling, grammar, 
and/or style changes throughout 
document
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
MK-8189 vs. placebo with active control in adults with acute 
schizophrenia
Trial Phase
Phase IIa
Clinical Indication
Treatment of Acute Episode of Schizophrenia
Trial Type
Interventional
Type of control
Placebo, active comparator 
Route of administration
Oral
Trial Blinding
Double-blind
Treatment Groups
Randomized to MK-8189, placebo, or risperidone
Number of trial subjects
Approximately 215 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 14 
months from the time the first subject signs the informed consent 
until the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for approximately 7 weeks, 
from the time the subject signs the Informed Consent Form (ICF) 
through the final contact.  After a Screening visit and tapering of 
prohibited medications of 3 (+4) days, each subject will be receiving 
assigned treatment for approximately 4 weeks.  After the end of 
treatment, each subject will be followed for 14 days.
A list of abbreviations used in this document can be found in Section 12.5.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a randomized, placebo-controlled, parallel-group, multi-site, double-blind trial of 
MK-8189 with placebo using risperidone as an active control in adult subjects experiencing 
an acute episode of schizophrenia, according to the criteria specified in the Diagnostic and 
Statistical Manual of Mental Disorders (DSM-5 ™), and to be conducted in conformance 
with Good Clinical Practices.
This trial will be up to 7 weeks in duration, with up to 7 site visits for each subject.  The 
study will consist of a Screening/tapering period (up to 1 week long), a 4-week treatment 
period, and a 14-day follow-up period. Subjects could be admitted to the hospital/inpatient 
unit as early as the day of consent signing but no later than the evening of Screening visit 
assessment collection completion.  Subjects may continue as an inpatient in this trial 
throughout the active treatment period.
Randomization Ratio
2:2:1 (MK-8189:placebo:risperidone)
 
 
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At Baseline (Visit 2/Day 1), subject eligibility will be reassessed and subjects found to be 
eligible to participate in the study will be randomly assigned to an investigational product
(IP) treatment group: MK-8189, placebo, or risperidone in a 2:2:1 distribution, respectively.
This is a double-dummy design.  The initial IP dose of MK-8189 will start 
 
 The initial dose of risperidone will start at 2 mg QD
and titrate up to 6 mg QD.  Initial dosing and titration of IP over the 7 day titration period are 
described in Section 5.2.1.2 (Dose Modification [Escalation/Titration/Other]).
Subjects who discontinue or complete the treatment period will have 2 follow-up phone call
visits (post treatment Days 3 and 14) and a follow-up clinic visit (post treatment Day 7) after 
their last dose of IP.
The primary endpoint will be the assessment of symptoms of schizophrenia, as measured by 
the Positive and Negative Syndrome Scale (PANSS) at 4 weeks, as well as safety and 
tolerability.  The secondary endpoint will assess the severity of schizophrenia at 4 weeks, as 
measured by the Clinical Global Impression-Severity of Illness (CGI-S) score. Exploratory 
endpoints will include the proportion of PANSS total responders (≥30% reduction in PANSS 
total score), as well as the mean change from baseline to 4 weeks in the PANSS negative and 
positive subscale scores.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
A standing internal Data Monitoring Committee (siDMC), which is comprised of members 
of Sponsor Senior Management, none of whom are directly associated with the conduct of 
this trial, will evaluate the unblinded safety and efficacy data to assess the overall risk and 
benefit to trial participants when approximately 25%, 50% and 75% of the subjects have had 
the opportunity to complete the study.
An interim unblinded efficacy (futility) analysis will be considered unless more than 50% of 
the subjects have been enrolled 4 months after the first subject was randomized into the 
study.
The interim analysis, which would be performed by an internal statistician not 
affiliated with the project, would occur when 50% of the subjects have completed or 
discontinued IP treatment and include all data collected (including partial data from subjects 
who were randomized, but did not yet have the opportunity to complete the study).  The 
siDMC would review the analysis results and recommend whether the study should continue.
 
 
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Trial Diagram
2.2
The trial design is depicted in Figure 1. 
Figure 1
Diagram of PN-005 Study Structure
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
In male or female subjects with schizophrenia according to the DSM-5™ criteria who are 
≥18 to ≤50 years of age, and currently experiencing an acute episode of schizophrenia:
 
 
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(1)
Objective: To evaluate the efficacy of MK-8189 compared to placebo after 4 weeks of 
treatment as measured by the PANSS total score.
Hypothesis:  MK-8189 is superior to placebo in reducing the overall symptoms of 
schizophrenia as assessed by the mean change from baseline in PANSS total score after 
4 weeks of treatment.
(2)
Objective:  To evaluate the safety and tolerability of MK-8189.
Secondary Objective(s) & Hypothesis(es)
3.2
In male or female subjects with schizophrenia according to the DSM-5™ criteria who are 
≥18 to ≤50 years of age, and currently experiencing an acute episode of schizophrenia:
(1)
Objective:  To evaluate the efficacy of MK-8189 compared to placebo after 4 weeks of 
treatment as measured by the CGI-S score.
Hypothesis:  MK-8189 is superior to placebo in improving global functioning as 
assessed by the mean change from baseline in CGI-S score after 4 weeks of treatment.
Other Objectives (e.g., Tertiary, Exploratory, etc.)
3.3
In male or female subjects with schizophrenia according to the DSM-5™ criteria who are 
≥18 to ≤50 years of age, and currently experiencing an acute episode of schizophrenia:
(1)
Objective: To evaluate the efficacy of MK-8189 compared to placebo after 4 weeks of 
treatment as measured by the proportion of PANSS total responders (≥30% reduction in 
PANSS total score).
(2)
Objective: To evaluate the efficacy of MK-8189 compared to placebo after 4 weeks of 
treatment as measured by the PANSS negative subscale score.
(3)
Objective: To evaluate the efficacy of MK-8189 compared to placebo after 4 weeks of 
treatment as measured by the PANSS positive subscale score.
(4)
Objective: To evaluate the efficacy of risperidone compared to placebo (for assay 
sensitivity) after 4 weeks of treatment as measured by the PANSS total score.
(5)
Objective:  To assess the plasma pharmacokinetics of multiple doses of MK-8189 
administered as monotherapy.
(6)
Objective:  To explore the relationship between genetic variation and response to the 
treatment(s) administered. Variation across the human genome will be analyzed for 
association with clinical data collected in this study.
 
 
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4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-8189.
Pharmaceutical and Therapeutic Background
4.1.1
MK-8189 is a potent and selective 
 that is 
being developed as a novel therapeutic for the treatment of schizophrenia. 
 
 
 
 
 
  
 
 
Information on Other Trial-Related Therapy
4.1.2
Risperidone is indicated for the treatment of schizophrenia.
Efficacy was established in 4 
short-term trials in adults, 2 short-term trials in adolescents (ages 13 to 17 years), and 1 long-
term maintenance trial in adults. See Appendix 12.6 for label information.  The goal of the 
current trial is to detect the clinical efficacy of MK-8189 for the treatment of acute 
schizophrenia in comparison to placebo.  Risperidone will act as the active control in this 
setting to provide validation of the trial design.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
This study will evaluate the efficacy and safety of MK-8189 in subjects experiencing an 
acute episode of schizophrenia according to the DSM-5 ™criteria.
Schizophrenia is a chronic debilitating disorder consisting of 3 symptom domains, including 
positive symptoms (eg, psychosis, hallucinations and delusions), negative symptoms (e.g., 
apathy and amotivation), and cognitive impairment (e.g., impaired memory and planning). 
The prevalence of schizophrenia is low but the disease burden is high.  Schizophrenia affects
about 1% of the population globally. It is believed that disruption of corticostriatal signaling, 
stemming from increased dopamine and decreased glutamate neurotransmission, results in 
the positive symptoms of schizophrenia, and may also contribute to cognitive impairment. 
Atypical antipsychotics are the current "gold standard" medications used for the treatment of 
schizophrenia.  However, a substantial portion of patients with schizophrenia are not 
adequately treated by these medications and ~70% of patients switch medications within a 
year due to either a dissatisfaction with efficacy or a general lack of tolerability due to a wide 
 
 
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array of adverse events.  The major adverse events associated with these medications include 
weight gain/metabolic effects, extrapyramidal effects, increased prolactin secretion and 
sedation.
MK-8189 was shown to be fully efficacious in 3 well-defined preclinical assays predictive of 
antipsychotic activity. 
 
 
 
Overall, the preclinical toxicity profile of MK-8189 via the oral route of administration 
supports the conduct of clinical trials up to 6 weeks in duration.  In the nonclinical toxicology 
program, there were no target organ toxicities identified in the 6-week toxicity studies in rats 
or monkeys.  MK-8189 was well-tolerated in adults with schizophrenia for up to 14 days 
(both mono and add-on therapy) at doses up to 16 mg.
The results of this study will be used to determine if MK-8189 is efficacious in the treatment 
of schizophrenia and has a safety profile supportive of continued clinical development.
In order to assess the efficacy and safety of MK-8189 in schizophrenia, subjects with 
schizophrenia who are currently experiencing an acute episode of the illness will be eligible.
The Positive and Negative Syndrome Scale (PANSS) is a 30-item clinician-rated instrument 
for assessing the symptoms of schizophrenia and will be used as the primary efficacy 
endpoint measure. The scale was developed to assess positive and negative symptoms of 
schizophrenia as well as general psychopathology. The PANSS is a well-characterized, 
standardized measurement technique used for measuring symptom severity of patients with 
schizophrenia and is widely used in the study of antipsychotic therapy. 
Rationale for Dose Selection/Regimen/Modification
4.2.2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.2.2.1
Rationale for the Use of Comparator/Placebo
Despite the seriousness of the indication, a placebo treatment arm is necessary to evaluate 
efficacy and safety.  Without the use of placebo, false assumptions regarding the true efficacy 
of new drugs may be made.  In the absence of a placebo control, it is nearly impossible to 
distinguish true drug effects from placebo effects in this study population.
Risperidone is an antipsychotic drug mainly used to treat schizophrenia (including adolescent 
schizophrenia), schizoaffective disorder, and the mixed and manic states of bipolar disorder.  
Risperidone is a second-generation atypical antipsychotic.  It is a dopamine antagonist 
possessing anti-serotonergic, anti-adrenergic and anti-histaminergic properties. 
The 
recommended starting dose of risperidone approved by the Food and Drug Administration
(FDA) for schizophrenia in adults is 2 mg (QD). Further dosage adjustments in 1 to 2 mg QD 
increments are recommended if necessary, to the recommended dose of 4 to 8 mg QD. 
Efficacy with risperidone in schizophrenia was demonstrated in a dose range of 4 to 16 mg 
QD in clinical trials according to the US approved label. However, doses above 6 mg per 
day for twice daily dosing were not demonstrated to be more efficacious than lower doses, 
were associated with more extrapyramidal symptoms and other adverse effects, and are 
generally not recommended.  The current trial will use a target dose of risperidone 6 mg QD 
as the active control to provide validation of the trial design.
Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
The Positive and Negative Syndrome Scale (PANSS), is a 30-item clinician-rated instrument 
for assessing the symptoms of schizophrenia and will be used as the primary efficacy 
endpoint measure. 
The positive scale consists of 7 items which measure delusions, 
conceptual 
disorganization, 
hallucinations, 
excitement, 
grandiosity,
suspiciousness/persecution, and hostility .  The negative subscale consists of 7 items which 
measure blunted affect, emotional withdrawal, poor rapport, passive/apathetic social 
withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, and 
stereotyped thinking.  The general psychopathology scale consists of 16 items which measure 
somatic concern, anxiety, guilt feelings, tension, mannerisms and posturing, depression, 
motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, 
lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation,
and active social avoidance. The change from baseline in the PANSS total score at 4 weeks 
is the primary efficacy endpoint. 
The Clinical Global Impression Severity of Illness (CGI-S) is a 7-point clinician-rated scale 
for assessing the global severity of the illness. The change in CGI-S score from baseline to 4 
weeks will be used as a secondary efficacy endpoint.
 
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Exploratory endpoints will consist of the proportion of PANSS total responders (≥30% 
reduction in PANSS total score), as well as the mean change from baseline to 4 weeks in the 
PANSS negative and positive subscale scores.
4.2.3.2
Safety Endpoints
Safety and tolerability will be assessed throughout the study by monitoring subjects for 
clinical adverse experiences.  Physical examinations, vital signs, 12-lead ECGs and 
laboratory safety tests will be performed routinely to detect any medically meaningful effects 
of the MK-8189 on physiology. 
Prospective assessment of suicidal ideation and behavior will be performed in this trial using 
the Columbia-Suicide Severity Rating Scale (C-SSRS).  This assessment is being conducted 
in compliance with the 2012 FDA guidance requiring prospective assessment in clinical trials 
conducted under investigational new drug (IND) applications and trials that are intended for 
submission in a new drug application (NDA) to the Neurology or Psychiatry Divisions of the 
FDA or biologics license application, as well as assessment in trials that fall within the 
guidance for other reasons (e.g., Central Nervous System [CNS] active/penetrant compounds, 
and known mechanisms or indications for which suicidal ideation/behavior has been 
previously identified as a potential concern).
Extrapyramidal symptoms will be documented with the Extrapyramidal Symptom Rating 
Scale–abbreviated (ESRS-A).
Pre-specified events of clinical interest (ECIs) (Section 7.2.3.2) in this study will include the 
following:
1. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) lab value 
that is greater than or equal to 3X the upper limit of normal and an elevated total bilirubin 
lab value that is greater than or equal to 2X the upper limit of normal and, at the same 
time, an alkaline phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled laboratory 
testing.
2. Suicidal ideation and/or behaviors reported in C-SSRS scores, Treatment Emergent 
Adverse Events (TEAEs) or any self-injurious behavior.
3. Dystonia
4. Tardive dyskinesia
5. QT corrected Fridericia (QTcF) interval of ≥500 msec (The average of the 3 QTcFs will 
be used)
4.2.3.3
Pharmacokinetic Endpoints
Blood will be drawn at time points specified in the Study Flow Chart for MK-8189 
pharmacokinetic (PK) measurements. The plasma samples will be used to evaluate the 
pharmacokinetics of MK-8189 in a subject population, and to enable the characterization of 
the pharmacokinetic/pharmacodynamic (PK/PD) and pharmacokinetic/adverse event 
(PK/AE) relationships.  Additional metabolites based on ongoing metabolites in safety 
 
 
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testing (MIST) analysis, may also be evaluated. These data will be used in pharmacokinetic 
model development and analysis.
The final decision as to which plasma samples will be assayed will be made by the Sponsor's
Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism (PPDM) and
the Clinical Monitor.  Information regarding the collection and shipping of plasma samples 
will be provided in the administrative binder.
4.2.3.4
Pharmacodynamic Endpoints
An exposure-response analysis of PANSS total score data will be performed to substantiate 
the efficacious dose range of MK-8189 for the treatment of schizophrenia and to assess the 
impact of factors such as exposure, patient population and drop-out on outcomes with 
MK-8189.
4.2.3.5
Planned Exploratory Biomarker Research
Planned Genetic Analysis
Understanding genetic determinants of drug response is an important endeavor during 
medical research.  This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation.  If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. Knowledge of the molecular basis of disease contributes to the 
development of novel biomarkers and the identification of new drug targets.  This research 
contributes to understanding genetic determinants of efficacy and safety associated with the 
treatments in this study. 
4.2.3.6
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
 
