Conditions: Negative Symptoms of Schizophrenia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 515
Healthy volunteers: no

Brief summary:
MIN-101C07 is a multicenter, multinational, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of roluperidone in adult schizophrenia patients.The primary objective is to evaluate the efficacy of 2 fixed doses of roluperidone compared to placebo in improving the negative symptoms of schizophrenia over 12 weeks of double-blind treatment as measured by the change in Positive and Negative Syndrome Scale (PANSS) Marder negative symptoms factor score (NSFS) over 12 weeks.

Detailed description:

Arms:
arm 1: Roluperidone 64 mg for entire study arm 2: Roluperidone mg for entire study arm 3: Placebo for 12 weeks followed by Roluperidone 64 mg during open-label extension arm 4: Placebo for 12 weeks followed by Roluperidone 32 mg during open-label extension

Interventions: intervention 1: Placebo Oral Tablet intervention 2: Roluperidone 32 mg intervention 3: Roluperidone 64 mg
Intervention descriptions: intervention 1: Placebo administered as a single dose once daily intervention 2: Roluperidone administered as a single dose once daily intervention 3: Roluperidone administered as a single dose once daily

Protocol document:
Prot_000.pdf: 
Minerva Neurosciences, Inc. 
Protocol MIN-101C07 
Confidential 
________________________________________________________________________ 
Amendment 2, 26 September 2018 
 1 
Minerva Neurosciences, Inc. 
Clinical Protocol 
A Multicenter, Randomized, Double-blind, Parallel-Group, Placebo-Controlled, 
Monotherapy, 12-Week Study to Evaluate the Efficacy and Safety of 2 Fixed Doses 
of MIN-101 in Adult Patients with Negative Symptoms of Schizophrenia, Followed 
by 40-Week Open-Label Extension 
Protocol MIN-101C07; Phase 3 
AMENDMENT 2 
MIN-101 
EudraCT NUMBER: 2017-003333-29 
Sponsor: 
Minerva Neurosciences, Inc. 
CRO: 
Status: 
Approved 
Issue Date: 
26 September 2018 
Prepared by: 
Document No.: 
MIN-101C07.v2.0 
Protocol Version 
Issue Date 
Original Protocol 
03 October 2017 
Amendment 1 
04 December 2017 
Amendment 2 
26 September 2018 
Compliance:  This study will be conducted in compliance with this protocol, Good Clinical Practice, and 
applicable regulatory requirements. 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. In 
any event, persons to whom the information is disclosed must be informed that the information is privileged 
or confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally 
to all future information supplied to you that is indicated as privileged or confidential. 
ClinicalTrials.gov ID: NCT03397134


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TABLE OF CONTENTS 
LIST OF IN-TEXT TABLES ...................................................................................................... 5 
LIST OF IN-TEXT FIGURES ..................................................................................................... 5 
SYNOPSIS ................................................................................................................................ 6 
TIME AND EVENTS SCHEDULE – DOUBLE-BLIND PHASE .............................................. 16 
TIME AND EVENTS SCHEDULE – OPEN-LABEL EXTENSION PHASE ............................ 19 
ABBREVIATIONS ................................................................................................................... 22 
1. 
INTRODUCTION ........................................................................................................ 25 
1.1. 
Background on the Disease ....................................................................................... 25 
1.2. 
Background on the Molecule ...................................................................................... 27 
1.3. 
Nonclinical Studies ..................................................................................................... 28 
1.3.1. 
Pharmacologic Profile ................................................................................ 28 
1.3.2. 
Pharmacological Effect of MIN-101 in Mice and Rats ................................ 29 
1.3.3. 
Safety Pharmacology ................................................................................. 29 
1.3.4. 
Toxicology .................................................................................................. 30 
1.3.5. 
Pharmacokinetic Profile ............................................................................. 32 
1.4. 
Clinical Studies ........................................................................................................... 34 
1.4.1. 
Healthy Subject Studies ............................................................................. 34 
1.4.1.1. 
Pharmacokinetics .................................................................................... 36 
1.4.1.2. 
Safety ...................................................................................................... 37 
1.4.2. 
Patient Studies ........................................................................................... 37 
1.4.2.1. 
Pharmacokinetics .................................................................................... 38 
1.4.2.2. 
Efficacy .................................................................................................... 39 
1.4.2.3. 
Safety ...................................................................................................... 40 
1.5. 
Benefit/Risk Assessment ............................................................................................ 44 
2. 
OBJECTIVES ............................................................................................................. 46 
2.1. 
Objectives and Endpoints ........................................................................................... 46 
2.2. 
Hypothesis .................................................................................................................. 47 
3. 
STUDY DESIGN AND RATIONALE .......................................................................... 47 
3.1. 
Overview of Study Design .......................................................................................... 47 
3.2. 
Study Design Rationale .............................................................................................. 50 
4. 
STUDY POPULATION ............................................................................................... 57 
4.1. 
Inclusion Criteria ......................................................................................................... 57 
4.2. 
Exclusion Criteria ........................................................................................................ 58 
4.3. 
Prohibitions and Restrictions ...................................................................................... 60 
4.4. 
Prior and Concomitant Therapy.................................................................................. 61 
4.4.1. 
Prior Therapy .............................................................................................. 61 
4.4.2. 
Concomitant Therapy ................................................................................. 61 
5. 
TREATMENT ALLOCATION AND BLINDING ......................................................... 62 
5.1. 
Randomization ............................................................................................................ 62 
5.2. 
Blinding ....................................................................................................................... 63 
6. 
DOSAGE AND ADMINISTRATION ........................................................................... 63 
7. 
TREATMENT COMPLIANCE .................................................................................... 64 
8. 
STUDY EVALUATIONS ............................................................................................. 65 
8.1. 
Study Procedures ....................................................................................................... 65 


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8.1.1. 
Overview .................................................................................................... 65 
8.1.2. 
Pre-Treatment Phase ................................................................................. 66 
8.1.2.1. 
Screening Period (Visit 1) ....................................................................... 66 
8.1.2.2. 
Hospitalization Period: Washout (Visit 2) and Baseline (Visits 3) ........... 67 
8.1.3. 
Double-Blind Treatment Phase .................................................................. 67 
8.1.3.1. 
Day 1/Randomization (Visit 4) ................................................................ 67 
8.1.3.2. 
Day 2 (Visit 5) to Week 8 (Visit 10) ......................................................... 67 
8.1.3.3. 
Telephone Contacts ................................................................................ 67 
8.1.3.4. 
Week 12 (Visit 11) ................................................................................... 68 
8.1.4. 
Open-label Extension Phase ...................................................................... 68 
8.1.4.1. 
Hospitalization Period Following Week 12 (Visits 12 and 13) ................ 68 
8.1.4.2. 
40-Week Open-Label Treatment Phase ................................................. 68 
8.2. 
Efficacy ....................................................................................................................... 69 
8.2.1. 
Assessments .............................................................................................. 69 
8.2.2. 
Efficacy Evaluations ................................................................................... 70 
8.3. 
Pharmacokinetic Evaluations ..................................................................................... 71 
8.3.1. 
Sample Collection and Handling ................................................................ 71 
8.3.2. 
Analytical Procedures................................................................................. 71 
8.3.3. 
Pharmacokinetic Evaluations ..................................................................... 71 
8.4. 
Safety Evaluations ...................................................................................................... 72 
9. 
PATIENT COMPLETION/WITHDRAWAL ................................................................. 77 
9.1. 
Completion .................................................................................................................. 77 
9.2. 
Withdrawal from the Study ......................................................................................... 77 
9.3. 
Stopping Rules ........................................................................................................... 77 
10. 
STATISTICAL METHODS ......................................................................................... 78 
10.1. 
Sample Size Determination ........................................................................................ 78 
10.2. 
Data Sets .................................................................................................................... 79 
10.3. 
Patient Information ..................................................................................................... 79 
10.4. 
Extent of Exposure and Treatment Compliance ......................................................... 80 
10.5. 
Efficacy Analyses ....................................................................................................... 80 
10.5.1. 
Primary Endpoint ........................................................................................ 81 
10.5.2. 
Secondary and Exploratory Endpoints ....................................................... 82 
10.6. 
Interim Analyses ......................................................................................................... 82 
10.7. 
Pharmacokinetics ....................................................................................................... 82 
10.8. 
Safety Analyses .......................................................................................................... 82 
10.8.1. 
Adverse Events .......................................................................................... 83 
10.8.2. 
Clinical Laboratory Tests ............................................................................ 83 
10.8.3. 
Vital Signs .................................................................................................. 83 
10.8.4. 
Electrocardiogram (ECG) ........................................................................... 83 
10.8.5. 
Physical Examination ................................................................................. 84 
10.8.6. 
Other Safety Parameters ........................................................................... 84 
10.8.6.1. 
Sheehan Suicidality Tracking Scale........................................................ 84 
10.9. 
Pharmacokinetic / Pharmacodynamic Analyses ........................................................ 84 
10.10. Extension Phase ......................................................................................................... 85 
10.11. Data Safety Monitoring Board .................................................................................... 85 
11. 
ADVERSE EVENT REPORTING ............................................................................... 85 
11.1. 
Definitions ................................................................................................................... 86 
11.1.1. 
Adverse Event Definitions and Classifications ........................................... 86 
11.1.2. 
Attribution Definitions ................................................................................. 87 
11.1.3. 
Severity Criteria .......................................................................................... 87 
11.2. 
Special Reporting Situations ...................................................................................... 87 
11.3. 
Procedures ................................................................................................................. 88 
11.3.1. 
All Adverse Events ..................................................................................... 88 


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11.3.2. 
Serious Adverse Events ............................................................................. 88 
11.3.3. 
Pregnancy .................................................................................................. 90 
11.4. 
Contacting Sponsor Regarding Safety ....................................................................... 90 
12. 
PRODUCT QUALITY COMPLAINT HANDLING ...................................................... 90 
12.1. 
Procedures ................................................................................................................. 90 
12.2. 
Contacting Sponsor Regarding Product Quality ......................................................... 90 
13. 
STUDY DRUG INFORMATION ................................................................................. 91 
13.1. 
Physical Description of Study Drug(s) ........................................................................ 91 
13.2. 
Packaging ................................................................................................................... 91 
13.3. 
Labeling ...................................................................................................................... 91 
13.4. 
Preparation, Handling, and Storage ........................................................................... 91 
13.5. 
Drug Accountability ..................................................................................................... 91 
14. 
STUDY-SPECIFIC MATERIALS................................................................................ 92 
15. 
ETHICAL ASPECTS .................................................................................................. 92 
15.1. 
Study-Specific Design Considerations ....................................................................... 92 
15.2. 
Regulatory Ethics Compliance ................................................................................... 94 
15.2.1. 
Investigator Responsibilities ....................................................................... 94 
15.2.2. 
Independent Ethics Committee or Institutional Review Board (IEC/IRB) .. 94 
15.2.3. 
Informed Consent ....................................................................................... 95 
15.2.4. 
Privacy of Personal Data ............................................................................ 96 
15.2.5. 
Country Selection ....................................................................................... 97 
16. 
ADMINISTRATIVE REQUIREMENTS ....................................................................... 97 
16.1. 
Protocol Amendments ................................................................................................ 97 
16.2. 
Regulatory Documentation ......................................................................................... 97 
16.2.1. 
Regulatory Approval/Notification ................................................................ 97 
16.2.2. 
Required Pre-Study Documentation .......................................................... 97 
16.3. 
Patient Identification, Enrollment, and Screening Logs .............................................. 98 
16.4. 
Source Documentation ............................................................................................... 98 
16.5. 
Case Report Form Completion ................................................................................... 99 
16.6. 
Data Quality Assurance/Quality Control ................................................................... 100 
16.7. 
Record Retention ...................................................................................................... 100 
16.8. 
Monitoring ................................................................................................................. 100 
16.9. 
Study Completion/Termination ................................................................................. 101 
16.9.1. 
Study Completion ..................................................................................... 101 
16.9.2. 
Study Termination .................................................................................... 101 
16.10. On-Site Audits........................................................................................................... 102 
16.11. Use of Information and Publication .......................................................................... 102 
16.12. Registration of Clinical Studies and Disclosure of Results ....................................... 103 
17. 
REFERENCES ......................................................................................................... 104 
ATTACHMENT 1: 
ALLOWED/PROHIBITED CONCOMITANT MEDICATIONS ........... 109 
ATTACHMENT 2: 
READINESS FOR DISCHARGE QUESTIONNAIRE ....................... 116 
ATTACHMENT 3: 
ABNORMAL INVOLUNTARY MOVEMENT SCALE (AIMS) ........... 118 
ATTACHMENT 4: 
BARNES AKATHISIA RATING SCALE (BARS) ............................. 120 
ATTACHMENT 5: 
POSITIVE AND NEGATIVE SYNDROME SCALE (PANSS) ........... 122 
ATTACHMENT 6: 
PERSONAL AND SOCIAL PERFORMANCE SCALE ..................... 135 
ATTACHMENT 7: 
CLINICAL GLOBAL IMPRESSION – SEVERITY RATING ............. 138 


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ATTACHMENT 9: 
COGNITIVE TESTING ...................................................................... 140 
 
 
ATTACHMENT 11: 
SHEEHAN SUICIDALITY TRACKING SCALE ................................ 143 
ATTACHMENT 12: 
SIMPSON-ANGUS SCALE ............................................................... 146 
LIST OF IN-TEXT TABLES 
Table 1. 
Overview of Clinical Pharmacology Studies of MIN-101 in Healthy Subjects ..... 35 
Table 2. 
Overview of Clinical Studies of MIN-101 in Schizophrenia Patients ..................... 38 
Table 3. 
Characteristics of the Treatment and Dosage per Fully Compliant Patient ......... 64 
Table 4. 
Estimated Blood Volume Drawna .............................................................................. 66 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Study Design Diagram .................................................................................... 49 
 
 
 
 
 
 


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SYNOPSIS 
Title, Protocol Number/Phase 
A 
Multicenter, 
Randomized, 
Double-blind, 
Parallel-Group, 
Placebo-Controlled, 
Monotherapy, 12-Week Study to Evaluate the Efficacy and Safety of 2 Fixed Doses of 
MIN-101 in Adult Patients with Negative Symptoms of Schizophrenia, Followed by 
40-Week Open-Label Extension. 
MIN-101C07 / Phase 3 
Objectives: 
Primary 
• To evaluate the efficacy of 2 fixed doses (32 mg and 64 mg) of MIN-101 compared to 
placebo in improving the negative symptoms of schizophrenia as measured by the 
change in the Positive and Negative Syndrome Scale (PANSS) Marder negative 
symptoms factor score (NSFS) over 12 weeks of double-blind treatment. 
Key Secondary 
• To assess the effect of MIN-101 compared to placebo on the Personal and Social 
Performance (PSP) total score, over 12 weeks of double-blind treatment. 
Secondary 
To assess the effect of MIN-101 compared to placebo over 12 weeks of double-blind 
treatment on: 
• Clinical Global Impression of Severity (CGI-S). 
• Safety and tolerability. 
Exploratory 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 


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Hypotheses 
The primary hypothesis is that after 12 weeks, MIN-101 will be superior to placebo on the 
change from Baseline in the PANSS Marder negative symptoms factor score. 
Study Design 
This will be a multicenter, multinational, randomized, double-blind, placebo-controlled, 
parallel-group study in approximately 501 schizophrenic patients who present with 
negative symptoms. 
Eligible patients will be randomized in equal proportion to receive once daily MIN-101 
64 mg, MIN-101 32 mg, or placebo, orally (PO), for 12 weeks.  Afterwards, all patients 
will continue treatment with active drug for an additional 40 weeks.  During the 40-week, 
open-label treatment extension, patients who were initially randomized to MIN-101 64 mg 
or MIN-101 32 mg will continue treatment with the same dose, while patients who were 
initially randomized to placebo will crossover to MIN-101 64 mg or MIN-101 32 mg in a 
1:1 ratio per the randomization schedule implemented on Day 1 (Visit 4).  The 
Week 12+1 Day onward dose is the extension phase dose. 
The 3-phase study will consist of: 
Pre-Treatment Phase 
o Screening Period (Visit 1), including a Screening visit that should take place no 
more than 28 days before the first administration of study drug on Day 1 (Visit 4). 
o Washout Period (Visit 2), an inpatient washout period starting on Day -2 to allow 
patients on antipsychotic medications or other psychotropics to be washed out from 
their previous medications.  Patients who did not receive any psychotropics will 
also be hospitalized on Day -2 before Baseline (Visit 3) in order to standardize study 
procedures in all patients. 
o Baseline Visit (Visit 3, Day -1), all inclusion and exclusion criteria will be verified 
and all assessments will be completed prior to initiation of the double-blind 
treatment phase. 
12-Week Double-Blind Treatment Phase  
A double-blind, placebo-controlled treatment phase lasting 12 weeks.  On Day 1 (Visit 4), 
patients will be randomized to treatment (MIN-101 64 mg, MIN-101 32 mg, or placebo) in 
equal proportions.  Patients can be discharged at the discretion of the Investigator from the 
investigator’s site on Day 2, after taking the blinded study medication, and having 
undergone 3 electrocardiogram (ECG) assessments (in triplicate) performed at pre-dose 
and at the approximate time of maximum drug concentration (Cmax) of MIN-101 and its 
metabolite BFB-520.  Hence, patients will be hospitalized for a minimum of 4 days (3 
nights).  Any authorization to leave the hospital will be done with the help of the Readiness 
for Discharge Questionnaire (RDQ).  On Day 2 (Visit 5), if discharged, the patient will 
come back for visits at Weeks 1, 2, 3, 4, 8, and 12 for efficacy and/or safety assessments.  
Hospitalization on Visits 6 and 7 will be at the discretion of the investigator to ensure per-
protocol ECG assessment and PK sampling are done.  The patient (or his/her care provider) 
will be contacted by phone at Weeks 5, 6, 7, 9, 10, and 11 to verify safety and to make sure 
the patient is doing well and is compliant with study medication.   


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In case of early termination during the double-blind phase, the Week 12 (Visit 11) must be 
completed as soon as possible.  
40-Week Open-Label Extension Phase   
At the end of the 12-week double-blind treatment period (Visit 11), patients will be 
immediately enrolled into the 40-week open-label extension phase.  Patients will be 
hospitalized for 2 days after the initiation of treatment with MIN-101 (all patients).  Patients 
who received placebo for 12 weeks during the double-blind phase will start receiving 64 mg 
or 32 mg of MIN-101 per the randomization schedule implemented on Day 1 (Visit 4).  
Patients will then be allowed to leave the hospital on Visit 13 (Week 12 + 2 days) at the 
discretion of the investigator and after drug intake and safety have been ascertained 
clinically, including having undergone 3 ECG assessments (in triplicate) performed at pre-
dose and at the approximate time of Cmax of MIN-101 and its metabolite BFB-520.  
However, the Investigator may decide to keep the patient hospitalized as needed.  RDQ 
will be completed prior to any authorization to leave the hospital.  Hospitalization on Visits 
14 and 15 will be at the discretion of the investigator to ensure per-protocol ECG 
assessment and PK sampling are done.  Visits 16 to 26 will be ambulatory. 
End-of-study (EOS) (Week 54 / Visit 27) assessments will be performed within 2 weeks 
following the last treatment visit (Week 52 / Visit 26). In case of early withdrawal, the End 
of Treatment visit (Week 52/ Visit 26) must be completed as soon as possible. It will be 
followed ±2 weeks later by the EOS visit (Week 54/Visit 27).   
Study Population  
Inclusion Criteria 
Each potential patient must satisfy all the following criteria to be enrolled in the study:   
1. 
Patient and patient's legal representative, if applicable, provided informed consent 
prior to the initiation of any study related procedures, and the patient is judged by the 
investigator as being capable of understanding the study requirements. 
2. 
Male or female patient, 18 to 55 years of age, inclusive, and body mass index (BMI) 
< 35 kg/m2 at Screening.  
3. 
Patient meets the diagnostic criteria for schizophrenia as defined in the Diagnostic and 
Statistical Manual of Mental Disorders-Fifth Edition (DSM-5), as established by a full 
psychiatric interview in conjunction with the Mini International Neuropsychiatric 
Interview (MINI)a. 
4. 
Has a caregiver or family member or health care personnel who can provide 
information towards assessment and support the patient in terms of compliance with 
the protocol.  The caregiver must have contacts with the patient frequently and is not 
expected to change during the trial.   
5. 
Documented diagnosis of schizophrenia for at least 1 year before screening into the 
trial. 
                                                 
a Current version for DSM-5. 


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6. 
Patient is stable in terms of both positive and negative symptoms of schizophrenia over 
the last 6 months according to his or her clinician and/or based on documentation in 
the clinical chart or medical records.  Patients with or without positive symptoms are 
allowed if these symptoms are stable for the last 6 months and the patients do not meet 
exclusion criterion # 2. 
7. 
Patient is currently an outpatient and has not been hospitalized for the last 6 months 
for acute exacerbation or symptoms worsening.  Patients hospitalized for any time 
period during the last 6 months for social reasons or are currently hospitalized for 
social reasons can be included only with Sponsor’s Responsible Medical Officer’s 
approval (in addition for Ukraine only, the following criteria must be fulfilled: the 
patient has permanent place of residence, is legally capable, and has a caregiver [see 
inclusion criterion # 4]).  The social reasons must be documented in the electronic case 
report form (eCRF). 
8. 
Patient with a score of > 20 on the PANSS negative subscore (the original PANSS 
scale [Sum of N1+N2+N3+N4+N5+N6+N7]) at Screening (Visit 1) and Baseline 
(Visit 3) AND < 4 points absolute difference between the 2 visits. 
9. 
Patients can be on any psychotropic before the trial if the psychotropics can be 
discontinued at the beginning of the washout phase without risking the patient’s 
clinical status or safety.   
10. No history of violence against self or others during the last 1 year.    
11. Female patient who are not of childbearing potential, defined as women who are 
post-menopausal (defined as spontaneous amenorrhoea for at least 1 year or 
spontaneous amenorrhoea for at least 6 months confirmed by follicle stimulating 
hormone result of ≥ 40 IU/mL) or permanently sterilized (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy). 
12. Female patient, if of childbearing potential, must test negative for pregnancy and must 
be using a double barrier contraceptive method. 
13. Patient must be extensive (normal) metabolizers for P450 CYP 2D6, defined as a 
subject that has at least one functional allele (e.g., *1, or *2), as determined by 
study-specific genotyping test before the first drug dose is administered.  
14. Patient and the caregiver are considered by the investigator to be reliable and likely to 
cooperate with the assessment procedures.  
Exclusion Criteria 
Any potential patient who meets any of the following criteria will be excluded from 
participating in the study: 
1. 
Current major depressive disorder, bipolar disorder, panic disorder, obsessive 
compulsive disorder, or intellectual disability (intellectual developmental disorder 
diagnosed by age 14). 
2. 
Patient with PANSS item score of > 4 on: 
• P4 Excitement/Hyperactivity 


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• P6 Suspiciousness/persecution 
• P7 Hostility  
• G8 Uncooperativeness  
• G14 Poor impulse control 
3. 
A CDSS total score > 6. 
4. 
A score of ≥ 2 on any 2 of items 1, 2, or 3, or a score of ≥ 3 on item 4 of the Barnes 
Akathisia Rating Scale (BARS).  
5. 
Patient’s condition is due to direct physiological effects of a substance (e.g., a drug of 
abuse, or medication) or a general medical condition. 
6. 
Has a current or recent history of serious suicidal behavior within the past 1 year.  
7. 
Patient has a history of substance use disorder within 3 months of the Screening visit 
(excluding caffeine and cigarette smoking).  
8. 
Positive urine drug screen for drugs of abuse (cocaine, methadone, amphetamines, 
cannabinoids, opiates, benzodiazepines, and barbiturates), tricyclic antidepressants 
(TCA), and alcohol (except for prescription benzodiazepines).  
9. 
Patient who cannot be discontinued from psychotropics other than those allowed. 
10. Patient who received clozapine within 6 months of the Screening visit except when 
used for insomnia at doses ≤ 100 mg per day.  
11. Patient receiving treatment with long-acting or depot antipsychotic medication unless 
his/her next scheduled dose will occur during the protocol Screening period and can 
be omitted to allow for sufficient washout before receiving the study drug.  
12. Patient with a history of significant other major or unstable neurological, neurosurgical 
(e.g., head trauma), metabolic, hepatic, renal, hematological, pulmonary, 
cardiovascular, metabolic, gastrointestinal, or urological disorder. 
13. Patient with a history of seizures (patient with a history of a single childhood febrile 
seizure may be enrolled in this study). 
14. Patient who has had electroconvulsive therapy (ECT), vagal nerve stimulation (VNS), 
or repetitive trans-cranial magnetic stimulation (r-TMS) within the 6 months prior to 
the Screening visit or who are scheduled for ECT, VNS, or r-TMS at any time during 
the study. 
15. Patient with clinically significant abnormalities in hematology, blood chemistry, ECG, 
or physical examination not resolved by the Baseline visit which according to 
Investigator can interfere with study participation. 
16. Current systemic infection (e.g., Hepatitis B, Hepatitis C, human immunodeficiency 
virus [HIV], tuberculosis).  Patients with positive Hepatitis B core antibody test and 
negative Hepatitis B Surface Antigen (HBsAg) may be included in the study if 
aminotransferase levels (alanine aminotransferase/ serum glutamic pyruvic 
transaminase [ALT/SGPT] and aspartate aminotransferase/ serum glutamic 


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oxaloacetic transaminase [AST/SGOT]) do not exceed 2 times upper limit of normal 
(ULN). 
17. Patient who requires or may require concomitant treatment with any other medication 
likely to increase QT interval (e.g., paroxetine, fluoxetine, duloxetine, amiodarone). 
18. Patient who requires medication inhibiting CYP 2D6 or CYP 3A4.  
19. Patient with a clinically significant ECG abnormality that could be a safety issue in 
the study, including QT interval value corrected for heart rate using the Fridericia’s 
formula (QTcF) > 430 msec for males and > 450 msec for females. 
20. Patient with a history of myocardial infarction based on medical history or ECG 
findings at Screening. 
21. Familial or personal history of long QT syndrome or with additional risk factors for 
Torsade de Pointes.  
22. Patient whose safety laboratory results show one or more of the following:  potassium 
< 3.4 mmol/L, or calcium < 2.07 mmol/L, or magnesium < 0.70 mmol/L. 
23. Patients with unexplained syncope.   
24. Woman of child-bearing potential, or man, who are unwilling or unable to use accepted 
methods of birth control.  
25. Woman with a positive pregnancy test, is lactating, or is planning to become pregnant 
during the study. 
26. Patient who participated in another clinical study within 3 months prior to Screening, 
or received MIN-101 previously, or has previously participated in > 2 clinical studies 
with experimental medication within the past 2 years (previous participation in 3 
clinical studies with experimental medication will require approval of the sponsor 
before eligibility is determined). 
Treatments 
Study Treatments 
Patients who meet all of the inclusion and none of the exclusion criteria will start the 
psychotropic washout period (if applicable), during which, all psychotropics 
(antidepressants, mood stabilizers, benzodiazepines, antipsychotics) will be stopped. 
Patients will then be randomized on Day 1 to receive:  
• MIN-101 64 mg for the entire study, or 
• MIN-101 32 mg for the entire study, or 
• Placebo for 12 weeks followed by MIN-101 64 mg dose during the open-label extension 
phase, or 
• Placebo for 12 weeks followed by MIN-101 32 mg dose during the open-label extension 
phase. 
Treatments will be administered PO, once a day in the morning with or without food. 