 
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receive the correct dose of the correct drug/vaccine at the correct time.  The details of this 
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
4.3
The safety monitoring practices employed by this protocol (i.e., physical examination, vital 
signs, 12-lead ECG, laboratory safety tests, C-SSRS assessments, and adverse events 
monitoring) are adequate to protect the subjects’ safety and should detect all adverse events.
There may be no direct health benefit for study participants from receipt of study medication, 
since it is still to be determined if treatment will improve, worsen or have no effect on the 
symptoms of schizophrenia.  We may learn more about this drug from this study that might 
benefit people in the future.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) for MK-8189, 
the label for risperidone and Informed Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
The eligibility criteria are designed to select subjects for whom treatment according to this 
protocol is considered appropriate. All relevant medical and non-medical conditions should 
be taken into consideration when deciding whether this protocol is suitable for a particular 
subject. All psychiatric diagnoses specified in the inclusion/exclusion criteria will be made 
according to the DSM-5 ™criteria by a qualified psychiatrist (Doctor of Medicine [MD]) or 
psychologist (Doctor of Philosophy [PhD]) or other equivalent degree. The diagnosis will be 
confirmed using the Mini International Neuropsychiatric Interview for Schizophrenia and 
Psychotic Disorders (MINI; Version 7).  Male or female subjects with schizophrenia
according to the DSM-5 ™criteria (295.90) who are ≥18 to ≤50 years of age, currently 
experiencing an acute episode of schizophrenia (worsening of active symptoms as listed in 
DSM-5 ™Criterion A) will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1.
Provide written informed consent for the trial.  The subject may also provide consent 
for Future Biomedical Research.  However, the subject may participate in the main trial 
without participating in Future Biomedical Research.
Note: the subject must have a 
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or not to participate in the study (i.e, if lack of decisional capacity is evident, the subject 
shall be excluded from the study).
2.
Be fluent in the language of the investigator, trial staff (including raters), and the 
informed consent.
3.
Be ≥18 to ≤50 years of age at Screening and of minimal legal age for signing the 
consent form.
4.
Meet one of the following categories:
a)
The subject is a male (there are no requirements pertaining to reproductive 
potential or contraceptive method).
b)
The subject is a female who is not of reproductive potential, defined as a female 
who either: (1) is postmenopausal (defined as at least 12 months with no menses 
in women ≥45 years of age); (2) has had a hysterectomy and/or bilateral 
oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion at 
least 6 weeks prior to Screening; OR (3) has a congenital or acquired condition 
that prevents childbearing.
c)
The subject is a female who is of reproductive potential and agrees to avoid 
becoming pregnant while receiving study drug and for 30 days after the last dose 
of study drug by complying with one of the following:  (1) practice abstinence†
from heterosexual activity OR (2) use (or have her partner use) acceptable 
contraception during heterosexual activity.  Acceptable methods of contraception 
are‡:
Combination method (requires use of two of the following):
•
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
•
cervical cap with spermicide (nulliparous women only)
•
contraceptive sponge (nulliparous women only) 
•
male condom or female condom (cannot be used together)
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
5.
Currently meet the diagnostic criteria for schizophrenia according to the DSM-5™
criteria (295.90); have a past diagnosis of schizophrenia with the onset of the first 
episode being ≥1 year prior to study entry; and illness duration of ≤20 years.
6.
Be confirmed (documented in the psychiatric intake evaluation form by the 
investigator, and reviewed / approved by the external sponsor designated medical 
 
 
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expert [SDME] prior to randomization) to be experiencing an acute episode of 
schizophrenia, as evidenced by ALL of the following:
a)
Onset of the current acute episode is ≤4 weeks prior to Screening,
b)
the subject’s current symptoms 
represent a marked and substantial change 
compared with the subject’s symptomatic state prior to the emergence of the 
current episode,
c)
the subject is in need of increased medical attention to treat worsening acute 
episode symptoms.
7.
Have a minimum PANSS total score of ≥80 at Screening (note the Screening minimum 
PANSS total score must be independently verified by an external expert rater 
designated by the Sponsor).
8.
Have a score of ≥4 (moderate) in three or more of the following items (delusions, 
conceptual 
disorganization, 
hallucinatory 
behavior, 
grandiosity, 
suspiciousness/persecution) in the positive subscale of the PANSS at Screening (note 
the Screening minimum scores in at least three PANSS positive items must be 
independently verified by an external expert rater designated by the Sponsor).
9.
Have a CGI-S score of ≥4 (moderately ill) at Screening.
10.
Be able to taper off psychotropic medications (including antipsychotics, antidepressants
and mood stabilizers) without significant destabilization or increased suicidality in the 
opinion of the investigator (see Section 5.5) with the last dose taken no later than the 
evening prior to the Baseline visit (Visit 2 / Day 1) (the dosing cycle of depot 
neuroleptics must end no later than the day prior to Baseline). For subjects who can 
skip the tapering period, last dose is to be taken no later than the day of Screening (the 
dosing cycle of depot neuroleptics must end no later than the day of Screening).  
11.
Have responded positively to an antipsychotic medication other than clozapine 
(Clozaril®) in a prior psychotic episode.
Subjects who have responded to another 
antipsychotic only when paired with clozapine would not qualify.
12.
Be willing and considered able by the investigator to participate in protocol 
assessments, including recordings of interviews, adhere to dose and visit schedules,
study procedures and restrictions.
13.
Subject must have an identified responsible person (e.g., family member, social worker, 
case worker, case manager, or nurse), referred to as the “external contact person” in the 
protocol, who has agreed to provide information about the subject’s location if needed 
during outpatient portion of the trial.  The site personnel must consider this identified 
responsible person a reliable contact person and somebody who has regular contact 
with the subject (the external contact person must have regular contact no less than 
once per week with the subject, and this frequency of contact is anticipated to continue 
(either in person or via telephone) during the follow-up period as well as the outpatient 
treatment period if the subject is discharged on Day 21.  If the subject does not have an 
external contact person that is considered reliable by the site, the site may designate a  
site representative to act as the subject’s external contact person, with the same 
responsibilities as described above.
 
 
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Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1.
Is currently participating in or has participated in an interventional clinical research 
study ≤6 months prior to the Screening visit of this current trial.
2.
Is currently under involuntary commitment because the subject is considered a danger 
to themselves or others.
3.
Is unwilling to remain hospitalized for the duration of the trial treatment.
4.
Has participated in more than one interventional clinical trial research study within 12 
months prior to Screening based on site experience or patient self-report.
5.
Is unwilling to allow audio/video taping of the MINI and/or PANSS interview at 
Screening and Baseline.
6.
Has a history of malignancy ≤five years prior to signing informed consent except for 
adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
7.
Has a body mass index (BMI) <18.5 or >40.0 kg/m2.
8.
Has a history of treatment resistance exhibited by any of the following:
a) no or minimal response to at least two periods of treatment in the past with 
antipsychotic agents (from at least two different chemical classes) at the maximally 
tolerated dose in treatments lasting six weeks or more.
b) history of Electroconvulsive Therapy (ECT) treatment for treatment resistant 
schizophrenia within the past 5 years.
c) past or current use of clozapine as single or adjunctive therapy within the past 5 
years.
9.
Is currently being treated with and benefiting from medications with a moderate or 
strong inhibiting or inducing effect on CYP3A and/or CYP2C9 and/or sensitive 
substrates of CYP2B6 or in the opinion of the investigator, cannot be safely tapered off 
these medications prior to Randomization.
10.
Has laboratory and/or clinical evidence of clinically significant hepatic conditions such 
as:
a)
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2x upper 
limit of normal (ULN) and total bilirubin >1.5x ULN.
b)
ALT or AST >3x ULN 
c)
A history of hepatitis or liver disease that, in the opinion of the investigator, has 
been active within the six months prior to Screening.
11.
Has a prolactin laboratory value of ≥ 5 X ULN at Screening.
12.
Has known cardiovascular disease (history of angina, myocardial infarction or 
ischemia, heart failure, or conduction abnormalities) or cerebrovascular disease. 
13.
Has a risk factor for QTc prolongation as defined by:
 
 
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a) a known history or current evidence of QTc interval >450 msec for males or > 470 
msec for females
b) a known history of risk factors for Torsades de Pointes (e.g.,
heart 
failure/cardiomyopathy or family history of long QT Syndrome)
c) hypokalemia or hypomagnesemia
(Note: Determination of QTc interval at Screening as a pretreatment reference will be 
based on the average of three measurements, using the Fridericia formula [QTcF] for 
correction. The average will be calculated by the site.)
14.
Has known renal disease or is experiencing renal insufficiency as defined by:
a) Estimated glomerular filtration rate (eGFR) of <70 mL/min/1.73m2 [as measured 
by Modification of Diet in Renal Disease (MDRD) formula]
15.
Has adverse events or clinically significant abnormal laboratory, vital sign, or physical 
examination, or ECG finding during Screening phase indicative of emerging or 
unstable medical conditions that potentially interfere with the ability to evaluate the 
safety, tolerability and the efficacy of the trial medication, according to the judgment of 
the investigator.
16.
As a female, has a positive serum pregnancy test at Screening or is nursing or plans to 
nurse children.
17.
Has a known history of untreated narrow angle glaucoma.
18.
Has ever been diagnosed with epilepsy or had any seizure disorder beyond one 
childhood febrile seizure.
19.
Has known serological evidence of human immunodeficiency virus (HIV) antibody.
20.
Has a history of neuroleptic malignant syndrome.
21.
Has a primary current diagnosis other than schizophrenia or a comorbid diagnosis that 
is primarily responsible for the current symptoms and functional impairment.
22.
Has a known history of the following 
a) borderline personality disorder, antisocial personality disorder, or bipolar disorder. 
b) traumatic brain injury causing ongoing cognitive difficulties, Alzheimer’s disease 
or another form of dementia, or any chronic organic disease of the central nervous 
system
c) intellectual disability of a severity that would impact the ability of the subject to 
participate in the trial
23.
Currently (within the past 6 months prior to screening) meets the DSM-5™criteria for 
substance use disorder (excluding nicotine dependence) or alcohol use disorder.
24.
Has a positive urine alcohol/drug screen at the Screening visit (subjects with positive 
psychotropic medication results for drugs permitted at time of screening may be 
included provided the finding can be accounted for by documented prescription use and 
the subject is able and willing to comply with protocol requirements regarding excluded 
 
 
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medications). 
Subjects with positive alcohol or cannabis results on the urine 
alcohol/drug screen may be included at the investigator’s discretion, provided the 
investigator does not feel the subject is a compliance risk and the subject does not fulfill 
the criteria for substance abuse or dependence.
25.
Has a current diagnosis of a psychotic disorder (other than schizophrenia) or a 
behavioral disturbance thought to be substance-induced or due to substance abuse.
26.
Is at imminent risk of self-harm or harm to others, in the investigator’s opinion based 
on clinical interview, MINI, or responses provided on the C-SSRS. Note that subjects 
must be excluded if they report suicidal ideation meeting the description of C-SSRS 
Type 4 or 5 (i.e., suicidal ideation with intent, with or without a plan) within the past 
two months or suicidal behavior (as described by the C-SSRS) within the past six 
months at Screening. Subjects must be excluded at Baseline if they report suicidal 
ideation of Type 4 or 5 or suicidal behavior, as measured by the C-SSRS between 
Screening and Baseline.
27.
Committed an act of violence (assaultive behavior) ≤2 years prior to the Screening
visit. Note: history of assaultive behavior which resulted in commitment or 
incarceration is not necessarily exclusionary if the behavior was verbal abuse only or if 
the investigator has a full understanding of the nature of the assaultive behavior in 
question and judges the past assaultive behavior as not indicative of a risk to personal 
or public safety.  The investigator should exclude enrollment of subjects who may be at 
risk for future assaultive behavior. 
28.
Is known to be repeatedly medically noncompliant in the management of their disease
as assessed by the investigator.
29.
Has a history of significant multiple and/or severe allergies (e.g., food, drugs, latex 
allergy), or has had an anaphylactic reaction or significant intolerability to prescription 
or non-prescription drugs or food.
30.
Has a known allergy or sensitivity to risperidone, active ingredients or other inert 
ingredients. 
31.
Has hypothyroidism, diabetes, high blood pressure, or chronic respiratory condition or 
other chronic medical conditions unless the condition is stable and the prescribed dose 
and regimen of medication are stable for ≥ 3 months prior to Screening and there are no 
expected changes in co-medication during the study.
32.
Presents any concern which in the opinion of the investigator may render the subject 
inappropriate for participation in the study.
33.
Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
 
 
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Trial Treatment(s)
5.2
The treatments to be used in this trial are outlined below in Table 1.
Table 1
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
MK-8189
(4 mg)
4 mg controlled 
release (CR) 
formulation
QD 
Oral
1 tablet/day, Visit 2
/Day 1 (3 [+1] days)
Experimental
treatment
Placebo for 
4-mg 
MK-8189
0 mg
QD
Oral
1 tablet/day, Visit 
2/Day 1 (3 [+ 1] days)
Placebo to 
experimental 
treatment
Risperidone
2 mg
2 mg
QD
Oral
1 capsule/day Visit 2 
/Day 1 (3[+1] days)
Comparator
Placebo for 
2-mg 
risperidone
0 mg
QD
Oral
1 capsule/day Visit 2 
/Day 1 (3[+1] days)
Placebo to 
comparator
MK-8189
(8 mg )
4 mg controlled 
release (CR) 
formulation
QD 
Oral
2 tablets/day,  Day 4
(3[+1] days)
Experimental
treatment
Placebo for 
8-mg 
MK-8189
0 mg
QD
Oral
2 tablets/day, Day 4
(3[+1]days)
Placebo to 
experimental 
treatment
Risperidone  
(4 mg)
2 mg
QD
Oral
2 capsules/day,  Day 4
(3[+1] days)
Comparator
Placebo for 
4-mg 
risperidone
0 mg
QD
Oral
2 capsules/day,  Day 4
(3[+1] days)
Placebo to 
comparator
MK-8189 
(12 mg)*
4 mg controlled 
release (CR) 
formulation
QD
Oral
3 tablets/day, Visits 3-6
Experimental
treatment
Placebo for   
12-mg 
MK-8189*
4 mg controlled 
release (CR) 
formulation
QD
Oral
3 tablets/day, Visits 3-6
Placebo to 
experimental 
treatment
Risperidone
6 mg *
2 mg
QD
Oral
3 capsules/day, Visits 
3-6
Comparator
Placebo for 
6-mg
risperidone*
0 mg
QD
Oral
3 capsules/day, Visits 
3-6
Placebo to 
comparator
*
Subjects may decrease dose to 8 mg MK-8189 / 4 mg risperidone QD if 12 mg MK-8189 / 6 mg risperidone QD is 
not tolerated. Subjects will be discontinued from IP if they cannot tolerate the 8 mg MK-8189 / 4 mg risperidone
QD dose.
Each subject will be randomized to study treatment MK-8189, placebo, or risperidone and 
receive a randomization number at Visit 2 (baseline visit). Randomization should not occur 
until all eligibility criteria have been assessed (i.e., the site has received and evaluated all 
pending reports from central ECG, central laboratory, and external SDME’s approval of 
eligibility based on the information provided in the psychiatric intake evaluation form).
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
 
 
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Dose Selection/Modification
5.2.1
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
5.2.1.2
Dose Modification (Escalation/Titration/Other)
Subjects who are found to be eligible to participate in the study will, at the Baseline (Visit 
2/Day 1) visit, be randomly assigned to MK-8189, placebo, or risperidone treatment groups 
in a 2:2:1 distribution, respectively.  Each dose per treatment group will be given in a double-
dummy and QD fashion. Subjects randomized to the MK-8189 treatment group will receive,
per dose, equal numbers of 4-mg MK-8189 active tablets and risperidone matching placebo 
capsules; subjects randomized to the risperidone treatment group will receive, per dose, equal 
numbers of 2-mg risperidone active capsules and MK-8189 matching placebo tablets; 
subjects randomized to the placebo treatment group will receive, per dose, equal numbers of 
risperidone matching placebo capsules and MK-8189 matching placebo tablets.  
Initial doses per treatment group will be given as 1 tablet and 1 capsule: the combination of 1 
tablet and 1 capsule will therefore result in the initial QD dose
2-mg 
risperidone for subjects randomized to MK-8189 and risperidone treatments groups, 
respectively, and placebo only for subjects randomized to placebo.   
For subjects in each randomized group, titration 
 
 
 
  

 
 
 
 

Subjects assigned to the placebo group will be titrated to a final target of 3 MK-8189 
matching placebo tablets and 3 risperidone matching placebo capsules using the 
following titration steps: on Day 4, the IP dose will be increased to 2 MK-8189 
matching placebo tablets and 2 risperidone matching placebo capsules; on Day 7, the 
dose will again be increased to 3 MK-8189 matching placebo tablets and 3
risperidone matching placebo capsules for the remainder of the trial, as tolerated.  

Subjects assigned to the risperidone group will be titrated to a final targeted dose of 
6-mg risperidone (3 capsules) and 3 MK-8189 matching placebo tablets using the 
 
 
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following titration steps: on Day 4, the IP dose will be increased to 2 risperidone 2-
mg capsules and 2 MK-8189 matching placebo tablets for a total of a 4-mg dose of 
risperidone; on Day 7, the dose will again be increased to 3 risperidone 2-mg capsules 
and 3 MK-8189 matching placebo tablets for a total of a 6-mg risperidone dose for 
the remainder of the trial, as tolerated.
 
 
 
  
Subjects will be discontinued from IP in the event that subjects cannot tolerate the dose of 
/ 4-mg risperidone QD.
All dosing should occur in the morning.  The dose titration schedule in the current trial is
based on previous clinical pharmacology trial data for the MK-8189 compound and the label 
for risperidone.  Decisions to change the dose are to be made by the primary investigator 
based on the subject’s symptomatology and tolerability. 
Once a subject has completed participation in the treatment phase at Day 28, the IP will no 
longer be available to the subject.  
Timing of Dose Administration
5.2.2
Subjects will receive double-blind IP on Visit 2 (Day 1) in the inpatient setting if they meet 
all eligibility criteria. The first dose will be administered after all baseline visit safety 
assessments and efficacy assessments are completed (including the collection of blood 
samples and pre-dose PK sample) and subsequent randomization.  Note: randomization and 
first dose must be done on the same day. While in the inpatient setting, subjects should be 
administered their IP at approximately the same time each morning. The IP dose can be 
taken without regard to food intake.  If a dose is missed in the morning, it can be taken any 
time up to 1 PM.  Subjects will be monitored for compliance.
Trial Blinding/Masking
5.2.3
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.
The subject, the investigator and Sponsor personnel or delegate(s) who are 
involved in the treatment or clinical evaluation of the subjects are unaware of the group 
assignments.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization or Treatment Allocation
5.3
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 3 treatment arms.  
 
 
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Subjects will be assigned randomly in a 2:2:1 ratio to MK-8189, placebo, or risperidone for 
the duration of the 4 weeks of treatment. 
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Listed below are specific restrictions for concomitant therapy during the course of the trial:
Medications specifically prohibited in the exclusion criteria are not allowed during the 
treatment period. Medications with a moderate or strong inhibiting or inducing effect on 
cytochrome P450 (CYP) 3A and/or CYP2C9 and/or the use of medications that are sensitive 
substrates of CYP2B6 are prohibited during the treatment period.
In addition, all 
psychotropic medications (including antipsychotics, antidepressants, mood stabilizers, other 
psychotropics) are prohibited during the treatment period, except as described in Table 3.  
The subject must be able to discontinue or, in the opinion of the investigator, safely taper off, 
of any prohibited treatment listed in Table 2 over 3 (+4) days prior to the Baseline visit (Visit 
2) without significant destabilization or increased suicidality.  
The following list is not to be considered an exhaustive list of the aforesaid medications. All 
current and recent medications taken by a potential subject should be reviewed to ensure they 
are not exclusionary to recruitment or screening.  The Investigator should seek guidance from 
the Sponsor when needed.
 
 
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Table 2
Prohibited Medications during the Treatment Period
CYP inducers, inhibitors and sensitive substrates a
CYP3A known inhibitors:
Strong: Boceprevir, clarithromycin, conivaptan, indinavir, traconazole, 
ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir,
posaconazole, ritonavir, saquinavir,  telaprevir, telithromycin, 
voriconazole, tipranavir, cobicistat
Moderate: Amprenavir, aprepitant, atazanavir, ciprofloxacin, 
darunavir/ritonavir, diltiazem, erythromycin, fluconazole, 
fosamprenavir, imatinib, verapamil, idelalisib, danoprevir, delavirdine
CYP3A known inducers
Strong: Carbamazepine, phenytoin, rifampin, mitotane, avasimibe, 
enzalutamide, St John's Wort extract, rifabutin, phenobarbital
Moderate: Bosentan, efavirenz, etravirine, modafinil, nafcillin; ritonavir 
and St. John’s Wort, tipranavir and ritonavir, genistein, thioridazine, 
talviraline, lopinavir, lersivirine
CYP2C9 known inhibitors
Strong: Piperine, miconazole, phenylbutazone, tienilic acid, 
azapropazone, bucolome, sulfaphenazole, benzbromarone
Moderate: Amiodarone, fluconazole, oxandrolone
CYP2C9 known inducers
Moderate: Carbamazepine, rifampin, enzalutamide, ritonavir
CYP2B6 known substrates with 
sensitive therapeutic range
Bupropion, efavirenz
Medications Supplements, Other Substances and Procedures
Antipsychotics (other than trial medication)
Antidepressants
Mood stabilizers
Stimulants such as Ritalin and amphetamines
MAO inhibitors b
Herbal drugs/dietary supplements, including and not limited to St John’s Wort, ginkgo, goldensealc
Antiemetics containing dopamine agonist
Illicit drugs
Medium and long-acting benzodiazepinesd
ECT
Individual therapy
MAO = Monoamine oxidase
ECT = Electroconvulsive Therapy
a
Sources include the FDA website 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabe
ling/ucm093664.htm#potency
b
The last dose of a MAO inhibitor must be 1 month prior to Screening.
c
Dietary supplements that are specifically marketed for psychiatric symptoms (e.g., valerian, Bach’s 
flower remedies) are prohibited. Supplements with broader applications for general health (such as 
omega-3-fatty acids, magnesium) are not prohibited
d
For countries where no short-acting benzodiazepine is approved, diazepam (up to 30 mg/day during the 
taper period and first 14 days of active treatment, up to 15 mg/day thereafter) is permitted to be used for 
the control of agitation, anxiety, and insomnia, if available. In the event diazepam is not available in 
countries where no short-acting benzodiazepine is approved, use of other benzodiazepines must first be 
discussed with and approved by SDME prior to use.
 
 
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Table 3
Medications and Procedures Permitted during the Treatment Period
Permitted medications post Baselinea
As-needed use non-psychotropic medications
Aspirin, 
Nonsteroidal 
anti-inflammatory 
drugs 
(NSAIDs), acetaminophens  
Chronic use medication
Chronic use of certain medications are allowed if the 
history of its use and subject’s condition meets 
specifications of the eligibility criteria 
Approved extrapyramidal symptoms (EPS)
medications
Anticholinergic or any other medications to treat 
EPS ongoing at the time of screening should be 
maintained through the treatment phase.  If EPS 
worsens, doses should be adjusted to treat symptoms 
during the trial as needed 
Lorazepam up to 6 mg/day during the taper period 
and the first 14 days of active treatment or the 
equivalent dose of short-acting benzodiazepines for 
the treatment of agitation, anxiety Remainder of days 
on active treatment: lorazepam up to 4 mg/day or an 
equivalent dose of short-acting benzodiazepine on a 
daily basis. b,c
To be used only on as-needed basis. For recording in 
the CRF, enter total daily dose for each day when 
recording benzodiazepine use. If a daily dose is the 
same for greater than a single day over consecutive 
days, recording of the consecutive date range for the 
same daily dose is acceptable.
Partial benzodiazepine agonists for the treatment of 
insomnia at recommended dose rangesc,d
Suvorexante
Zolpidem (2.5 to 10 mg/day), zaleplon (5 to 
20 mg/day), zopiclone (7.5 to 15 mg/day), or any 
equivalent short half-life non-benzodiazepine 
hypnotic may also be used for insomnia/sleep
disturbance if zolpidem, zaleplon, or zopiclone are 
not available in specific countries. To be used only 
on an as-needed basis: Suvorexant (10 mg-20 mg)
a
Chronic use of certain medications are allowed if the subject’s condition is stable, and the dose was 
stabilized prior to the first dose on Day 1 and they are not strong or moderate CYP3A known inhibitors 
and inducers, strong or moderate CYP2C9 known inhibitors and  inducers, and CYP2B6 known 
substrates with sensitive therapeutic range.
b
To be used on as-needed basis. For countries where no short-acting benzodiazepine is approved, 
diazepam (up to 30 mg/day during the taper period and first 14 days of active treatment, up to 15mg/day 
thereafter) is permitted to be used for the control of agitation, anxiety, and insomnia. In the event 
diazepam is not available in countries where no short-acting benzodiazepine is approved, use of other 
benzodiazepines must first be discussed with and approved by SDME prior to use.
c
The use of drugs to treat agitation, anxiety, or insomnia or with known sedative effects have the potential 
to impact efficacy assessments.  The sites should consider avoiding their use within the 4 to 8  hours 
prior to efficacy assessments.
d
Any equivalent short half-life non-benzodiazepine hypnotic may also be used for insomnia/sleep 
disturbance if zolpidem, zaleplon, or zopiclone are not available in specific countries.
e
In countries where approved (USA, Japan).
All medications used in the last 3 months prior to screening should be recorded. Reasons for 
use for each medication (prior and concomitant) should also be recorded.
Rescue Medications & Supportive Care
5.6
See Section 5.5 regarding the use of EPS medications and permitted medications for treating 
insomnia, agitation and anxiety during the trial.  After last day of IP treatment and after all 
 
 
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assessments have been completed the subject may begin standard of care treatment for the 
disease under study.
Diet/Activity/Other Considerations
5.7
Subjects should refrain from the consumption of more than 1 grapefruit or 1 glass (8 ounces) 
of grapefruit juice a day, throughout the entire study period. Otherwise, subjects are allowed 
to consume their usual diet throughout the study period.
Subject Withdrawal/Discontinuation Criteria
5.8
Discontinuation of Treatment
5.8.1
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment will still continue to participate in the trial as specified in 
Section 6.0 - Trial Flow Chart and Section 7.1.4.1. – Withdrawal/Discontinuation.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
○
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
The subject has a medical condition, or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the subject at unnecessary risk or does not allow 
the subject to adhere to the requirements of the protocol. 
o
The subject experiences a further increase of psychotic symptoms or suicidal 
ideation/behavior during the study which, in the opinion of the investigator and/or 
Sponsor, places the subject at unnecessary risk or does not allow the subject to adhere to 
the requirements of the protocol.
o
The subject has a positive serum pregnancy test.
o
The subject has a positive urine alcohol/drug screen (excluding allowed concomitant 
medications) with the exception of the screening visit urine alcohol/drug screen, as 
described in Section 7.1.3.3.
 
 
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o
The subject experiences one of the following elevated liver enzyme conditions, which is 
confirmed by repeat testing:
o
ALT or AST >3x ULN and total bilirubin >2x ULN,
o
ALT or AST >5x UNL
o
ALT or AST >3x ULN for more than 2 weeks
o
ALT or AST >3x ULN with the appearance of jaundice, worsening of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or 
eosinophilia.
o
The subject has an absolute neutrophil count of <1000 per mm3, and after repeat testing 
within 48 hours, the values are not normalized or increased.
o
Subjects who report suicidal ideation with intent, with or without a plan or method (i.e., 
a positive response to items 4 or 5 in the assessment of suicidal ideation on the C-SSRS) 
or suicidal behavior may meet discontinuation criteria. Please refer to Section 7.1.2.2.3
and the ECI guidance document for details.
o
The subject has eGFR of < 60 mL/min/1.73m2.
o
The subject has a QTcF interval of ≥500 msec (The average of the three QTcFs will be 
used).
o
The subject cannot tolerate a dose of 8-mg MK-8189 QD/4-mg risperidone QD.
In the event of any reason for discontinuation from treatment, all procedures for the study 
discontinuation visit (V6) should be performed.  The subject should be followed-up per the 
Study Flow Chart Post-Treatment period to assess for safety. 
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
see Section 6.0 – Trial Flow Chart, and Section 7.1.4.1 – Withdrawal/Discontinuation for 
those procedures to be completed at each specified visit.
Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
Withdrawal from the Trial
5.8.2
Subjects may withdraw from the trial at any time for any reason.  If a subject withdraws from 
the trial, they will no longer receive treatment or be followed at scheduled protocol visits.
A subject must be withdrawn from the trial if:
○
The subject or subject’s legally acceptable representative withdraws consent from the 
trial.
○
The subject is lost to follow-up.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including specific details regarding withdrawal from Future Biomedical Research are 
outlined in Section 7.1.4 – Other Procedures.
 