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Efficacy Evaluations 
Efficacy will be evaluated based on the change from Baseline in PANSS NSFS after 
12 weeks of treatment or at early withdrawal.  In addition, other efficacy evaluations will 
be based on the change from Baseline in the score on the PSP, CGI-S 
  
The PANSS total and subscale scores, the Marder factor scores, CDSS, and cognition 
(verbal fluency test) will also be used to evaluate efficacy at specific time points as 
outlined in the Time and Events Schedules.  
Pharmacokinetic Evaluations 
Plasma levels of MIN-101 and its metabolite(s) will be tabulated. Standard population 
pharmacokinetic parameters (e.g., area under the concentration-time curve [AUC], PO 
clearance [CL/F], etc.) will be estimated at specified time-points as outlined in the Time 
and Events Schedules. 
Safety Evaluations 
Safety will be evaluated by an analysis of adverse events (AEs), vital signs, ECG, physical 
examination results, and clinical laboratory tests (including blood and urine analyses), 
Abnormal Involuntary Movement Scale (AIMS), BARS, Simpson-Angus Scale (SAS) and 
Sheehan-Suicidality Tracking Scale (Sheehan-STS) scale, at specified time-points during 
the study as outlined in the Time and Events Schedules. 
Statistical Methods  
Sample Size Determination 
The sample size for this study is based on the assumption of a treatment difference of 
3 points in the mean change from Baseline to Week 12 in PANSS negative subscale score 
based on the Marder negative factor score between any MIN-101 dose group and placebo. 
A standard deviation of 6.5 in the change in PANSS negative subscale score from Baseline 
is used.  Assuming an equal allocation to placebo and each of the 2 MIN-101 doses, 
100 patients in each treatment arm are required to detect the treatment difference of 3 points 
with a power of 90% at an overall 2-sided significance level of 0.05.  When adjusted for a 
rate of about 40% of patients who will not have either Baseline or at least 1 on-treatment 
efficacy assessments, the required number of patients becomes 167 in each treatment arm. 
Therefore, the total number of patients enrolled across the 3 treatment arms will be 501. 
Data Set 
The intent-to-treat (ITT) analysis set is defined as all randomized patients who receive at 
least one dose of study drug during the 12-week double-blind treatment phase regardless 
of any protocol deviation.  This analysis set will be used for efficacy analyses of the 
12-week double-blind treatment phase.  Analyses of change from Baseline will include 
only patients who have both Baseline and post-Baseline data during the 12-week 
double-blind treatment phase.
The Safety Population will consist of all patients who took at least 1 dose of the study drug.  
Patients will be analyzed based on treatment received. 


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Efficacy Analyses 
Primary Efficacy Analysis 
The primary efficacy endpoint will be the change in the NSFS from baseline to Week 12 
(the double-blind treatment period).  This endpoint will be analyzed using mixed-effect 
model repeated measurement (MMRM) with treatment arm (MIN-101 64 mg, MIN-101 
32 mg, and placebo), pooled study center (by country or region based on enrollment), visit, 
and treatment arm-by-visit interaction as fixed effects, patient nested in treatment as 
random effect, and Baseline NSFS as covariate.  An unstructured covariance matrix will be 
used to model the covariance of within-patient scores.  The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom.  These analyses will be performed 
based on all post-Baseline scores using only the observed cases (OCs) without imputation 
of missing values.  Comparison against placebo will be performed with the MIN-101 64 mg 
and 32 mg doses.   
The overall type I error rate for testing the 2 MIN-101 doses versus placebo for the primary 
and the key secondary endpoint will be controlled at the 2-sided 0.05 level.  The primary 
family of hypotheses (corresponding to the primary endpoint) and the secondary family of 
hypotheses (corresponding to the key secondary endpoint, the change from Baseline in PSP 
Total score) will be tested in a sequential manner with suitable adjustment for multiplicity 
within the family of primary hypotheses and within the family of the secondary hypotheses.  
The key secondary endpoint will not be ordered within the family of secondary hypotheses. 
The adjustment for multiplicity within the family of primary hypotheses will utilize the 
Hochberg procedure for the purpose of reporting of results.  This procedure will allow the 
null hypothesis of no treatment difference for both the 64 mg and 32 mg doses versus 
placebo to be rejected if largest p-value of comparing either of these 2 doses versus placebo 
is at or below 0.050.  Otherwise, the lowest of these 2 p-values must be at or below 0.025 
to allow for rejecting the null hypothesis for the representative dose. 
Key Secondary & Exploratory Efficacy Analyses 
The change from Baseline in PSP total scores will be analyzed similarly to the primary 
endpoint with MMRM.  The change from Baseline in CGI-S scores and the 
 
 
 and Baseline CGI-S score 
as a covariate. 
The change from Baseline for the remaining efficacy endpoints will be analysed similarly 
to primary endpoint. 
The cumulative distribution function for the primary and key secondary endpoint will also 
be evaluated, as appropriate. 
Interim Analyses 
No formal interim analyses are planned for this study.  Data from the double-blind 12-Week 
phase are the primary focus of this study and will be analyzed once the last patient 
completes Visit 11 assessments and the database has been locked.   


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Additionally, an external data safety monitoring board (DSMB) will be established to 
review the safety data and formulate recommended decisions/actions in accordance with 
the charter of the DSMB.  
Pharmacokinetic Analyses 
Individual plasma levels of MIN-101 and its metabolite(s) will be tabulated by MIN-101 
dose with the corresponding time related to study drug administration.  Descriptive 
statistics will be summarized by MIN-101 doses. 
Population PK analysis of plasma concentration-time data of MIN-101 and its metabolite(s) 
will be performed using nonlinear mixed-effects modeling.  Data may be combined with 
those of a selection of Phase 1 studies to support a relevant structural model.  Available 
patient characteristics (demographics, laboratory variables, etc.) will be tested as potential 
covariates affecting PK parameters.  Details will be given in a population PK analysis plan 
and results of the population PK analysis will be presented in a separate report. 
Safety Analyses 
All patients randomized to treatment who receive at least one dose of double-blind study 
drug will be included in the safety analyses.  Summary statistics will be provided for all 
safety data using appropriate descriptive statistics adverse events, Sheehan-STS, laboratory 
tests, ECGs, vital signs, AIMS, BARS, and SAS.   
For QTcF, an ANCOVA model by assessment times (visit and timepoint within visit) using 
the change from baseline (as dependent variable) with treatment arm (MIN-101 32 mg, 
MIN-101 64 mg, and placebo) as a factor, and Baseline value as covariate.  Estimates for 
the difference at each assessment time for each dose group versus placebo, standard error 
of the mean, and the upper bound of the 2-sided 90% confidence intervals will be presented. 
Pharmacokinetic / Pharmacodynamic Analyses 
The effect of coincidentally measured (time-matched) plasma concentrations of MIN-101 
and BFB-520 as compared to placebo on QTcF changes from Baseline will be analyzed 
utilizing the plasma concentration bin method.  This analysis will pool all assessment 
times at which both the QTcF and PK data are available and will treat the bins as separate 
groups using quartile distribution.  Plasma concentration data from placebo-treated patients 
will be set to 0 (zero).  Repeated measures ANCOVA model will be used and will include 
PK concentration Bin Group and per-protocol assessment times as fixed effects, Baseline 
QTcF as a covariate, and patient nested in treatment as a random effect.  
Furthermore, the analysis will be repeated by using the largest QTcF increase value (worst 
case) per patient, with the matched plasma concentration level independent of time of 
assessment, will also be performed using ANCOVA model with PK concentration Bin 
Group as fixed effects, Baseline QTcF as a covariate, and patient nested in treatment as a 
random effect.  Analysis of the largest time-matched mean difference from Baseline will 
also be explored, as applicable. 
P-value and the least squares means difference, and the corresponding upper bound of the 
two-sided 90% confidence intervals for the change from baseline versus placebo will 
be computed for each bin.   


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These analyses will be performed for MIN-101 plasma concentration and its main 
metabolites, as separate analyses. 
Extension Phase 
Patients enrolled in the 40-week open-label extension phase will receive either MIN-101 
64 mg or 32 mg.  Patients who received placebo in the double-blind 12-week treatment 
phase will receive one of the 2 MIN-101 doses according to the randomization schedule 
used at the beginning of the double-blind phase (Day 1).  Data from all patients enrolled in 
the 40-week extension phase will be summarized descriptively, as appropriate, by treatment 
arm sequence (MIN-101 64 mg, MIN-101 32 mg, placebo to MIN-101 64 mg, placebo to 
MIN-101 32 mg, overall MIN-101, overall placebo to MIN-101, and overall) as 
appropriate, and by visit.   
DSMB 
An external DSMB will be established to review the safety data and formulate 
recommended decisions/actions in accordance with the charter of the DSMB.  The DSMB 
will consist of 2 clinicians (psychiatrist and cardiologist), and a statistician, one of whom 
will chair the board.  The DSMB will review the outputs from statistical summaries of 
demographics and safety data prepared by the contract research organization managing the 
study on behalf of the sponsor who are not otherwise affiliated by the study team. 
Further details regarding the safety analysis will be specified in a separate DSMB charter.






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NOTE: Patients to be contacted via phone at Weeks 5, 6, 7, 9, 10, and 11 to verify safety and to make sure the patient is doing well and is compliant with study medication. 
Abbreviations: AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Scale;
 
CGI-S = Clinical Global Impression-Severity Scale; CYP = cytochrome; ECG = electrocardiogram; EOS = end-of-study; HbA1c = hemoglobin A1c; HBsAg = surface 
antigen of hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; MINI = Mini International Neuropsychiatric Interview; PANSS = Positive and Negative 
Syndrome Scale; PSP = Personal and Social Performance; RDQ = Readiness for Discharge Questionnaire; SAS = Simpson-Angus Scale; STS = Suicidality Tracking Scale.  
Footnotes: 
a Visits 7 to 13 may occur ± 2 days from scheduled visit.  
b Visits 2-5 hospitalization may be extended at the discretion of the investigator.  Hospitalization on Visits 6 and 7 are at the discretion of the investigator to ensure per-protocol ECG 
assessment and PK sampling are done.  Hospitalization includes admission to a hospital or the utilization of an inpatient facility. 
c Vital signs (blood pressure, heart rate, respiratory rate, and oral or aural body temperature) obtained after the patient is resting in supine position for ≥ 5 minutes.  Vital signs during 
hospitalization are assessed pre-dose within 30 minutes of dosing, and at about 4 hours post dosing.  All other assessments are at about 4 hours post dosing. 
d Height only at Screening Visit; Patients will be weighed clothed (lightly) and without shoes at every indicated visit. 
e Scheduled ECG recordings (in triplicate) should be obtained after the patient is resting in supine position for ≥ 10 minutes.  Three triplicate ECG assessments (9 assessments) should be 
performed on Day -1 to serve as the Baseline value.  Scheduled ECG recording during hospitalization (Visits 4 through 7 and Visit 11) should be done prior to the planned PK sample at 
pre-dose within 30 minutes of dosing, and at the approximate time of maximum plasma concentration of both MIN-101 (6 to 8 hours post dosing) and BFB-520 (9 to 12 hours post dosing).  
Scheduled ECG recordings on Visits 8 to 10 should be done prior to the planned PK sample 2-4 hours post dosing after all other assessments have been completed. 
f Safety laboratory tests include haematology, serum chemistry (including serum lipid profile, and fasting blood glucose) and prolactin. Patients must fast for 8 hours before the blood sample 
is taken. Baseline safety laboratory tests will be performed no later than Day -2 (and not earlier than Day -5) to ensure results are available prior to the first study drug administration. 
g Dipstick urinalysis will be completed on site at Screening, Baseline, and Weeks 4, 8, 12 (or early termination).  Urine specimen will only be sent to the central laboratory for microscopic 
analysis in the event the dipstick results are abnormal. 
h All females of childbearing potential will have a serum pregnancy test at Screening and Week 12 / Visit 11 (or in case of early termination); urine samples will be collected at Baseline 
(Day-2) and Visits 9, 10, and 11.  The samples will be tested at the study sites using urine dipstick test.  Any patient with a positive or doubtful urine pregnancy test must have a negative 
serum test performed at the central laboratory prior to enrollment or continuation in the study. 
i On Day 2 or prior to any discharge authorization if later than Day 2. 
j Pre-dose samples (may be done along with the safety laboratory samples, when scheduled) during Visits 4 through 7 and Visit 11 and at the approximate time of maximum plasma 
concentration of both MIN-101 (6 to 8 hours post dosing) and BFB-520 (9 to 12 hours post dosing).  PK samples during Visits 8 to 10 should be done pre-dose and 2-4 hours post dosing.  
A concomitant medication blood sample should be collected coincidental with the PK sample scheduled at the approximate time of maximum plasma concentration of MIN-101 (6 to 8 
hours post dosing) during Visit 4 through 7 and Visit 11, and 2-4 hours after dosing during Visits 8 to 10.  PK samples should follow the ECG (in triplicate) assessments, when applicable.   
k At each visit, when new medication blisters are dispensed, the patient should start taking drug from the new blisters except at Week 12 (Visit 11) where medication from blisters dispensed 
during Week 8 (Visit 10) should be used.   
l Patient’s drug intake diary should be collected and reviewed, and new diary dispensed with the new medication blisters. 
m Every attempt must be made to complete Week 12 (Visit 11) in case of early termination during the double-blind phase.  






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d Vital signs (blood pressure, heart rate, respiratory rate, and oral or aural body temperature) obtained after the patient is resting in supine position for ≥ 5 minutes.  Vital signs during hospitalization 
are assessed pre-dose within 30 minutes of dosing, and at about 4 hours post dosing.  All other assessments are at about 4 hours post dosing. 
e Abbreviated physical examinations at Visits 18, 19, 21, 22, 24 and 25. 
f Scheduled ECG recording on Visits 12 through 15 should be done prior to the planned PK sample at pre-dose within 30 minutes of dosing, and at the approximate time of maximum plasma 
concentration of both MIN-101 (6 to 8 hours post dosing) and BFB-520 (9 to 12 hours post dosing).  Scheduled ECG recordings on Visits 16 through 26 should be done prior to the planned PK 
sample 2-4 hours post dosing after all other assessments have been completed. 
g Safety laboratory tests include haematology, serum chemistry (including serum lipid profile, and fasting blood glucose) and prolactin.  Patients must fast for 8 hours before the blood sample is taken 
h On Week 12 + 2 days or prior to discharge authorization if later than Week 12 + 2 days.   
i Pre-dose samples (may be done along with the safety laboratory samples, when scheduled) during Visits 12 through 15 and at the approximate time of maximum plasma concentration of both MIN-101 
(6 to 8 hours post dosing) and BFB-520 (9 to 12 hours post dosing).  PK samples during Visits 16 through 26 should be done pre-dose and 2-4 hours post dosing.  One sample will be collected at 
Visit 27 along with the safety laboratory samples.  A concomitant medication blood sample should be collected coincidental with the PK sample scheduled at the approximate time of maximum 
plasma concentration of MIN-101 (6 to 8 hours post dosing) during Visit 12 through 15, and 2-4 hours after dosing during Visits 16 through 26.  PK samples should follow the ECG (in triplicate) 
assessments.    
j At Week 12 (Visit 11), drug dispensed at Week 8 (Visit 10) must be administered.   
k At Visits 12 - 25 when new blisters are dispensed, the patient should start taking drug from the new blisters. 
l Patient’s drug intake diary should be collected and reviewed, and new diary dispensed with the new medication blisters. 
m Every attempt must be made to complete both the Week 52 (Visit 26) and EOS/Week 54 (Visit 27) in case of early termination during the open-label extension phase.  


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ABBREVIATIONS 
5-HT2A 
5-hydroxytryptamine-2A  
AAA 
anhedonia, avolition, and asociality 
ADME 
absorption, distribution, metabolism, and excretion 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve  
BARS 
Barnes Akathisia Rating Scale 
b.i.d 
twice daily 
BMI 
body mass index 
BNSS 
Brief Negative Symptom Scale 
BUN 
blood urea nitrogen 
 
 
 
 
CGI-S 
Clinical Global Impression - Severity Scale 
CIAS 
Cognitive Impairment Associated with Schizophrenia  
CL/F 
oral clearance 
Cmax 
maximum drug concentration (in plasma or serum) 
CNS 
central nervous system 
CO 
cross-over 
CPK 
creatine phosphokinase 
CYP 
cytochrome 
DA 
dopamine 
DB 
double-blind 
DOPAC 
3,4-dihydroxyphenylacetic acid 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
eCOA 
clinical outcome assessments 
eCRF 
electronic case report form 
ECT 
electroconvulsive therapy 
ED50 
median effective dose 
EE 
emotional expressivity 
EM 
extensive metabolizer 
EMA 
European Medicines Agency 
EOS 
end-of-study 
EPS 
extrapyramidal symptoms 
F 
female 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 


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HbA1C 
hemoglobin A1c 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL 
high-density lipoprotein 
HIV 
Human immunodeficiency virus 
HV 
healthy volunteer 
HVA 
homovanillic acid 
IC50 
half-maximal inhibitory concentration 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IKr 
delayed rectifier potassium current 
IR 
immediate-release 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous, intravenously 
IWRS 
Interactive Web Response System 
JP 
Japanese Pharmacopeia 
Ki 
inhibitory constant 
LDH 
lactic acid dehydrogenase 
LDL 
low-density lipoprotein 
LOCF 
last observation carried forward 
M 
male 
MAP 
methamphetamine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini International Neuropsychiatric Interview 
MMRM 
Mixed Model Repeated Measures 
MoA 
mechanism of action 
MR 
modified release 
NF 
National Formulary 
NMDA 
N-methyl-D-aspartic acid 
NOAEL 
No-observed-adverse-effect level 
NSFS 
Negative Symptoms Factor Score 
OCs 
observed cases 
OL 
open-label 
PANSS 
Positive and Negative Syndrome Scale 
PC 
placebo-controlled 
PD 
pharmacodynamics(s) 
PK 
pharmacokinetic(s) 
PM 
poor metabolizer 
PO 
oral, by mouth (orally) 
PP 
per-protocol 
PQC 
product quality complaint 
PRN 
Pro Re Nata (as needed or rescue medication) 
PSP 
Personal and Social Performance 


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QTc 
QT interval value corrected for heart rate 
QTcB 
QT interval value corrected for heart rate using Bazett’s formula 
QTcF 
QT interval value corrected for heart rate using Fridericia’s formula 
RDQ 
Readiness for Discharge Questionnaire 
RBC 
red blood cells 
r-TMS 
repetitive trans-cranial magnetic stimulation 
SAE 
serious adverse event 
SAP 
SAS 
Statistical Analysis Plan 
Simpson-Angus Scale  
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
Sheehan-STS 
Sheehan-Suicidality Tracking Scale  
SMA 
spontaneous motor activity 
SR 
sustained-release 
t1/2 
terminal elimination half-life 
TCA 
tricyclic antidepressants 
TD 
tardive dyskinesia 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum drug concentration (in plasma or serum) 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
VLDL 
very low-density lipoprotein 
VNS 
vagal nerve stimulation 
WBC 
white blood cells 
WHO 
World Health Organization 


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1.
INTRODUCTION
1.1. 
Background on the Disease 
Schizophrenia is a complex, challenging, and heterogeneous psychiatric condition, affecting 
up to 0.7% of the world population according to the World Health Organization (WHO 2006). 
Schizophrenia is characterized by positive symptoms (including delusions and hallucinations), 
negative symptoms (blunted affect, alogia, asociality, anhedonia, and avolition) and pervasive 
cognitive deficits, often described as cognitive impairment associated with schizophrenia 
(CIAS).  In addition to these symptoms, some comorbid symptoms might be present, like sleep 
disorders (insomnia, hypersomnia, deep sleep disorders, and overall biological rhythms 
dysregulations (Chouinard et al. 2004, Wulff et al. 2012).  Much of the morbidity of the illness 
is related to its negative symptoms and cognitive impairment, which lead to functional 
impairment and withdrawal from social and occupational activities.  
The relative success of currently marketed antipsychotics in treating positive symptoms is 
limited by the fact that a substantial number of patients are refractory to current medications 
and by their lack of direct effect on negative and cognitive symptoms, which often determine 
the level of functional impairment (Buchanan et al. 2005, Hill et al. 2010, Keefe et al. 2007, 
Kirkpatrick et al. 2006).  Another limiting aspect of the currently available antipsychotics is 
their high incidence of side effects such as sedation, extrapyramidal symptoms (EPS), 
increased prolactin plasma levels, weight gain, and metabolic disorders or syndrome (Boettger 
et al. 2015).  
All antipsychotics share some common mechanism of action (MoA), characterized by 
dopamine D2 postsynaptic partial or complete blockade and serotonin 2A (5-HT2A) blockade. 
Despite major efforts involving attempts to pharmacologically manipulate N-methyl-D-
aspartic acid (NMDA)/glutamate neurotransmission and glycine reuptake, no therapeutic 
progress has been made.  In a recent review updating the MoA of antipsychotics, the authors 
strongly suggested that new MoA are needed to both improve the side effect profile and to 
address unmet medical needs, like negative symptoms and cognitive impairment (Correll 
2014).  
Clinical practice, guidelines and trials indicating that continuous administration of 
antipsychotics (long-term maintenance) reduces the risk of exacerbation or periodic worsening 
of psychotic symptoms (Leucht et al. 2012a, Leucht et al. 2012b, Leucht et al. 2017).  However, 
this practice has been criticized on several grounds.  First, most of the maintenance trials last 
6-12 months which is a relatively short period in a life-long disease.  Hence, concluding that 
patients need life-long antipsychotic treatment based on 6-12 months trials, is not particularly 
convincing.  It is possible that drugs that have been effective for a period of time, subsequently 
lose their effectiveness (Harrow et al. 2012).  Second, the outcomes measurements used to 
show that maintenance with antipsychotics is superior to placebo remains controversial. 
Change in PANSS scores, hospitalization, agitation, violence of any degree, and almost any 
unusual event that removes the patient from the trial, is considered an outcome.  Indeed, 
antipsychotics or as they were initially called major tranquilizers, reduce the global magnitude 
of all events and activities (Moncrieff 2015).  However, it is doubtful for example if any


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episode of agitation reflects illness worsening or exacerbation rather than an amplified reaction 
to a routine life event in an individual with questionable social skills.  Third, recent research 
indicates that in a subgroup of schizophrenia patients, symptoms do not worsen despite absence 
of maintenance antipsychotics for lengthy periods of time (Häfner et al. 2013, Harrow et al. 
2012, Harrow et al. 2014, Wunderink et al. 2013, Wils et al. 2016).  While the methods 
of some of these studies have been criticized in the literature, the absolute need for 
continuous and indefinite antipsychotic maintenance treatment for all non-actively 
psychotic schizophrenia patients, has also been questioned by academics (Insel 2013) and 
practicing psychiatrists (Moncrieff 2015).  On the negative side, it is not inconceivable that 
long term continuous administration of antipsychotics is associated with parenchymal 
brain lesions (Nopoulos et al. 2001) in addition to the metabolic and endocrine adverse effects.  
Furthermore, one cannot ignore the dissatisfaction of many patients with continuous 
antipsychotic treatment as evidenced by very poor compliance with medications. 
In an attempt to address these and related concerns, a National Institute of Mental Health 
workshop was held in 2005 on the methodological issues related to the design of trials of 
pharmacological agents for improving negative symptoms in schizophrenia (Kirkpatrick et al. 
2006).  Since then, several meetings have taken place, which helped refine the methodology to 
be used in clinical trials (Marder et al. 2011, Marder et al. 2013) and initiatives have been set 
up to create new instruments able to capture effects of drugs on negative symptoms and 
cognitive impairments. 
There are currently no drugs approved for the treatment of negative symptoms, with the 
exception of amisulpride in some European countries.  However, the efficacy of amisulpride 
against negative symptoms is questioned by regulators, investigators, and clinicians and has 
been supported mostly by post-hoc analysis.  A number of investigational pharmacological 
targets are being (or have been) studied in clinical trials.  Among those, glutamatergic and 
nicotinergic pathways have received most attention.  Glycine transporter inhibitors used 
adjunctively with antipsychotics failed to improve negative symptoms of schizophrenia (Goff 
2014).  
An adjunctive alpha-7 nicotinic acetylcholine receptor agonist was reported to have some 
efficacy in 1 study (Hilt 2013), but no efficacy in most other studies on negative and cognitive 
symptoms.  Agents that act at the glycine site of the NMDA glutamatergic receptor (glycine 
or D-cycloserine) were found not to be effective for the treatment of negative symptoms or 
cognitive impairments (Buchanan et al. 2007).  Minocycline an antibiotic, has improved 
negative symptoms (Chaudhry et al. 2012) in 1 study but not in most others.   
In summary, the idea that second generation antipsychotics (or atypicals) are significantly more 
effective than first generation antipsychotics or that second generation antipsychotics can 
benefit primary negative symptoms, cognitive impairment, or social and vocational 
functioning is not supported by data or hard-core outcome measurements.  Hence, there is a 
need of new pharmacological treatments, using novel mechanisms of action which are inducing 
less side-effects, are controlling better positive symptoms, and can also improve negative 
symptoms and CIAS.  MIN-101 is currently developed for this purpose. 


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1.2. 
Background on the Molecule 
MIN-101 is a novel cyclic amido derivative, which has specific affinities for sigma2, 5-HT2A 
and at lower affinity levels, α1-adrenergic receptors.  MIN-101 exhibits very low or no 
affinity for other receptors including dopaminergic, muscarinic, cholinergic, and 
histaminergic receptors.  In vivo functional studies have established that MIN-101 is an 
antagonist at both 5-HT2A and sigma2 receptors.
For 5-HT2A receptor antagonists, the most known and described effect is a beneficial effect in 
reducing EPS occurrence in patients treated with drugs blocking post-synaptic D2 receptors. 
A recent paper, summarizing the effects of 5-HT2A antagonists on psychotic, positive 
symptoms, shows that these drugs might also have an antipsychotic effect of their own, as 
they show superiority to placebo but they are probably less effective than antipsychotics 
(Ebdrup et al. 2011).  Furthermore, some recent data with pimavanserin (a drug targeting 
5-HT2A and 5-HT2C), show that the drug might be a new treatment for Parkinson’s 
disease-associated psychosis (Meltzer & Roth 2013).  Finally, 5-HT2A antagonists are also 
known to improve sleep, particularly by increasing sleep maintenance parameters and by 
increasing the amount of deep sleep (Al-Shamma et al. 2010).
Sigma receptors are known to affect several behavioral domains (Skuza 2012) and have 
potential therapeutic roles in disorders, like anxiety, depression, schizophrenia and drug 
addiction (Banister & Kassiou 2012).  Two subtypes of sigma receptors have been described, 
and active research effort is going on to further characterize sigma2 subtypes.  It is possible 
that sigma2 receptors are implicated in the modulation of dopaminergic (DA) (Katz et al. 
2011, Lever et al. 2014), glutamatergic pathways (Skuza 2012), and calcium neuronal 
modulation (Vilner & Bonen 2000).  Recent literature on sigma receptors also shows new 
bindings sites, like the progesterone receptor membrane component 1 (Xu et al. 2011).  This 
later hypothesis has been recently challenged, since the sigma2 receptor has been purified 
from tissue, revealing its identity as TMEM97, an endoplasmic reticulum-resident 
transmembrane protein that regulates the sterol transporter NPC1 (Alon et al. 2017).  
Taken together, it might be hypothesized that sigma2 receptors are involved in 
counteracting dysregulations in key neurotransmitter pathways, like dopamine and 
glutamate. 
Interestingly, some of the pharmacological effects described above are demonstrated with 
MIN-101 in preclinical models of positive and negative schizophrenia symptoms.  For 
example, DA turnover, DA metabolites such as dihydroxy-phenyl acetic acid and 
homovanillic acid and prolactin are elevated at high doses of MIN-101, suggesting that the 
molecule behaves like a weak antagonist at the DA receptor.  This effect occurs, despite the 
fact that there is no direct binding to DA receptors, consistent with an intrinsic antipsychotic 
effect in addition to the rest of the pharmacological effects.  Furthermore, antipsychotic 
effects (control of positive symptoms) of MIN-101 were supported by behavioral models.  
Similar to other antipsychotics, MIN-101 inhibited abnormal behaviors induced by DA 
agonists such as apomorphine and methamphetamine (please refer to the MIN-101 
Investigator’s Brochure for detailed results).  Finally, MIN-101 improved social interaction 
impairment induced by phencyclidine and impairment of spontaneous alternation behavior 




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 antipsychotics for which increase in prolactin concentrations occurred at 
lower dose levels. 
1.3.2. 
Pharmacological Effect of MIN-101 in Mice and Rats 
The potential of MIN-101 to induce 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
1.3.3. 
Safety Pharmacology 
 
 
  


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1.3.4. 
Toxicology 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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1.3.5. 
Pharmacokinetic Profile 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.4. 
Clinical Studies 
1.4.1. 
Healthy Subject Studies 
To date, 6 clinical pharmacology studies (MT-210-E01, MT-210-E02, MT-210-E03, 
MT-210-E04, MT 210-A01, and MIN-101C02) have been conducted in healthy subjects to 
evaluate the safety, tolerability, pharmacodynamic (PD), and PK profiles of MIN-101.  
MIN-101C02 was a reformulation and safety study conducted to support a modified-release 
tablet, which was used in the Phase 2b study carried out in patients suffering from 
schizophrenia (MIN-101C03).  Three more clinical pharmacology studies (MIN-101C04, 
MIN-101C05, and MIN-101C06) have completed the subject assessment phases and results 
are expected by the end of 4Q2017.  
An overview of the clinical pharmacology studies is presented in Table 1. 