 
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Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.11
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
 
 
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6.0 TRIAL FLOW CHART
Trial Period:
Screening
Treatment
Post-treatment
Inpatient
Visit Number/Title:
1
Screening
Taperinga
2
Baselineb
Rand
3
Treatment
4
Treatment
5
Treatmentc
6
End of 
Treatmentd/DCe
7
TCf
8
Follow-
up
9
TCf
Scheduled Days:
-3
1
7
14
21
28
Post 3 
days
Post 7 
days
Post 14 
days
Scheduling Window, Days:
+4
±1
±1
±1
±1
±1
±3
±3
Administrative Procedures
Informed Consent
X
Informed Consent for Future Biomedical Research 
(FBR) 
X
Inclusion/Exclusion Criteria
X
X
Subject Identification Cardg
X
Medical and Psychiatric History 
X
Substance, Alcohol /Smoking History
X
Social History
X
Psychiatric Intake Evaluationh
X
MINIi
X
Identify external contact person j
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
Treatment Allocation/Randomization
X
Call/log into IVRS/IWRS
X
X
X
X
X
X
IP Dispensing via IVRS/IWRS
X
X
X
X
Clinical Procedures/Assessments
Physical Examination
X
X
Height
X
Weight, Waist Circumference
X
X
X
12-Lead Electrocardiogramk
X
X
X
Vital Signs (heart rate, blood pressure)
X
X
X
X
X
X
PANSSi,l
X
X
X
X
X
X
CGI-S 
X
X
X
X
X
X
C-SSRSm
X
X
X
X
X
Xn
ESRS-A 
X
X
X
X
X
X
Monitor compliance with Trial Medication
X
X
X
X
X
Adverse Events Monitoring
X
X
X
X
X
X
X
X
X
 
 
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Trial Period:
Screening
Treatment
Post-treatment
Inpatient
Visit Number/Title:
1
Screening
Taperinga
2
Baselineb
Rand
3
Treatment
4
Treatment
5
Treatmentc
6
End of 
Treatmentd/DCe
7
TCf
8
Follow-
up
9
TCf
Scheduled Days:
-3
1
7
14
21
28
Post 3 
days
Post 7 
days
Post 14 
days
Scheduling Window, Days:
+4
±1
±1
±1
±1
±1
±3
±3
Laboratory Procedures/Assessments
Blood Drawo
X
X
X
X
Insulin
X
X
X
Lipid Panel
X
X
X
Prolactin
X
X
X
Serum β-Human Chorionic Gonadotropin (β-hCG) –
if applicablep
X
Serum Follicle Stimulating Hormone (FSH) - if 
applicablep
X
HIV Screen (Per site SOPs and at the discretion of 
the investigator
X
Hepatitis Screen (Per site SOPs and at the discretion 
of the investigator
X
Blood for Genetic Analysisq  
X
Thyroid Stimulating Hormone (TSH)
X
X
X
Urine Specimen Collectionr
X
X
X
X
Additional Urine Specimen Collection –if applicable r
X
X
Urine Alcohol/Drug Screenp, r
X
X
Urine Pregnancy Test – if applicablep, r
X
X
X
X
X
X
Urinalysis
X
X
X
X
Residual urines
X
X
PK Sampleb,t
X
X
Xu
TC = Telephone contact, DC = discontinuation, MINI = Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders, PANSS = Positive and Negative 
Syndrome Scale, CGI-S = Clinical Global Impression Scale-Severity, C-SSRS = Columbia Suicide Severity Rating Scale, ESRS-A = Extrapyramidal Symptoms Rating Scale-
Abbreviated, PK = Pharmacokinetics
a)
During this tapering period, any psychotropic medications prohibited in Section 5.5 of the protocol (antipsychotics, antidepressants, and mood stabilizers) should be tapered 
under the direct supervision of the investigator (last dose to be taken no later than the evening prior to baseline) (Visit 2).  If it is the clinical judgment of the investigator that 
the -3(+4) day tapering period may be skipped for an individual subject, trial medication may begin as early as the morning after the Screening procedures, provided all of the 
eligibility criteria have been met.  
b)
For subjects who skip the tapering period, the Baseline PK assessments must be completed on the screening day.  Screening assessments that are normally repeated at Baseline 
need not be repeated for subjects who skip the tapering period with the following exceptions: blood draw should be repeated on the morning of Day 1, prior to the first dose of 
trial medication, if the Screening blood draw was not taken in a fasting state (no food or drink other than water ≥10 hours).
 
 
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c)
Hospital discharge may occur on Day 21 if the subject is ready for discharge according to the specifications of the protocol. Subjects that are discharged on Day 21 will be 
discharged after completion of assessments and may continue in the treatment phase as outpatients.  The day after discharge and approximately mid-week after discharge, the 
subject should be telephoned to ensure that he or she has understood dosing instructions, to assess adverse events, and to remind the subject of the Day 28 visit. Subjects who 
are discharged on Day 21 will have their end of treatment assessments on Day 28.
d)
Subjects that are discharged on Day 28 will be discharged after completion of assessments.  Subjects who are not ready to be discharged on Day 28 will have their end of 
treatment assessments on Day 28. Approval is required to extend the hospitalization past Day 28.
e)
In the event of premature discontinuation from treatment, end of treatment assessments (V6) are administered at the time of treatment discontinuation and all post-treatment 
follow-up phone contacts and site visit will be conducted unless there is withdrawal of consent.
f)
Virtual phone visits will be conducted 3 and 14 days post-treatment after the subject completes or discontinues from treatment.  
g)
Subject will receive a subject identification card at Screening. If the subject is randomized, the card will be updated with the subject’s randomization number.
h)
The Psychiatric Intake Evaluation must be reviewed/approved by the external SDME prior to randomization.   
i)
PANSS and MINI interview process will include video and/or audio technology which must be reviewed/approved by the external SDME prior to randomization.
j)
Subjects must have an identified responsible person (e.g., family member, social worker, case worker, case manager, or nurse), referred to as the “external contact person” in 
this protocol, to be considered eligible for enrollment. Site personnel must assure that the external contact person will be available to help the site locate the trial subject when a 
phone contact or visit is missed.  
k)
Determination of QTc interval at Screening and QTc prolongation will be based on the average of three measurements, using the Fridericia formula for correction.
l)
To avoid the influence of subject fatigue on the diagnostic and primary outcome data, the PANSS interviews should be conducted early in each applicable visit.
m)
During the Screening visit, the subject’s symptoms and actions over the past 6 months should be evaluated with the C-SSRS (C-SSRS Screening Version). For all other visits, 
the subject’s symptoms and actions since the last assessment should be evaluated (C-SSRS Since Last Visit Version). 
n)
The investigator should be aware of the C-SSRS scores upon discontinuation from treatment. Subjects with scores showing suicidality (e.g., any suicidal ideation of Type 4 or 5 
and/or any suicidal behavior) should be thoroughly evaluated by the investigator.  
o)
Blood collected at all time points for “blood draw” is used for analysis of Chemistry and Hematology (as specified in Table 4). Insulin, TSH, Lipid Panel, Prolactin, Serum β-
hCG, FSH, and Genetic Analysis are analyzed at time points specified in this Flow Chart. HIV screening and/or viral hepatitis panel screen may be performed (at discretion of 
investigator). Fasting blood draws at Screening are encouraged. During the inpatient phase, including Baseline, blood samples (for clinical laboratory evaluations and pre-dose 
PK) are drawn with subjects in the fasting state before breakfast prior to the morning dose.  It is anticipated that blood samples for laboratory and pre-dose PK evaluations are 
drawn at the same time.  
p)
In addition to the testing at the required times specified in the table, urine/alcohol/drug tests, urine pregnancy tests, and serum pregnancy tests may be performed at the 
investigator’s discretion throughout the course of the trial. Urine and serum pregnancy tests will be performed for only women of child-bearing potential.  Note that local urine 
alcohol drug screen can be done for determining eligibility if the central laboratory results are pending.  
q)
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response.  If there is either a documented law or regulation 
prohibiting collection, or if the institutional review board/ethics committees (IRB/IEC) does not approve the collection of the sample for these purposes, then this sample will 
not be collected at that site. If the sample is collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned 
genetic analysis is not approved, but FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
r)
Urine is collected for all subjects at every visit except visits 3 and 5, when urine is collected only for women of child bearing potential. Collected urine will be used for  urine
alcohol/drug tests, urine pregnancy tests, and urinalysis (as specified in Table 4)  at time points specified in the Flow Chart.  Residual urine at time points specified in the Flow 
Chart will also be sent to the central laboratory.  
s)
Leftover residual urine will be stored for future biomedical research, if the subject consents to future biomedical research.  
t)
PK samples are collected at time points relative to dosing as follows: Day 1 pre-dose (baseline); Day 14 pre-dose, 4 hr and 10 hr post-dose; and Day 28 pre-dose.
u)
PK sample will not be collected if the subject discontinues from treatment.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed at Visit 1 and Visit 2 by the investigator 
or qualified designee to ensure that the subject qualifies for the trial.  For assessments that 
require reviewing by a central reader or vendor for eligibility qualification, please refer to the 
specific guidance documents relating to that particular assessment.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history (including any pre-existing clinically significant medical conditions) will 
be obtained by the investigator or qualified designee.  Clinically significant findings in 
physical examination, laboratory tests, ECGs, and other physical evaluations during 
Screening are to be noted in the medical history page of the electronic case report form 
(eCRF). Clinically significant changes from the Screening evaluation during the trial should 
be captured on the AE page of the eCRF. Psychiatric conditions and symptoms including 
those captured in the MINI evaluation should be recorded in the medical history form.
7.1.1.4.1 Substance/Alcohol/Smoking History/ Social History
Personal and social history such as living/employment/arrest and substance/alcohol/smoking 
will be reviewed. Arrest history will also be assessed. Note: history of assaultive behavior 
which resulted in commitment or incarceration which was verbal abuse only (not violent, 
aggressive or physical in nature) is not necessarily exclusionary. The investigator should 
exclude enrollment of subjects who may be at risk for future assaultive behavior.
7.1.1.5
Psychiatric History
Diagnostic eligibility will be assessed based on a psychiatric evaluation of the subject by
reviewing the subject's psychiatric history including other information sources (e.g., medical 
 
 
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charts, health care provider or paraprofessional), and confirmation of the diagnosis of 
schizophrenia using the MINI Version 7.  All psychiatric diagnoses specified in the 
inclusion/exclusion criteria will be made according to the DSM-5™.
7.1.1.5.1
Psychiatric Intake Evaluation and MINI 
The subject’s history of the presenting problem, a detailed description of the current acute 
exacerbation (onset, duration, precipitants, differentiation from symptom status prior to the 
current episode, functional impairment, and corroboration of a current acute exacerbation by 
available sources [e.g., medical charts, health care provider, or paraprofessional]), psychiatric 
and treatment history (response/nonresponse to previous antipsychotics as described in the 
inclusion criteria), medical history, mental status, diagnosis and treatment plan must be 
documented in the source documents. Identification of the source of this information must 
be included; if this information was obtained from a verbal account by a healthcare 
professional or paraprofessional, the relationship and duration of the relationship between the  
professional and the subject must be included in the description. A family member may be 
considered as the sole source for corroboration only in the event that corroboration cannot be 
provided through medical records or through a health professional, and the subject lives with 
a family member who is considered a reliable informant by the investigator.
Diagnostic eligibility will be assessed based on interview with the subject, review of the 
subject's history including other information sources (listed above) and documented during
psychiatric intake evaluation.
All psychiatric diagnoses specified in the inclusion/exclusion criteria will be made according 
to the DSM-5 ™criteria.  The diagnosis will be confirmed using the MINI Version 7.
The eligibility criteria require an illness duration of ≤20 years. The PI will use his/her best 
estimate, based on available resources (including medical charts, patient self-report, family 
member, health or paraprofessional report) to determine illness duration.
A psychiatric intake evaluation form containing key elements of the psychiatric evaluation 
must be forwarded to the external SDME for review, to ensure that the subject meets 
diagnostic eligibility criteria prior to randomization. Additionally, the external SDME will 
take into account the independent PANSS ratings of the central rater for the final 
determination of the subject’s eligibility.
The completed psychiatric intake evaluation form should be sent no more than 2 days after 
the screening visit to ensure a timely review by the external SDME.
Subjects cannot be 
randomized without the approval of the external SDME. 
For subjects who skip the taper period, the investigator must contact the external SDME by 
telephone to review critical elements of the psychiatric intake evaluation form and must 
receive verbal agreement that the subject’s acute exacerbation and diagnostic status meet 
entry criteria. This telephone review must be documented and a copy kept in the subject’s 
source documents. 
 
 
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7.1.1.6
Identify External Contact Person
Subjects must have an identified responsible person (e.g., family member, social worker, 
case worker, case manager, or nurse) to be considered eligible for enrollment. The subject 
must provide the name and contact information of his/her external contact person.
Site 
personnel must confirm that this person (referred to as the “external contact person”) will be 
available to locate the subject in the event that the subject cannot be contacted. The site must 
interview the potential external contact person and consider the external contact person to be 
reliable; the external contact person must confirm that they anticipate to have contact no less 
than once per week with the subject as an outpatient during the trial; either in person or via 
telephone. The source documents must record the external contact person’s agreement to act 
as the subject’s contact person. If the subject does not have an external contact person that is 
considered reliable by the site, the site may designate a site representative to act as the 
subject’s external contact person, with the same responsibilities as described above. The 
investigator may not act as the external contact person. In the event the designated external 
contact person has been designated for more than 1 subject, the investigator is responsible for 
documenting in the source that the external contact person will have the time to devote to 
each subject as defined by the protocol requirements.
7.1.1.7
Prior and Concomitant Medications Review
7.1.1.7.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified tapering requirement, and record prior medication taken by the subject 
within 3 months before Visit 2.
The subject must be able to discontinue or, in the opinion of the investigator, safely taper off,
of any prohibited treatment listed in Table 2 prior to the Baseline visit (Visit 2) without 
significant destabilization or increased suicidality. 
7.1.1.7.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial and reasons for medication use.  If the subject reports taking any prohibited 
medications during the screening or treatment period, this should be recorded as a study 
deviation.  Concomitant medications should preferably not be changed during the course of 
treatment period, without first consulting the investigator, except in cases of medical 
emergencies or other obvious exceptions.
7.1.1.8
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
 
 
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7.1.1.9
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
7.1.1.10 Interactive Voice Response System/Integrated Web Response System
The investigator or designee will call/log into IVRS/IWRS as specified in the Trial Flow 
Chart.  Upon confirmation of a subject’s eligibility at Visit 2, the investigator or designee 
will call IVRS or log into IWRS to randomize the subject.  Subjects who do not meet 
eligibility criteria at Visit 2 will be screen-failed in IVRS/IWRS.  For all randomized 
subjects, the investigator or designee will continue to call/log into IVRS/IWRS as per the 
Trial Flow Chart.  For completed or discontinued subjects, the investigator or designee will 
make the final call/web action into IVRS/IWRS at their last treatment visit.
7.1.1.11 Trial Medication Dispensing
At the visits specified in the Trial Flow Chart, the site will dispense trial medication using the
IVRS/IWRS system. 
7.1.1.12 Trial Compliance (Medication/Diet/Activity/Other)
Medication compliance during the trial will be monitored and determined by IP count (total 
IP count as well as separate tablet/capsule counts).
For all subjects who are eligible for 
outpatient status, IP count will be monitored and determined by subject interview, entries 
into the dosing diary, and by tablet/capsule count at Visit 6.  Instances of trial medication 
non-compliance should be documented as follows:

Less trial medication was taken than prescribed: Instances where a subject failed to 
take trial medication as prescribed and missed a dose should be documented.  A 
missed IP dose is defined as taking less of either IP type (less tablets and/or less 
capsules of IP) than required in a single 24 hour period (see Table 1 for the number of
IP tablets and capsules taken per QD dose).

More trial medication was taken than prescribed: Taking more medication of either 
IP type (more tablets and/or more capsules of IP) than prescribed for a subject is 
considered an AE of "overdose".  See Section 7.2.1 for details regarding reporting of 
overdoses. An overdose of IP is defined as taking more than the maximum number of 
either IP type (capsules and/or tablets) specified for a single dose in one day.
Note that a subject is counted as an overdose and also as a missed dose if the subject
takes more than either IP type and less of the other (tablets or capsules) specified in a 
dose.  
 
 
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
For subjects who are discharged as outpatients at Day 21, overdose or under-dose 
may need to take into account the investigator’s best judgment if IP tablets/capsules 
were lost or taken in the event that the drug return, entries into the dosing diary, 
and/or subject contact recollection does not match.
Interruptions from the protocol specified dosing for ≥3 consecutive days at any time point 
during the active treatment phase require consultation between the investigator and the 
Sponsor and written documentation of the collaborative decision on subject management.
All individuals who dispense trial medication to the subject should monitor the subject to 
ensure doses are taken as directed, and record relevant dosing information (including number 
of tablets/capsules and exact time taken) in source documents.
If the subject is discharged from the hospital at Day 21, they will continue as outpatients for 
the remainder of the active treatment period (to Day 28). See Section 7.1.4.5 (Administer 
Trial Medication) for additional instructions pertaining to outpatient training.
In addition to routine surveillance of IP count (tablets and capsules), outpatient subjects will 
be given an IP dosing diary to help subjects record the number of tablets and capsules taken 
from each bottle and the time that each dose was taken. 
When the outpatient returns to the clinical site at Visit 6, the outpatient should return their 
completed dosing diary and trial medication, including empty bottles. The site will perform 
an IP (tablet and capsule) count and also review the entries in the dosing diary to verify IP
count and any possible missed or extra doses taken.  If there is a discrepancy between the 
bottle and the dosing diary, the subject verbal account and site judgment will be used to 
determine the final decision on documenting IP count in the eCRF.
Discrepancies and the reasoning for what was ultimately recorded in the eCRF should be 
documented in the site’s source documents.  For outpatient subjects who discontinue trial 
medication early, site personnel should ensure the subject returns all trial medication.
Clinical Procedures/Assessments
7.1.2
7.1.2.1
Physical Assessments/Examinations
7.1.2.1.1 Physical Examination/Neurological Examination
A physical examination (PE) will be performed at Screening, Endpoint or in the event of 
early discontinuation by a primary investigator or sub-investigator (M.D., Doctor of 
Osteopathic Medicine [D.O.]) or by a Physician’s Assistant (P.A.) or Nurse Practitioner 
(N.P.) in areas where P.A.s and N.P.s are licensed to perform PEs. 
If a physical or neurological abnormality is noted post-treatment, the investigator will 
indicate whether or not the result is clinically significant and if it constitutes an adverse 
experience.
 
 
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7.1.2.1.2 Body Height/Weight/Waist Circumference 
Height (inches/centimeter [in/cm]), body weight (pounds/kilograms [lbs/kg]) and waist 
circumference (in/cm) will be collected and recorded. Measurements should be recorded to 
the nearest inch/centimeter and pound/kilogram.  Body weight data will be collected without 
shoes and with heavy clothing (such as coats) removed.  It is recommended that body weight 
measurement should be performed on the same scale for the same individual throughout the 
study (this may not be possible if weight is measured in an inpatient versus outpatient 
setting).  Abdominal waist circumference should be measured by encircling the subject’s 
body at the navel with a cloth measuring tape or similar pliable measuring device.
7.1.2.1.3 12-Lead Electrocardiogram
A 12-lead electrocardiogram will be performed according to the instructions in a separate 
ECG Instruction Manual by the central ECG vendor which will also provide a cardiologist 
read of each ECG. Triplicate measurements of ECG will be required at the Screening Visit. 
See exclusion criteria pertaining to the three Screening QTcFs.  A single ECG is required at 
post-screening visits unless there is an observation of a QTc prolongation (QTcF interval of 
≥500 msec). An additional 2 ECGs will be required and an average taken to determine the 
QTc interval for that visit.
The subject’s ECGs are to be repeated ideally at 2-5 minute 
intervals.  
For subjects who skip the taper period, the triplicate screening ECGs must be printed and 
reviewed by a qualified cardiologist and can be used as a guide to determine subject 
eligibility.
7.1.2.1.4 Vital Signs
Heart Rate and Blood Pressure: Subjects should be resting in a semi recumbent position for 
at least 5 minutes prior to having vital sign measurements obtained. For blood pressure 
readings, the correct size of the blood pressure cuff and the correct positioning on the 
subjects’ arm is essential to increase the accuracy of blood pressure measurements.
The same method for measuring heart rate and blood pressure (e.g., manual or automated) is 
recommended for all measurements for each individual subject and should be the same for all 
subjects throughout the study.
7.1.2.2
Clinical Assessment
The efficacy assessments PANSS and CGI-S as well as the safety assessments C-SSRS and 
ESRS-A will be performed at each center by qualified raters. The required qualifications of 
the raters are specified in an external manual. Prior to the start of rating subjects in the trial, 
candidate raters will participate in rating scale training.  Certification is required for the 
PANSS raters. The Sponsor or an appointed representative, prior to the start of the trial, will 
implement the training and certification process. Quality monitoring of the MINI and 
PANSS will include video and/or audio technology.
 
 
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Additional detailed information concerning administration, scoring and recording of the 
aforesaid assessments will be provided in an external manual. 
Some or all of the PANSS recorded interviews will be reviewed and scored by an external 
vendor’s rater (referred to in this protocol as the central rater). Site raters will be provided 
feedback on the quality of their interviews and ratings by the central rater to help develop and 
maintain good inter-rater reliability. Additionally, the site rater’s consideration of the central 
rater’s feedback may be used to refine the PANSSs scores entered by the site for an 
individual rating.
For the screening visit, the external SDME will review the diagnostic decisions of the site as
determined through the MINI (see Section 7.1.1.5.1). 
While concerns have been raised that recording assessments via audiotaping or videotaping 
could theoretically compromise subjects’ privacy, this issue must be balanced with the need 
to conduct methodologically adequate and scientifically rigorous trials that are capable of 
testing key hypotheses. 
Given that the key endpoints in this trial involve subjective 
judgments, monitoring the adequacy of subject interviews and ratings is essential and part of 
strong research methodology. Prior studies suggest that the failure to adequately monitor 
such ratings can substantially increase the risk of failed trials [5]. Recorded interviews will 
be encrypted using state of the art methods to ensure privacy. Additional steps will be taken 
to ensure anonymity of specific private health information.
Recordings will be reviewed 
only by approved trial personnel for quality control purposes and will be destroyed in 
accordance with current retention requirements.
Each assessment scale may require different raters, but it is strongly encouraged that the 
same rater evaluates the same subject throughout his/her participation in the trial for a 
particular scale. 
7.1.2.2.1
Positive and Negative Symptom Scale (PANSS)
The Structured Clinical Interview for the Positive and Negative Syndrome Scale (Sci-
PANSS), a 30-item clinician-rated instrument for assessing the symptoms of Schizophrenia
[6], will be used.  
To avoid the influence of subject fatigue on the diagnostic and primary outcome data, it is 
recommended that the PANSS interviews be conducted early in each applicable visit.
7.1.2.2.2 Clinical Global Impression Scale-Severity (CGI-S)
The Clinical Global Impressions Scale Severity, a 7-point clinician-rated scale for assessing 
the global severity of the illness, will be used.
7.1.2.2.3 C-SSRS
The C-SSRS is an instrument designed to systematically assess and track suicidal AEs 
(behavior and ideation).  The C-SSRS will be administered at each visit (as indicated in the
 
 
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Trial Flow Chart, as well as at unscheduled visits as clinically indicated) by a qualified, 
trained individual who has been approved by the Sponsor to administer the instrument.  
During the Screening visit, the subject’s symptoms and actions over the past 6 months should 
be evaluated with the C-SSRS.  The C-SSRS is not explicit about whether the subject 
specifically has ideation at the time of screening.  If a subject reports a prior history of 
ideation/behavior, the assessor should also inquire and document if this is also present at the 
time of the screening visit.
For all other assessments, the subject’s symptoms and actions since the last assessment 
should be evaluated.  Subjects must be excluded if they report suicidal ideation meeting the
description of C-SSRS Type 4 or 5 (i.e., suicidal ideation with intent with or without a plan) 
within the past 2 months or suicidal behavior within the past 6 months at Screening.  
Subjects must be excluded at Baseline if they report suicidal ideation of Type 4 or 5 or 
suicidal behavior, as measured by the C-SSRS between Screening and Baseline.
If during the trial the subject demonstrates emerging or increasing suicidal ideation and/or 
behavior, in the investigator’s opinion or based on responses provided on the C-SSRS (e.g., 
any suicidal ideation of Type 4 or 5 and/or any suicidal behavior), he or she should be
thoroughly evaluated by the investigator and should be considered for
treatment 
discontinuation.  Subjects should continue treatment only if their suicidal ideation is passive, 
they expressly deny any intent to act, and who, after evaluation, the investigator feels it is 
safe and in the subject’s best interest.  In case subjects are discontinued from treatment, sites 
should ensure adequate clinical supervision to ensure subject’s well-being.  In case subject 
withdraws consent it is recommended that clinical supervision continues outside the scope of 
the trial.
Prior to discharge from the hospital at Day 21 or Day 28, the investigator should be aware of 
the C-SSRS score. For subjects with scores showing suicidality (e.g., any suicidal ideation of 
Type 4 or 5 and/or any suicidal behavior), the investigator should discuss discharge readiness 
with the SDME prior to discharge.
In the event an AE related to suicidality occurs during treatment, an additional C-SSRS 
should be performed and external sources (e.g., family members, external contact) may be 
used if patient is not available.  In addition, all adverse events of suicidal ideation or behavior 
must be recorded as an Event of Clinical Interest (See Section 7.2.3.2).  
7.1.2.2.4 Monitoring of Extrapyramidal Symptoms
Extrapyramidal symptoms include parkinsonism, dyskinesia, akathisia, and dystonia.
Extrapyramidal symptoms will be documented with the Extrapyramidal Symptom Rating 
Scale-Abbreviated (ESRS-A).
It is strongly encouraged that the same rater evaluates the same subject throughout his/her
participation in the trial for the scale. 
 
 
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Extrapyramidal symptoms present at Screening must be recorded in the medical history. In 
addition, if a) clinically significant movement disorder side effects are observed by trial staff 
or volunteered by the subject during the study, or b) a clinically significant movement 
disorder already present at Screening increases in severity during the study, or c) concomitant 
therapy for increasing or emerging EPS symptoms is initiated, increased, or reinstated while 
the subject is participating in the trial, these symptoms must be recorded as an AE.
Tardive dyskinesia and dystonia are considered events of clinical interest (ECI) (Section 
7.2.3.2).
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in Appendix 12.4.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 4. 
Fasting blood draws/urine collection at Screening are encouraged. 
It is anticipated that blood samples (laboratory and pre-dose PK) should be obtained fasting 
and pre-dose. For subjects who are discharged from the hospital at Day 21, as outpatients 
they will be instructed to fast overnight if possible and withhold their dose of IP prior to 
clinical laboratory sample collection at Day 28. The self-reported fasting/non-fasting state of 
the subject will be noted on the laboratory requisition form (no food or drink other than water 
≥10 hours is considered fasting).
Subjects who skip the tapering period will have duplicate laboratory specimens collected, 
with 1 specimen being sent to the local laboratory for immediate analysis of all Screening 
parameters and the other processed at the central laboratory. The local laboratory results will 
be used as a guide to determine subject eligibility. If the Screening laboratory samples were 
not taken in a fasting state (no food or drink other than water ≥10 hours), clinical laboratory 
assessments should be repeated on the morning of Day 1, prior to the first dose of trial 
medication.
At any time during the trial, if the investigator determines that immediate local laboratory 
results for protocol-specified parameters are needed to further evaluate the subject’s 
condition, a duplicate set of sample(s) should be collected and sent to the central laboratory.
The site and Sponsor will remain blinded to the prolactin levels of the blood samples taken 
after the Baseline visit until database lock.  Local laboratories will not analyze prolactin 
levels after the Baseline visit.
 
 
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Table 4
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Appearance
(macroscopic exam)
Follicle Stimulating 
Hormone (FSH) female 
only, if applicable
Hemoglobin
Alkaline phosphatase
Bacteria
Serum β-human chorionic 
gonadotropin (β-hCG
female only, if applicable)
Platelet count
Alanine aminotransferase (ALT)
Bilirubin
Free Thyroxine (T4) (TSH 
Reflex to Free T4 if TSH 
abnormal)
White Blood Cells 
(WBC) (total and 
differential)
Aspartate aminotransferase (AST)
Blood
Bicarbonate
Color
Viral hepatitis panel (at the 
discretion of the 
investigator)
Calcium
Glucose
HIV (at the discretion
of the investigator)
Chloride
Ketone
Urine Alcohol Drug Screen
(Amphetamine
Barbiturates
Cannabinoids
Cocaine metabolites
Ethyl Alcohol
Methadone
Opiates
Phencyclidine
Propoxyphene
Cocaine Metabolites)
Creatinine phosphokinase, total
Microscopic exam, if 
abnormal appearance  
results are noted (RBC, 
WBC and bacteria)
Creatinine
pH
eGFR (estimated glomerular filtration rate  
(eGFR) [as measured by Modification of 
Diet in Renal Disease (MDRD) formula]
Protein
Glucose
Red Blood Cells (RBC)
count
Lactate Dehydrogenase
Specific gravity
Phosphorus
WBC count
Potassium
Nitrate
Sodium
Leukocyte esterase
Total Bilirubin  
Direct Bilirubin and indirect Bilirubin if 
total bilirubin is elevated above the upper 
limit of normal
Total protein
Blood Urea Nitrogen
Special
Lipid Panel
Thyroid Stimulating Hormone
Total cholesterol
Insulin
High Density Lipoproteins 
(HDL)
Prolactin
Low Density Lipoproteins 
(LDL)
Triglycerides
 
 
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Laboratory safety tests will be performed after at least a 10-hour fast.  
7.1.3.2
Pregnancy Testing
For women of childbearing potential, blood samples for β-human chorionic gonadotropin 
(β-hCG) will be obtained at Screening. Urine pregnancy tests will be done at all visits.  A 
positive urine pregnancy test must be confirmed with a serum pregnancy test. A blood 
sample for serum pregnancy testing is to be collected for central laboratory testing; a 
duplicate sample for local laboratory testing is recommended if local test results would be 
made available sooner.  Dosing should be interrupted until serum pregnancy test results from 
either local or central laboratory results are available, and if the serum pregnancy test result is
negative, subject may resume dosing. See Section 7.1.4.5 for information on missed doses. If 
the serum pregnancy test result is positive, note the criteria for discontinuation of treatment 
has been met (see Section 5.8.1). A female may forego pregnancy testing if she is not of 
reproductive potential according to the criteria specified in Section 5.1.2.  In addition, 
pregnancy tests may be performed at the investigator’s discretion throughout the course of 
the trial. See Section 7.2.2 for procedures that must be followed regarding pregnancy 
reporting and follow-up. Any female subject who has a positive serum pregnancy test result 
during treatment should be discontinued from trial medication.
7.1.3.3
Urine Alcohol Drug Screen
A urine alcohol/drug test will be done at Screening. The urine sample will be collected along 
with the other laboratory specimens and will be analyzed and reported by the central 
laboratory. Any positive finding will require confirmation by the central laboratory prior to 
reporting final drug screen results. At any time during the trial, if the investigator determines 
that immediate local urine alcohol/drug screening results are needed to evaluate eligibility or 
further evaluate the subject’s condition, a duplicate set of sample(s) should be collected and 
sent to the central laboratory. Provided there is no exclusionary evidence of substance use 
disorder in the past 6 months (Section 5.1.3), a positive Screening finding of alcohol, 
cannabinoid drugs, or prohibited psychotropic medications will not necessarily exclude the 
subject from participation. However, the investigator should interview the subject and ensure 
the subject understands that he/she must refrain from using cannabinoid drugs and prohibited 
psychotropic medications throughout his/her participation in the trial. Alcohol use during the 
trial should also be discouraged. This discussion must be noted in the source documents or 
on the laboratory report. The investigator may enroll the subject if he/she feels confident that 
the subject will comply with instructions. Additional tests may be scheduled post-Screening 
at the discretion of the investigator. If a subject is considered to be under the influence of 
illegal drugs or is believed to have taken a prohibited psychoactive drug, or if he or she meets 
the DSM-5™criteria for substance use disorder (excluding nicotine) within a 1-week period, 
the investigator may consider the subject for discontinuation.
 
 
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7.1.3.4
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.4.1 Blood Collection for Plasma MK-8189
Sample collection, storage and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual. 
7.1.3.5
Planned Genetic Analysis Sample Collection 
Sample collection, storage, and shipment instructions for Planned Genetic Analysis samples 
will be provided in the laboratory manual provided by the central laboratory.
7.1.3.6
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA for future research
See Appendix 12.2 for the Collection and Management of Specimens for Future 
Biomedical Research.