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Table 1. Overview of Clinical Pharmacology Studies of MIN-101 in Healthy Subjects 
Study / 
Status 
Main Objectives and Design 
Drug 
Doses/Form 
Study 
Population 
Sex (M/F) 
Number of 
Subjects 
Enrolled/ 
Completed 
MT-210-E01 
Complete 
Ascending single-dose study in 
sequential cohorts. 
DB, PC, Safety/ Tolerability/PK/PD 
Placebo, 0.5 
to 32 mg IR 
HV 64M 
64/64 
MT-210-E02 
Complete 
Single dose administration under fed 
and fasted conditions. 
OL, 2x CO, Safety/ Tolerability/PK 
24 mg IR 
HV 14M 
14/13 
MT-210-E03 
Complete 
Group A: Single dose administration 
under fasted condition. 
 
Group B: Single dose administration 
under fed and fasted conditions. 
OL, 2x CO, Safety/Tolerability/PK 
24 mg  
Group A 
IR vs SR 
 
Group B SR 
HV 29M 
29/26 
MT-210-E04 
Complete 
Multiple dose administration 
DB, PC, Safety/Tolerability/PK/PD 
Placebo, 8 
mg b.i.d. 
SR 
HV 12M 
EM 
12/12 
MT-210-A01 
Complete 
Single dose administration. OL, 
Safety/Tolerability/PK 
16 mg IR 
HV 12M/12F 
24/23 
MIN-101C02  
Complete 
Part 1: Single dose administration. 
OL, Safety/ Tolerability/PK 
PK; select MR formulation for Part 2  
 
Part 2: Multiple dose administration 
DB, PC, Safety/ Tolerability/PK, 
changes in QT/QTc interval 
32 and 40 mg 
MR 
 
 
Placebo, 16 
and 32 mg 
MR 
HV 12M  
EM 
 
 
HV 
16M/4F  
EM 
12/10 
 
 
 
20/19 
 
 
MIN-101C04 
Ongoing 
ADME 
16 mg single 
dose (oral 
solution) 
HV (M) 
4-6 EM 
6/6 
MIN-101C05 
Ongoing 
Poor versus Extensive Metabolizer 
PK & Safety 
4 mg, 8 mg, 
16 mg (oral 
solution) 
HV (M&F) 
12 – 16 EM 
12 – 16 PM 
10/8 PM, 
13/12 EM  
 
MIN-101C06 
Ongoing 
Re-formulation PK & Food Effect 
32 mg 
(tablets) 
HV (M&F) 
16 EM 
14 EM 
ADME = absorption, distribution, metabolism, and excretion; b.i.d. = twice daily; CO = cross-over; DB = double-
blind; EM = extensive metabolizer; F = females; HV = healthy volunteer; IR = immediate-release formulation; 
M 
= 
males; 
MR = modified-release 
formulation; 
OL 
= 
open-label; 
PC 
= 
placebo-controlled; 
PD = pharmacodynamics; PK = pharmacokinetics; PM = poor metabolizer; SR = sustained-release formulation 


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1.4.1.1. 
Pharmacokinetics 
The MIN-101 immediate-release (IR) formulation was tested 
 
 
 
  
 
  
Data obtained from the urine analysis showed that according to the mean renal clearance 
estimates, the primary mechanism for MIN-101 elimination appeared to be non-renal 
clearance. 
Administration of a standard breakfast delayed the IR MIN-101 absorption by 1 hour and the 
peak plasma concentration was around half that observed in the fasted condition.  Gender 
differences were tested using the 16 mg dose.  The PK of MIN-101 was not different in males 
and females except for a higher Cmax of BFB-999 in females. 
With single PO dose administration of the sustained-release (SR) MIN-101 formulation, the 
Tmax occurred 1.5 hours after PO administration.  Cmax was around 70% lower as compared to 
IR administration.  The estimates suggested a reduction of extent of exposure (AUCt) for SR 
formulation compared to IR formulation of 16%.  In healthy subjects, the t1/2 of MIN-101 in 
plasma after SR administration was about 5 hours.  Administration of a standard meal delayed 
SR MIN-101 absorption by around 2 hours. 
With the slow modified-release (MR) formulation in Part 1 of Study MIN-101C02, Cmax and 
AUC24 for MIN-101 at 32 and 40 mg doses under fasted condition showed an increase that 
was slightly more than dose-proportional.  Median t1/2 ranged from 6.4 to 8.1 hours, for the 32 
and 40 mg doses, respectively, and median Tmax ranged from 2.2 to 2.5 hours, respectively.  
Similar findings were noted for BFB-520 and BFB-999, with Tmax occurring at about 2 hours 
post that of the parent compound (MIN-101). 
In using the 32 mg MR formulation, food had a positive effect on Cmax (increase by 2-fold), 
Tmax (increased by almost 3-fold), and t1/2 (decreased to 3.2 hours).  Food had no noticeable 
effect on AUC.  Similar findings were noted for BFB-520 and BFB-999. 
After repeated PO SR MIN-101 administration, mean Tmax was 2.3 hours.  The mean 
accumulation factor was 1.22.  The t1/2 of SR MIN-101 was not significantly different after 
single (7.5 hours) and multiple doses (8.6 hours).  The coefficients of variability were high 
indicating a high inter-individual variability. 
A few subjects in the different studies (healthy subjects and patients) showed higher exposure 
to MIN-101 and BFB-520.  These elevated concentrations could be explained by the poor or 
intermediate metabolizer status of these subjects.  
In Part 2 of Study MIN-101C02 where 16 and 32 mg doses were tested under fasted conditions 
for 7 days in a crossover, randomized, placebo-controlled study design, the 2 doses exhibited 
dose-proportional PK properties for all exposure parameters, for all 3 analytes.  Tmax was 
shortest for MIN-101 with BFB-520 and BFB-999 showing a 1-hour lag.  Accumulation as 


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measured by the ratio of AUC24 at Day 7 as compared to that of Day 1 was highest for BFB-520 
(> 2-fold) and similar for MIN-101 and BFB-999 (< 2-fold).  Assessment of pre-dose (trough) 
levels on Days 3 to 7 suggested steady state was achieved by Day 7. 
1.4.1.2. 
Safety 
Single doses of MIN-101 in healthy subjects were generally well tolerated up to 24 mg (IR and 
SR formulations) and up to 40 mg (MR formulation).  No serious adverse events (SAEs) and 
no deaths were reported.  Dose limiting postural hypotensions were reported at the 32 mg dose 
level with the IR formulation. 
In all single-dose studies, ECG evaluation employed single assessment of ECG that was read 
locally, and QT was corrected in most cases, through Bazett formula.  Mild QT prolongations 
were observed following MIN-101 single-dose administration.  No increase from Baseline in 
QT interval value corrected for heart rate using Bazett’s formula (QTcB) or QTcF of ≥ 60 msec was 
reported with the exception of 1 occurrence in MT-210-E02 (24 mg IR, QTcB).  QTcB/QTcF 
values remained < 480 msec except in 1 female subject in MT-210-A01 (16 mg IR), who had 
3 episodes of post-dose QTcF value > 480 msec (max 498 msec 4 hours post dose). 
Multiple doses of MIN-101 in healthy subjects were generally well tolerated up to 16 mg (SR 
formulation) and up to 32 mg (MR formulation).  No SAEs and no deaths were reported.  
No postural hypotension and no significant changes in ECG parameters were reported.  No 
subject had a QTc > 480 msec or an increase from Baseline in QTc ≥ 60 msec.  No EPS were 
observed in healthy subjects.  MIN-101 did not seem to induce any relevant change in safety 
laboratory parameters.  Only 2 cases of mild increase (< 3 ULN) in liver enzymes were 
reported.   
1.4.2. 
Patient Studies 
Three clinical studies (MT-210-A02, CYR-101C01, and MIN-101C03) have been conducted 
in schizophrenia patients.  Two different formulations have been used to date, the SR and the 
MR.  The dose ranges tested in these studies were between 16 and 96 mg for MIN-101 SR 
(8 mg to 48 mg given twice daily [b.i.d.]) and 32 and 64 mg for MIN-101 MR tablet. 
An overview of the clinical studies is presented in Table 2.  


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Table 2. Overview of Clinical Studies of MIN-101 in Schizophrenia Patients  
Study / 
Status 
Phase 
Main Objectives and 
Design 
Drug 
Doses/Form 
Study 
Population 
Sex (M/F) 
No. of 
Subjects 
Enrolled/ 
Completed 
MT-210-A02 
Complete 
1 
Multiple-dose rising 
study in sequential 
cohorts 
DB, PC, Safety/ 
Tolerability/ PK/ 
preliminary efficacy 
8 to 48 mg b.i.d. 
SR for 12 days 
Schizophrenia 
patients 
11M/1F 
12/5 
CYR-101C01 
Complete 
2a 
A Multi-center, 
Inpatient and 
Ambulatory, Phase 2, 
DB, Randomized, PC, 
Proof of Concept 
Study of CYR-101 in 
Patients with DSM-5 
Schizophrenia 
Dose adjustment 
period 8, 16 and 
32 mg SR b.i.d. 
for two days each. 
Then fixed dose- 
period at the 
optimal dose, 
maximum of 32 
mg b.i.d.; Placebo 
Schizophrenia 
patients 
49M/47F 
96/30 
MIN-101C03 
Complete 
2b 
Multi-center, DB, 
Randomized, Parallel-
group, PC, Study to 
Evaluate Efficacy, 
Tolerability and Safety 
of MIN-101 in 
Patients with 
Persistent, Stable, 
Predominant Negative 
Symptoms of 
Schizophrenia, 
followed by 24 weeks 
of open-label 
extension 
Placebo, 32 and 
64 mg MR for 
total of 36 weeks. 
Schizophrenia 
patients 
137M/107F 
244 
(randomized) 
/ 165 
(completed 
double-blind 
phase*) / 88 
(completed 
36 weeks) 
* Include patients who dropped out after completion of the 12-Week double-blind phase. 
b.i.d. = twice daily; DB = double-blind; F = females; M = males; MR = modified-release formulation; 
PC = placebo controlled; PK = pharmacokinetics; SR = sustained-release formulation. 
1.4.2.1. 
Pharmacokinetics 
In the first 2 patient studies, SR MIN-101 was administered using an up-titration dosing 
regimen.  In Study MT-210-A02, 8, 16, 32, and 48 mg were administered b.i.d, 3 days at each 
dose-level for a total of 12 days.  In this study, Tmax was achieved in approximately 3 hours 
and the PK profile was dose-proportional through Day 12.  One poor metabolizer for CYP 2D6 
patient was enrolled by error and showed plasma concentrations of the metabolite BFB-520 
that were extremely high. 


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In Study CYR-101C01, 8, 16, and 32 mg were administered b.i.d, 2 days at each dose level.  It 
was followed by a fixed dose-period at the optimal dose, maximum of 32 mg b.i.d until Day 84 
(12 weeks).  In this study, during the dose adjustment period (Day 2 to Day 6), mean post-dose 
plasma concentrations for MIN-101, BFB-520, and BFB-999 increased with dose, while mean 
pre-dose concentrations did not significantly increase.  During the fixed dose period (Day 6 to 
Day 14), mean post-dose plasma concentrations slightly increased towards a steady-state, 
which was achieved by Day 14.  Mean pre-dose plasma concentrations slightly increased for 
BFB-520 only but remained almost constant for the MIN-101 metabolite MT-210 and 
BFB-999.  
During the ambulatory period (Day 14 to Day 84), mean post-dose plasma concentrations were 
similar to steady-state.  Pre-dose plasma concentrations increased notably for MIN-101 until 
Day 56 (pre-dose Day 14 was 3.97 ng/ml; pre-dose Day 56 was 17.4 ng/ml) increased slightly 
for BFB-999 but remained stable for BFB-520.  Coefficients of variability were high indicating 
a high inter-individual variability. 
In Study MIN-101C03, 32 mg and 64 mg MR daily doses were administered for up to 36 
months.  PK samples were collected during the double-blind and open-label extension period.  
The PK data analysis is ongoing and is focused on assessing the PK/PD relationship with 
regards to both efficacy and QT changes using the bin concentration method that utilizes 
concentration data rather than dose.   
Concentration data of MIN-101, BFB-520, and BFB-999 were also summarized by dose and 
sampling times exhibited dose proportionality for MIN-101 and BFB-520, and slightly more 
than dose-proportional for BFB-520.  Geometric mean values were consistent with the 
absorption and elimination profile of MIN-101 and its 2 metabolites. 
The exposure-response analysis using data from the MIN-101C03 study showed that an 
exposure-response relationship could be identified, and that arguably, exposure is more 
important than dose in determining response.  This is implied by the fact that there was an 
overlap in the exposure for the 32 and 64 mg dose cohort.  Such conclusion must be evaluated 
in the context of sparse sampling and intersubject variability with regards to compliance, 
metabolism, and other intrinsic (body weight, gender, genotype, etc.) and extrinsic 
(concomitant medication, food intake, etc.) factors.  
The population PK QT modeling using data from all studies, as appropriate, of data from 
revealed the effect of MIN-101 concentration on QTcF was best described by a linear effect 
model.  The effect of BFB-520 concentration on QTcF was best described by an Emax model 
as the linear effect model overestimated the observed QTc data at higher concentrations and 
underestimated at the lower concentrations, most likely due to the scarcity of the higher 
concentrations.   
1.4.2.2. 
Efficacy 
Study MT-210-A02 was not designed to assess efficacy.   
In Study CYR-101C01, there was no statistically significant difference between MIN-101 and 


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placebo in the PANSS total score after one and three months of treatment although a numerical 
superiority of MIN-101 over placebo was seen after 3 months of treatment in the per-protocol 
completers group (point estimates decrease of -17.9, (p < 0.001) and -24.1, (p < 0.001), for 
placebo and MIN-101 respectively).  PANSS Negative sub-score demonstrated a superiority 
of MIN-101 over placebo at Day 28, which was further confirmed at Day 84 with a statistical 
difference in favor of MIN-101 (least squares means decrease of -3.2, [p = 0.049] and -7.5, 
[p < 0.001], for placebo and MIN-101, respectively, with statistically significant treatment 
difference in favor of MIN-101 over placebo [p = 0.0178]).  Cognitive performances were also 
better in the MIN-101 group (token motor task, list learning task, and verbal fluency) although 
the difference between the 2 treatment groups were not statistically significant.  Throughout 
the study, MIN-101 showed greater decreases in the negative scale scores when compared to 
placebo, and the difference between the 2 groups seemed to increase with treatment duration.  
Relapse of schizophrenia was twice more frequent with placebo (12 subjects, 25%) compared 
to MIN-101 (6 subjects, 13%). 
In Study MIN-101C03, PANSS negative factor scores improved significantly with MIN-101 
beginning at Week 2, and after 8 weeks, both MIN-101 treatment groups showed statistically 
significant improvements as compared to placebo (at Week 12 MIN-101 32 mg group 
estimated treatment effect of -1.54, p ≤ 0.0240; MIN-101 64 mg group estimated treatment 
effect -1.97, p ≤ 0.0036) (Davidson et al. 2017).  A linear trend of improvement continued 
during the open-label extension phase for patients of the placebo group who crossed over to 
MIN-101 treatment as well as for the whole study period in patients treated from the beginning 
of the study with MIN-101.   
Secondary/exploratory efficacy analyses showed statistically significant improvements in the 
MIN-101 64 mg group compared to placebo after 12 weeks of the double-blind phase for the 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
1.4.2.3. 
Safety 
MIN-101 was generally well-tolerated.  The most common treatment-emergent adverse events 
(TEAEs) were headache, insomnia, agitation, somnolence, nausea, anxiety, and worsening of 
schizophrenia symptoms.  No postural hypotension was reported.  MIN-101 did not induce any 


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significant change in safety laboratory parameters nor in prolactin levels.  The incidence of 
extrapyramidal symptoms with MIN-101 was low and similar to that observed with placebo.  
Mean change in body weight was similar with MIN-101 and placebo.  No deaths and no 
instances of Torsade de Pointes, seizures or myocardial ischemia were reported in patient 
studies 
In study MT-210-A02, 50% of patients in the MIN-101 and placebo treatment groups had at 
least 1 TEAE.  Half of the patients who reported TEAEs had events considered possibly or 
probably related to study drug.  The most common TEAEs in the MIN-101 treatment group 
were headache, dizziness, and nausea.  There were no severe TEAEs.  A total of 3 patients in 
the MIN-101 treatment group and 1 patient in the placebo treatment group discontinued due to 
an AE occurrence.  All 3 patients, regardless of treatment, discontinued for mild to moderate 
prolongation of QTc intervals and/or tachycardia. 
In study CYR-101C01, 62.5% of patients receiving placebo and 68.1% of patients receiving 
MIN-101 reported at least 1 TEAE.  Most of the reported TEAEs were classified as unrelated 
or unlikely related to the study treatment.  
The System Organ Class most commonly affected by TEAEs were psychiatric disorders 
(placebo 45.8% patients; MIN-101: 46.8% patients), followed by gastrointestinal disorders and 
nervous system disorders.  The TEAEs most commonly reported were: nausea, somnolence, 
agitation, anxiety, insomnia, and schizophrenia. 
The majority of TEAEs were mild or moderate in intensity.  There were 17 severe TEAEs, 11 
of which occurred in the MIN-101 group and 6 in the placebo group.  All were classified in 
the System Organ Class of psychiatric disorders: agitation, anxiety, depression, hostility, 
negativism, restlessness, schizophrenia, suicide attempt, and tension. 
Worsening of schizophrenia was twice as frequent in the placebo group compared to the 
MIN-101 group.  The following symptoms were monitored as extrapyramidal events: muscle 
rigidity, oculogyric crisis, akathisia, dyskinesia, and tremor.  They were observed in 2 patients 
in the MIN-101 group (muscle rigidity and dyskinesia) and in 3 patients of the placebo group 
(oculogyric crisis, muscle rigidity, akathisia and tremor).  Weight increase was observed in 
only 1 patient of the MIN-101 group (weight increase of 6.4 kg) and in none of the placebo 
group. 
Overall, 4 SAEs were reported in 3 patients: worsening of psychotic symptoms (placebo), 
suicide attempt (MIN-101), auditory hallucination, and persecutory delusion (same patient, 
placebo).  Only 1 was judged to be related to MIN-101: 
• CYR-101C01: 64 mg SR, 30-year-old female, suicide attempt. 
In study MIN-101C03, overall, 62.7% of patients experienced TEAEs, 61.2% of patients who 
received MIN-101 32 mg, 58.8% of patients who received MIN-101 64 mg, and 43.4% of 
patients who only received placebo during the double-blind phase.  The most commonly 
reported TEAEs in the double-blind phase (≥ 5% in any treatment group) were schizophrenia, 
headache, anxiety, asthenia, and insomnia.  During the whole study period, headache remained 
the most common TEAE reported in the MIN-101 groups with a higher incidence compared 


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to the placebo group (8.8% for total MIN-101 and 3.6% for placebo).  However, over the 
24 weeks of the extension phase, electrocardiogram QT prolonged was reported by 5.9% of 
the 64 mg dose of MIN-101 but not by subjects taking either the 32 mg dose or placebo.  
Insomnia and schizophrenia continued to have a higher incidence for placebo than for 
MIN-101 subjects. 
Most TEAEs were mild or moderate in intensity.  Severe TEAEs were reported by 10 (4.1%) 
patients; 1 patient in the placebo group reported psychotic disorder, 7 patients (psychotic 
disorder, schizophrenia, agitation, and acute psychosis) in the 32 mg MIN-101 treatment, and 
2 patients (psychiatric decompensation, and bradycardia) in the 64 mg MIN-101 group. 
A total of 38 patients (15.6%) withdrew from the study due to adverse events (AEs) during the 
double-blind phase (placebo: 12 patients, 32 mg MIN-101:  13 patients, 64 mg MIN-101:  13 
patients).  The main reason for withdrawal was psychiatric disorders with the highest incidence 
with placebo (13.3%) and the lowest incidence with 64 mg MIN-101 (9.6%).  A total of 4 
patients withdrew due to an AE of cardiac origin: bradycardia, sinus bradycardia, ECG QT 
prolonged, and ECG T-wave inversion.  All the concerned patients received 64 mg MIN-101.  
TEAEs leading to patient’s withdrawal were mild or moderate in intensity except for 
bradycardia, which was assessed as severe and led to the patient’s hospitalization and was 
therefore reported as a SAE.  After completing the double-blind phase, 13 further patients were 
withdrawn due to TEAEs during the open-label extension phase (8 patients in the MIN-101 
32 mg group and 5 patients in the MIN-101 64 mg group), 9 previously treated with MIN-101 
and 4 previously treated with placebo.  All TEAEs were psychiatric disorders, except one 
(cholecystitis).  They were all mild to moderate in intensity except 2 that were assessed as 
severe (schizophrenia, 32mg MIN-101) 
Overall, 12 SAEs were reported in 12 patients.  In all cases the seriousness criterion was the 
need for (or prolongation of) hospitalization in all cases.  Of these, 6 were judged to be related 
to MIN-101: 
• MIN-101C03:  placebo, 44-year-old female, schizophrenia. 
• MIN-101C03:  64 mg MR, 47-year-old female, abdominal pain and vomiting. 
• MIN-101C03:  64 mg MR, 58-year-old female, bradycardia. 
• MIN-101C03:  64 mg MR, 27-year-old female, psychiatric decompensation. 
• MIN-101C03:  32 mg MR, 30-year-old male, acute psychosis. 
• MIN-101C03:  32 mg MR, 53-year-old male, schizophrenia. 
Among the TEAEs reported, the following symptoms were identified as possible 
extrapyramidal symptoms: extrapyramidal disorder, tremor and restlessness.  Extrapyramidal 
disorder was reported in 1 patient in the 32 mg group and none in the placebo and 64 mg 
groups.  Tremor was reported in 1 patient each in the placebo group and in the 32 mg group, 
and none in the 64 mg group.  Restlessness was reported in 1 patient in the placebo group, 4 
patients in the 32 mg group and 3 patients in the 64 mg group.  All cases were mild in intensity 
except one, which was assessed as moderate (64 mg group). 


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Total abnormal involuntary movement scale score was low at baseline and similar across dose 
groups.  No significant change from baseline was observed in any treatment group. 
In the patient studies, increases in QTc interval were observed and were related to the dose of 
MIN 101 administered or to the systemic exposure to the BFB-520 metabolite.  Increases in 
QTcF relative to Baseline were mostly transient and mild.  Observed cases of QTc > 480 msec 
and/or increase > 60 msec from Baseline were exclusively observed at the 64 mg dose level. 
One episode of ventricular tachycardia was reported by the central reader in the MT-210-A02 
study at the 32 mg dose level (16 mg b.i.d).  No record of the ECG tracing is available and the 
duration of ventricular tachycardia was not provided.  No harm was caused to the patient, and 
the patient was not withdrawn immediately from the study and ventricular tachycardia did not 
recur either during the residual period at the same dose level (16 mg b.i.d) or at next dose level 
(32 mg b.i.d).  
In Study MT-210-A02 study, there were no patients with QTcB/QTcF values over 480 msec.  
The mean increase from Baseline in QTc in the MIN-101 SR treatment group was greater at 
the highest dose level, when the patients were being treated with 48 mg b.i.d.  Mean changes 
from Baseline, on Day 10, Day 11, and Day 12 at dose level 48 mg b.i.d, in QTcB/QTcF were 
33.3 msec/19.8 msec, 38.3 msec/25.5 msec, and 17.8 msec/19.6 ms, respectively.  The number 
of patients with QTcB values > 450 msec was greater in the MIN-101 SR group than in the 
placebo group (50.0% versus 0.0%).  Changes in the QTcB > 30 msec were also more common 
in the MIN-101 SR treatment group than in the placebo treatment group (75.0% versus 25.0%).   
In Study CYR-101C01 study, the maximum dose administered was 32 mg twice daily.  QTc 
(B or F) changes from Baseline were higher with MIN-101 at all time-points when compared 
to placebo, but they were lower than changes in QTc observed in Study A02.  The maximum 
mean change from Baseline in QTcB was +14.1 msec on Day 14 in MIN-101 group, and the 
maximum mean change from Baseline in QTcF was +11.7 msec on Day 14 with MIN-101.  
Mean changes from Baseline in QTcB increased from Day 2 to Day 14, and then remained 
constant until the end of the study.  With regards to QTcF, mean changes from Baseline 
increased from Day 2 to Day 28, and then slightly decreased (mean values always < 10 msec) 
until the end of study.  
Two patients who took the 64 mg dose in the MIN-101C03 study had a significant absolute 
value in QTcF of > 500 msec and a prolongation > 60 msec from Baseline, 1 of them being 
symptomatic (syncope, bradycardia).  Both QTcF outlier patients had very high exposure to 
the BFB-520 metabolite.  For the patient with syncope this high exposure to the metabolite 
was observed as early as the second day of treatment, approximately 8 days prior to the 
reported syncope/SAE.   
None of the 78 patients who received the 32 mg dose or the 83 who received placebo exhibited 
absolute value in QTcF of > 500 msec or prolongation > 60 msec from Baseline of their 
respective QTcF interval.   


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1.5. 
Benefit/Risk Assessment  
MIN-101 is being developed for the treatment of schizophrenia and in particular, the negative 
symptoms of schizophrenia, which are considered as an unmet medical need.  After a Phase 2a 
study (CYR-101-C01) in patients suffering from schizophrenia, which showed promising 
efficacy signals, a Phase 2b study in schizophrenic patients (MIN-101C03) was conducted.  
The results were confirmed with MIN-101 showing statistically significant benefit over 
placebo in improving negative symptoms.  The effect was shown for both doses tested:  32 mg 
dose and 64 mg.  
In the present study, patients will receive double-blind treatment for a period of 12 weeks 
during which active study drug (MIN-101) or placebo will be administered.  Patients may not 
benefit from the study in terms of long-term improvement of their symptoms, however they 
may benefit from the extensive medical review and disease follow-up during the study.  
The main risk of enrolling in this trial is that patients in whom maintenance treatment with 
antipsychotics has been discontinued, may experience symptomatic worsening and/or display 
behaviors which may endanger them or others.  The immediate benefit of enrolling in the trial 
is that for some of the patients assigned to placebo it may be revealed that maintenance 
treatment with antipsychotics is no longer necessary, and hence avoiding the adverse effects 
of antipsychotics.  Furthermore, some patients assigned to experimental drug may experience 
symptomatic and/or long-term improvement. 
To date, a total of 458 subjects have been exposed to MIN-101 in 12 clinical studies. 
Thorough review of safety information relevant to the use of MIN-101 indicates that MIN-101 
is generally safe and well tolerated, with the most frequently reported TEAEs being headache, 
anxiety, asthenia, and insomnia in patients with schizophrenia.  None of the “classical” side 
effects generally associated with the currently marketed typical or atypical antipsychotic 
treatments were observed, such as sedation, prolactin and weight gain increases, or 
extrapyramidal symptoms.  QT prolongation was observed in clinical trials with MIN-101.  
The risk for QT prolongation is dose related, the main driver for QT prolongation being 
BFB-520 plasma levels.  In the MIN-101C03, 2 patients receiving the highest dose (64 mg) of 
MIN-101 MR formulation, presented with a significant increase in QTcF.  These 2 patients 
were found to be outliers for BFB-520 levels and were identified within the first 4 weeks of 
treatment. 
To mitigate the risks of antipsychotic discontinuation, patients who entered this trial will be 
closely followed by the treating/research team by frequent face to face visits and phone calls 
between visits.  This will enable the treatment/research team to intervene promptly as soon as 
patients experience symptomatic worsening or display behaviors that endanger themselves or 
others. 
To mitigate the risk for QT prolongation, a new formulation will be used in the present study 
that was developed to specifically avoid the presence of high levels of drug and metabolite 
concentrations while resulting in the same bioavailability (AUC) observed with the 
formulation used in the Phase 2b study, which resulted in positive treatment effect. 