Leftover residual urine will be stored for future research.
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final treatment visit (Visit 6) should be performed at the time of 
discontinuation. 
 
Any 
adverse 
events 
which 
are 
present 
at 
the 
time 
of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 7.2 - Assessing and Recording Adverse Events. In addition, subjects who 
discontinue from treatment should have 2 follow-up phone call visits (post treatment Days 3 
and 14) and a follow-up clinic visit (post treatment Day 7) after their last dose of IP.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
 
 
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In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
When the investigator or sub-investigator needs to identify the drug used by a subject and the 
dosage administered in case of emergency e.g., the occurrence of serious adverse 
experiences, he/she will contact the emergency unblinding call center by telephone and make 
a request for emergency unblinding.  As requested by the investigator or sub-investigator the 
emergency unblinding call center will provide the information to him/her promptly and 
report unblinding to the sponsor.  The emergency unblinding call center will make a record 
promptly however, the investigator or sub-investigator must enter the intensity of the adverse 
experiences observed,   their relation to study drug, the reason thereof, etc., in the medical 
chart etc., before unblinding is performed.  
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded.
7.1.4.3
Domiciling
Not applicable
7.1.4.4
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:
The central ECG vendor will provide documentation of calibration from the ECG 
manufacturer.
 
 
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7.1.4.5
Administer Trial Medication
Trial medication is administered by the trial or inpatient staff during the inpatient phase. All 
personnel who will administer trial medication must receive training 1) at the investigator 
meeting, 2) on-site from a Sponsor representative, or 3) on-site from trial staff or lead 
inpatient personnel who received training at the Investigator meeting or previously from a 
Sponsor representative.
All individuals who dispense trial medication to the inpatient subject should monitor the 
subject to ensure doses are taken as directed, and record relevant dosing information 
(including number of tablets and exact time taken) in source documents.  For subjects who 
are discharged at Day 21, trial medication will be self-administered starting the day after 
discharge from the hospital.  Prior to discharge, the subject will be educated by a member of 
the trial staff on dosing requirements and self-administration. Subjects will be provided with 
a dosing diary. The day after discharge from the hospital at Day 21 and approximately mid-
week after discharge, the outpatient subject should be telephoned to ensure that he or she has 
understood dosing instructions, to assess adverse events and to remind the subject of site visit 
on Day 28. 
Interruption from protocol specified dosing for ≥ 3 consecutive days at any time point during 
the active treatment period requires consultation between the investigator and the Sponsor 
and written documentation of the collaboration decision on the subject management.  Failure 
to take prescribed capsules and/or tablets per IP dosing as listed in Table 1 constitutes a 
missed dose.
All IP dose units (tablets and capsules) will be administered by the study staff / inpatient staff
QD (approximately 8:00 AM) to the inpatient.
If a subject misses an IP morning dose or does not take the full IP morning dose he/she 
should not complete that day’s dose after 1 PM or attempt to double that dose the next day.
The subject will miss that day’s dose, and will resume IP dosing the next morning with one 
IP dose.
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening
Approximately 3 (+4) days prior to treatment allocation/randomization, potential subjects 
will be evaluated to determine if they fulfill the entry requirements as described in Section 
5.1.  Screening procedures may be repeated after consultation with the Sponsor.
Informed consent should be obtained on the day of the Screening visit prior to the start of any 
study-specific procedures.  The Screening/tapering period will begin after the consent form is 
completed.  During the Screening visit, a psychiatric diagnostic assessment will be performed 
and recorded using the Mini International Neuropsychiatric Interview for Schizophrenia and 
 
 
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Psychotic Disorders (MINI, Version 7).  All psychiatric diagnoses specified in the 
inclusion/exclusion criteria will be made according to the DSM-5 ™ criteria by a qualified 
psychiatrist (MD) or psychologist (PhD) or other equivalent degree.  The subject’s medical 
history, prior medications, and demographic information will also be obtained to determine 
eligibility as well as additional assessments of psychiatric symptoms [Positive and Negative 
Syndrome Scale (PANSS), Clinical Global Impression-Severity of Illness (CGI-S) score, and 
Columbia-Suicide Severity Rating Scale (C-SSRS)].  If the subject meets the Screening 
eligibility criteria for which results are available, the subject will begin the tapering period. 
Note: laboratory results, final electrocardiogram [ECG] results, corroboration of acuity and 
prior antipsychotic treatment response by available sources as documented in the psychiatric 
intake evaluation form with subsequent documented review and approval by the external 
sponsor designated medical expert [SDME] may still be pending at the start of the tapering 
period.
If the subject is deemed ineligible based upon review and corroboration of the 
Screening eligibility criteria, the subject will be considered a screen failure prior to the 
Baseline visit (Visit 2).
The tapering period will begin after the Screening visit is completed and provides a period of 
time in which the subject will taper off prohibited medication. All subjects must be safely 
tapered off prohibited medications (antipsychotics, antidepressants and mood-stabilizers, See 
Section 5.5) during the Screening/tapering period in a manner consistent with local medical 
practices.  If it is the investigator’s clinical judgment that the tapering period can be skipped 
for an individual subject, Investigational Product (IP) dosing may begin as early as the 
morning following the Screening procedures, provided all of the eligibility criteria have been 
met.  For assessments that are not repeated at Baseline, for those subjects skipping the 
tapering period, the Screening assessments will serve as the pre-treatment reference level.
The subject will identify an external contact person at the time of Screening who may be 
contacted in the event that the subject cannot be reached between Day 21 and Day 28 (if the 
subject is an outpatient) and during the 14-day follow-up period.  (See inclusion criterion 13).
Note that subjects who are screen failures may not repeat screening.
7.1.5.1.1 Hospitalization During the Trial
For those subjects who were already hospitalized when approached for recruitment into this 
trial, the start of hospitalization under this trial is the day of the signing of the consent form.  
For subjects who are outpatients when approached for recruitment into this trial, subjects 
could be admitted to the hospital as early as the day of consent signing but no later than the 
evening of Screening visit assessment collection completion.  Subjects will remain 
hospitalized throughout the tapering and treatment period. 
Hospital discharge will occur on Day 28 after end of treatment assessments (V6 are 
completed).  Exceptions to a 28-day inpatient stay may occur on Day 21 only if, after 
completion of Day 21 assessments, the following conditions are met: the subject’s current 
clinical symptoms and functioning are much improved and thus continued treatment can 
occur safely (subject is not at risk to self or others) in a less restrictive environment; the 
subject can self-administer the study drug correctly, and can abide by all study procedures as 
 
 
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an outpatient as described in the protocol.  Subjects who meet these conditions may continue 
in the treatment phase as outpatients.  On the day of discharge, the outpatient subject will be 
given visit schedule, dosing instructions, a dosing diary and site will ensure the subject has 
their patient ID card.  The day after discharge and approximately mid-week after discharge 
on Day 21, the subject should be telephoned by study staff to ensure that he or she has 
understood dosing instructions, to assess adverse events, and to remind the subject of the Day 
28 visit.
During the inpatient phase of the trial, subject will not be treated as an outpatient (i.e., visits 
are not to be performed in a setting that requires the subject to leave the hospital or other 
research unit in which the inpatient unit is located).  During the inpatient stay, an occasion 
may arise which requires the subject to leave the inpatient unit for social or personal reasons. 
In that event, subjects may be permitted to temporarily leave the unit during the day at any 
time during the inpatient phase of the study, provided they are escorted at all times during 
that leave by site personnel, at the discretion of the investigator and as per hospital 
regulations.  If the subject was not discharged at Day 21, the subject will be discharged from 
the inpatient unit at Day 28 (±1).  At Day 28 (±1), all final study assessments (End of 
treatment visit assessments) will be performed for all subjects, whether the subject was 
discharged at Day 21 or Day 28 as per the Study Flow Chart.  
The Sponsor is to be contacted if it is anticipated that the subject will not be ready to be 
discharged from the hospital after screen fail, treatment discontinuation, or after V6 
assessments are completed on Day 28.  Subjects will begin their follow-up period after the 
treatment period termination or completion.
If the subject is hospitalized during the follow-up period of the trial, it is anticipated that 
these specified contacts will still take place, but may be conducted between the site personnel 
and subject in person.
7.1.5.2
Treatment Period Visit 2 through Visit 6
Each visit should be performed as noted in the Trial Flow Chart. For visits that require 
additional explanations, please see those specific visits below.
Visit 2
Subjects will be assessed for final eligibility per Inclusion/Exclusion criteria as described in
Section 5.1.  The subject may be randomized into the trial and will be assigned a 
randomization number (via IVRS/IWRS) only after ensuring that the subject meets all 
criteria.  For trial IP titration, please refer to Section 5.2.1.2.
Visit 5
At Visit 5, assessments will be conducted as stated in the Trial Flow Chart. For details on 
subject eligibility for outpatient status and subject requirements, please refer to Section 
7.1.5.1.1.
 
 
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Visit 6
Subjects that were outpatients for the last week of treatment will return for their final site 
visit, Visit 6.  Subjects should refrain from eating and should not take that morning dose of 
IP.  Subjects will be instructed to arrive at the site in the morning.  Subjects should be 
instructed to bring all trial supplies (e.g., dosing diary, IP) to the site for final compliance and 
accountability.
7.1.5.3
Telephone Contact Procedures
The principal investigator is responsible for ensuring that all phone contacts are performed 
by a site staff member, who is a healthcare professional qualified to elicit a discussion with 
the subject that will lead to a clinically meaningful disclosure on the subject’s well-being. 
Phone contacts must be documented immediately in a contact log for review by the PI within 
24 hours of log entry. In the event of worsening symptoms reported by either the subject or 
the external contact person, the site’s ensuing action steps must be recorded. The site must 
follow-up on any report of worsening symptoms by contacting the subject to schedule an 
immediate visit. In the event that the subject cannot be reached by phone at the regularly 
scheduled time or misses a visit, the site should make at least three attempts (in addition to 
the initial phone call) to contact the subject within 48 hours of the missed scheduled time. 
The last contact attempt should represent stronger action by the site to contact the subject 
(i.e., a visit to the subject’s residence, an attempt to reach the external contact person 
identified at the time of Screening) in the event that the subject cannot be reached on the 
third attempt. All phone contacts, attempted contacts, and home visits should be recorded in 
source documents.
7.1.5.4
Post-Treatment Contact (phone and visit)
Subjects will have 2 phone calls (at 3 and 14 days post dose) and one clinic visit at Visit 7 (7 
days post dose) after the last dose of trial drug (regardless of the date of the Discontinuation 
Visit, if applicable) to determine if any AEs have occurred during the post-trial clinic 
contacts. See Section 7.2 for further detail on collection of AEs post-treatment.
Refer to Section 7.1.5.3 regarding phone contact procedures.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
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 (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
 
 
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Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose is any dose higher than the maximum number of either IP type 
(capsules and/or tablets) specified for a single dose in 1 calendar day (accidental or 
intentional).
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a non-serious adverse event, unless other serious
criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious adverse event, using the terminology “accidental or intentional 
overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reportin g 
procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies
and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies  must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization [Notable exceptions a) any 
admission solely for social reasons, b)any extended hospitalization past last day of study 
drug treatment for subjects not clinically ready to be discharged is not in itself an SAE. 
The PI instead should consider whether the events associated with extended 
hospitalization meet the definition of an SAE. Extended hospitalization must be discussed 
with the Sponsor Designated Medical Expert (SDME) and the reasons for extended 
hospitalizations must be documented in the medical record daily until discharge.];
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements.
 
 
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●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 5 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
 
 
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upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
2. Suicidal ideation and/or behavior as reported in C-SSRS scores, TEAEs or any self-
injurious behavior
3. Dystonia
4. Tardive dyskinesia
5. QTcF interval of ≥500 msec (the average of the three QTcFs will be used)
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 5. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 5 for instructions in evaluating adverse events.
 
 
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Table 5
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.   (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Overdose, although not serious per ICH definition, whether accidental or intentional, with or without an accompanying adverse event/serious adverse event, is 
reportable to the Sponsor within 24 hours to meet certain local requirements.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event?   The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor's 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Scientific Advisory Committee
7.3.1
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Executive Oversight Committee
7.3.2
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the
standing internal Data Monitoring Committee (siDMC) regarding the trial.
Data Monitoring Committee
7.3.3
To supplement the routine monitoring outlined in this protocol, a separate Standing Internal 
Data Monitoring Committee (siDMC) will monitor the interim data from this trial. The 
siDMC comprises members of Sponsor Senior Management, none of whom are directly 
associated with the conduct of this trial. The siDMC will monitor the trial at an appropriate 
frequency (see Section 8.7 - Interim Analyses) for evidence of adverse effects of trial 
treatment and efficacy/futility, as described in the detailed monitoring guidelines. The 
siDMC will determine whether the trial should continue (or other modifications, pre-
specified or otherwise, should be made) according to the protocol, considering the overall 
risk and benefit to trial participants. The siDMC will also make recommendations to the 
Sponsor protocol team regarding steps to ensure both subject safety and the continued ethical 
integrity of the trial.
Specific details regarding responsibilities of the siDMC will be described in a separate 
charter that is reviewed and approved by the siDMC.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9).  Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to 
unblinding, will be documented in the Clinical Study Report (CSR) for the study.  Post hoc 
exploratory analyses will be clearly identified in the CSR.
 
 
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Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2-8.12.
Study Design Overview
A Phase IIa, Randomized, Double-Blind, Placebo-Controlled Clinical 
Trial of the Efficacy and Safety of MK-8189 in the Treatment of 
Adult Subjects with Schizophrenia
Treatment Assignment
Subjects will be randomly assigned to MK-8189, placebo or 
risperidone in a 2:2:1 distribution, and will receive MK-8189
 
 
 
 
 placebo (3 tablets/capsules QD) or risperidone 
(6 mg QD) for the remainder of the trial, as tolerated.
Analysis Populations
Efficacy:  Full Analysis Set (FAS)
Safety:  All Subjects as Treated (ASaT)
Primary Endpoint
1) Positive and Negative Syndrome Scale (PANSS) total score –
Change from baseline at Week 4
Key Secondary Endpoints
1) Clinical Global Impression Severity of Illness (CGI-S) score –
Change from baseline at Week 4
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
The primary efficacy hypothesis will be evaluated by comparing 
MK-8189 to placebo with respect to the mean change from baseline in 
PANSS total score after 4 weeks of treatment using a longitudinal 
analysis of covariance (ANCOVA) method.
Statistical Methods for Key 
Safety Analyses
The count and percentage of adverse events will be provided.  95% 
confidence intervals for between-group comparisons will be 
calculated using the unstratified Miettinen and Nurminen method [7].
Interim Analyses
An internal data monitoring committee will evaluate the unblinded
safety and efficacy data to assess the overall risk and benefit to trial 
participants when approximately 25%, 50%, and 75% of the subjects 
have had the opportunity to complete the study.
One interim unblinded efficacy (futility) analysis may also be performed 
in this study.  Results would be reviewed by the internal data monitoring 
committee.  This interim analysis is summarized below.  Details are 
provided in Section 8.7.

Trigger: Interim analysis will be considered unless more than 
50% of the subjects have been enrolled 4 months after the first 
subject was randomized into the study.

Timing: To be performed when 50% of the subjects have 
completed or discontinued IP treatment.