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The following measures have also been implemented in the protocol to further mitigate the risk 
for QT prolongation:  
• 
Only CYP 2D6 extensive metabolizer patients, will be enrolled. 
• 
Drugs likely to increase QT as well as drugs inhibiting CYP 2D6 and CYP3A4/5 (likely to 
increase MIN-101 and BFB-520 levels) are not allowed during study participation. 
• 
Exclusion of patients with known personal or familial history of QT prolongation 
(including congenital long QT syndrome), or with recent acute myocardial infraction, or 
with uncompensated heart failure. 
• 
Exclusion of patients presenting with risk factors such as hypokalemia, hypomagnesemia, 
hypocalcemia or bradycardia. 
• 
Close monitoring of the patients, who will be hospitalized during the first 2 days of 
treatment.  
• 
Close ECG monitoring during the first 2 weeks of treatment with triplicates ECGs 
performed weekly at the Cmax of both MIN-101 and the BFB-520 metabolite.  
• 
Stopping rules criteria defined in the protocol in order to exclude patients presenting with 
abnormal safety finding (notably QTc prolongation) that could put them at risk. 
• 
An external DSMB will be established to review the safety data and formulate 
recommended decisions/actions in accordance with the charter of the DSMB. 
The risk/benefit of MIN-101 is therefore positive and the currently available safety and 
efficacy data support the proposed MIN-101C07 clinical trial to investigate efficacy of 
MIN-101 after 12 weeks of once daily dosing in subjects suffering from schizophrenia. 
More detailed information about the known and expected benefits and risks of MIN-101 may 
be found in the latest version of the MIN-101 IB (Version 3.1, 2018). 
 
 


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2. 
OBJECTIVES 
2.1. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of 2 fixed doses 
(32 mg and 64 mg doses) of MIN-101 
compared to placebo in improving the negative 
symptoms of schizophrenia over 12 weeks of 
double-blind treatment. 
• 
Change from Baseline in the Positive and 
Negative 
Syndrome 
Scale 
(PANSS) 
Marder negative symptoms factor score 
(NSFS) 
Key Secondary 
To assess the effect of MIN-101 compared to 
placebo 
on 
the 
Personal 
and 
Social 
Performance (PSP) over 12 weeks of double-
blind treatment 
• 
Change from Baseline in the PSP Total 
score  
Secondary 
To assess the efficacy of MIN-101 compared 
to placebo on the Clinical Global Impression of 
Severity (CGI-S) over 12 weeks of double-
blind treatment 
• 
Change from Baseline in the CGI-S score 
To assess the safety and tolerability of 
MIN-101 compared to placebo in patients with 
schizophrenia 
• 
Safety assessments, including adverse 
events, laboratory values, ECG, vital signs, 
physical exam, AIMS, BARS SAS, and the  
Sheehan-STS. 
AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; CGI-S = Clinical 
Global Impression of Severity; NSFS = Marder negative symptoms factor score; PANSS = Positive and Negative 
Syndrome Scale; PSP = Personal and Social Performance; SAS=Simpson-Angus Scale; STS = Suicidality 
Tracking Scale. 
In addition, the exploratory objectives are: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   


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•
Refer to Section 8, Study Evaluations for evaluations related to endpoints. 
2.2. 
Hypothesis 
The primary hypothesis is that after 12 weeks, MIN-101 will be superior to placebo on the 
change from Baseline in the PANSS Marder NSFS. 
3.
STUDY DESIGN AND RATIONALE
3.1. 
Overview of Study Design
This will be a multicenter, multinational, randomized, double-blind, placebo-controlled, 
parallel-group study in approximately 501 schizophrenic patients who present with negative 
symptoms. 
Eligible patients will be randomized in equal proportions to receive once daily MIN-101 
64 mg, MIN-101 32 mg, or placebo, PO, for 12 weeks.  Afterwards, all patients will continue 
treatment with active drug for an additional 40 weeks.  During the 40-week, open-label 
treatment extension, patients who were initially randomized to MIN-101 64 mg or MIN-101 
32 mg will continue treatment with the same dose, while patients who were initially 
randomized to placebo will crossover to MIN-101 64 mg or MIN-101 32 mg in a 1:1 ratio per 
the randomization schedule implemented on Day 1 (Visit 4).  The Week 12+1 Day onward 
dose is the extension phase dose. 
This 3-phase study, as depicted in Figure 1, will consist of: 
Pre-Treatment Phase:  
o
Screening Period (Visit 1), including a Screening visit that should take place no more
than 28 days before the first administration of study drug on Day 1 (Visit 4).
o
Washout Period (Visit 2), an inpatient washout period starting on Day -2 to allow
patients on antipsychotic medications or other psychotropics to be washed out from
their previous medications.  Patients who did not receive any psychotropics will also
be hospitalized on Day -2 before Baseline (Visit 3) in order to standardize study
procedures in all patients.
o
Baseline Visit (Visit 3, Day -1), all inclusion and exclusion criteria will be verified and
all assessments will be completed prior to initiation of the double-blind treatment
phase.
12-Week Double-Blind Treatment Phase:
A double-blind, placebo-controlled treatment phase lasting 12 weeks.  On Day 1 (Visit 4), 
patients will be randomized to treatment (MIN-101 64 mg, MIN-101 32 mg, or placebo) in 
equal proportions.  Patients can be discharged at the discretion of the Investigator from the 


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investigator’s site on Day 2, after taking the blinded study medication, and having undergone 
3 ECG assessments (in triplicate) performed at pre-dose and at the approximate time of Cmax 
of MIN-101 and its metabolite BFB-520.  Hence, patients will be hospitalized for a minimum 
of 4 days (3 nights).  Any authorization to leave the hospital will be done with the help of the 
Readiness for Discharge Questionnaire (RDQ, Attachment 2).  On Day 2 (Visit 5), if 
discharged, the patient will come back for visits at Weeks 1, 2, 3, 4, 8, and 12 for efficacy 
and/or safety assessments.  Hospitalization on Visits 6 and 7 will be at the discretion of the 
investigator to ensure per-protocol ECG assessment and PK sampling are done.  The patient 
(or his/her care provider) will be contacted by phone at Weeks 5, 6, 7, 9, 10, and 11 to verify 
safety and to make sure the patient is doing well and is compliant with study medication. 
In case of early termination during the double-blind phase, the Week 12 (Visit 11) must be 
completed as soon as possible.   
40-Week Open-Label Extension Phase:
At the end of the 12-Week double-blind treatment period (Visit 11), patients will be 
immediately enrolled into the 40-week open-label extension phase.  Patients will be 
hospitalized for 2 days after the initiation of treatment with MIN-101 (all patients).  Patients 
who received placebo for 12 weeks during the double-blind phase will start receiving 64 mg 
or 32 mg of MIN-101 per the randomization schedule implemented on Day 1 (Visit 4).  Patients 
will then be allowed to leave the hospital on Visit 13 (Week 12 + 2 days) at the discretion of 
the investigator and after drug intake and safety have been ascertained clinically, including 
having undergone 3 ECG assessments (in triplicate) performed at pre-dose and at the 
approximate time of Cmax of MIN-101 and its metabolite BFB-520.  However, the Investigator 
may decide to keep the patient hospitalized as needed.  RDQ will be completed prior to any 
authorization to leave the hospital.  Hospitalization on Visits 14 and 15 will be at the discretion 
of the investigator to ensure per-protocol ECG assessment and PK sampling are done.  Visits 
16 to 26 will be ambulatory. 
EOS (Week 54 / Visit 27) assessments will be performed within 2 weeks following the last 
treatment visit (Week 52 / Visit 26).  In case of early withdrawal, the End of Treatment visit 
(Week 52/ Visit 26) must be completed as soon as possible. It will be followed ±2 weeks later 
by the EOS visit (Week 54/Visit 27).   


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Figure 1. Study Design Diagram  
 
Study Evaluations 
All study-specific assessments including efficacy, safety, will be performed as outlined in the 
Time and Events Schedules that appear after the synopsis. 
Efficacy will be evaluated based on the change from Baseline to Week 12 (or at early 
withdrawal) in the PANSS NSFS.  Additionally, the changes from Baseline in PSP total score 
and subscale (socially useful activities, personal and social relationships, self-care, and 
disturbing and aggressive behaviors) scores, CGI-S, 
 
 
 
 
 
 
 
 
 
 
   
Safety will be evaluated by monitoring the frequency, severity, and timing of AEs, clinical 
laboratory test results, 12-lead triplicate ECGs, vital signs measurements, body weight, waist 
circumference, physical examinations, and pregnancy testing for women of childbearing 
potential.  Laboratory assessments will be monitored throughout the study.  For each ECG 
(performed in triplicate), the QTcF will be measured and evaluated.  Specific rating scales also 
used in the study include the AIMS, BARS, and SAS to assess the extrapyramidal symptoms, 
and Sheehan-STS to assess suicidal ideation/behavior. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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Blood samples (4 mL) for assessing MIN-101 concentration in plasma will be obtained 
throughout the study with extensive monitoring during the first 4 weeks of both the 
double-blind and the open-label phases at pre-dose and approximate time of Tmax of the 
MIN-101 and BFB-520 plasma levels.  Additional samples will be taken during the study to 
evaluate the presence of prohibited concomitant medications.  These samples may be assayed 
to aid with the interpretation of any ECG abnormalities detected during the visit.   
3.2. 
Study Design Rationale 
This Phase 3 study is intended to extend and replicate the results obtained in the previous 
Phase 2b study of MIN-101, with a schizophrenia patient population that is generalizable to 
patients seen in clinical practice.  Consequently, patients with negative symptoms and without 
severe symptoms of suspiciousness, agitation, hostility, or impulsivity will be recruited for 
participation in this study.  This will ensure that relatively stable yet symptomatic patients in 
terms of negative symptoms will be included.  Interestingly, recent literature and the 
experience with the MIN-101 recently completed Phase 2b study show that such a design with 
the eligibility criteria proposed in this study might be the best approach to achieve the primary 
and secondary objectives, yet it will also be representative of the real patient population to be 
treated when the drug will be used in clinical practice (Dunayevich et al. 2014). 
Negative, positive, and global PANSS scores will be assessed, as well as functioning and 
cognition.  The Marder NSFS, derived from the administration of the complete PANSS test 
will be the primary endpoint after 12 weeks of double-blind treatment.  Personal and social 
performance will constitute the key secondary endpoint.  
 
 
 
  
MIN-101 will be administered during 12 weeks in a double-blind, placebo-controlled manner.  
Because additional MIN-101 benefits seem to build up over time, patients who complete the 
12-Week double-blind treatment phase will be given the opportunity to participate in a 
40-week, open-label treatment extension, in which all patients will receive active drug (32 mg 
or 64 mg).  This will also provide data on the persistence of the therapeutic effect as well as 
long-term safety.   
Two doses of MIN-101 and placebo will be assessed over the first 12 weeks.  Both doses (daily 
32 and 64 mg) of the newly formulated MIN-101 tablets, with gastro-resistant coating, 
expected to be equivalent to the ones investigated in the Phase 2b study with regards to AUC, 
but with a lower Cmax, will be investigated. 
The study is intended to extend and replicate results from the previous placebo-controlled 
studies of MIN-101 where a statistically significant improvement in negative symptoms was 
observed as early as 2 weeks that persisted through the primary objective time point at Week 
12.  In the present study, schizophrenic patients with negative symptoms will be included as 
they are likely to benefit from the treatment with MIN-101. 


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Although the primary objective of this study is the effect of MIN-101 on negative symptoms, 
it remains unclear whether there are common neurobiological mechanisms that underlie 
cognitive deficits and negative symptoms of schizophrenia (Buchanan et al. 2010).  In the 
previous patient study, MIN-101 showed a trend to an improvement in cognition in parallel to 
the improvement in negative symptoms; therefore, verbal fluency will be assessed in the 
present study. 
Randomization will be used to minimize bias in the assignment of patients to treatment groups, 
to increase the likelihood that known and unknown patient attributes (e.g., demographic and 
Baseline characteristics) are evenly balanced across treatment groups, and to enhance the 
validity of statistical comparisons across treatment groups.  
Blinded treatment will be used to reduce potential bias during data collection and evaluation 
of clinical endpoints. 
Parallel-group design rather than cross-over design has been chosen to avoid ambiguous 
interpretation of results due to carryover effects.  Blinding of the investigators and the patients 
to actual treatment reduces bias that would otherwise be introduced. 
The use of an open-label extension phase allows patients initially randomized to placebo to 
gain exposure to MIN-101, and for the extended exposure of patients to MIN-101 who may be 
benefiting from the treatment.  It also allows for the assessment of the persistence of effect 
beyond the 12-week double-blind phase, albeit in an open-label fashion. 
Study Population 
The study population will consist of adult men and women (aged 18 to 55 years, inclusive) 
with a diagnosis of schizophrenia as defined in DSM-5, established by a full psychiatric 
interview in conjunction with the MINI.  The threshold for negative symptoms will be defined 
by PANSS negative subscore (N1+N2+N3+N4+N5+N6+N7) of > 20.  Additionally, to 
ascertain patients’ cooperation with the study, stability and safety, patients must have PANSS 
item score of ≤ 4 on items P4 (excitement/hyperactivity), P6 (suspiciousness), P7 (hostility), 
G8 (uncooperativeness), and G14 (Poor impulse control).    
Choice of Control Groups 
A placebo control will be used to establish the frequency and magnitude of changes in clinical 
endpoints (efficacy and safety) that may occur in the absence of active treatment.  No active 
control group can be included since there are currently no approved treatments that could serve 
as positive control. 
Most schizophrenia studies have demonstrated that simply participating in a study produces a 
certain improvement in symptoms.  This improvement is probably related to the nursing care 
and attention awarded by the clinicians and investigators, the patients’ altruistic pride of 
contributing to science, and many other non-specific factors.  
The following observations also favor the use of a placebo comparator in this study: 
• The trend to improve on placebo has slowly but progressively increased in studies carried 
out over the last 20 years (Kemp et al. 2010).  The Phase 2b study with MIN-101 confirms 


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this tendency because some patients who received placebo completed the 12-week 
treatment duration with some improvement on the efficacy measures.   
• In studies recruiting chronically ill patients and using an active control in addition to 
placebo, the active control (verifiably effective drugs) has not been more effective than 
placebo (i.e., all groups showed significant improvement compared to Baseline (Kinon et 
al. 2011).  
• Currently, there are no objective biological outcome measurements for treatment effect, 
and despite the best investigator training, outcome measurements remain partially 
subjective.  Therefore, demonstrating symptom improvement in an investigational 
medication group relative to Baseline without a placebo group would be meaningless and 
would expose patients to an investigational medication without any scientific benefit.  
• Consistent with The Declaration of Helsinki, studies may be ethically acceptable even if 
proven therapies are available (which is not the case for negative symptoms in patients 
suffering from schizophrenia) under the following circumstances:  
o Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or 
o Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention, and the 
patients who receive any intervention less effective than the best proven one, placebo, 
or no intervention will not be subject to additional risks of serious or irreversible harm 
as a result of not receiving the best proven intervention. 
• The use of placebo is also recommended by the European Medicines Agency (EMA) to 
allow for an accurate analysis of the data.  In the “Guideline for investigation of medicinal 
products, 
including 
depot 
preparations 
in 
the 
treatment 
of 
schizophrenia” 
(EMA/CHMP/40072/2010 Rev.1 2012), EMA states that “…assay sensitivity cannot be 
guaranteed even in well designed and conducted trials if a placebo arm is not included…a 
placebo control…is also highly desirable so that the ‘absolute’ effects (both therapeutic 
and adverse) of a product can be ascertained”. 
• Findings from short-term, placebo-controlled studies also suggest that there is no higher 
risk of death, suicide, or suicide attempts among patients treated with placebo for short 
durations (Isaac & Koch 2010, Storosum et al. 2003). 
• Finally, to minimize the risk of patients receiving placebo, only one-third of the patients 
will receive placebo during the 12-week, double-blind, placebo-controlled, treatment 
phase.  
Washout and Monotherapy 
In any trial of a new drug there is a risk in removing regular medications and starting an 
investigational compound.  To minimize the risks, patients will undergo a Screening period, 
including hospitalization during the Washout Period and at least during the first 2 days of the 


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new treatment (Washout Period from Day -2; Baseline assessment on Day -1, and treatment 
on Days 1 and 2).  Patients will be allowed to leave the hospital on Day 2, after the 
administration of the second dose of treatment and after completion of the RDQ and safety 
check.  However, the investigator may decide to keep the patient hospitalized as needed. 
Patients will then be seen weekly for the first 4 weeks of the double-blind phase, with the first 
visit occurring within 5 days after being discharged.  Additional hospitalization on Visits 6 and 
7 will be at the discretion of the investigator to ensure per-protocol ECG assessment and PK 
sampling are done. 
The same procedures will apply after the completion of the double-blind treatment phase.  This 
approach will apply to all participating patients to ensure patients previously treated with 
placebo and are exposed to MIN-101 for the first time undergo extensive safety monitoring.  
As such, all patients will be hospitalized at Week 12 (Visit 11) through the start of the open-
label treatment period.  Patients will be allowed to leave the hospital on Day 2 (Visit 13), after 
the administration of the second dose of treatment and after completion of the RDQ and safety 
check.  However, the investigator may decide to keep the patient hospitalized as needed. 
Patients will then be seen weekly for the first 4 weeks of the open-label phase, with the first 
visit occurring within 5 days after being discharged.  Additional hospitalization on Visits 14 
and 15 will be at the discretion of the investigator to ensure per-protocol ECG assessment and 
PK sampling are done. 
Also, when antipsychotic medication is discontinued, some patients manifest less avolition and 
sedation, as well as no EPS or metabolic adverse events.  Some of the patients from whom 
antipsychotic medication is discontinued might have symptomatic worsening.  However, this 
is also true for some patients maintained on medication.  Antipsychotic maintenance treatment 
only reduces the risk of symptomatic worsening, but it does not prevent it as many patients’ 
symptoms worsen and are exacerbated while on medication (Leucht et al. 2012a). Also, many 
chronically ill but stable patients who in the first years of illness might have benefited from 
antipsychotics cease to benefit after 5 to 10 years of use (Harrow et al. 2014). 
MIN-101 monotherapy has been selected for this study based on efficacy and safety data from 
the previous Phase 2a and 2b studies which also used a monotherapy design.  The possibility 
of conducting an add-on study in which all patients would be given an antipsychotic treatment 
followed by MIN-101 or placebo was considered and ruled out.  In an add-on design, in order 
to obtain the necessary statistical power, many thousands of patients will have to be exposed 
to the investigational medication instead of a few hundred patients in a classic monotherapy 
design.  Furthermore, it is possible that the interference of the dopamine blocking 
antipsychotics with the dopamine mediated pleasure circuits obliterate the possibility of 
improvement in negative symptoms due to pharmacological intervention.   
Because MIN-101 likely has antipsychotic effects, the effects of MIN-101 would be difficult 
to ascertain if all patients were treated with an antipsychotic drug.  Moreover, antipsychotic 
drugs induce negative symptoms (e.g., secondary negative symptoms which are hardly 
distinguishable from primary negative symptoms).  Treating all patients with antipsychotic 
drugs would confound the potential effects of MIN-101 on primary negative symptoms. 


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Furthermore, attempts to improve negative symptoms and/or CIAS in add-on designs have 
been unsuccessful to date (Goff 2014). 
Study Duration 
Study drug will be administered during 12 weeks in a double-blind, placebo-controlled 
treatment phase, which is consistent with the treatment duration of the previous Phase 2b study 
with the same patients.  Although several patients prematurely dropped out of the 12-week 
treatment period, significant benefits were observed in the MIN-101-treated patients after 12 
weeks.  
Twelve weeks of treatment was also used in a previous study exploring the effects of 
amisulpride, with a primary emphasis on effects on negative symptoms (Boyer et al. 1995, 
Loo et al. 1997, Danion et al. 1999).  Based on the fact that long-term data may be required, 
an extension phase of 40 weeks is planned in this study.  In this open-label extension phase, all 
patients who successfully completed the 12-week, double-blind treatment phase, will be 
randomized to receive either MIN-101 32 mg/day or 64 mg/day in the 40-week, open-label 
treatment extension.  
Dose Selection and Dose Administration  
The daily doses in this study are 64 mg and 32 mg.  Both doses are equivalent to the doses 
which were given to patients in the previous Phase 2b study and proved to be efficacious.  The 
newly formulated 32-mg tablet was tested in clinical Study MIN-101C06 along with the 
previously used MR tablet (reference formulation) of the same strength in a crossover design.  
The MIN-101 AUCinf ratio (test to reference) was 0.98 (90% CI:  0.81, 1.19), and the BFB-520 
AUCinf ratio was 0.96 (90% CI:  0.86, 1.07), consistent with the reformulation design 
specification.  Furthermore, the Cmax data for both MIN-101 and BFB-520 were also consistent 
with the reformulation specifications that targeted achieving a reduction in the maximum 
concentration levels: test to reference ratio of 0.66 (90% CI:  0.53, 0.83) for MIN-101, and 
0.74 (90% CI:  0.60, 0.92) for BFB-520.   
Both doses (daily 32 and 64 mg) have now been reformulated with gastro-resistant coating.  
By giving these 2 doses in this well powered study, it is expected that their therapeutic effects 
will be confirmed.  Furthermore, using 2 doses may allow for determination of a dose-response 
effect.  Therefore, the planned dose range for this study (32 mg and 64 mg) was selected based 
on anticipated efficacious dose levels and plasma exposure. 
Drug administration will be in the morning, with or without food.  This will be a deviation 
from the dose administration implemented in the Phase 2b study which required dosing in the 
fasted state.  The newly formulated tablets have been tested in study MIN-101C06 under both 
fasted and fed conditions and the results of the AUCinf and Cmax comparison suggest food intake 
will have minimal, but acceptable differences that are within the reformulation design 
specifications.  


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Measurement Tools 
Primary Efficacy Measure 
Marder NSFS:  For the effects of MIN-101 on negative symptoms, the Marder NSFS will be 
used.  The NSFS has been the most frequently used scale in schizophrenia clinical studies 
focusing on negative symptoms since it was published in 1997 (Marder et al. 1997).  The NSFS 
consists of the sum of the PANSS items N1, N2, N3, N4, N6, G7, and G16, and the primary 
duration of assessment is over 12 weeks of treatment.  The PANSS scale is the most frequently 
used scale in schizophrenia clinical studies worldwide, and is available in many languages.  
The NSFS is psychometrically robust, reliable, with well documented construct and content 
validity, inter-rater reliability, sensitivity, and specificity (Edgar et al. 2014).   
Secondary Efficacy Measures 
PSP:  Social functioning will be evaluated using the PSP scale, which is one of most used 
scales to evaluate the effect of treatment with antipsychotic drugs on functional performance.  
The PSP was derived from the Social and Occupational Functioning Assessment Scale in 2000, 
and is available in several languages.  The PSP is easy to administer and measures 4 areas of 
functioning and its anchors only take into consideration the functioning of the individual, 
independently of symptomatology.  The PSP considers 4 areas of social and individual 
performance (socially useful activities, including work and study; personal and social 
relationships; self-care; disturbing and aggressive behaviors).  For filling it, the clinician must 
assign an initial six-degree of severity to each area (absent, mild, manifest, marked, severe or 
very severe).  Then, in a table with levels of score set the correspondent decimal (e.g., 21-30), 
according to the observed performance and, within the decimal range, the assigned unit to 
determine the final score (e.g., within the range 21-30, the performance corresponds to the 
score 24).  The resulting final value is a single measurement from zero to 100% of functioning. 
This single value will be the key secondary endpoint for this study. 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
CGI-S and 
  The CGI-S 
will be used as an anchor-based approach of the 
global impression of the clinician, and to assist in the interpretation of the changes in the NSFS 
and PSP total score.  The 2 CGI measures are also widely used in psychiatric clinical trials and 


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have shown robust construct and content validity, inter-rater reliability, sensitivity, and 
specificity.  
Cognitive Assessment:  Cognitive performance will be assessed since it is possible that there 
are common neurobiological mechanisms that underlie cognitive deficits and negative 
symptoms in schizophrenia (Buchanan et al. 2010).  Verbal fluency test will be used to 
represent cognitive performance. This is an established test, simple to administer and perform, 
and addresses improvement in attention, abstract thinking and categorization, and is available 
in many languages.   
  
 
 
 
  
 
  
 
 
Pharmacokinetic Assessments 
A population PK analysis using PK data from a selection of Phase 1 and Phase 2 studies will 
be performed at the completion of the study.  The purpose of the planned population PK 
analysis will be to assess the PK of MIN-101 and the metabolite BFB-520 in the target patient 
population, and the potential impact of covariates.  PK collection will also enable the 
evaluation of the relationship between parent drug concentration and metabolites, and the 
exploration of the correlation of exposure to efficacy or safety measures.  These analyses will 
be helpful in identifying optimal exposure to evaluate in subsequent studies. 
Safety Evaluations 
Standard safety evaluations including collection of adverse events with special focus on 
adverse events of special interest, and concomitant medications, physical examination, body 
weight, waist circumference, vital signs, 12-lead ECG, pregnancy testing, and clinical 
laboratory tests will be performed to monitor subject safety throughout the study. 
Drug-induced EPS will be monitored using the clinician-administered AIMS, BARS, and SAS.  
The AIMS measures involuntary movements or tardive dyskinesia (TD).  TD is a disorder that 
sometimes develops as a side effect of long-term treatment with neuroleptic (antipsychotic) 
medications.  The SAS measure drug-induced extrapyramidal syndromes.  Extrapyramidal 
syndromes are any of a group of clinical disorders marked by abnormal involuntary 
movements, alterations in muscle tone, and postural disturbances; the group includes 
parkinsonism, chorea, athetosis.  The BARS evaluates the severity of drug-induced akathisia.  
The scale includes objective, subjective, and global items such as the level of the patient's 
restlessness.  
Emergence of suicidal ideation will be assessed using the Sheehan-STS.  The Sheehan-STS 
has been used frequently in clinical studies and it is a standard measure for suicidal ideation 
assessment; its use is in accordance with Food and Drug Administration guidance. 


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4. 
STUDY POPULATION 
Patient eligibility per all the inclusion and exclusion criteria must be met and assumes the 
investigators exercised their best judgment in reaching the decision to include or exclude any 
one patient. 
The inclusion and exclusion criteria for enrolling patient in this study are described in the 
following 2 subsections.  If there is a question about the inclusion or exclusion criteria below, 
the investigator should consult with the appropriate sponsor representative before enrolling a 
patient in the study.  Exceptional and limited re-testing of abnormal screening values, including 
laboratory values, vital signs, and ECGs that potentially lead to exclusion are allowed using an 
unscheduled visit during the screening period to reassess eligibility. 
If a patient does not meet all inclusion and exclusion criteria at initial screening visit (e.g., a 
screen failure), but in the future is expected to meet the eligibility criteria, the patient may be 
rescreened on one occasion only.  This should be discussed with and approved by the sponsor’s 
medical monitor prior to re-screening.  Patients cannot be rescreened if they failed screening 
on DSM-5 criteria for schizophrenia, or PANSS negative symptom score. Patients who are 
rescreened will be assigned a new subject number, undergo the informed consent process, and 
then restart a new screening phase. 
4.1. 
Inclusion Criteria 
Each potential patient must satisfy all the following criteria to be enrolled in the study: 
1. Patient and patient's legal representative, if applicable, provided informed consent prior to 
the initiation of any study related procedures, and the patient is judged by the investigator 
as being capable of understanding the study requirements. 
2. Male or female patient, 18 to 55 years of age, inclusive, and BMI< 35 kg/m2 at Screening.  
3. Patient meets the diagnostic criteria for schizophrenia as defined in the DSM-5, as 
established by a full psychiatric interview in conjunction with the MINI.a 
4. Has a caregiver or family member or health care personnel who can provide information 
towards assessment and support the patient in terms of compliance with the protocol.  The 
caregiver must have contacts with the patient frequently and is not expected to change 
during the trial. 
5. Documented diagnosis of schizophrenia for at least 1 year before screening into the trial. 
6. Patient is stable in terms of both positive and negative symptoms of schizophrenia over the 
last 6 months according to his or her treating clinician and/or based on documentation in 
the clinical chart or medical record.  Patients with or without positive symptoms are 
allowed if these symptoms are stable for the last 6 months and the patients do not meet 
exclusion criterion # 2. 
                                                 
a Current version for DSM-5. 


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7. Patient is currently an outpatient and has not been hospitalized for the last 6 months for 
acute exacerbation or symptoms worsening.  Patients hospitalized for any time period 
during the last 6 months for social reasons or are currently hospitalized for social reasons 
can be included only with Sponsor’s Responsible Medical Officer’s approval (in addition 
for Ukraine only, the following criteria must be fulfilled: the patient has permanent place 
of residence, is legally capable, and has a caregiver [see inclusion criterion # 4]).  The 
social reasons must be documented in the eCRF. 
8. Patient with a score of > 20 on the PANSS negative subscore (the original PANSS scale 
[Sum of N1+N2+N3+N4+N5+N6+N7]) at Screening (Visit 1) and Baseline (Visit 3) AND 
< 4 points absolute difference between the 2 visits. 
9. Patients can be on any psychotropic before the trial if the psychotropics can be discontinued 
at the beginning of the washout phase without risking the patient’s clinical status or safety.   
10. No history of violence against self or others during the last 1 year.    
11. Female patient who are not of childbearing potential, defined as women who are 
post-menopausal (defined as spontaneous amenorrhoea for at least 1 year or spontaneous 
amenorrhoea for at least 6 months confirmed by follicle stimulating hormone result of 
≥ 40 IU/mL) or permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy). 
12. Female patient, if of childbearing potential, must test negative for pregnancy and must be 
using a double barrier contraceptive method.  
13. Patient must be extensive (normal) metabolizers for P450 CYP 2D6, defined as a subject 
that has at least one functional allele (e.g., *1, or *2), as determined by study-specific 
genotyping test before the first drug dose is administered.  
14. Patient and the caregiver are considered by the investigator to be reliable and likely to 
cooperate with the assessment procedures. 
4.2. 
Exclusion Criteria 
Any potential patient who meets any of the following criteria will be excluded from 
participating in the study: 
1. 
Current major depressive disorder, bipolar disorder, panic disorder, obsessive compulsive 
disorder, or intellectual disability (intellectual developmental disorder diagnosed by age 
14). 
2. 
Patient with PANSS item score of > 4 on: 
• P4 Excitement/hyperactivity 
• P6 Suspiciousness/persecution 
• P7 Hostility  
• G8 Uncooperativeness  


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• G14 Poor impulse control. 
3. 
A CDSS total score > 6. 
4. 
A score of ≥ 2 on any 2 of items 1, 2, or 3, or a score of ≥ 3 on item 4 of the BARS.  
5. 
Patient’s condition is due to direct physiological effects of a substance (e.g., a drug of 
abuse, or medication) or a general medical condition. 
6. 
Has a current or recent history of serious suicidal behavior within the past 1 year.  
7. 
Patient has a history of substance use disorder within 3 months of the Screening visit 
(excluding caffeine and cigarette smoking).  
8. 
Positive urine drug screen for drugs of abuse (cocaine, methadone, amphetamines, 
cannabinoids, opiates, benzodiazepines, and barbiturates), TCA, and alcohol (except for 
prescription benzodiazepines).  
9. 
Patient who cannot be discontinued from psychotropics other than those allowed. 
10. Patient who received clozapine within 6 months of the Screening visit except when used 
for insomnia at doses ≤ 100 mg per day.  
11. Patient receiving treatment with long-acting or depot antipsychotic medication unless 
his/her next scheduled dose will occur during the protocol Screening period and can be 
omitted to allow for sufficient washout before receiving the study drug.    
12. Patient with a history of significant other major or unstable neurological, neurosurgical 
(e.g., head trauma), metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, 
metabolic, gastrointestinal, or urological disorder. 
13. Patient with a history of seizures (patient with a history of a single childhood febrile 
seizure may be enrolled in this study). 
14. Patient who has had ECT, VNS, or r-TMS within the 6 months prior to the Screening visit 
or who are scheduled for ECT, VNS, or r-TMS at any time during the study. 
15. Patient with clinically significant abnormalities in hematology, blood chemistry, ECG, or 
physical examination not resolved by the Baseline visit which according to Investigator 
can interfere with study participation. 
16. Current systemic infection (e.g., Hepatitis B, Hepatitis C, HIV, tuberculosis).  Patients 
with positive Hepatitis B core antibody test and negative HBsAg may be included in the 
study if aminotransferase levels (ALT/SGPT and AST/SGOT do not exceed 2 times ULN. 
17. Patient who requires or may require concomitant treatment with any other medication 
likely to increase QT interval (e.g., paroxetine, fluoxetine, duloxetine, amiodarone). 
18. Patient who requires medication inhibiting CYP 2D6 or CYP 3A4.  
19. Patient with a clinically significant ECG abnormality that could be a safety issue in the 
study, including QT interval value corrected for heart rate using QTcF > 430 msec for 
males and > 450 msec for females. 


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20. Patient with a history of myocardial infarction based on medical history or ECG findings
at Screening.
21. Familial or personal history of long QT syndrome or with additional risk factors for
Torsade de Pointes.
22. Patient whose safety laboratory results show one or more of the following:  potassium
< 3.4 mmol/L, or calcium < 2.07 mmol/L, or magnesium < 0.70 mmol/L.
23. Patients with unexplained syncope.
24. Woman of child-bearing potential, or man, who are unwilling or unable to use accepted
methods of birth control.
25. Woman with a positive pregnancy test, is lactating, or is planning to become pregnant
during the study.
26. Patient who participated in another clinical study within 3 months prior to Screening, or
received MIN-101 previously, or has previously participated in > 2 clinical studies with
experimental medication within the past 2 years (previous participation in 3 clinical
studies with experimental medication will require approval of the sponsor before
eligibility is determined).
4.3. 
Prohibitions and Restrictions 
In general, concomitant medications with primary CNS activity, as well as CYP 2D6 and 
CYP 3A4/5 inhibitors and concomitant medications likely to increase QT interval are not 
allowed in this study (refer to Attachment 1).  The following are examples of 
prohibited medications/therapies during the study: 
•
Oral or injectable antipsychotic medications other than study drug medication
•
Depot antipsychotic medication
•
Clozapine
•
ECT
•
VNS
•
r-TMS
•
Antidepressants
•
Lithium
Patients should be discontinued from the study if any of the above prohibited medications are 
used during the study (the Sponsor’s Responsible Medical Officer can allow exceptions). 
For a complete list of prohibited therapies, please refer to Attachment 1 (Allowed 
and Prohibited Concomitant Medications).  Of note, grapefruit and Seville oranges (and 
their juices) are CYP 3A4 inhibitors and must not be consumed during the study. 
Additional restrictions include female patients of childbearing potential, and men, who are 
unwilling to use an accepted method of contraception during the course of the study. 


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4.4. 
Prior and Concomitant Therapy  
4.4.1. 
Prior Therapy  
Any medication (including, but not limited to, over-the-counter medicines such as aspirin, 
antacids, vitamins, mineral supplements, and herbal preparations) that the patient is receiving 
at the time of Screening, or receives during the study, must be recorded on the appropriate 
eCRF along with the reason for use, dates of administration, and dosages. 
An attempt will be made to gather information on any previous antipsychotics used to treat 
schizophrenia during the last 1 year and these will be recorded at the Screening Visit. 
Information on the dose, date of last administration, length of time on medication will be 
collected in the source documents and appropriate eCRF pages.  
4.4.2. 
Concomitant Therapy  
All medications, including anticholinergics and other anti-EPS, except study drug, 
administered to a patient during the study (post-randomization), should be documented in the 
eCRF as concomitant medications.  
The following rescue medications, not exceeding the doses allowed by the local approvals, will 
be allowed for the treatment of the following conditions and must be documented on the 
appropriate eCRFs.  After symptoms have resolved, the Pro Re Nata (as needed, rescue) (PRN) 
dosage should be reduced as much as possible, and discontinued as soon as possible: 
Episodic insomnia, agitation, anxiety, and restlessness complaints 
• zolpidem 
• zolpidem CR 
• zaleplon 
• zopiclone 
• lorazepam (PO or IM) or equivalent benzodiazepine  
Extrapyramidal Symptoms 
Anticholinergic medication should be discontinued no later than at the Baseline visit (Visit 3).  
If treatment for EPS is clinically indicated afterwards, allowed anticholinergics may be given 
at the approved dose range throughout the study as needed. 
The use of anticholinergic medication as prophylaxis for extrapyramidal symptoms is 
prohibited.   
Allowed medications for treatment of EPS include:  
• anticholinergics, 
• benztropine mesylate, 
• biperiden, 
• procyclidine, and  


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• trihexyphenidyl (benzhexol) 
Contraception 
Patients who are sexually active must use, with their partner, 2 approved methods of highly 
effective contraception from the time of investigational medicinal product administration until 
90 days after the last dose of investigational medicinal product. 
The following are considered as highly effective contraception methods:  
• Surgical sterilization (i.e., bilateral tubal ligation/salpingectomy, hysterectomy for female 
patients or partners; vasectomy for male patients or partners). 
• Placement of an intrauterine device or intrauterine system. 
• Hormonal contraception (implantable, patch, oral, injectable). 
• Barrier methods.  
• for male patients, this must be a condom or their partner’s use of an occlusive cap 
[diaphragm or cervical/vault caps] 
• 
for female patients, either their partner’s use of a condom or the patient’s use of an 
occlusive cap [diaphragm or cervical/vault caps]  
5. 
TREATMENT ALLOCATION AND BLINDING 
5.1. 
Randomization 
Central randomization will be implemented in this study.  Patients will be randomized based 
on a computer-generated randomization schedule prepared by or under the supervision of the 
sponsor before the study. The randomization will be balanced by using randomly permuted 
blocks and will be stratified by region (United States, all other countries).  The Interactive Web 
Response System (IWRS) will assign a unique treatment code, which will dictate the treatment 
assignment and matching study drug kit for the patient. 
Patients will be randomized at Baseline to 1 of 4 treatment arms in a 2:2:1:1 ratio as follows: 
• MIN-101 64 mg for the entire study, or 
• MIN-101 32 mg for the entire study, or 
• Placebo for 12 weeks followed by MIN-101 64 mg dose during the open-label extension 
phase, or 
• Placebo for 12 weeks followed by MIN-101 32 mg dose during the open-label extension 
phase. 
The investigator will not be provided with randomization codes.  The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for 
an individual patient, if needed. 


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5.2. 
Blinding 
Under normal circumstances, the blind should not be broken until all patients have completed 
the double-blind phase of study and the database is finalized.  Otherwise, the blind should be 
broken only if specific emergency treatment/course of action would be dictated by knowing 
the treatment the patient is receiving.  In such cases, the investigator may in an emergency 
determine the identity of the treatment by IWRS.  Telephone contact with the sponsor or its 
designee will be available 24 hours per day, 7 days per week.   
In the event the blind is broken, the sponsor must be informed as soon as possible.  The date, 
time, and reason for the unblinding must be documented by the investigator, in the appropriate 
section of the eCRF, and in the source document.  The documentation received from the IWRS 
indicating the code break must be retained with the patient’s source documents in a secure 
manner (e.g., sealed envelope) so as not to unblind the treatment assignment to the study site, 
sponsor/contract research organization personnel.  The investigator is also advised not to reveal 
the study treatment assignment to the study site or sponsor personnel. 
6. 
DOSAGE AND ADMINISTRATION
On Day 1 (Visit 4) of the double-blind treatment phase, patients will be randomized to receive 
once daily MIN-101 32 mg or 64 mg doses, or placebo for 12 weeks, followed by a 40-week 
open-label treatment extension phase when all patients will receive MIN-101 (Table 3).   
Study drug will be packaged using a double-blind design.  Drug supplies of the study drug will 
be packaged using blister card each containing 9 tablets, the equivalent of 1 week of treatment 
plus 2 tablets (security margin).  The patients will receive sufficient medication at 
the scheduled visits per the Time and Events Schedule.  Daily dosing will consist of 1 tablet 
each containing the intended dose.  Placebo and MIN-101 tablets are identically 
matched in appearance and the MIN-101 tablets are available in 32 mg and 64 mg strength.    


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Table 3. Characteristics of the Treatment and Dosage per Fully Compliant Patient  
 
Tablet Strength 
 
Total Number of Tablets 
Treatment/ 
daily  
dosage 
MIN-101 
(mg) 
No. of 
placebo 
tablets 
 
During  
12-week 
Double-
blind  
Phase 
MIN-101 
Tablets During  
40-week 
Open-label 
Phase 
Total 
MIN-101 
Tablets 
Administered 
Placebo then 32 mg 
0 mg 
1 
 
84 (0 mg) 
280 (32 mg) 
280 (32 mg) 
Placebo then 64 mg 
0 mg 
1 
 
84 (0 mg) 
280 (64 mg) 
280 (64 mg) 
32 mg  
32 mg 
0 
 
84 (32 mg) 
280 (32 mg) 
364 (32 mg) 
64 mg 
64 mg 
0 
 
84 (64 mg) 
280 (64 mg) 
364 (64 mg) 
The study drug should be administered in a single dose in the morning at approximately the 
same time each day, with or without food and no later than 2 PM (local time).  Tablets should 
be swallowed whole with water and not divided, crushed, chewed, or placed in water.  Patients 
who are fully compliant will take up to 84 tablets during the double-blind phase, and a total of 
up to 364 tablets for the whole study, including the 40-week extension phase.  If a patient 
misses a dose, the dose can be taken up to 2 PM (local time) on the day of dosing.  Otherwise 
the dose must be skipped.  The next dose will be taken on the next morning.  The patient must 
not take 2 doses in any one day.  
Patients (or their designees, if appropriate) must be provided with a “study card” indicating the 
name of the investigational study drug, the study number, the investigator’s name, a 24-hour 
emergency contact number, and excluded concomitant medications (e.g., QT active drugs). 
7. 
TREATMENT COMPLIANCE 
On Days 1 and 2, patients will receive their first dose of study drug after an overnight stay at 
the hospital.  While out-patient, the drug will be self-administered by the patient at their 
residence.   
The number of study drug tablets dispensed for self-administration by patients will be recorded 
and compared with the number returned during each scheduled visit.  Patients are required to 
record the administration of study drug in diaries and record the time of drug intake.  The 
diaries will be checked and verified against the pill counts and the patients will be counseled 
regarding compliance at every scheduled visit. 
The investigator or designated study center personnel will maintain a log of all study drug 
dispensed and returned during the study.  Patients who have < 75% compliance by Week 8 
(Visit 10) may be discontinued from the study following consultation with the study medical 
monitor. 


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8.
STUDY EVALUATIONS
8.1. 
Study Procedures 
8.1.1. 
Overview 
The Time and Events Schedule that follows the Synopsis summarizes the frequency and timing 
of efficacy, PK, and safety measurements applicable to this study. 
Additional urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local law or regulation, to establish the absence of pregnancy 
throughout the study.   
During the 12-week double-blind phase, the total blood volume to be collected from each 
patient will be 226.5 mL:  110.5 mL for safety laboratory tests, 84 mL for PK, and 32 mL for 
concomitant medications.   
During the 40-week open-label phase, an additional 334 mL of blood will be collected: 
134 mL for safety laboratory tests, 140 mL for PK, and 60 mL for concomitant medications. 
These estimates are for required blood samples and do not include additional blood samples 
that may be collected at the investigator’s discretion for drug level monitoring or other clinical 
laboratory tests deemed necessary for appropriate patient care in case of occurrence of AEs 
(Table 4).  


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Table 4. Estimated Blood Volume Drawna 
Phase: 
  Type of Sample 
Volume per 
Sample 
(mL) 
No. of 
Samples per 
Patient 
Total Volume 
of Blood 
(mL)b 
12-Week Double-Blind Treatment Phase:
Safety: 
Hematology 
2 
5 
10 
Chemistry + hormones 
16 
5 
80 
HbA1c 
2 
3 
6 
Serologyc
8.5 
1 
8.5 
Genotype 
6 
1 
6 
Concomitant Medication Evaluation 
4 
8 
32 
Pharmacokinetic 
4 
21 
84 
Subtotal 
44 
226.5 
40-Week Open-Label Extension Phase:
Safety (including end-of-study evaluations):
Hematology 
2 
7 
14 
Chemistry + hormones  
HbA1c 
16 
2 
7 
4 
112 
8 
Concomitant Medication Evaluation 
4 
15 
60 
Pharmacokinetic 
4 
35 
140 
Subtotal 
68 
334 
Total 
112 
560.5 
aEstimates are based on maximum amount of blood drawn for protocol-specific procedures. 
bCalculated as number of samples multiplied by amount of blood per sample. 
cIncludes HBsAg, anti-HCV, and anti-HIV. 
8.1.2. 
Pre-Treatment Phase 
The pretreatment phase should not exceed 28 days but can be as short as 1 week. 
8.1.2.1. 
Screening Period (Visit 1) 
At the Screening visit, a signed informed consent form for study participation will be obtained.  
Informed consent must be freely given by the patient and the patient’s legal representative (if 
applicable) and documented by signature before any procedures are performed.  Screening 
procedures will be performed as outlined in the Time and Events Schedule that follows 
the Synopsis.   
Screening procedures should be performed within 28 days before study drug is administered 
on Day 1.   
Psychiatric history and diagnosis of schizophrenia will be made using the MINI and the DSM-5 
Diagnostic Criteria.  Patients will have a physical examination and specific laboratory tests as 
outlined in the Time and Events Schedules.  All Screening procedures/scales should 
be completed and laboratory results, including genotyping, should be available prior to 
the Baseline visit (Visit 3). 


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If a patient does not meet all inclusion and exclusion criteria at initial screening visit (e.g., a 
screen failure), but in the future is expected to meet the eligibility criteria, the patient may be 
rescreened on one occasion only, as described in Section 4. 
8.1.2.2. 
Hospitalization Period: Washout (Visit 2) and Baseline 
(Visits 3) 
All inclusion and exclusion criteria will be reviewed prior to patients entering the washout 
phase of the study.  Eligible patients will be hospitalized during the washout period and the 
first 2 days of treatment (washout period for 2 full days starting on Day -2; Baseline assessment 
on Day -1; and study Day 1 and Day 2).  On Day -2 (and no earlier than Day-5), baseline safety 
laboratory assessments including urine drug screen and pregnancy test will be sampled.  On 
Day -1 (Baseline or Visit 3), efficacy and the remaining safety assessments will be performed 
as outlined in the Time and Events Schedule.  Eligibility criteria will be verified 
before randomization on Day 1.  The results of the safety laboratory assessments including 
the urine drug screen as well as the analysis of the baseline ECGs by the central reader must 
be reviewed by the site prior to randomization.  The randomization must be postponed if 
these results are not available for review. 
8.1.3. 
Double-Blind Treatment Phase 
8.1.3.1. 
Day 1/Randomization (Visit 4) 
While remaining hospitalized on Day 1 (Visit 4), all patients will be randomized to 1 of 
3 treatment groups:  MIN-101 64 mg, MIN-101 32 mg, or placebo and will receive the 
first dose of study drug.  Pharmacokinetic blood samples will be drawn as per the Time and 
Events Schedule.   
8.1.3.2. 
Day 2 (Visit 5) to Week 8 (Visit 10) 
Patients will be allowed to leave the hospital on Day 2, after the administration of the second 
dose of treatment, and after having undergone 3 ECG assessments (in triplicate) and PK 
evaluation performed at pre-dose and at the approximate time of Cmax of MIN-101 and its 
metabolite BFB-520, and after completion of the RDQ.  However, the Investigator may decide 
to keep the patient hospitalized as needed.  RDQ will be completed prior to any authorization 
to leave the hospital on Day 2 or prior to any discharge authorization if later than Day 2.  If 
discharged, patients will come back for visits at Week 1, 2, 3, 4, 8, and 12 for efficacy and 
safety assessments.  Hospitalization on Visits 6 and 7 will be at the discretion of the 
investigator to ensure per-protocol ECG assessment and PK sampling are done. 
8.1.3.3. 
Telephone Contacts 
Participating patients or their caregivers will be contacted by phone weekly when the patients 
are not scheduled for site visits to inquire about the patients’ well-being, compliance with 
treatment, and to remind them of the scheduled site visits, as appropriate.  These phone calls 


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should occur on Weeks 5, 6, 7, 9, 10, and 11, and will utilize structured questions for that 
purpose. 
8.1.3.4. 
Week 12 (Visit 11) 
This is the last visit of the double-blind phase.  Patients should be administered their last dose 
of the double-blind medication at this visit (i.e., study drug medication from the blister they 
received at Week 8).  Any patient who terminates early from the study will undergo Week 12 
(Visit 11) procedures.  Also, patients with ongoing adverse events at the time of the EOS visit 
(Visit 11) will be followed until all significant changes have resolved or become medically 
stable. 
8.1.4. 
Open-label Extension Phase 
8.1.4.1. 
Hospitalization Period Following Week 12 (Visits 12 and 13)  
The 40-week, open-label extension phase commences with a required overnight hospitalization 
(i.e., Week 12 or Visit 11) for all patients for 2 nights.  Patients will be allowed to leave the 
hospital on Day 2 (Week 12 + 2 days or Visit 13) of the extension phase after drug 
administration and after safety has been ascertained clinically and including 3 ECG 
assessments (in triplicate) and PK evaluation performed at pre-dose and at the approximate 
time of Cmax of MIN-101 and its metabolite BFB-520, and with the help of the RDQ.  The 
RDQ will be completed prior to any authorization to leave the hospital. 
8.1.4.2. 
40-Week Open-Label Treatment Phase 
Patients who received MIN-101 during the double-blind treatment phase will continue to 
receive the same treatment and dose.  Patients who previously received placebo will receive 1 
of the 2 MIN-101 doses in 1:1 ratio per the randomization at Visit 4 (at the start of the 
double-blind phase).  As such, the descriptor “open-label” is being used loosely to inform that 
all patients are receiving MIN-101 without knowledge of the dose given or the treatment 
received during the double-blind phase.  
Hospitalization on Visits 14 and 15 will be at the discretion of the investigator to ensure 
per-protocol ECG assessment and PK sampling are done. 
Participating patients and/or their caregivers will be contacted by phone weekly when the 
patients are not scheduled for site visits to inquire about the patients’ well-being, compliance 
with treatment, and to remind them of the scheduled site visits, as appropriate.  These phone 
calls should occur on Weeks 18, 22, 26, 30, 34, 38, 42, 46, and 50, and will utilize structured 
questions for that purpose. 
Any patient who terminates early from this phase, and therefore from the study, will undergo 
the End of Treatment visit (Week 52/ Visit 26) as soon as possible. It will be followed ±2 
weeks later by the EOS visit (Week 54/Visit 27). If any of the laboratory results indicate an 
abnormality that warrants repeating the test, the patient should be fasting for the repeat 


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assessment.  Patients with ongoing adverse events at the time of the EOS visit will be followed 
until all significant changes have resolved or become medically stable. 
8.2. 
Efficacy 
8.2.1. 
Assessments 
The following efficacy assessments will be performed at the time points indicated in the 
Time and Events Schedule.  Every effort should be made to ensure that all clinician 
reported objective measurements are completed by the same individual who made the initial 
Baseline determinations. 
 
 
 
 
 
 
 
 
 
  
 
 
Personal and Social Performance (PSP) Scale is a validated clinician-rated scale that 
measures personal and social functioning in 4 domains:  socially useful activities (e.g., work 
and study), personal and social relationships, self-care, and disturbing and aggressive 
behaviors.  PSP is a hundred-item scale, divided in 10 similar intervals.  The score is based on 
the assessment of a patient’s performance in the 4 domains.  It is a reliable, quick measure of 
personal and social functioning of patients with schizophrenia and can be used on patients in 
the acute and stable stage.  See Attachment 6 for an example of this scale. 
Clinical Global Impression- Severity 
 – The CGI-S 
is a clinician-rated scale that is designed to rate the severity of the patient's illness at the time 
of assessment, including knowledge of the patient’s history, psychosocial circumstances, 
symptoms, behavior, and the impact of the symptoms on the patient’s ability to function 
relative to the clinician's past experience with patients who have the same diagnosis and 
improvement with treatment.  Considering total clinical experience, a patient is assessed on 
severity of mental illness at the time of rating, according to: normal (not at all ill) = 1; 
borderline mentally ill = 2; mildly ill = 3; moderately ill = 4; markedly ill = 5; severely ill = 6; 
or extremely ill = 7.  
 
 
 
  
 
   


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Cognitive Testing has been widely used in clinical trials with intended features of brief 
administration and scoring time, portability, repeatability, and availability of alternate forms. 
The verbal fluency test is such a test.  The test is fully portable, and is designed to be easily 
administered by a variety of testers, including study coordinators, psychologists, psychiatrists, 
neurologists, social workers, and other mental health workers.  It is designed to require about 
5 minutes of testing time with minimal extra time for scoring and minimal training demands 
(Attachment 9).   
 
 
  
 
 
 
 
This study will use electronic clinical outcome assessments (eCOA) to capture questionnaire 
data.  The data will be transmitted electronically to a centralized database at the eCOA vendor. 
Data may be reviewed by site staff via secure access.  eCOA data will be collected using a 
device provided by the eCOA vendor.  The device is designed for entry of data in a way that 
is compliant with regulations for electronic records. 
8.2.2. 
Efficacy Evaluations 
Efficacy will be evaluated based on the change from Baseline in PANSS negative subscale 
score after 12 weeks of treatment or at early withdrawal.  In addition, other efficacy evaluations 
will be based on the change from Baseline in the scores on the PSP, and CGI-S Scales, 
cognitive assessment, CDSS, 
 
The following efficacy evaluations will be performed at the scheduled visits in the following 
order and in the morning (between 8:00 a.m. to 1:00 p.m.) during the 12-week, double-blind 
treatment phase, and as applicable, during the 40-week, open-label extension phase: 


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•
 at Screening, Baseline, and Weeks 2, 4, 8, 12, and at Weeks 14, 16, 24, 32, 40, 48,
52, and 54 (EOS, or early withdrawal).
•
PSP at Baseline and Weeks 4, 8, 12, and at Weeks 16, 24, 32, 40, 48, and 52 (or early
withdrawal).
•
CGI-S at Screening, Baseline, and Weeks 2, 4, 8, 12, and at Weeks 14, 16, 20, 24, 28, 32,
36, 40, 44, 48, 52, and 54 (EOS, or early withdrawal).
•
 at Weeks 2, 4, 8, 12, and at Weeks 14, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and 54
(EOS, or early withdrawal).
•
Cognitive assessments at Baseline and Weeks 4, 12, and at Weeks 16, 24, 36, and 52 (or
early withdrawal).
•
 at Screening, Baseline, and Weeks 4, 8, 12, and at Weeks 16, 24, 36, and 52 (or
early withdrawal).
8.3. 
Pharmacokinetic Evaluations 
8.3.1. 
Sample Collection and Handling 
Blood sample (4 mL) will be collected for assessing MIN-101 plasma and its metabolites 
BFB-520 and BFB-999 concentration during the double-blind and open-label extension 
phases at every visit per the Time and Events Schedule.  Additionally, 1 sample to test 
for any prohibited concomitant medications will be collected at the at the approximate 
time of maximum plasma concentration of MIN-101 (6 to 8 hours post dosing) or 2-4 hours 
post dosing per the Time and Events Schedule.  Actual time and date of blood drawn must be 
accurately recorded on Lab Requisition Form and eCRF.  
8.3.2. 
Analytical Procedures 
Plasma samples will be analyzed to determine concentrations of MIN-101 and its metabolite(s) 
using validated, specific, and sensitive liquid chromatography-mass spectrometry methods 
under the supervision of the sponsor’s bioanalytical facility or designee.  Similar methodology 
will be utilized for assessing the prohibited concomitant medication levels. 
Plasma samples will be disposed after the clinical study report is finalized. 
8.3.3. 
Pharmacokinetic Evaluations 
Plasma levels of MIN-101 and its metabolite(s) will be tabulated. 
Population PK analyses will be performed on the data of this study in combination with data 
pooled from other studies.  An objective of these analyses is to continue and refine the existing 
population PK model for the potential effects of covariates, such as demographics and 
concomitant drugs, on the pharmacokinetics of MIN-101.  An integrated population 
pharmacokinetic model for MIN-101 will be used combining the data sets of Phase 1 and 2 
studies.  Standard population pharmacokinetic parameters (e.g., AUC, CL/F, etc.) will be 
estimated.  The effects of demographic characteristics, concomitant medications, laboratory 


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values, and other covariates on MIN-101 PK will be evaluated.  Results of the population PK 
analysis will be presented in a separate report. 
Additionally, the data from this study will also be used to amend the datasets already used for 
exposure QTcF modeling to continue to investigate the effect of MIN-101 and BFB-520 on 
the QTcF interval.   
8.4. 
Safety Evaluations 
The collection of adverse events and concomitant medications will start after the informed 
consent has been signed and will continue until the follow-up visit.  All safety assessments 
listed below will be performed as specified in the Time and Events Schedule. 
Any clinically relevant changes occurring during the study must be recorded on the AE section 
of the eCRF. 
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule: 
Adverse Events 
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legal representative) for the duration of the study.  AEs will be followed by the 
investigator as specified in Section 11, AE Reporting. 
Adverse Events of Special Interest 
The following AEs are considered to be of special interest in this study: 
•
Episodes of palpitations or abnormal heart rhythms
•
Episode of dizziness or syncope
•
Episode of seizure
Investigators are instructed to inquire about the occurrence of such events during the collection 
of AEs at each visit.  When reported, the investigator will be required to complete a detailed 
summary of the event and its clinical course utilizing the eCRF page as soon as information 
on the outcome (recovered, resolving, or ongoing) is available.  Note:  If the event meets the 
seriousness criteria (see Section 11.1.1), the SAE Form must also be completed according to 
the SAEs reporting timeline described in Section 11.3.2, i.e., within 24 hours of having 
become aware of the event, even if all details are not available. 
Clinical Laboratory Tests 
Blood samples for serum chemistry (collected after an overnight fast), prolactin and 
hematology and urine samples for urinalysis will be collected according to the Time and 
Events Schedules.  In addition, a urine sample for drug and alcohol testing and urine 
samples from 