Testing: Inferential analyses for the change from baseline in 
the PANSS total score at 4 weeks will be provided.
Multiplicity
A small amount of alpha (α=0.0001) will be allocated to each of the 3 
interim analyses.  The effect of the alpha spending for the interim 
analyses on the alpha to be used at the time of the final analysis is 
negligible.  If the test of the primary efficacy hypothesis is statistically 
significant (i.e., p-value is less than or equal to 0.05), then the 
secondary hypothesis will be tested to control the overall type-I error 
at the 5% level (two-sided).  That is, MK-8189 would be compared to 
placebo with respect to the mean change from baseline in CGI-S score 
after 4 weeks of treatment using α=0.05 (two-sided).
 
 
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Sample Size and Power 
The planned number of subjects to be randomized is 215 (86, 86 and 
43 in the MK-8189, placebo and risperidone groups, respectively). 
For the PANSS total score change from baseline at Week 4, the trial 
has 72% power (if no futility analysis is performed) or 65% power (if 
the planned futility analysis is performed) to demonstrate that 
MK-8189 is superior to placebo at an overall two-sided 5% alpha 
level, if the underlying treatment difference (MK-8189 minus 
placebo) is -8.0.  For assay sensitivity, the trial has 67% power to 
demonstrate that risperidone is superior to placebo at an overall one-
sided 5% alpha level, if the underlying treatment difference 
(risperidone minus placebo) is -8.0.
Responsibility for Analyses/In-House Blinding
8.2
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures.  
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.  Randomization will be implemented in an interactive voice 
response system (IVRS).
The planned interim analyses are described in Section 8.7.  Study enrollment is likely to be 
ongoing at the time of the interim analyses.  Blinding to treatment assignment will be 
maintained at all investigational sites.  The results of the interim analyses will not be shared 
with the investigators prior to the completion of the study.  Subject-level unblinding will be 
restricted to an internal unblinded statistician and scientific programmer performing the 
interim analyses, who will have no other responsibilities associated with the study.
Treatment-level results and/or subject-level data of the interim analyses will be provided by 
the unblinded statistician to the standing internal Data Monitoring Committee (siDMC) 
which consists of Sponsor personnel.  Limited additional Sponsor personnel may be 
unblinded to the treatment level results of the interim analyses, if required, in order to act on 
the recommendations of the siDMC.  The extent to which individuals are unblinded with 
respect to results of the interim analyses will be documented by the unblinded statistician.
The processes by which recommendations and decisions are reached and communicated are 
documented in the siDMC charter for the Sponsor.  Prior to final study unblinding, 
individuals who have been unblinded at any level will not be involved in any discussions 
regarding modifications to the protocol, statistical methods, identification of protocol 
deviations, or data validation efforts after the interim analyses.
Hypotheses/Estimation
8.3
Objectives and hypotheses of the study are stated in Section 3.0.
 
 
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Analysis Endpoints
8.4
Efficacy and safety endpoints that will be evaluated are listed below.
Efficacy Endpoints
8.4.1
The Positive and Negative Syndrome Scale (PANSS) is a 30-item clinician-rated instrument 
for assessing the symptoms of schizophrenia.  Increases in the PANSS total score represent a 
worsening of symptoms.  The change from baseline in the PANSS total score at 4 weeks is 
the primary efficacy endpoint.
The Clinical Global Impression Severity of Illness (CGI-S) is a 7-point clinician-rated scale 
for assessing the global severity of the illness.  Increases in the CGI-S score represent a 
worsening of symptoms.  The change from baseline in the CGI-S score at 4 weeks is a key 
secondary efficacy endpoint.
Exploratory endpoints will consist of the proportion of PANSS total responders (≥30% 
reduction in PANSS total score), as well as the mean change from baseline to 4 weeks in the 
PANSS negative and positive subscale scores.
Safety Endpoints
8.4.2
Safety and tolerability will be assessed throughout the study by monitoring subjects for 
clinical adverse experiences.  Physical/neurological examinations, vital signs, 12-lead ECGs 
and laboratory safety tests will be performed periodically to detect any medically meaningful 
effects of MK-8189 on physiology. 
The Columbia Suicide Severity Rating Scale (C-SSRS) will be used to systematically and 
prospectively ascertain and document the occurrence of suicidal events (i.e., ideation and 
behavior).  Responses on the C-SSRS are classified according to 11 prespecified categories 
as described in Appendix 12.7.  The most severe treatment-emergent ideation and behavior 
event reported at a visit will be used for analysis and reporting.  An event is considered 
treatment-emergent during the assessment phase if it newly emerged or is more severe 
compared to recent history (i.e., protocol-defined recent history prior to entering the trial as 
stated in the inclusion/exclusion criteria for suicidal ideation/behavior, up to and including 
the randomization visit).
Extrapyramidal symptoms will be documented with the Extrapyramidal Symptom Rating 
Scale–abbreviated (ESRS-A).
Analysis Populations
8.5
Efficacy Analysis Populations
8.5.1
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study.  The FAS population consists of all randomized subjects who:

receive at least 1 dose of study treatment
 
 
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
have at least 1 post-randomization observation for the analysis endpoint subsequent to 
at least 1 dose of study treatment

have baseline data for those analyses that require baseline data
Subjects will be included in the treatment group to which they are randomized for the 
analysis of efficacy data.  Details on the approach to handling missing data are provided in 
Section 8.6, Statistical Methods.
Safety Analysis Populations
8.5.2
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized subjects who received at least 1
dose of study treatment. Subjects will be included in the treatment group corresponding t o 
the study treatment they actually received for the analysis of safety data using the ASaT 
population.  For most subjects, this will be the treatment group to which they are randomized.  
Subjects who take incorrect study treatment for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.6, Statistical Methods.
Statistical Methods
8.6
Statistical testing and inference for safety analyses are described in 8.6.2.  Efficacy results 
that will be deemed to be statistically significant after consideration of the Type I error 
control strategy are described in Section 8.8, Multiplicity.  Nominal p-values may be
computed for other efficacy analyses, but should be interpreted with caution due to potential 
issues of multiplicity, sample size, etc.  Unless otherwise stated, all statistical tests will be 
conducted at the α=0.05 (two-sided) level.
Statistical Methods for Efficacy Analyses
8.6.1
This section describes the statistical methods that address the primary and secondary 
objectives.
The primary efficacy hypothesis will be evaluated by comparing MK-8189 to placebo with 
respect to the mean change from baseline in PANSS total score after 4 weeks of treatment 
using a longitudinal analysis of covariance (ANCOVA) model.  The analysis model will 
include terms for treatment, baseline PANSS total score, age, duration of illness, week, and 
the interaction of week by treatment (Table 6).  The treatment difference in terms of the 
mean change from baseline to a given time point will be estimated and tested from this 
model.  An unstructured covariance matrix will be used to model the correlation among 
 
 
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repeated measurements.  The criterion for declaring MK-8189 superior to placebo in terms of 
PANSS total score change from baseline is that the p-value is less than or equal to 0.05.
An additional sensitivity analysis using the tipping-point approach will be used to assess the 
robustness of the primary analysis approach.  The Variant 3 of the tipping point as described 
in Ratitch, et al. (2013) [8] will be applied.  In that approach, missing data are first imputed 
for all visits under the missing-at-random (MAR) assumption, and then a worsening/shift is 
applied.  This is repeated until the result is no longer statistically significant (i.e., p>0.05).  
This tipping point (smallest worsening/shift in which the significant result turns non-
significant) provides a measure of robustness of the primary result. 
Table 6
Analysis Strategy for Key Efficacy Variables 
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method‡
Analysis 
Population
Missing Data 
Approach
Primary Hypothesis
Positive and Negative Syndrome 
Scale (PANSS) total score –
  Change from baseline at Week 4
P
Longitudinal analysis of 
covariance (ANCOVA) 
model§
FAS
Model-based
Positive and Negative Syndrome 
Scale (PANSS) total score –
  Change from baseline at Week 4
S
Longitudinal analysis of 
covariance (ANCOVA) 
model§
FAS
Tipping-point 
Analysis
Secondary Hypothesis
Clinical Global Impression Severity 
of Illness (CGI-S) score –
Change from baseline at Week 4
P
Longitudinal ANCOVA 
model║
FAS
Model-based
 †
P=Primary approach;  S=Supportive approach.
  ‡
Statistical model is described in further detail below:
  §
Longitudinal ANCOVA model includes terms for treatment, baseline PANSS total score, age, duration of illness, 
week, and the interaction of week by treatment.
  ║Longitudinal ANCOVA model includes terms for treatment, baseline CGI-S score, age, duration of illness, week, and 
the interaction of week by treatment.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints is 
described in Section 8.8, Multiplicity.
Statistical Methods for Safety Analyses
8.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 7).  The tiers differ with 
respect to the analyses that will be performed.  Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier-1” safety endpoints that will be 
subject to inferential testing for statistical significance with p-values and 95% confidence 
intervals provided for between-group comparisons.  Other safety parameters will be 
considered Tier 2 or Tier 3.  Tier-2 parameters will be assessed via point estimates with 95% 
 
 
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confidence intervals provided for between-group comparisons; only point estimates by 
treatment group will be provided for Tier-3 safety parameters.
Adverse experiences (specific terms as well as system organ class terms) that are not pre-
specified as Tier-1 endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on 
the number of events observed.  Membership in Tier 2 requires that at least 4 subjects in any 
treatment group exhibit the event; all other adverse experiences will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences.  Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences.
Continuous measures, such as changes from baseline in laboratory, vital signs, and ECG 
parameters, will be considered Tier-3 safety parameters.  Summary statistics for baseline, on-
treatment, and change from baseline values will be provided by treatment group in table 
format.
For this protocol, there are no pre-specified events of interest, i.e., no Tier-1 events.  In 
addition, the broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, a drug-related AE, a serious AE, an AE which is both drug-related and 
serious, who discontinued due to an AE, and who discontinued due to a drug-related AE will 
be considered Tier-2 endpoints.  For these endpoints, 95% confidence intervals will be 
provided for between-treatment differences (MK-8189 minus placebo) in the percentage of 
subjects with events; these analyses will be performed using the unstratified Miettinen and 
Nurminen method [7], an unconditional, asymptotic method.
The percentage of subjects with any treatment-emergent suicidal ideation, with any 
treatment-emergent suicidal behavior, or with any treatment-emergent self-injurious 
behavior, no suicidal intent, will be analyzed per the tiered analysis strategy outlined above, 
and will be considered as either Tier-2 or Tier-3 events, depending on the number of subjects 
with an event observed within each treatment group. Additionally, the 11 pre-specified 
categories of suicidal ideation and behavior will be summarized.  Subject counts (and 
cumulative counts) for each category will be based upon the most severe treatment-emergent 
event observed during the assessment period.
The percentage of subjects having their dose up-titrated (per protocol), maintained or reduced 
will also be considered as Tier-3 events.
 
 
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Table 7
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any drug-related AE
X
X
Any serious AE
X
X
Any serious and drug-related AE
X
X
Discontinuation due to an AE
X
X
Discontinuation due to a drug-related AE
X
X
Specific AEs, SOCs or C-SSRS treatment-emergent 
events‡ (incidence ≥4 subjects in at least 1 of the 
treatment groups)
X
X
Tier 3
Specific AEs, SOCs or C-SSRS treatment-emergent 
events§ (incidence <4 subjects in each of the 
treatment groups)
X
Change from baseline results (labs, vital signs, ECGs, 
ESRS-A)
X
Dose up-titrated (per protocol), maintained or reduced
X
†
Adverse Experience references refer to both clinical and laboratory AEs.
‡
Any ideation, any behavior, or any self-injurious behavior, no suicidal intent.
§
Includes only those endpoints not already pre-specified as Tier-2 endpoints.
Note: SOC = System Organ Class;
C-SSRS = Columbia-Suicide Severity Rating Scale;
ESRS-A = Extrapyramidal Symptoms Rating Scale-Abbreviated;
X = results will be provided.
Demographic and Baseline Characteristics
8.6.3
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables.  No statistical hypothesis tests will be performed on these characteristics.  
The number and percentage of subjects screened, randomized, the primary reasons for 
screening failure, and the primary reason for discontinuation will be displayed.  Demographic 
variables (e.g., age, gender, race), baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
Interim Analyses
8.7
A standing internal Data Monitoring Committee (siDMC), which will consist of Sponsor
personnel not affiliated with the project, will evaluate the unblinded safety and efficacy data
to assess the overall risk and benefit to trial participants when approximately 25%, 50% and 
75% of the subjects have had the opportunity to complete the study.
An interim unblinded efficacy (futility) analysis will be considered unless more than 50% of 
the subjects have been enrolled 4 months after the first subject was randomized into the 
study.
The interim analysis, which would be performed by an internal statistician not 
 
 
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affiliated with the project, would occur when 50% of the subjects have completed or 
discontinued IP treatment and include all data collected (including partial data from subjects 
who were randomized, but did not yet have the opportunity to complete the study).  The 
siDMC would review the analysis results and recommend whether the study should continue.
If the study is stopped early, the CSR will comprise all available data up to and including the 
close-out visits, which include the data used to draw the conclusion in the decisive interim 
analysis plus the remaining data obtained afterwards (from additional visits and close-out 
visits).  This approach to include all available information is in line with the International
Council for Harmonisation (ICH)-E9 guideline, the intent-to-treat (ITT) principle and the 
Committee for Medicinal Products for Human Use (CHMP) guideline on adaptive designs.
Futility of Primary Outcome
8.7.1
The futility analysis would be performed to assess whether it would be highly unlikely for 
MK-8189 to be declared superior to placebo with respect to the change from baseline in the 
PANSS total score at 4 weeks.  The primary efficacy analysis will be performed on the Full 
Analysis Set. The siDMC will review the analysis results and recommend whether the study 
should continue. The stopping boundaries for the futility analysis will be based on the 
Gamma spending function [9] with parameter 1. The study may be stopped with early 
rejection of the alternative hypothesis (i.e., MK-8189 will not be considered superior to 
placebo with respect to the change from baseline in the PANSS total score at 4 weeks) if the
test statistic crosses the pre-specified stopping boundaries (i.e., the value of the test statistic is
greater than the value of the Gamma stopping boundary at the time of the futility analysis, 
suggesting that MK-8189 is not superior to placebo).
Table 8 displays the operating characteristics of the futility analysis. Assuming that the 
futility analysis is performed when 108 subjects have completed or discontinued IP treatment
and an observed standard deviation of the change from baseline in the PANSS total score of 
17.0, the study may be stopped if the mean change in PANSS total score is <4.6 better than 
that observed in the placebo group.  This corresponds to the conditional power of the study 
being <26% at the time of the futility analysis (i.e., at the time of the futility analysis, if the 
observed difference in the mean change in PANSS total score between the MK-8189 and 
placebo groups (MK-8189 minus placebo) is -4.6, then there would be a 26% chance that 
MK-8189 would be declared superior to placebo at the time of the final analysis).
 