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women of childbearing potential for pregnancy testing will be collected (refer to the Time 
and Events Schedules).  The investigator must review the laboratory report, document this 
review, and record any clinically relevant changes occurring during the study in the AE 
section of the eCRF.  The following tests will be performed by the central laboratory. 
a Fasting glucose can be completed anytime during the Screening period. 
b Only at Screening visit. 
•
Hematology:
- hemoglobin
- platelet count
- hematocrit
- red blood cell (RBC) count
- white blood cell (WBC) count
with differential
•
Serum Chemistry:
- sodium
- creatine phosphokinase (CPK)
- potassium
- lactic acid dehydrogenase (LDH)
- chloride
- magnesium
- uric acid
- bicarbonate (HCO3-)
- blood urea nitrogen (BUN)
- calcium
- creatinine
- phosphorous (inorganic)
- glucosea (fasting)
- albumin
- AST
- total protein
- ALT
- cholesterol (total)
- total bilirubin
- triglycerides
- alkaline phosphatase
- high-density lipoprotein (HDL)
- HbA1c
- low-density lipoprotein (LDL)
- gamma-glutamyl transferase
- very low-density lipoprotein (VLDL)
(GGT)
- prolactin
- thyroid stimulating hormoneb (TSH)
•
Urinalysis
Dipstick
Sediment (if dipstick result is abnormal) 
- specific gravity
- RBC
- pH
- WBC
- glucose
- epithelial cells
- protein
- crystals
- blood
- casts
- ketones
- bacteria
- bilirubin
- urobilinogen
- nitrite
- leukocyte esterase


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If dipstick result is abnormal, the sediment will be examined microscopically. 
Other clinical laboratory tests include: 
•
CYP 2D6 genotype
•
Serum pregnancy test at Screening and Week 12 / Visit 11 (or in case of early
termination)
•
Urine pregnancy testing for women of childbearing potential only:  Pregnancy will be 
tested at study sites with urine dipstick test according to the Time and Events Schedules. 
In the case of positive urine pregnancy test result, the serum pregnancy assessment will be 
performed centrally.  If result of the urine pregnancy test is positive, the patient must stop 
taking the study medication pending the results of the serum pregnancy test.  It the serum 
pregnancy test is doubtful or positive, the patient will be excluded or withdrawn from the 
study.  If the serum pregnancy test is negative, the study drug administration may be 
resumed.
•
Serology (HIV antibody, HBsAg, and HCV antibody)
•
Urine drug screen and urine alcohol:  Potential patients will be tested for drugs of abuse 
(cocaine, methadone, amphetamines, cannabinoids, opiates, benzodiazepines, and 
barbiturates), TCA, and alcohol at Screening and Day -2 according to the Time and Events 
Schedules.  Additionally, urine drug screen will be tested at the study sites with dipstick 
tests on Day -2.  If the results of the urine drug screen (except for prescription 
benzodiazepines) or the urine alcohol test are positive at Screening or Day -2 (by laboratory 
or dipstick testing), the patient will not be enrolled (but may be rescreened one time, as 
described in Section 4) or will be discontinued.  Also, if the screen is positive for 
cannabinoids, they will be excluded (no rescreen authorized).
Electrocardiogram (ECG)  
Three 12-lead digitalized ECGs will be recorded 1 minute apart (and to be completed within a 
5-minute timeframe) while the patient is supine for at least 10 minutes according to the Time 
and Events Schedules.
Twelve-lead ECGs will be recorded at a paper speed of 25 mm per second until 4 regular 
consecutive complexes are available.  Computer-generated interpretations of ECGs should be 
reviewed for data integrity and reasonableness.  
A central ECG reader will measure the following intervals: HR, RR, PR, QRS, and QT. 
Electrocardiogram monitoring will include the evaluation of lengthening of the QTc interval 
using QTcF. 
Vital Signs  
Vital signs will include PO/aural temperature, respiratory rate, pulse, and blood pressure. 
Three consecutive blood pressure and pulse readings will be taken at each assessment per the 
Time and Events Schedules.  Blood pressure and pulse should be taken in the arm with the 


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highest pressure, using the same arm for each reading and for all visits.  An appropriately sized 
arm cuff will be used, and the size of the cuff should remain constant for all visits. 
Blood pressure and pulse will be taken after the patient has been resting in supine position for 
5 minutes. 
Physical Examination 
Complete and abbreviated physical examinations (including anthropomorphic measurements 
[height, weight, and waist circumference]) will be performed at the times specified in the 
Time and Events Schedules.   
Any abnormalities present at Baseline, or subsequent changes, will be documented in the 
appropriate sections of the eCRF.  Any clinically significant abnormalities persisting at the end 
of the study will be followed by the investigator until resolution or until reaching a clinically 
stable endpoint. 
Abnormal Involuntary Movement Scale (AIMS) is rating scale that was designed in the 
1970s to measure TD will be performed at the times specified in the Time and Events 
Schedules.  TD is a disorder that sometimes develops as a side effect of long-term treatment 
with neuroleptic (antipsychotic) medications.  The AIMS test is used not only to detect TD but 
also to follow the severity of a patient's TD over time.  The AIMS test is usually given every 
3 to 6 months to monitor the patient for the development of TD.  For most patients, TD 
develops 3 months after the initiation of neuroleptic therapy; in elderly patients, however, TD 
can develop after as little as one month.  The entire test can be completed in about 10 minutes. 
The AIMS test has a total of 12 items rating involuntary movements of various areas of the 
patient's body.  These items are rated on a 5-point scale of severity from 0–4.  The scale is 
rated from 0 = none, 1 = minimal, 2 = mild, 3 = moderate, 4 = severe.  Two of the 12 items 
refer to dental care.  The patient must be calm and sitting in a firm chair that doesn't have arms, 
and the patient cannot have anything in his or her mouth.  The clinician asks the patient about 
the condition of his or her teeth and dentures, or if he or she is having any pain or discomfort 
from dentures.   
The remaining 10 items refer to body movements themselves.  The clinician or rater asks the 
patient about body movements.  The rater also looks at the patient in order to note any unusual 
movements first hand.  The patient is asked if he or she has noticed any unusual movements 
of the mouth, face, hands or feet.  If the patient says yes, the clinician then asks if the 
movements annoy the patient or interfere with daily activities.  Next, the patient is observed 
for any movements while sitting in the chair with feet flat on the floor, knees separated slightly 
with the hands on the knees.  The patient is asked to open his or her mouth and stick out the 
tongue twice while the rater watches.  The patient is then asked to tap his or her thumb with 
each finger very rapidly for 10–15 seconds, the right hand first and then the left hand.  Again, 
the rater observes the patient's face and legs for any abnormal movements.  
After the face and hands have been tested, the patient is then asked to flex (bend) and extend 
one arm at a time.  The patient is then asked to stand up so that the rater can observe the entire 
body for movements.  Next, the patient is asked to extend both arms in front of the body with 


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the palms facing downward.  The trunk, legs and mouth are again observed for signs of TD. 
The patient then walks a few paces, while his or her gait and hands are observed by the rater 
twice.  
See Attachment 3 for an example of the AIMS. 
Barnes Akathisia Rating Scale (BARS) is a multiple-choice questionnaire that clinicians may 
use to provide an assessment of akathisia will be performed at the times specified in the Time 
and Events Schedules.  Akathisia is a state of motor restlessness, sometimes produced by 
neuroleptic medication that ranges from a feeling of inner distress to an inability to sit still.  
The clinician or rater is instructed to observe the subject while standing and while sitting, at 
least 2 minutes each (total of at least 4 minutes in total).  There are 4 areas where the subject 
is to be evaluated, 1 of these is objective, 2 are subjective, and the final is a global assessment.  
This scale was generated in 1989 (Barnes 1989), and was derived from the findings of studies 
exploring the clinical features of antipsychotic-induced akathisia both in acute psychiatric 
admissions and schizophrenic out-patients on maintenance medication.  Subsequently, its 
validity and reliability have been established, and it has been used extensively in clinical 
studies worldwide.   
See Attachment 4 for an example of the BARS. 
Simpson-Angus Scale (SAS) is an established reliable and valid rating scale that measures 
drug-induced extrapyramidal syndromes using 10 items rated from 0= not present to 
4 = extremely severe (Simpson & Angus 1970).  It consists of one item measuring gait 
(hypokinesia), six items measuring rigidity (arm dropping, shoulder shacking, elbow rigidity, 
wrist rigidity, leg pendulousness, and head dropping) and three items measuring glabella tap, 
tremor and salivation.  As such, the range of scores is 0 to 40, with increased scores indicate 
increased severity.   
See Attachment 12 for an example of the SAS. 
Sheehan Suicidality Tracking Scale (Sheehan-STS) is a prospective rating scale that tracks 
both treatment-emergent suicidal ideation and behaviors will be performed at the times 
specified in the Time and Events Schedules.  The Sheehan-STS is a scale that can be 
administered by the clinician or the patient through self-report.  Each item is scored on a 
5-point Likert scale (0 = not at all, 1 = a little, 2 = moderately, 3 = very, and 4 = extremely). 
Data from the Sheehan-STS can be analyzed as individual item scores, and total score 
(calculated by add scores from Questions 1a (only if 1b is coded YES), + 2 through 11 + [the 
highest of 12 or any row of 16] + [the highest of 14 or any row of 15] + 17 + 20.  The Sheehan-
STS was adapted from the Suicidality Module of the MINI Structured Diagnostic Interview 
for DSM-5 (Coric et al. 2009).
See Attachment 11 for an example of this scale. 
Pharmacokinetic and Concomitant Medication Samples Associated with Safety Signals 
Every reasonable effort should be made to collect additional PK and concomitant medication 
samples as closely to the onset of any untoward safety signal (e.g., AE of special interest, SAE, 


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QTc prolongation, etc.) as possible, to aid with the interpretation of the causality of such 
signals, including the use of prohibited concomitant medications.  This procedure is also 
applicable should a patient is withdrawn due to safety reasons. 
9. 
PATIENT COMPLETION/WITHDRAWAL 
9.1. 
Completion 
A patient will be considered to have completed the study if he or she has completed all 
scheduled assessments through Week 12.  Patients who prematurely discontinue study 
treatment for any reason before completion of all scheduled assessments will not be considered 
to have completed the study.  The investigational drug will not be available after the completion 
of the study, unless required under local law or regulation and approved by the sponsor. 
9.2. 
Withdrawal from the Study 
Throughout the study, patients will be discontinued from the study for any of the following 
reasons: 
• Withdrawal of consent 
• Failure to use an acceptable method of birth control 
• The patient becomes pregnant  
• Repeated non-adherence to protocol procedures 
• Discretion of the investigator 
If a patient discontinues treatment before the double-blind phase ends, attempts to obtain Week 
12 (Visit 11) assessments must be made.  In case a patient is lost to follow-up, every possible 
effort must be made by the study site personnel to contact the patient and determine the reason 
for discontinuation/withdrawal.  The measures taken to follow-up must be documented.  When 
a patient withdraws before completing the study, the reason for withdrawal is to be documented 
in the eCRF and in the source document.  Study drug assigned to the withdrawn patient may 
not be assigned to another patient.  Patients who withdraw will not be replaced. 
9.3. 
Stopping Rules 
In addition, specific stopping rule criteria for a patient’s withdrawal are described below: 
1. Increase from Baseline in PANSS total score of 25% and an increase of 3 points or more 
on the hallucinations, suspiciousness/paranoia, hostility, delusions, or uncooperativeness 
PANSS items.  
2. CGI-S worsening of more than 2 points.   
3. Suicidal ideations or behavior. 
4. Occurrence of an AE, which may jeopardize the patient’s health as per investigator opinion.   


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5. Worsening of psychotic symptoms or occurrence of any dangerous behavior against self or 
others as per investigator opinion. 
6. Patient with significant increase in ALT (i.e., > 5 ULN). 
7. Patient with abnormal laboratory results with simultaneous increases of total bilirubin 
(> 2 ULN), ALT or AST (> 3 ULN) with alkaline phosphatases (< 1.5 ULN). 
8. Patient with sustained mean QTcF value > 500 msec (confirmed by a second ECG under 
strict resting position and at minimum at ½ hour [30 minutes] duration from the first 
measurement).  Patient’s treatment must be discontinued until mean QTcF values are 
obtained from the ECG central-reader. If values are confirmed, the patient must be 
discontinued from the study, else treatment is restarted at the discretion of the investigator. 
9. Patient with sustained mean increase of > 60 msec in the QTcF compared to Baseline 
(confirmed by a second ECG under strict resting position and at minimum at ½ hour 
[30 minutes] duration from the first measurement).  Patient’s treatment must be 
discontinued until mean QTcF values are obtained from the ECG central-reader.  If values 
are confirmed, the patient must be discontinued from the study, else treatment is restarted 
at the discretion of the investigator. 
10. If the patient for any reason requires treatment with another therapeutic agent that has been 
demonstrated to increase the QT interval or inhibit CYP 2D6 or CYP 3A4.  In this case, 
discontinuation from the study occurs prior to introduction of the new agent. 
11. If the patient experiences a syncope or dizziness not explained by other known causes, such 
as documented orthostatic hypotension, Ménière disease, etc.  
12. Patient has an overt seizure or reports seizure-like activity (loss of consciousness, 
uncontrollable tremor not due to EPS).  A seizure or seizure like activity will be 
followed-up on-site using SAE follow-up forms, neurological examination, and EEG 
monitoring.  
If a patient is withdrawn from the study for safety reason, a PK sample and a concomitant 
medication sample and a blood sample for biochemistry analysis should be drawn as soon as 
possible together with any relevant safety assessment, prior to the EOS visit if applicable. 
10. 
STATISTICAL METHODS 
Statistical analysis will be performed by the sponsor or under the authority of the sponsor. A 
general description of the statistical methods to be used to analyze the efficacy and safety data 
is outlined below.  
Specific details will be provided in the Statistical Analysis Plan (SAP). 
10.1. 
Sample Size Determination 
The sample size for this study is based on the assumption of a treatment difference of 3 points 
in the mean change from Baseline to Week 12 in PANSS negative subscale score based on the 
Marder negative factor score between any MIN-101 dose group and placebo.  A standard 


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deviation of 6.5 in the change in PANSS negative subscale score from Baseline is used.  
Assuming an equal allocation to placebo and each of the 2 MIN-101 doses, 100 patients in 
each treatment arm are required to detect the treatment difference of 3 points with a power of 
90% at an overall 2-sided significance level of 0.05.  When adjusted for a rate of about 40% 
of patients who will not have either Baseline or at least 1 on-treatment efficacy assessments, 
the required number of patients becomes 167 in each treatment arm.  Therefore, the total 
number of patients enrolled across the 3 treatment arms will be 501. 
10.2. 
Data Sets 
Three populations will be considered in the statistical analysis of the study: 
Intent-to-treat (ITT):  This population will consist of all patients who were randomly 
assigned to study drug and received at least 1 dose of study drug.   
Safety:  This population will consist of all patients who were randomly assigned to study drug 
and received at least 1 dose of study drug.  The safety analysis set is the same as the ITT. 
Per-protocol (PP):  This population will include all patients in the ITT Population who do not 
present major protocol violations, i.e., violations thought to interfere with efficacy results such 
as erroneous diagnosis, insufficient compliance (< 80%), or intake of prohibited concomitant 
medication.  Major protocol violations will be identified before breaking the randomisation 
code. 
Patients’ assignment to analysis sets will be performed during the pre-analysis review meeting 
while the data remain blinded. 
Taking into account the nature of this Phase 3 study, all efficacy analyses will be performed 
on both the ITT and PP sets, and eventual discrepancies between the results obtained in both 
sets will be discussed.  
10.3. 
Patient Information 
For all patients who received at least 1 dose of study drug, descriptive statistics by treatment 
arm, MIN-101 dose group, totaled over all MIN-101 dose groups, and as appropriate, totaled 
over all treatment arms, will be provided for age, BMI, weight in kilograms, and height in 
centimeters.  Gender will be tabulated by dose group and overall.  The BMI will be calculated 
and presented using the following formula: BMI = weight in kg/height in meters2. 
The number and percentage of patients who complete the double-blind treatment period and 
of patients who prematurely discontinue during the same period will be presented for each 
treatment arm and pooled across treatment arms for the Safety Population.  The reasons for 
premature discontinuation from the double-blind treatment period as recorded on the 
termination pages of the eCRFs will be summarized (number and percentage) by treatment arm 
for the Safety Population.  The percentage of premature discontinuations will be compared 
overall and for each discontinuation reason between treatment groups using the Fisher exact 
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The number and percent of patients with a current or historical presence of abnormal finding 
in medical history will be summarized by dose group and totaled over all dose groups. 
10.4. 
Extent of Exposure and Treatment Compliance 
Investigational Product 
Exposure to double-blind treatment for the Safety Population during the double-blind treatment 
period will be summarized for treatment duration, calculated as the number of days from the 
date of the first dose of double-blind treatment taken to the date of the last dose taken, inclusive, 
for the double-blind treatment period.  Descriptive statistics will be presented by treatment 
group. 
Prior and Concomitant Medications 
Prior medications are defined as any medication taken before the date of the first dose of 
double-blind treatment.  Concomitant medications are defined as any medication taken on or 
after the date of the first dose of double-blind treatment. 
Both prior medication use and concomitant medication use (during the double-blind treatment 
period) will be presented in data listings, and only concomitant medication will be summarized 
by the number and proportion of patients in each treatment arm receiving each medication 
within each therapeutic class for the Safety Population.  Multiple medication use by a patient 
will only be counted once.  
Measurement of Treatment Compliance 
Dosing compliance for a specified period is defined as the total number of tablets actually 
taken by a patient during that period divided by the number of tablets prescribed during the 
same period multiplied by 100.  The total number of tablets actually taken will be calculated 
from the study medication record.  The number of tablets prescribed for a specific treatment 
period will be calculated by multiplying the number of days in that period by the number of 
tablets prescribed per day.  Descriptive statistics for treatment compliance will be presented by 
treatment arm for each period between 2 consecutive visits when medication dispensation 
occurred, as well as for the entire double-blind treatment period. 
10.5. 
Efficacy Analyses  
Primary Estimand 
The primary estimand, the main clinical quantity of interest to be estimated in the study, is 
defined by the following 3 components: 
Population:  stable patients with schizophrenia with a predefined minimum PANSS negative 
symptom score. 
Endpoint:  change in PANSS Marder NSFS from baseline to the end of Week 12. 
Measure of Intervention:  the effect of the initially randomized treatment that would have 
been observed had all patients remained on their treatment throughout the double-blind phase. 


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The primary efficacy analysis will be based on the ITT Population.  Baseline for efficacy is 
defined as values recorded at Visit 3 (Baseline).   
Analyses of change from baseline will include only subjects who have both baseline and 
post-baseline data during the 12-week double-blind period. 
All statistical tests will be 2-sided hypothesis tests performed at the 5% level of significance. 
All confidence intervals will be 2-sided 95% confidence intervals, unless stated otherwise.  
Additionally, by-visit analyses will be done for all efficacy parameters using the MMRM and 
last observation carried forward (LOCF) approaches (described in Section 10.5.1), unless 
stated otherwise. 
10.5.1. 
Primary Endpoint 
The primary efficacy endpoint will be the change in the NSFS from baseline to Week 12 (the 
double-blind treatment period).  This endpoint will be analyzed using MMRM with treatment 
arm (MIN-101 64 mg, MIN-101 32 mg, and placebo), pooled study center (by country or region 
based on enrollment), visit, and treatment arm-by-visit interaction as fixed effects, patient 
nested in treatment as random effect, and Baseline NSFS as covariate.  An unstructured 
covariance matrix will be used to model the covariance of within-patient scores.  The 
Kenward-Roger approximation (Kenward & Roger 1997) will be used to estimate denominator 
degrees of freedom.  These analyses will be performed based on all post-Baseline scores using 
only the observed cases without imputation of missing values.  Comparison against placebo 
will be performed with the MIN-101 64 mg and 32 mg doses.   
The adjustment for multiplicity within the family of primary hypotheses will utilize the 
conventional Hochberg procedure for the purpose of reporting of results.  This procedure will 
allow the null hypothesis of no treatment difference for both the 64 mg and 32 mg doses versus 
placebo to be rejected if largest p-value of comparing either of these 2 doses versus placebo is 
at or below 0.050.  Otherwise, the lowest of these 2 p-values must be at or below 0.025 to allow 
for rejecting the null hypothesis for the representative dose. 
The overall type I error rate for testing the 2 MIN-101 doses versus placebo for the primary 
and the key secondary endpoint will be controlled at the 2-sided 0.05 level.  The primary family 
of hypotheses (corresponding to the primary endpoint) and the secondary family of hypotheses 
(corresponding to the key secondary endpoint, the change from Baseline in PSP Total score) 
will be tested in a sequential manner with suitable adjustment for multiplicity within the family 
of primary hypotheses and within the family of the secondary hypotheses such that a MIN-101 
dose versus placebo null hypothesis contrast testing within the secondary family can be 
evaluated only when the same null hypothesis contrast in the primary family was rejected. 
Sensitivity analyses of the primary endpoint will also be performed and will be detailed further 
in the SAP.  These may include an ANCOVA model with factors for treatment and 
region and Baseline NSFS as a covariate.  In this analysis, subjects without a NSFS at Week 
12 will have an earlier postbaseline score imputed using the LOCF method.  Other sensitivity 
analyses may also be performed to investigate the robustness of treatment estimates to the 
observed pattern of, and/or reason for, early withdrawals.   


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Additional details will be provided in the SAP, including pre-specified sensitivity analyses 
under “non-ignorable” missing data mechanisms to assess the potential impact of the incorrect 
missing data assumption made for the primary analysis. 
10.5.2. 
Secondary and Exploratory Endpoints 
The change from Baseline in PSP total scores will be analyzed similarly to the primary 
endpoint with MMRM.  The change from Baseline in CGI-S scores and 
 
will be analyzed by means of an ANCOVA of ranked data, with treatment (MIN-101 
64 mg, 32 mg, and placebo) as a factor, and Baseline CGI-S score as a covariate. 
The change from Baseline for the remaining efficacy endpoints will be analysed similarly to 
primary endpoint. 
The cumulative distribution function for the primary and key secondary endpoint will also be 
evaluated, as appropriate. 
10.6. 
Interim Analyses  
No formal interim analyses are planned for this study.  Data from the double-blind 12-week 
phase are the primary focus of this study and will be analyzed once the last patient completes 
Visit 11 assessments and the database has been locked.   
Additionally, an external DSMB will be established to review the safety data and formulate 
recommended decisions/actions in accordance with the charter of the DSMB. 
10.7. 
Pharmacokinetics  
Individual plasma levels of MIN-101 and its metabolite(s) will be tabulated by MIN-101 dose 
with the corresponding day and time point.  Descriptive statistics will be summarized by 
MIN-101 doses.   
Population PK analysis of plasma concentration-time data of MIN-101 and its metabolite(s) 
will be performed using nonlinear mixed-effects modeling.  Data will be combined with 
ongoing modeling dataset.  Available patient characteristics (demographics, laboratory 
variables, etc.) will be tested as potential covariates affecting pharmacokinetic parameters.  
Post-hoc Bayesian individual estimates of PK parameters will be generated from the 
population PK analysis for potential use in exposure-response analysis.   
Details will be given in a population PK analysis plan and results of the population 
pharmacokinetic analysis will be presented in a separate report. 
10.8. 
Safety Analyses 
The safety analysis will be performed for the double-blind treatment period and double-blind 
period using the Safety Population.  Safety variables include AEs, clinical laboratory 
parameters, physical examination, vital signs, and ECG parameters. 


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For each safety parameter, the last assessment made before the first dose of double-blind 
treatment, or in case of ECG, the mean of the 3 triplicates (9 assessments) performed on Day 
-1, will be used as the baseline for all analyses of that safety parameter. 
10.8.1. 
Adverse Events 
The verbatim terms used in the eCRFs by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA).  All reported AEs with 
onset during the 12-week double-blind period (i.e., TEAE) will be included in the analysis.  
For each AE, the percentage of patients who experienced at least one occurrence of the given 
event will be summarized by treatment group.  
Special attention will be given to those patients who died, or who discontinued treatment due 
to an AE, or who experienced an SAE (e.g., summaries, listings, and narrative preparation may 
be provided, as appropriate). 
Adverse events of special interest are episodes of palpitations or abnormal heart rhythms 
episode of dizziness or syncope, and episode of seizure.  Subjects with AEs of special interest 
may be presented separately. 
An AE that occurs > 14 days after the date of the last dose of treatment will not be considered 
TEAE, but will be included in the patient data listings but not the summary tables.  
10.8.2. 
Clinical Laboratory Tests 
Laboratory data will be summarized by type of laboratory test.  Reference ranges and markedly 
abnormal results (specified in the SAP) will be used in the summary of laboratory data.  
Descriptive statistics will be calculated for each laboratory analyte at Baseline and at each 
scheduled time point.  Changes from Baseline results will be presented in pre- versus post-
treatment cross tabulations (with classes for below, within, and above normal ranges).  A listing 
of patients with any laboratory results outside the reference ranges will be provided.  A listing 
of patients with any markedly abnormal laboratory results will also be provided. 
10.8.3. 
Vital Signs 
Descriptive statistics of body temperature, pulse, respiratory rate, and blood pressure (systolic 
and diastolic) values and changes from Baseline will be summarized at each scheduled time 
point.  The percentage of patients with values beyond clinically important limits will be 
summarized.  Clinically important limits will be defined in the SAP. 
10.8.4. 
Electrocardiogram (ECG) 
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations.  These tables will include observed values and changes from Baseline 
values (mean of Day -1 ECG assessments will be used as Baseline) to allow detection of 
clinically relevant changes in individuals. 


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The ECG variables that will be analyzed are HR, RR, PR interval, QRS interval, QT interval, 
and QTcF interval.  QTcF values will be tabulated for their absolute values and also tabulated 
relative to Baseline measurements in order to detect individual QTcF changes (ICH 2005).   
Descriptive statistics of QTcF intervals and changes from Baseline will be summarized at each 
scheduled time point. The percent of patients with QTc interval > 450 msec, > 480 msec, or 
> 500 msec will be summarized as will the percent of patients with QTcF interval increases 
from Baseline of > 30 to 60 msec or > 60 msec. 
For QTcF, an ANCOVA model by assessment times (visit and timepoint within visit) using 
the change from baseline (as dependent variable) with treatment arm (MIN-101 32 mg, 
MIN-101 64 mg, and placebo) as a factor, and Baseline value as covariate.  Estimates for the 
difference at each assessment time for each dose group versus placebo, standard error of the 
mean, and the upper bound of the 2-sided 90% confidence intervals will be presented. 
All important abnormalities in ECG waveform that are changes from the Baseline readings 
will be reported (e.g., changes in T-wave morphology or the occurrence of U-waves). 
10.8.5. 
Physical Examination 
Physical examination abnormalities will be listed.  Observed and change from Baseline values 
of weight and waist circumference will be summarized descriptively. 
10.8.6. 
Other Safety Parameters  
Observed and changes from Baseline in AIMS, BARS, and SAS values will be summarized in 
tabular format showing descriptive statistics. 
10.8.6.1. 
Sheehan Suicidality Tracking Scale  
On the basis of the data collected using the Sheehan-STS, potential suicide-related events will 
be categorized by the investigator using the event report (page 2 of the scale).  
Descriptive statistics of score values and changes from Baseline will be summarized at each 
scheduled time point.  The endpoint of interest will be the proportion of patients with a 
suicide-related outcome.   
10.9. 
Pharmacokinetic / Pharmacodynamic Analyses  
The effect of coincidentally measured (time-matched) plasma concentrations of MIN-101 and 
BFB-520 as compared to placebo on QTcF changes from Baseline will be analyzed utilizing 
the plasma concentration bin method.  This analysis will pool all assessment times at which 
both the QTcF and PK data are available and will treat the bins as separate groups using 
quartile distribution.  Plasma concentration data from placebo-treated patients will be set to 0 
(zero).  Repeated measures ANCOVA model will be used and will include PK concentration 
Bin Group and assessment times as fixed effects, Baseline QTcF as a covariate, and patient 
nested in treatment as a random effect.  


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Furthermore, the analysis will be repeated by using the largest QTcF increase value (worst 
case) per patient, with the matched plasma concentration level independent of time of 
assessment, will also be performed using ANCOVA model with PK concentration Bin Group 
as fixed effects, Baseline QTcF as a covariate, and patient nested in treatment as a random 
effect.  Analysis of the largest time-matched mean difference from Baseline will also be 
explored, as applicable. 
P-value and the least squares means difference, and the corresponding upper bound of the two-
sided 90% confidence intervals for the change from baseline versus placebo will be computed 
for each Bin.   
These analyses will be performed for MIN-101 plasma concentration and its main metabolites, 
as separate analyses. 
10.10. 
Extension Phase 
Patients enrolled in the 40-week open-label extension phase will receive either MIN-101 64 mg 
or 32 mg.  Patients who received placebo in the double-blind 12-week treatment phase will be 
randomized on Day 1 (Visit 4) to receive one of the two MIN-101 doses.  Data from all patients 
enrolled in the 40-week extension phase will be summarized descriptively, as appropriate, by 
treatment arm sequence (MIN-101 64 mg, MIN-101 32 mg, placebo to MIN-101 64 mg, 
placebo to MIN-101 32 mg, overall MIN-101, overall placebo to MIN-101, and overall) as 
appropriate, and by visit.     
All data from the 40-week extension phase will be analyzed separately upon last patient 
enrolled in this study has Visit 27 assessments.  Change from Baseline data for the patients 
treated with placebo and crossed-over to MIN-101 doses will be presented twice, based on 
Baseline being defined as the original study Baseline (Visit 3) and as the last assessment on 
placebo at Week 12 (Visit 11), as appropriate.  
10.11. 
Data Safety Monitoring Board 
An external DSMB will be established to review the safety data and formulate recommended 
decisions/actions in accordance with the charter of the DSMB.  The DSMB will consist of 
2 clinicians (psychiatrist and cardiologist), and a statistician, one of whom will chair the board.  
The DSMB will review the outputs from statistical summaries of demographics and safety data 
prepared by the contract research organization managing the study on behalf of the sponsor 
who are not otherwise affiliated by the study team. 
Further details regarding the safety analysis will be specified in a separate DSMB charter. 
11. 
ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical 
studies are crucial for the protection of patients, investigators, and the sponsor, and are 
mandated by regulatory agencies worldwide.  


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11.1. 
Definitions 
11.1.1. 
Adverse Event Definitions and Classifications 
Adverse Event 
An AE is any untoward medical occurrence in a clinical study patient administered a medicinal 
(investigational or non-investigational) product.  An AE does not necessarily have a causal 
relationship with the treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product (definition per International Council 
on Harmonisation [ICH]). 
This includes any occurrence that is new in onset or aggravated in severity or frequency from 
the Baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
Note:  The sponsor collects adverse events starting with the signing of the informed consent 
form (refer to Section 11.3.1, all Adverse Events for time of last AE recording). 
Serious Adverse Event 
An SAE is defined as any AE that results in any of the following: 
•
Death:  The patient died as the result of the event.
•
Life-threatening event:  Any AE that places the patient, in the view of the Investigator or
Sponsor, at immediate risk of death from the AE as it occurred, i.e., does not include an
AE that had it occurred in a more severe form, might have caused death.
•
Required or prolonged inpatient hospitalization:  The AE resulted in hospitalization or
prolonged an existing hospitalization.  Since hospitalization may be part of the study, only
hospitalizations that are longer than expected based on Investigator judgment, will be
considered prolonged hospitalizations.
•
Persistent or significant disability/incapacity:  An AE that results in a substantial
disruption of a person’s ability to conduct normal life functions.
•
Congenital anomaly/birth defect:  A congenital anomaly/birth defect that occurs in the
offspring of a patient exposed to the IP.
•
Important medical events:  An AE that may not result in death, be life-threatening, or
require hospitalization may be considered an SAE when, based upon appropriate medical
judgment, the event may jeopardize the patient and may require medical or surgical
intervention to prevent one of the outcomes listed above.
Note:  Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in situations other than those listed above.  For example, important 
medical events may not be immediately life threatening or result in death or hospitalization but 
may jeopardize the patient or may require intervention to prevent one of the outcomes listed in 


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the definition above (e.g., suspected transmission of an infectious agent by a medicinal product 
is considered an SAE).  Any AE is considered a SAE if it is associated with clinical signs or 
symptoms judged by the investigator to have a significant clinical impact. 
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An unlisted AE, the nature or severity of which is not consistent with the applicable product 
reference safety information.  For an investigational product, the expectedness of an AE will 
be determined by whether or not it is listed in the Investigator's Brochure.  
Adverse Events Associated with the Use of the Drug 
An AE is considered associated with the use of the drug if the attribution is possible, probable, 
or definitely by the definitions listed in Section 11.1.2. 
11.1.2. 
Attribution Definitions 
•
Unrelated:  An AE that is not related to the use of the drug.
•
Possibly/probably related:  An AE that might be due to the use of the drug.  An alternative
explanation, e.g., concomitant drug(s), concomitant disease(s), is inconclusive or unlikely.
The relationship in time is reasonable; therefore, the causal relationship cannot be
excluded.
•
Definitely:  An AE that cannot be reasonably explained by an alternative explanation,
e.g., concomitant drug(s), concomitant disease(s).  The relationship in time is very
suggestive.
11.1.3. 
Severity Criteria 
An assessment of severity grade will be made using the following general categorical 
descriptors: 
•
Mild:  Awareness of symptoms that are easily tolerated causing minimal discomfort and
not interfering with everyday activities.
•
Moderate:  Sufficient discomfort is present to cause interference with normal activity.
•
Severe:  Extreme distress causing significant impairment of functioning or incapacitation.
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the intensity of events not directly 
experienced by the patient (e.g., laboratory abnormalities). 
11.2. 
Special Reporting Situations 
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to: 
•
Overdose of a sponsor study drug, defined as 3 x daily dose within any 24-hour period.
•
Suspected abuse/misuse of a sponsor study drug.


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•
Accidental or occupational exposure to a sponsor study drug.
•
Medication error involving a sponsor product (with or without subject/patient exposure to
the sponsor study drug, e.g., name confusion).
•
Exposure to a sponsor study drug during pregnancy or breastfeeding.
Special reporting situations should be recorded in the eCRF.  Any special reporting situation 
that meets the criteria of a SAE should be recorded on the SAE page of the eCRF. 
11.3. 
Procedures 
11.3.1. 
All Adverse Events 
All AEs, whether serious or non-serious, will be reported from the time a signed and dated 
informed consent form is obtained until completion of the last study-related procedure (may 
include contact for follow-up of safety).  SAEs, including those spontaneously reported to the 
investigator within 30 days after the last dose of study drug, must be reported using the SAE 
Form.  The sponsor will evaluate any safety information that is spontaneously reported by an 
investigator beyond the time frame specified in the protocol. 
All events that meet the definition of a SAE will be reported as SAEs, regardless of whether 
they are protocol-specific assessments.  
All AEs, regardless of seriousness, severity, or presumed relationship to study therapy, must 
be recorded using medical terminology in the source document and the eCRF.  Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
“upper respiratory infection”).  Investigators must record in the eCRF their opinion concerning 
the relationship of the AE to study therapy.  All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions. 
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory 
authorities.  The sponsor will also report to the investigator all SAEs that are unlisted 
(unexpected) and associated with the use of the drug.  The investigator (or sponsor where 
required) 
must 
report 
these 
events 
to 
the 
appropriate 
Independent 
Ethics 
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise 
required and documented by the IEC/IRB.  
Patients (or their designees, if appropriate) must be provided with a “study card” indicating the 
name of the investigational study drug, the study number, the investigator’s name, a 24-hour 
emergency contact number, and, if applicable, excluded concomitant medications. 
11.3.2. 
Serious Adverse Events 
All SAEs occurring during the study must be reported by the investigational staff within 
24 hours 
of 
their 
knowledge 
of 
the 
event 
via 
the 
following 
email: 
 


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In the event that transmission is unsuccessful, the following back up fax numbers are available: 
• For the US/Canada cases: 
 
• For Europe/Rest of the world cases: 
 
Information regarding SAEs will be transmitted to the sponsor using the SAE Form, which 
must be completed and signed by a member of the investigational staff, and transmitted to the 
sponsor within 24 hours.  The initial and follow-up reports of a SAE should be made by email. 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the patient’s participation in the study, must be followed until any of the 
following occurs: 
• The event resolves. 
• The event stabilizes. 
• The event returns to Baseline, if a Baseline value is available. 
• The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct. 
• It becomes unlikely that any additional information can be obtained (patient or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts). 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a patient’s participation in a clinical study must be reported as a SAE, except 
hospitalizations for the following: 
• Extended hospitalization beyond Day 2 after randomization for continued monitoring of a 
patient. 
• Social reasons in absence of an AE. 
• Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). 
• Hospitalization for the purpose of assessing ECG and collecting PK samples during the 
first 4 weeks of the double-blind and open-label phases as required by the protocol. 
• Hospitalization at the end of the double-blind phase and the initiation of the open-label 
treatment phase as required by the protocol.  
Suspected transmission of an infectious agent by a medicinal product should be reported as a 
SAE.  
The cause of death of a patient in the study within 30 days of the last dose of study drug, 
whether or not the event is expected or associated with the study drug, is considered a SAE.   


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11.3.3. 
Pregnancy 
All initial reports of pregnancy must be reported to the sponsor by the investigational staff 
within 24 hours of their knowledge of the event using the appropriate pregnancy notification 
form.  Abnormal pregnancy outcomes are considered SAEs and must be reported using the 
SAE Form.  Any patient who becomes pregnant during the study must be promptly withdrawn 
from the study. 
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male 
patients included in the study will be reported by the investigational staff within 24 hours of 
their knowledge of the event using the appropriate pregnancy notification form. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in 
the infant will be required. 
11.4. 
Contacting Sponsor Regarding Safety 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document. 
12.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, i.e., any dissatisfaction relative to the identity, quality, 
durability, and reliability of a product, including its labeling or package integrity.  PQCs may 
have an impact on the safety and efficacy of the product.  Timely, accurate, and complete 
reporting and analysis of PQC information from clinical studies are crucial for the protection 
of patients, investigators, and the sponsor, and are mandated by regulatory agencies worldwide.  
The sponsor has established procedures in conformity with regulatory requirements worldwide 
to ensure appropriate reporting of PQC information; all clinical studies conducted by the 
sponsor or its affiliates will be conducted in accordance with those procedures. 
12.1. 
Procedures 
All initial PQCs must be reported to the sponsor by the investigational staff as soon as possible 
after being made aware of the event. 
If the defect is combined with an SAE, the investigational staff must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 11.3.2, SAEs).  A sample 
of the suspected product should be maintained for further investigation if requested by the 
sponsor. 
12.2. 
Contacting Sponsor Regarding Product Quality 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document. 


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13. 
STUDY DRUG INFORMATION 
13.1. 
Physical Description of Study Drug(s) 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
13.2. 
Packaging 
The study drug will be packaged in individual patient kits containing child resistant blister 
cards with sufficient medication, with overage, for 1 week of treatment.  
13.3. 
Labeling 
The kits of MIN-101 tablets will have a product and study-specific label containing 
information that meets the applicable regulatory requirements.  The study dispensing labels 
will contain dosing instructions, quantity of product dispensed, and spaces to record patient 
number, visit number, date dispensed and investigator’s name.  
13.4. 
Preparation, Handling, and Storage  
All study drugs must be stored in a controlled environment at room temperature (i.e., 15 - 25 
degrees Celsius), with excursions permitted up to 40 °C (inclusive).   
13.5. 
Drug Accountability 
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study.  The dispensing of study drug to the patient, and the 
return of study drug from the patient (if applicable), must be documented on the drug 
accountability form.  Patients will be instructed to return all original containers, whether empty 
or containing study drug.  They will also be asked to fill a daily drug administration diary to 
record the time of drug intake and time of first food intake.  Study drug returned by study 
patients will be stored and disposed of according to the sponsor’s instructions.  Site staff must 
not combine contents of the study drug containers. 
Study drug must be handled in strict accordance with the protocol and the container label and 
will be stored in a limited access area or in a locked cabinet under appropriate environmental 
conditions.  Unused study drug, and study drug returned by the patient (if applicable), must be 
available for verification by the sponsor’s site monitor during on-site monitoring visits.  The 
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documented on the Drug Return Form.  When the site is an authorized destruction unit and 
study drug supplies are destroyed on site, this must also be documented on the Drug Return 
Form. 
Study drug should be dispensed under the supervision of the investigator, a qualified member 
of the investigational staff, or by a hospital/clinic pharmacist.  Study drug will be supplied only 
to patients participating in the study.  Returned study drug must not be dispensed again, even 
to the same patient.  Returned study drug may not be relabeled or reassigned for use by other 
patients.  The investigator agrees neither to dispense the study drug from, nor store it at, any 
site other than the study sites agreed upon with the sponsor. 
14. 
STUDY-SPECIFIC MATERIALS 
The investigator will be provided with the following supplies: 
• eCRF and infrastructure, including tablets that will be used to capture all efficacy 
assessments. 
• Forms and questionnaires for special assessments. 
• PK and prohibited concomitant medication blood sampling supplies. 
• Safety laboratory blood sampling supplies. 
• Urine dipsticks and urine pregnancy kits. 
• Patient education material. 
• ECG devices. 
15. 
ETHICAL ASPECTS 
15.1. 
Study-Specific Design Considerations 
Clinical Trial in Schizophrenia 
Schizophrenia is a severe, chronic and often life-threatening illness.  It is a major cause of 
disability worldwide (WHO 2006).  There is a clear need to develop novel and improved 
therapeutics for schizophrenia. 
MIN-101 has shown anti-schizophrenia-like effects in animal models and has unique 
mechanism of action and good tolerability.  These characteristics make MIN-101 an attractive 
compound to test for efficacy in schizophrenia.  
Selection of Patients 
The primary aim of the study is to evaluate the efficacy, safety and tolerability of MIN-101 for 
the treatment of negative symptoms in schizophrenia.  Thus, the study cannot be completed in 
healthy subjects.  Patients selected in the study will have adequate capacity to give consent for 
participation in the study (and via their legal representative, if applicable). 


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Justification for Using Placebo 
Assessing the potential efficacy of a new compound for the treatment of schizophrenia requires 
adequate and well-controlled clinical studies.  For a new compound, this can be achieved either 
through a placebo-controlled study or through a study comparing it to an active comparator 
through a non-inferiority design.  For non-inferiority studies, previous placebo-controlled 
studies have shown consistently the superiority of the active standard drug to placebo.  A large 
proportion of studies with antipsychotics fail even with previously proven antipsychotics, 
making assay sensitivity difficult to establish and thus, a non-inferiority design invalid 
(Laughren 2001).  Furthermore, non-inferiority trials require much larger sample sizes 
compared to placebo-controlled trials hence, exposing a larger number of patients to an 
experimental drug of yet unproven efficacy.  Therefore, randomized, controlled studies that 
rely on comparison with standard antipsychotic alone may generate unreliable results with 
limited assay sensitivity.  
Though some continue to consider it unethical to do placebo-controlled studies due to the 
potential risk of irreversible harm (Rothman & Michels 1994), the use of a placebo-controlled 
study design remains the gold standard for assessment of efficacy of new compound to allow 
for scientifically meaningful results.  Placebo-controlled studies in schizophrenia are 
ethically and scientifically justifiable (Temple & Ellenberg 2000, Laughren 2001). 
Precautions to Ensure Patient Safety in the Study 
Patients may participate in the study only if they (and their legal representative, if applicable) 
have adequate capacity to give consent and after fully understanding the potential risks and 
giving an informed consent.  Patients may discontinue the study at any time.  The probability 
of receiving placebo and the concept of random assignment will be explained to the patient. 
The duration of the study is short, minimizing the time on placebo.  Potential disadvantages 
and AEs of participating in the study and alternative treatment options will be discussed. 
Patients at high risk of suicide or self-harm will be excluded from participating.  Patients who 
do not improve during the study may drop out during the study and clinical care will be 
provided according to local standards of care.   
Compensation for any study requirements or procedure will be fair per local standards and 
approved by the participating sites IRB in order to not offer any undue incentive to participate 
in the study. 
Specific entry criteria, including exclusion of patients with clinically apparent laboratory 
abnormalities, and other medically unstable systemic diseases test results at Screening, will 
further ensure the appropriate selection and safety of patients who enter the study.   
Only highly qualified and experienced investigators will be participating in the study. 


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15.2. 
Regulatory Ethics Compliance 
15.2.1. 
Investigator Responsibilities 
The investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable 
regulatory and country-specific requirements. 
GCP is an international ethical and scientific quality standard for designing, conducting, 
recording, and reporting studies that involve the participation of human patients.  Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
patients are protected, consistent with the principles that originated in the Declaration of 
Helsinki and that the clinical study data are credible. 
15.2.2. 
Independent Ethics Committee or Institutional Review 
Board (IEC/IRB)  
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents: 
• Final protocol and, if applicable, amendments. 
• Sponsor-approved informed consent form (and any other written materials to be provided 
to the patients). 
• Investigator’s Brochure (or equivalent information) and amendments. 
• Sponsor-approved patient recruiting materials. 
• Information on compensation for study-related injuries or payment to patients for 
participation in the study, if applicable. 
• Investigator’s curriculum vitae or equivalent information (unless not required, as 
documented by IEC/IRB). 
• Information regarding funding, name of the sponsor, institutional affiliations, other 
potential conflicts of interest, and incentives for patients. 
• Any other documents that the IEC/IRB requests to fulfill its obligation. 
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any), the informed consent form, applicable recruiting materials, and 
patient compensation programs, and the sponsor has received a copy of this approval.  This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved. 
During the study the investigator (or sponsor where required) will send the following 
documents and updates to the IEC/IRB for their review and approval, where appropriate:  
• Protocol amendments. 


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• Revision(s) to informed consent form and any other written materials to be provided to 
patients. 
• If applicable, new or revised patient recruiting materials approved by the sponsor. 
• Revisions to compensation for study-related injuries or payment to patients for 
participation in the study, if applicable. 
• Investigator’s Brochure amendments or new edition(s). 
• Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually). 
• Reports of AEs that are serious, unlisted, unexpected, and associated with the 
investigational drug. 
• New information that may adversely affect the safety of the patients or the conduct of the 
study. 
• Deviations from or changes to the protocol to eliminate immediate hazards to the patients. 
• Report of deaths of patients under the investigator's care. 
• Notification if a new investigator is responsible for the study at the site. 
• Annual Safety Report and Line Listings, where applicable. 
• Any other requirements of the IEC/IRB. 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for patients, data or trial conduct), the amendment and applicable informed 
consent form revisions must be submitted promptly to the IEC/IRB for review and approval 
before implementation of the change(s).  
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion. 
15.2.3. 
Informed Consent 
Each patient (and a legal representative, if applicable) must give written consent according to 
local requirements after the nature of the study has been fully explained.  The consent form 
must be signed before performance of any study-related activity.  The consent form that is used 
must be approved by both the sponsor and by the reviewing IEC/IRB.  The informed consent 
should be in accordance with principles that originated in the Declaration of Helsinki, current 
ICH and GCP guidelines, applicable regulatory requirements, and sponsor policy. 
Before enrollment in the study, the investigator or an authorized member of the investigational 
staff must explain to potential patients (or their legal representatives) the aims, methods, 
reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail.  Patients will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time.  They will be informed 


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that choosing not to participate will not affect the care the patient will receive for the treatment 
of his or her disease.  Patients will be told that alternative treatments are available if they refuse 
to take part and that such refusal will not prejudice future treatment.  Finally, they will be told 
that the investigator will maintain a patient identification register for the purposes of long-term 
follow-up if needed and that their records may be accessed by health authorities and authorized 
sponsor staff without violating their confidentiality, to the extent permitted by the applicable 
law(s) or regulations.  By signing the informed consent form the patient (or legal 
representative) is authorizing such access, and agrees to allow his or her study physician to 
re-contact the patient for the purpose of obtaining consent for additional safety evaluations, if 
needed, or to obtain information about his or her survival status. 
The patient (or legal representative) will be given sufficient time to read the informed consent 
form and the opportunity to ask questions.  After this explanation and before entry into the 
study, consent should be appropriately recorded by means of either the patient's or his or her 
legal representative's personally dated signature.  After having obtained the consent, a copy of 
the informed consent form must be given to the patient. 
If the patient (and legal representative, if applicable) is unable to read or write, an impartial 
witness should be present for the entire informed consent process (which includes reading and 
explaining all written information) and should personally date and sign the informed consent 
form after the oral consent of the patient (and legal representative) is obtained. 
Written assent should be obtained from patients who are able to write.  After having obtained 
the assent, a copy of the assent form must be given to the patient, and the patient's legal 
representative. 
15.2.4. 
Privacy of Personal Data 
The collection and processing of personal data from patients enrolled in this study will be 
limited to those data that are necessary to investigate the efficacy, safety, quality, and utility of 
the investigational study drug(s) used in this study. 
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations.  Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must 
be put in place.  Sponsor personnel or designee whose responsibilities require access to 
personal data agree to keep the identity of study patients confidential. 
The informed consent obtained from the patient (and legal representative, if applicable) 
includes explicit consent for the processing of personal data and for the investigator to allow 
direct access to his or her original medical records for study-related monitoring, audit, IEC/IRB 
review, and regulatory inspection.  This consent also addresses the transfer of the data to other 
entities and to other countries. 
The patient has the right to request through the investigator access to his or her personal data 
and the right to request rectification of any data that are not correct or complete.  Reasonable 


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steps will be taken to respond to such a request, taking into consideration the nature of the 
request, the conditions of the study, and the applicable laws and regulations. 
15.2.5. 
Country Selection 
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product if the need for the product persists, unless 
explicitly addressed as a specific ethical consideration in Section 15.1, Study-Specific Design 
Considerations.   
16.
ADMINISTRATIVE REQUIREMENTS
16.1. 
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment.  
All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator.  Protocol amendments must not be implemented without prior IEC/IRB approval, 
or when the relevant competent authority has raised any grounds for non-acceptance, except 
when necessary to eliminate immediate hazards to the patients, in which case the amendment 
must be promptly submitted to the IEC/IRB and relevant competent authority.  Documentation 
of amendment approval by the investigator and IEC/IRB must be provided to the sponsor or 
its designee.  When the change(s) involves only logistic or administrative aspects of the study, 
the IRB (and IEC where required) only needs to be notified. 
During the course of the study, in situations where a departure from the protocol is 
unavoidable, the investigator or other physician in attendance will contact the appropriate 
sponsor representative (see Contact Information pages provided separately).  Except in 
emergency situations, this contact should be made before implementing any departure from 
the protocol.  In all cases, contact with the sponsor must be made as soon as possible to discuss 
the situation and agree on an appropriate course of action.  The data recorded in the CRF and 
source documents will reflect any departure from the protocol, and the source documents will 
describe this departure and the circumstances requiring it. 
16.2. 
Regulatory Documentation 
16.2.1. 
Regulatory Approval/Notification 
This protocol and any amendment(s) must be submitted to the appropriate regulatory 
authorities in each respective country, as applicable.  A study may not be initiated until all 
local regulatory requirements are met. 
16.2.2. 
Required Pre-Study Documentation 
The following documents must be provided to the sponsor before shipment of study drug to 
the investigational site: 
•
Protocol and amendment(s), if any, signed and dated by the investigator.


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• A copy of the dated and signed written IEC/IRB approval of the protocol, amendments, 
informed consent form, any recruiting materials, and if applicable, patient compensation 
programs.  This approval must clearly identify the specific protocol by title and number 
and must be signed by the chairman or authorized designee. 
• Name and address of the IEC/IRB including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations.  If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list.  If an investigator 
or a member of the investigational staff is a member of the IEC/IRB, documentation must 
be obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study. 
• Regulatory authority approval or notification, if applicable. 
• Documentation of investigator qualifications (e.g., curriculum vitae). 
• Completed investigator financial disclosure form from the investigator, where required. 
• Signed and dated clinical trial agreement, which includes the financial agreement. 
• Any other documentation required by local regulations. 
The following documents must be provided to the sponsor before enrollment of the first 
patient: 
• Documentation of subinvestigator(s) qualifications (e.g., curriculum vitae). 
• Name and address of any local laboratory conducting tests for the study, and a dated copy 
of current laboratory normal ranges for these tests. 
• Local laboratory documentation demonstrating competence and test reliability 
(e.g., accreditation/license), if applicable. 
16.3. 
Patient Identification, Enrollment, and Screening Logs 
The investigator agrees to complete a patient identification and enrollment log to permit easy 
identification of each patient during and after the study.  This document will be reviewed by 
the sponsor site contact for completeness. 
The patient identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file.  To ensure patient confidentiality, no copy will be made.  
All reports and communications relating to the study will identify patients by initials and 
assigned number only. 
The investigator must also complete a patient-screening log, which reports on all patients who 
were seen to determine eligibility for inclusion in the study. 
16.4. 
Source Documentation 
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the 
following: patient identification, eligibility, and study identification; study discussion and date 


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of signed informed consent; dates of visits; results of safety and efficacy parameters as required 
by the protocol; record of all AEs and follow-up of AEs; concomitant medication; drug 
receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable.  
The author of an entry in the source documents should be identifiable. 
Specific details required as source data for the study and source data collection methods will 
be reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document). 
At a minimum, the type and level of detail of source data available for a study patient should 
be consistent with that commonly recorded at the site as a basis for standard medical care.  
Specific details required as source data for the study will be reviewed with the investigator 
before the study and will be described in the monitoring guidelines (or other equivalent 
document). 
The minimum source documentation requirements for Section 4.1, Inclusion Criteria 
and Section 4.2, Exclusion Criteria that specify a need for documented medical history 
are as follows: 
•
Complete medical and psychiatric history and / or discharge summaries or
•
Documentation of a telephone call with the treating clinician or letter from the treating
clinician if full records are unavailable
Inclusion and exclusion criteria not requiring documented medical history must be verified at 
a minimum by subject interview or other protocol required assessment (e.g., physical 
examination, laboratory assessment) and documented in the source documents. 
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (e.g., electronic source documents) as well 
as the clinical study-specific data fields as determined by the protocol.  This data is 
electronically extracted for use by the sponsor.  If electronic source is utilized, references made 
to the eCRF in the protocol include the electronic source system, but information collected 
through electronic source may not be limited to that found in the eCRF.  Data in this system 
may be considered source documentation. 
16.5. 
Case Report Form Completion 
Case report forms are provided in the eCRF for each patient who was randomized and received 
at least one dose of study drug.  Screen failures will not be entered.  
Data must be entered into eCRFs in English.  The investigator must verify that all data entries 
in the eCRFs are accurate and correct.  All eCRF entries, corrections, and alterations must be 
made by the investigator or other authorized study-site personnel. 