 
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Table 8
Operating Characteristics of the Futility Analysis†
Number of randomized subjects at the time of the futility analysis
108
Observed difference between groups that would stop the study 
(futility analysis)
> -4.6
P-value (two-sided) for stopping the study
> 0.30
Conditional power‡ for stopping the study
< 26%
Probability that the study will be stopped
(MK-8189 is ineffective; difference§ = 0)
70%
Probability that the study will be stopped
(MK-8189 is effective; difference = -8)
22%
Observed difference between groups that would result in superiority 
(final analysis)
≤ -6.2
†
Sample size is the total number of subjects randomized (2:2:1 ratio in MK-8189, placebo and risperidone 
groups, respectively); Expected drop-out rate = 30%; Differences and probabilities are based on the 
primary treatment comparison (i.e., MK-8189 vs. placebo).  The futility boundary is non-binding.
‡
Calculated under the assumption that the observed data trend at the time of the futility analysis will 
continue to the end of the trial.
§
Difference = MK-8189 – placebo.
Multiplicity
8.8
A small amount of alpha (α=0.0001) will be allocated to each of the 3 interim analyses.  The 
effect of the alpha spending for the interim analyses on the alpha to be used at the time of the 
final analysis is negligible.
The secondary hypothesis will only be formally tested if the test of the primary efficacy 
hypothesis is statistically significant (i.e., p-value is less than or equal to 0.05), thus
controlling the overall type-I error over the primary and secondary hypotheses at the 5% 
level (two-sided).  That is, MK-8189 would be compared to placebo with respect to the mean 
change from baseline in CGI-S score after 4 weeks of treatment using α=0.05 (two-sided).
If the primary efficacy hypothesis test is not statistically significant, then a nominal p-value 
would be displayed for the secondary hypothesis test, but statistical significance (i.e., 
superiority to placebo) would not be concluded for this test.
Sample Size and Power Calculations
8.9
The planned number of subjects to be randomized is 215 (86, 86, and 43 in the MK-8189, 
placebo and risperidone groups, respectively). For the PANSS total score change from 
baseline at Week 4, the trial has 72% power (if no futility analysis is performed) or 65% 
power (if the planned futility analysis is performed) to demonstrate that MK-8189 is superior 
to placebo.
 
 
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The power and sample size are based on the following assumptions:

α = 0.05 (two-sided)

True treatment difference (MK-8189 minus placebo) = −8.0

Standard deviation = 17.0

Drop-out rate = 30%
The criterion for success is that the p-value for the between-treatment difference in the mean 
PANSS total score change from baseline (MK-8189 minus placebo) will be less than or equal 
to 0.05.  Given the above assumptions, this may occur when the observed difference between 
treatment groups is approximately ≤ -6.2.  The power calculations for the primary 
comparison are summarized under various assumptions in Table 9 (assuming that a futility 
analysis is not performed) and Table 10 (assuming that a futility analysis is performed).
Table 9
Power† (%) Under Various Assumptions With 215 Subjects Randomized if 
Futility Analysis is Not Performed
True Standard 
Deviation of Change 
from Baseline
True Difference‡ in Change from Baseline in PANSS§ Total Score
-10.0
-9.5
-9.0
-8.5
-8.0
-7.5
-7.0
-6.5
-6.0
15.0
95
93
90
87
83
78
72
65
58
16.0
92
90
86
82
78
72
66
60
53
17.0
89
86
82
78
72
67
61
55
48
18.0
86
82
78
73
68
62
56
50
44
† Assumptions:  α = 0.05 (two-sided);  drop-out rate = 30%;
60 subjects per treatment group (MK-8189 and placebo) expected to be included in the analysis.
‡ Difference = MK-8189 − placebo.
§ PANSS = Positive and Negative Syndrome Scale.
 
 
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Table 10
Power† (%) Under Various Assumptions With 215 Subjects Randomized if 
Futility Analysis is Performed
True Standard 
Deviation of Change 
from Baseline
True Difference‡ in Change from Baseline in PANSS§ Total Score
-10.0
-9.5
-9.0
-8.5
-8.0
-7.5
-7.0
-6.5
-6.0
15.0
92
89
86
81
76
71
65
58
51
16.0
88
85
81
76
71
65
59
53
46
17.0
84
80
76
71
65
60
54
48
42
18.0
80
75
71
66
60
55
49
44
38
† Assumptions:  α = 0.05 (two-sided);  drop-out rate = 30%;
60 subjects per treatment group (MK-8189 and placebo) expected to be included in the analysis.
‡ Difference = MK-8189 − placebo.
§ PANSS = Positive and Negative Syndrome Scale.
For assay sensitivity, the trial has 67% power to demonstrate that risperidone is superior to 
placebo at an overall one-sided 5% alpha level, if the underlying treatment difference 
(risperidone minus placebo) is -8.0.
Subgroup Analyses and Effect of Baseline Factors
8.10
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoint will be estimated within each category of the following classification variables:

Age category (≤35 years, > 35 years)

Gender (female, male)

Race (white, Asian, other)

Duration of illness (≤10 years, > 10 years)

Baseline PANSS total score (≤95, > 95)
Compliance (Medication Adherence)
8.11
In this study, as part of the routine recording of the amount of study treatment taken by each 
subject, the number of tablets and capsules remaining in study packaging will be counted, 
reviewed, and recorded at regular intervals.  These results will be used to calculate subject 
compliance.
A day within the study will be considered an “On-Therapy” day if the subject takes the 
required number of IP tablets and capsules, as noted in Section 5.2.
For a subject who is followed for the entire study period, the “Number of Days Should be on 
Therapy” is the total number of days from randomization to the last scheduled day for 
treatment administration for that subject.  For a subject who discontinued from the study 
 
 
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permanently, the “Number of Days Should be on Therapy” is the total number of days from 
randomization to the date the subject discontinued from the study.
For each subject, percent compliance will then be calculated using the following formula:
Summary statistics will be provided on percent compliance by treatment group for the FAS 
population.
Extent of Exposure
8.12
The extent of exposure to study treatment will be evaluated by summary statistics (N, mean, 
range) and frequencies (number of subjects exposed to study treatment for various durations, 
e.g., within 1-week intervals over the course of the study) for the “Number of Days on 
Therapy” by treatment group.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 11.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 11
Product Descriptions
Product Name & Potency
Dosage Form
MK-8189 4 mg
tablet
Placebo to MK-8189 4 mg
tablet
Risperidone 2 mg
capsule
Placebo to risperidone 2 mg
capsule
All placebos were created by the Sponsor to match the active product.
 
 
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Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
For the tablet of capsule formulation, subjects will receive blinded bottles (each containing a 
1 week supply of the study therapy). No kitting is required. 
Clinical Supplies Disclosure
9.3
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind subjects and to unmask treatment identity. In the event that the emergency 
unblinding call center is not available for a given site in this trial, the central electronic 
treatment allocation/randomization system (IVRS/IWRS) should be used in order to unblind 
subjects and to unmask treatment/vaccine identity.
The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
 
 
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Standard Policies
9.6
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
 
 
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Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
 
 
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The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
 
 
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ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
 
 
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Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
 
 
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the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
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.
11.0 LIST OF REFERENCES
[1]
Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular 
regulation to clinical use. Pharmacol Rev 2006;58:488-520.
[2]
Seeger TF, Bartlett B, Coskran TM, Culp JS, James LC, Krull DL, et al. 
Immunohistochemical localization of PDE10A in the rat brain. Brain Res 
2003;985:113-26.
[3]
Grauer SM, Pulito VL, Navarra RL, Kelly MP, Kelley C, Graf R, et al. 
Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, 
cognitive, and negative symptoms of schizophrenia. J Pharmacol Exp Ther 
2009;331(2):574-90.
[4]
Schmidt CJ, Chapin DS, Cianfrogna J, Corman ML, Hajos M, Harms JF, et al. 
Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new 
therapeutic approach to the treatment of schizophrenia. J Pharmacol Exp Ther 
2008;325(2):681-90.
 
 
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[5]
Khan A, Yavorsky WC, Liechti S, DiClemente G, Rothman B, Opler M. et al. 
Assessing the sources of unreliability (rater, subject, time-point) in a failed 
clinical trial using items of the Positive and Negative Syndrome Scale (PANSS). 
J Clin Psychopharmacol. 2013 Feb;33(1):109-17.
[6]
Kay SR, Fiszbein  A, Opler LA. The positive and negative syndrome scale 
(PANSS) for schizophrenia. Schizophr Bull 1987;13(2):261-76.
[7]
Miettinen O, Nurminen M. Comparative analysis of two rates. Statist Med 
1985;4:213-26.
[8]
Ratitch B, O'Kelly M, Tosiello R. Missing data in clinical trials: from clinical 
assumptions to statistical analysis using pattern mixture models. Pharm Stat. 
2013 Nov-Dec;12(6):337-47.
[9]
Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type 
I error probability spending functions. Stat Med 1990;9:1439-45.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.6 – Future Biomedical 
Research will be used to study various causes for how subjects may respond to a 
drug/vaccine.  Future biomedical research specimen(s) will be stored to provide a 
resource for future trials conducted by Merck focused on the study of biomarkers 
responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease.  The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
 
 
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present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
to any specimens, test results, or medical information once the specimens have been 
rendered de-identified
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
 
 
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At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
 
 
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specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial
administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
 
 
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international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e. only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
 
 
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12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Pharmacogenetics Informational Brochure for IRBs/IECs & Investigational Site Staff
12.3
 
 
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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
12.4
Sample Types
Trial Visit/Cycle/etc:
Screening
Visits 1-
Treatment 
Visit 2
Treatment
Visit 4
Treatment 
Visit 6
Post-
Treatment
Blood Parameter 
Approximate Blood Volume (mL)
Hematology
2
2
2
2
Serum/Plasma Chemistry
8.5
8.5
8.5
8.5
Serum 
β-Human 
Chorionic 
Gonadotropin (β-hCG)a
3.5
Serum 
Follicle 
Stimulating 
Hormone (FSH)b
3.5
HIV/Hepatitis Screen (at the 
discretion of the investigator
and/or per site SOPs)b
3.5
Blood for Genetic Analysis
(DNA) 
8.5
Prolactin
3.5
3.5
3.5
PK
6
18
6
Lipids
3.5
3.5
3.5
Fasting glucose
2
2
2
2
Insulin
2
2
2
Expected Total (mL)
32.0
36.0
30.5
27.5
a.
For female subjects of child bearing potential only
b.
if applicable and dependent upon site SOP
 
 
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Abbreviations
12.5
Abbreviation
Definition
AAP
Atypical Antipsychotic
AE 
Adverse event/experience
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
ASaT
All subjects as treated
AST
Aspartate aminotransferase
βhGC
Beta human Chorionic Gonadotropin 
BL 
Baseline
BMI 
Body mass index
BUN Blood urea nitrogen
Blood urea nitrogen
CGI-S 
Clinical Global Impression Scale-Severity
CHMP
Committee for Medicinal Products for Human Use
cm
Centimeter
CNS
Central Nervous System
CR
Controlled release
C-SSRS 
Columbia Suicide Severity Rating Scale
CYP 
Cytochrome P450 enzyme
DC
Discontinuation
DNA
Deoxyribonucleic Acid
DO
Doctor of Osteopathic Medicine
DSM-5™
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition
ECG 
Electrocardiogram
ECI
Event of Clinical Interest
eCRF
Electronic Case Report Form
ECT
Electroconvulsive Therapy 
eGFR
Estimated Glomerular Filtration Rate
 
 
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CCI
CCI
CCI
CCI
 
 
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Abbreviation
Definition
EO
Enzyme Occupancy
EPS 
Extrapyramidal Symptoms
ESRS-A 
Extrapyramidal Symptom Rating Scale-Abbreviated
FAS
Full Set Analysis
FBR
Future Biomedical Research
FDA 
Food and Drug Administration, USA
FDAMA
Food and Drug Administration Modernization Act
FDAAA
Food and Drug Administration Amendments Act
FSH
Follicle Stimulating Hormone
GCP 
Good Clinical Practice
HDL 
High density lipoprotein
HIV 
Human Immunodeficiency Virus
IB 
Investigator’s Brochure
ICF 
Informed Consent Form
ICH 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use
IEC 
Independent Ethics Committee
in
Inches
IND
Investigational New Drug
IP 
Investigational Product.  This term is interchangeable with 
the terms “study drug” and “study medication” as used in this 
protocol.  IP refers to MK-8189 tablets , risperidone capsules 
and their respective placebos in the dosage form and 
strengths specified in the protocol
IP Dose
The quantity of investigational product taken at one dose For 
this protocol, subjects will take a specified equal number of 
IP tablets and capsules.
IRB 
Institutional Review Board
ITT
Intent to Treat
IVRS 
Interactive Voice Response System
IWRS 
Integrated Web Response System
kg
Kilograms
 
 
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Abbreviation
Definition
lb
Pounds
LDL 
Low density lipoprotein
MAO
Monoamine oxidase
MAR
Missing at Random
MD
Doctor of Medicine
MDRD
Modification of Diet in Renal Disease (calculation) 
MINI 
Mini International Neuropsychiatric Interview for 
Schizophrenia and Psychotic Disorders
MIST
Metabolites in Safety Testing
NDA
New Drug Application
NP
Nurse Practitioner
NSAID 
Nonsteroidal anti-inflammatory drug
PA
Physician’s Assistant
PANSS 
Positive and Negative Syndrome Scale
PC 
Phone Call
PD 
Pharmacodynamics
PE 
Physical Exam
PhD
Doctor of Philosophy 
pH
Numeric scale to measure acidity or basicity
PGt 
Pharmacogenetic
PK 
Pharmacokinetic(s)
PPDM
Department of Pharmacokinetics Pharmacodynamics and 
Drug Metabolism
QD 
Once daily
QTcF
QT (waves) corrected-Fridericia 
Rand
Randomization
RBC 
Red Blood Cell
RNA
Ribonucleic acid
SAE 
Serious Adverse Event
(S)AE 
All Adverse Events, including Serious Adverse Events
 
 
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CCI
 
 
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Abbreviation
Definition
SDME 
Sponsor designated medical expert: a medically qualified 
sponsor representative who consults with sites on protocol-
specific activities, such as the review of the Screening 
psychiatric evaluation intake forms to verify subject 
eligibility. An “external” SDME refers to a vendor SDME.
siDMC
Standard Internal Data Monitoring Committee 
SME
Subject Matter Expert
SOC
System Organ Class
SOP
Standard Operating Procedure
T4 
Thyroxine
TEAE
Treatment Emergent Adverse Events
TC
Telephone Contact
TSH 
Thyroid Stimulating Hormone
ULN 
Upper limit of normal
US, USA 
United States of America
WBC 
White Blood Cell
 
 
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Risperidone Label
12.6
 
 
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PPD
PPD
PPD
PPD
PPD
PPD
 
 
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PPD
PPD
 
 
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PPD
PPD
 
 
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PPD
PPD
 
 
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PPD
PPD
 
 
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PPD
PPD
 
 
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PPD
PPD
 
 
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Mapping Between the 11 Categories of Suicidal Ideation and Behavior and the 
12.7
C-SSRS and CDR for Programming Standard Tables
Mapping Between the 11 Categories of Suicidal Ideation and Behavior and the C-SSRS
Category
C-SSRS Questions (from eCRF)*
Suicidal ideation
Passive
1. Wish to be dead
Active – nonspecific (no method, intent or 
plan)
2. Non-specific active suicidal thoughts
Active – method, but no intent or plan, 
3. Active suicidal ideation with any 
methods (not plan) without intent to 
act
Active – intent, with or without a method, 
but no plan
4. Active suicidal ideation with some 
intent to act, without a plan
Active – method, intent and plan
5. Active suicidal ideation with specific 
plan and intent
Suicidal behavior
Preparatory actions toward imminent 
suicidal behaviors
Preparatory acts or behavior
Aborted attempt
Aborted attempt
Interrupted attempt 
Interrupted attempt
Suicide attempt
Actual attempt
Completed suicide
Completed suicide
Self-injurious behavior, no suicidal 
attempt
Has subject engaged in non-suicidal self-
injurious behavior?
*Data are “Yes” of “No”
 
 
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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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