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16.6. 
Data Quality Assurance/Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers, review of protocol procedures with the investigator 
and associated personnel before the study, and periodic monitoring visits by the sponsor.  
Written instructions will be provided for collection, preparation, and shipment of blood, 
plasma, and urine samples.  
Guidelines for eCRF completion will be provided and reviewed with study personnel before 
the start of the study.  
The sponsor or designee will review eCRFs for accuracy and completeness during on-site 
monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with 
the investigator or designee, as appropriate.  After upload of the data into the clinical study 
database they will be verified for accuracy.  
16.7. 
Record Retention 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each patient, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory 
requirement(s).  The investigator/institution will take measures to prevent accidental or 
premature destruction of these documents. 
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and 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.  These documents will 
be retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor.  It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility.  The sponsor must be notified in writing of the name and address of 
the new custodian.  Under no circumstance shall the investigator relocate or dispose of any 
study documents before having obtained written approval from the sponsor. 
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator must permit access to such reports. 
Local laws and regulations regarding record retention policies will be followed. 
16.8. 
Monitoring 
The sponsor or designee will perform on-site monitoring visits as frequently as necessary.  The 
monitor will record dates of the visits in a study center visit log that will be kept at the site.  
The first post-initiation visit will be made as soon as possible (but no later than 2 weeks) after 


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enrollment has begun.  At these visits, the monitor will compare the data entered into the eCRFs 
with the hospital or clinic records (source documents).  The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
eCRF are known to the sponsor and investigational staff and are accessible for verification by 
the sponsor site contact.  If electronic records are maintained at the investigational site, the 
method of verification must be discussed with the investigational staff.  
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data.  
Findings from this review of eCRF and source documents will be discussed with the 
investigational staff.  The sponsor expects that, during monitoring visits, the relevant 
investigational staff will be available, the source documentation will be accessible, and a 
suitable environment will be provided for review of study-related documents.  The monitor 
will meet with the investigator on a regular basis during the study to provide feedback on the 
study conduct. 
16.9. 
Study Completion/Termination 
16.9.1. 
Study Completion 
The study is considered completed with the last visit of the last patient participating in the 
study.  The final data from the investigational site will be sent to the sponsor (or designee) after 
completion of the final patient visit at that site.  Investigational sites will be closed upon study 
completion.  An investigational site is considered closed when all required documents and 
study supplies have been collected and a site closure visit has been performed. 
16.9.2. 
Study Termination 
The sponsor reserves the right to close the investigational site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Investigational sites will be closed 
upon study termination.  An investigational site is considered closed when all required 
documents and study supplies have been collected and a site closure visit has been performed. 
The investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended closure. 
Reasons for the early closure of an investigational site by the sponsor or investigator may 
include but are not limited to: 
• Failure of the investigator to comply with the protocol, the sponsor’s procedures, or GCP 
guidelines. 
• Inadequate recruitment of patients by the investigator. 
• Discontinuation of further drug development. 


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16.10. On-Site Audits 
Representatives of the sponsor’s clinical quality assurance department may visit the site at any 
time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy.  These audits will require access to all study 
records, including source documents, for inspection and comparison with the eCRF.  Patient 
privacy must, however, be respected.  The investigator and staff are responsible for being 
present and available for consultation during routinely scheduled site audit visits conducted by 
the sponsor or its designees.  
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of 
a regulatory submission.  The investigator should immediately notify the sponsor if they have 
been contacted by a regulatory agency concerning an upcoming inspection. 
16.11. Use of Information and Publication 
All information, including but not limited to information regarding MIN-101 or the sponsor’s 
operations (e.g., patent application, formulas, manufacturing processes, basic scientific data, 
prior clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data generated as a result of this study, are considered 
confidential and remain the sole property of the sponsor.  The investigator agrees to maintain 
this information in confidence and use this information only to accomplish this study, and will 
not use it for other purposes without the sponsor’s prior written consent. 
The investigator understands that the information developed in the clinical study will be used 
by the sponsor in connection with the continued development of MIN-101, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies.  To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study. 
The results of the study will be reported in a clinical study report generated by the sponsor and 
will contain eCRF data from all investigational sites that participated in the study.  Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of 
the study will be used to determine a coordinating investigator, if needed.  Any work created 
in connection with performance of the study and contained in the data that can benefit from 
copyright protection (except any publication by the investigator as provided for below) shall 
be the property of the sponsor as author and owner of copyright in such work.  
The sponsor shall have the right to publish such data and information without approval from 
the investigator.  If an investigator wishes to publish information from the study, a copy of the 
manuscript must be provided to the sponsor for review at least 60 days before submission for 
publication or presentation.  Expedited reviews will be arranged for abstracts, poster 
presentations, or other materials.  If requested by the sponsor in writing, the investigator will 
withhold such publication for up to an additional 60 days to allow for filing of a patent 
application.  In the event that issues arise regarding scientific integrity or regulatory 


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compliance, the sponsor will review these issues with the investigator.  The sponsor will not 
mandate modifications to scientific content and does not have the right to suppress information.   
For multicenter study designs and substudy approaches, results may need to be published in a 
given sequence (e.g., substudies) should not generally be published before the primary 
endpoints of a study have been published.  Similarly, investigators will recognize the integrity 
of a multicenter study by not publishing data derived from the individual site until the 
combined results from the completed study have been published in full, within 12 months after 
conclusion, abandonment, or termination of the study at all sites, or the sponsor confirms there 
will be no multicenter study publication.  Authorship of publications resulting from this study 
will be based on the guidelines on authorship, such as those described in the Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals, which state that the named 
authors must have made a significant contribution to the design of the study or analysis and 
interpretation of the data, provided critical review of the paper, and given final approval of the 
final version. 
16.12. 
Registration of Clinical Studies and Disclosure of Results 
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law. 
 
 
 


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17. 
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review of Bayesian meta-analysis, and meta-regression of efficacy predictors. AJP in Advance, 
doi: 10.1176/appi.ajp.2017.16121348. 
Lever, J.R., Miller, D.K., Green, C.L., Fergason-Cantrell, E.A., Watkinson, L.D., Carmack, 
T.L., et al. (2014). A selective Sigma-2 receptor ligand antagonizes cocaine-induced 
hyperlocomotion in mice. Synapse 68, 73-84. 
Loo, H., Poirier-Littre, M.F., Theron, M., Rein, W., and Fleurot, O. (1997).  Amisulpride 
versus placebo in the medium-term treatment of the negative symptoms of schizophrenia. Br. 
J. Psychiatry 170, 18-22. 
Marder, S.R., Davis, J.M., and Chouinard, G. (1997). The effects of Risperidone on the five 
dimensions of schizophrenia derived by factor analysis: combined results of the North 
American trials. J. Clin. Psychiatry 58, 538-546. 


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Marder, S.R., Daniel, D.G., Alphs, L., Awad, A.G., and Keefe, R.S. (2011). Methodological 
issues in negative symptom trials. Schizophr. Bull. 37(2), 250-254. 
Marder, S.R., Alphs, L., Anghelescu, I.G., Arango, C., Barnes, T.R., Caers, I., et al. (2013). 
Issues and perspectives in designing clinical trials for negative symptoms in schizophrenia. 
Schizophr. Res. 150(2-3), 328-333. 
Meltzer, H.Y., and Roth, B. (2013). Lorcaserin and pimavanserin: emerging selectivity of 
serotonin receptor subtype-targeted drugs. J. Clin. Invest. 123(12), 4986-4991. 
Moncrieff, J. (2015). Antipsychotic maintenance treatment: time to rethink? PLOS Med. 12(8), 
e1001861. 
Nopoulos, P.C., Ceilley, J.W., Gailis, E.A., and Andreasen, N.C. (2001). An MRI study of 
midbrain morphology in patients with schizophrenia: relationship to psychosis, neuroleptics, 
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Rothman, K.J., and Michels, K.B. (1994). The continuing unethical use of placebo controls. N. 
Engl. J. Med. 331(6), 394-398. 
Simpson, G.M., and Angus, J.W.S. (1970).  A rating scale for extrapyramidal side effects. Acta 
Psychiatrica Scandinavica. 212, 11-19. 
Skuza, G. (2012). Pharmacology of sigma () receptor ligands from a behavioral perspective. 
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Storosum, J.G., van Zwieten, B.J., Wohlfarth, T., de Haan, L., Khan, A., vand an den Brink, 
W. (2003). Suicide risk in placebo vs active treatment in placebo-controlled trials for 
schizophrenia. Arch. Gen. Psychiatry 60(4), 365-368. 
Temple, R., and Ellenberg, S.S. (2000). Placebo-controlled trials and active-control trials in 
the evaluation of new treatments. Part 1: ethical and scientific issues. Ann. Intern. Med. 133(6), 
455-463. 
Vilner, B., and Bowen, W.D. (2000). Modulation of cellular calcium by sigma-2 receptors: 
release from intracellular stores in human SK-N-SH neuroblastoma cells. J. Pharmacol. Exp. 
Ther. 293(3), 900-911. 
Wils, R.S., Gotfredsen, D.R., Hjorthøj, C., Austin, S.F., Albert, N., Secher, R.G., et al. (2016). 
Antipsychotic medication and remission of psychotic symptoms 10 years after a first-episode 
psychosis. Schizophr. Res. doi10.1016/j.schres.2016.10.030. 
World Health Organization (WHO). (2006). The global gurden of disease: 2004 update. 
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http://www.who.int/healthinfo/global_burden_disease/2004_report_update/en/index.html. 
Wulff, K., Dijk, D.J., Middleton, B., Foster, R.G., and Joyce, E.M. (2012). Sleep and circadian 
rhythm disruption in schizophrenia. Br. J. Psychiatry 200(4), 308-336. 
Wunderink, L., Nieboer, R.M., Wiersma, D., Sytema, S., and Nienhuis, F.J. (2013). Recovery 
in remitted first-episode psychosis at 7 years of follow-up of an early dose 


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reduction/discontinuation of maintenance treatment strategy: long-term follow-up of a 2-year 
randomized clinical trial. JAMA Psychiatry 70(9), 913-920. 
Xu, J., Zeng, C., Chu, W., Pan, F., Rothfuss, J.M., Zhang, F., et al. (2011). Identification of the 
PGRMC1 protein complex as the putative sigma-2 receptor binding site. Nat. Commun. 2, 380. 


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ATTACHMENT 1: ALLOWED/PROHIBITED CONCOMITANT MEDICATIONS 
Drug Class 
As 
Needed 
Chronic 
Use 
Restrictions 
Analgesics 
Y 
N 
Only non-opiate analgesics are allowed.  
Anorexics 
N 
N 
 
Antacids 
Y 
Y 
H2 antagonists and proton pump inhibitors not 
allowed, 
Antianginal Agents 
N 
N 
 
Antiarrhythmics 
N 
N 
 
Antiasthma Agents 
Y 
Y 
Inhaled agents only. 
Antibiotics 
Y 
N 
Some macrolides, quinolones and other antibiotics not 
allowed.(refer to the next table) 
Anticholinergics 
N 
N 
Only rescue medications are allowed (refer to 
protocol) 
Anticoagulants 
N 
Y 
Only aspirin (max. 325 mg/day) is allowed as chronic 
anti-platelet treatment. 
Anticonvulsants 
N 
N 
 
Antidepressants 
N 
N 
 
Antidiarrheal Preparations 
Y 
N 
 
Antifungal Agents: 
 
 
 
 
- Systemic 
N 
N 
 
 
- Topical 
Y 
Y 
 
Antihistamines 
Y 
N 
Only fexofenadine, loratadine, cetirizine are allowed. 
Antihypertensives (*) 
N 
Y 
Calcium channel blockers and ACE inhibitors 
allowed. Isradipine and nicardipine not authorized. 
Anti-inflammatory Drugs 
Y 
Y 
Systemic corticosteroids are not allowed. 
Antinauseants 
Y 
N 
Domperidone, droperidol, odansetron 
Antineoplastics 
N 
N 
 
Antiobesity 
N 
N 
 
Antipsychotics 
N 
N 
 
Anxiolytics 
N 
N 
Only rescue medication are allowed; see Section 4.4.2  
Cough/Cold Preparations 
Y 
N 
Use of cough and cold preparations containing 
pseudoephedrine or phenylpropanolamine is not 
permitted. Decongestants containing narcotics are not 
permitted. Dextrometorphan and codeine are not 
authorized 
Diuretics 
N 
Y 
Allowed if stable dose 1 month before enrollment. 
Furosemide, HCTZ not allowed (refer to next table) 
H2-Blockers 
N 
N 
 
Hormones 
N 
Y 
Only 
thyroid 
hormone 
replacement, 
oral 
contraceptives and estrogen replacement therapy are 
allowed. 
Hypoglycemic Agents 
N 
N 
 
Hypolipidemics 
N 
Y 
 
Insulin 
N 
N 
 
Muscle Relaxants 
N 
N 
 
Psychotropic drugs not 
otherwise specified 
(including herbal products) 
N 
N 
No drugs with psychomotor effects or with anxiolytic, 
stimulant, antipsychotic, or sedative properties are 
allowed. 
Sedatives/Hypnotics 
N 
N 
Zolpidem, zopiclone and zaleplon allowed 


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Note: All antihypertensives must be at stable dose >3 months prior to enrollment and must be continued at the 
same dose during the study. 
Key: 
Red: known risk of TdP;  
Blue-bold: possible risk of TdP;  
Black: conditional risk of TdP: e.g., in case of overdose, DDI or electrolytes imbalance. 
 


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Drugs inducing QT prolongation 
CYP 2D6 inhibitors 
CYP 3A4 inhibitors 
Anesthetic 
Sevoflurane 
Propofol 
 
Anticonvulsivants 
Ezogabine (retigabine) 
Felbamate 
 
Anti-histamines 
Diphenhydramine 
Hydroxyzine 
 
Anti-infectives  
Amantadine 
Artenimol+ piperaquine 
Azithromycin 
Bedaquiline 
Chloroquine 
Ciprofloxacin 
Clarithromycin  
Delamanid 
Erythromycin  
Fingolimod 
Garenoxacin 
Gemifloxacin 
Halofantrine  
hydrochloroquine 
Levofloxacin 
norfloxacin 
Metronidazole 
Moxifloxacin 
Ofloxacin 
Quinine 
Roxithromycin 
Telavancin 
Telithromycin 
 
Antifungal 
Amphotericin B 
Fluconazole  
Itraconazole 
Ketoconazole 
Pentamidine 
Posaconazole 
Voriconazole 
Antiviral 
Anti-infectives 
Chloroquine 
Quinacrine 
Cardiovascular 
Amiodarone 
Aprindine 
Mibefradil  
Propafenone 
Labetalol 
Quinidine 
 
Antidepressants 
Amitriptyline 
Citalopram 
Clomipramine 
Doxepin 
Duloxetine 
Escitalopram 
Fluoxetine 
Fluvoxamine 
Paroxetine 
Sertraline 
 
Antipsychotics 
Chlorpromazine 
Fluphenazine 
Haloperidol 
Levomepromazine 
Perphenazine 
Promethazine 
Risperidone (weak) 
Sertindole 
Thioridazine 
 
Others 
Bupropion 
Celecoxib 
Cinacalcet 
Chlorpheniramine  
Cimetidine 
Clemastine 
cocaine 
Codeine 
Delavirdine 
Dextropopoxyphene 
Diltiazem 
Anti-infectives 
Chloramphenicol 
Clarythromycin 
Ciprofloxacin 
Erythromycin 
Norfloxacin 
Telithromycin 
 
Anti-Viral 
Boceprevir 
Delvirdine 
Indinavir 
Nelfinavir 
Ritonavir 
Saquinavir 
Telaprevir 
 
Antifungal 
Fluconazole 
Itraconazole 
Ketoconazole 
Voriconazole 
 
Antidepressants 
Fluvoxamine 
Nefazodone 
Norfluoxetine 
 
Others 
Amiodarone 
Aprepitant 
Cimentidine 
Diltiazem 
Gestodene 
Grapefruit juice 
Imatinib 
Mibefradil 
Mifepristone 
Suboxone 
Verapamil 


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atazanavir 
Efavirenz 
Nelfinavir 
Ritonavir 
Saquinavir 
Telaprevir 
Voriconazole 
 
Cardiovascular:  
 
Antianginal 
Ivabradine 
Ranolazine   
 
Antiarrhythmics  
Amiodarone 
Disopyramide  
Dofetilide 
Dronedarone  
Flecainide 
Ibutilide 
Pilsicainide 
Procainamide  
Quinidine  
Sotalol  
 
Calcium Channel Blockers 
Isradipine 
Nicardipine 
 
Diuretics 
Bendorflumethiazide 
Furosemide 
Hydrochlorothiazide 
Indapamide 
Torasemide 
 
Anti HTA 
ketanserin Moexipril/HCTZ 
 
Cholinesterase inhibitor 
Donepezil 
Galantamine 
 
Psychotropics: 
 
Antidepressants  
Diphenhydramine 
Doxorubicin 
Entacapone (high doses) 
Halofantrine 
Hydroxyzine 
Indinavir 
Imatinib 
Lobelin 
Lomustine 
Methadone 
Moclobemide 
Metoclopramide 
Midodrine 
Moclobemide 
Nortuloxeline 
Ranitidine 
Ritonavir 
Ticlopidine 
Tripelennamine 
Vinblastine 
Vincristine 
Vinorelbine 
Yohimbine 


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Amitriptyline  
Citalopram/escitalopram  
Clomipramine 
cyamepromazine 
Desipramine  
Doxepin 
Imipramine 
Fluoxetine 
Fluvoxamine 
Mirtazapine 
Nortriptyline 
Paroxetine 
Sertraline 
Trazodone 
Trimipramine 
Venlafaxine  
 
Antipsychotics  
Aripiprazole 
Asenapine 
Chlorpromazine 
Clozapine   
Flupentixol 
Haloperidol 
Iloperidone 
levosulpride 
Melperone  
Olanzapine 
paliperidone 
Pimavanserin 
Pipamperone 
Pimozide 
Promethazine 
Prothipendyl 
Perphenazine  
Quetiapine  
Risperidone 
Sertindole 
Sulpiride 
sultopride 
Thioridazine 
ziprasidone 
Zotepine 
 
Antimanic 
Lithium 
 


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Sedative, hypnotics 
Choral hydrate 
Dexmedetomidine 
 
Antiemetics  
Domperidone  
Droperidol  
Ondansetron 
Granisetron/ Dolasetron, 
Tropisetron 
Metoclopramide 
 
Others: 
Phospho-diesterase 3 inhibitor: 
Anagrelide 
cilostazol 
 
Protein kinase inhibitors: Lapatinib, 
Sunitinib, Bosutinib, Ceritinib, 
Crizotinib, Dabrafenib, Dasatinib, 
Lenvatinib, Nilotinib, Osimertinib, 
Pazopanib, Ribociclib, Sorafenib 
Apomorphine 
Alfuzosin 
Atomoxetine 
Capecitabine 
Cocaine 
Degarelix 
Esomeprazole 
Eribulin 
Famotidine 
Hydrocodone 
Ibogaine 
Lanzoprazole 
Leuprolide 
Levomethadyl 
Loperamide 
Methadone  
Mifepristone 
Mirabegron 
Necitumumab 
Nusinersen 
Omeprazole 
Oxytocin 
Pantoprazole 
Panobinostat 
Papaverine 


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Pasireotide 
Romidepsin 
Solifenacin 
Tacrolimus 
Tamoxifen 
Terlipressin 
Terolidine  
Tetrabenazine 
Tiapride 
Tizanidine  
Tolterodine 
Toremifene 
Vandetanib 
Vardenafil 
Vemurafenib 
Vorinostat 


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ATTACHMENT 2: READINESS FOR DISCHARGE QUESTIONNAIRE 
This tool is to be used for research purposes only and should not be utilized in determining 
actual eligibility for discharge 
Note: The items below should be rated independently of social or economic factors. 
 
Please circle your response to each question: 
1) The subject is not actively suicidal or homicidal. 
Strongly Agree 
Agree 
Disagree 
Strongly Disagree 
2) The subject has adequate control over aggression and impulsivity. 
Strongly Agree 
Agree 
Disagree 
Strongly Disagree 
3) The subject has the ability to carry out basic ADLs (Activities of daily living). 
Strongly Agree 
Agree 
Disagree 
Strongly Disagree 
4) The subject has the ability to take medicine independently (from the hospital/medical staff). 
Strongly Agree 
Agree 
Disagree 
Strongly Disagree 
5) The subject's delusions and hallucinations do not significantly interfere with functioning. 
Strongly Agree 
Agree 
Disagree 
Strongly Disagree 
6) Does the subject have a CGI-Severity of ≤ 4? (see below) 
Yes 
No 
 
 
• Rate the patient's CGI-Severity. Considering your total clinical experience with this population, how 
mentally ill is the patient at this time? 
0 = Not assessed 
4 = Moderately ill 
1 = Normal, not mentally ill 
5 = Markedly ill 
2 = Borderline Mentally ill 
6 = Severely ill 
3 = Mildly ill 
7 = Among the most extremely ill patients 
 
• Using the above items as a guide only, please answer the following: 
Based on your clinical judgment of symptomatic improvement, and independent of social or 
economic factors, is this subject ready for discharge? 
 
 
 
 
 
 
 
 
 
 
 
 


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This tool is to be used for research purposes only and should not be utilized in determining 
actual eligibility for discharge 
Note: The items below should be rated independently of social or economic factors. 
 
Please circle your response to each question: 
Yes 
No 
 
 
 
 
 
 
 


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ATTACHMENT 3: ABNORMAL INVOLUNTARY MOVEMENT SCALE (AIMS) 
Public Health Service 
NAME: ______________________________________________ 
Alcohol, Drug Abuse, and Mental Health Administration 
DATE: ______________________________________________ 
National Institute of Mental Health 
Prescribing Practitioner: _______________________________ 
 
CODE: 
0 = None 
 
 
1 = Minimal, may be extreme normal 
INSTRUCTIONS: 
 
2 = Mild 
Complete Examination Procedure (attachment d.) 
 
3 = Moderate 
before making ratings 
 
4 = Severe 
MOVEMENT RATINGS: Rate highest severity observed. Rate 
movements that occur upon activation one less than those observed 
spontaneously. Circle movement as well as code number that applies 
RATER 
Date 
RATER 
Date 
RATER 
Date 
Facial and  
Oral  
Movements 
1. Muscles of Facial Expression 
 
e.g., movements of forehead, eyebrows, 
periorbital area, cheeks, including 
frowning, blinking, smiling, grimacing 
0   1   2   3   4 
0   1   2   3   4 
0   1   2   3   4 
 
2. 
Lips and Perioral Area 
 
e.g., puckering, pouting, smacking 
0   1   2   3   4 
0   1   2   3   4 
0   1   2   3   4 
 
3. 
Jaw e.g., biting, clenching, chewing, 
mouth opening, lateral movement 
0   1   2   3   4 
0   1   2   3   4 
0   1   2   3   4 
 
4. 
Tongue Rate only increases in movement 
both in and out of mouth. NOT inability to 
sustain movement. Darting in and out of 
mouth. 
0   1   2   3   4 
0   1   2   3   4 
0   1   2   3   4 
Extremity 
Movements 
5. 
Upper (arms, wrists, hands, fingers) 
Include choreic movements (i.e., rapid, 
objectively purposeless, irregular, 
spontaneous) athetoid movements 
(i e., slow, irregular, complex, serpentine). 
DO NOT INCLUDE TREMOR 
(i e., repetitive, regular, rhythmic) 
0   1   2   3   4 
0   1   2   3   4 
0   1   2   3   4 
 
6. 
Lower (legs, knees, ankles, toes) 
e.g., lateral knee movement, foot tapping, 
heel dropping, foot squirming, inversion 
and eversion of foot 
0   1   2   3   4 
0   1   2   3   4 
0   1   2   3   4 
Trunk 
Movements 
7. 
Neck, shoulders, hips e.g., rocking, 
twisting, squirming, pelvic gyrations 
0   1   2   3   4 
0   1   2   3   4 
0   1   2   3   4 
Global  
Judgments 
8. 
Severity of abnormal movements overall 
0   1   2   3   4 
0   1   2   3   4 
0   1   2   3   4 
 
9. 
Incapacitation due to abnormal 
movements 
0   1   2   3   4 
0   1   2   3   4 
0   1   2   3   4 
 
10. Patient’s awareness of abnormal 
movements. Rate only patient’s report 
No awareness  
0 
Aware, no distress 
1 
Aware, mild distress 
2 
Aware, moderate distress 
3 
Aware, severe distress 
4 
 
 
0 
       1 
             2 
                    3 
                        4 
 
 
0 
       1 
             2 
                    3 
                        4 
 
 
0 
       1 
             2 
                    3 
                        4 
Dental Status 
11. Current problems with teeth and/or 
dentures? 
No                Yes 
No                Yes 
No                Yes 
 
12. Are dentures usually worn? 
No                Yes 
No                Yes 
No                Yes 


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13. Edentia? 
No                Yes 
No                Yes 
No                Yes 
 
14. Do movements disappear in sleep? 
No                Yes 
No                Yes 
No                Yes 
Final:  9/2000 
 


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ATTACHMENT 4: BARNES AKATHISIA RATING SCALE (BARS) 
Instructions:  Patient should be observed while they are seated, and then standing while 
engaged in neutral conversation (for a minimum of two minutes in each position).  Symptoms 
observed in other situations, for example while engaged in activity on the ward, may also be 
rated.  Subsequently, the subjective phenomena should be elicited by direct questioning.    
Objective  
0 
Normal, occasional fidgety movements of the limbs  
1 
Presence of characteristic restless movements:  shuffling or tramping movements of 
the legs/feet, or swinging of one leg while sitting, and/or rocking from foot to foot or 
“walking on the spot” when standing, but movements present for less than half the 
time observed  
2 
Observed phenomena, as described in (1) above, which are present for at least half the 
observation period  
3 
Patient is constantly engaged in characteristic restless movements, and/or has the 
inability to remain seated or standing without walking or pacing, during the time 
observed  
Subjective  
Awareness of restlessness  
0 
Absence of inner restlessness  
1 
Non-specific sense of inner restlessness  
2 
The patient is aware of an inability to keep the legs still, or a desire to move the legs, 
and/or complains of inner restlessness aggravated specifically by being required to 
stand still  
3 
Awareness of intense compulsion to move most of the time and/or reports strong 
desire to walk or pace most of the time  
Distress related to restlessness  
0 
No distress  
1 
Mild  
2 
Moderate  
3 
Severe  
Global Clinical Assessment of Akathisia  
0 
Absent.  No evidence of awareness of restlessness.  Observation of characteristic 
movements of   akathisia in the absence of a subjective report of inner restlessness or 
compulsive desire to move the legs should be classified as pseudoakathisia  


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1 
Questionable.  Non-specific inner tension and fidgety movements.  
2 
Mild akathisia.  Awareness of restlessness in the legs and/or inner restlessness 
worse when required to stand still.  Fidgety movements present, but characteristic 
restless movements of akathisia not   necessarily observed.  Condition causes little or 
no distress.    
3 
Moderate akathisia.  Awareness of restlessness as described for mild akathisia 
above, combined with characteristic restless movements such as rocking from foot to 
foot when standing.  Patient finds the condition distressing.  
4 
Marked akathisia.  Subjective experience of restlessness includes a compulsive 
desire to walk or pace.  However, the patient is able to remain seated for at least five 
minutes.  The condition is obviously   distressing.    
5 
Severe akathisia.  The patient reports a strong compulsion to pace up and down 
most of the time.    Unable to sit or lie down for more than a few minutes.  Constant 
restlessness which is associated with intense distress and insomnia.    
Scoring the Barnes Akathisia Rating Scale 
The Barnes Akathisia Rating Scale is scored as follows:  
Objective Akathisia, Subjective Awareness of Restlessness and Subjective Distress 
Related to Restlessness are rated on a 4-point scale from 0 – 3 and are summed yielding a 
total score ranging from 0 to 9.    
The Global Clinical Assessment of Akathisia uses a 5-point scale ranging from 0 – 4.    
 
 
 
 
 
 
 
 
 
 
 


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ATTACHMENT 5: POSITIVE AND NEGATIVE SYNDROME SCALE (PANSS) 
POSITIVE AND NEGATIVE SYNDROME SCALE (PANSS) RATING CRITERIA 
GENERAL RATING INSTRUCTIONS 
Data gathered from this assessment procedure are applied to the PANSS ratings. Each of the 30 items 
is accompanied by a specific definition, as well as detailed anchoring criteria for all seven rating points. 
These seven points represent increasing levels of psychopathology, as follows: 
1 – absent 
2 – minimal 
3 – mild 
4 – moderate 
5 – moderate severe 
6 – severe 
7 – extreme 
In assigning ratings, one first considers whether an item is at all present, as judging by its definition. If 
the item is absent, it is scored 1, whereas if it is present, one must determine its severity by reference 
to the particular criteria from the achorning points. The highest applicable rating point is always 
assigned, even if the patient meets criteria for lower points as well. In judging the level of severity, the 
rater must utilise a holistic perspective in deciding which anchoring point best characterises the patient’s 
functioning and rate accordingly, whether or not all elements of the description are observed. 
The rating points of 2 to 7 correspond to incremental levels of symptom severity: 
• 
A rating of 2 (minimal) denotes questionable or subtle or suspected pathology, or it also may 
allude to the extreme end of the normal range. 
 
• 
A rating of 3 (mild) is indicative of a symptom whose presence is clearly established but not 
pronounced and interferes little in day-to-day functioning.  
 
• 
A rating of 4 (moderate) characterises a symptom which, though representing a serious 
problem, either occurs only occasionally or intrudes on daily life only to a moderate extent. 
 
• 
A rating of 5 (moderate severe) indicates marked manifestations that distinctly impact on one’s 
functioning but are not all-consuming and usually can be contained at will. 
 
• 
A rating of 6 (severe) represents gross pathology that is present very frequently, proves highly 
disruptive to one’s life, and often calls for direct supervision. 
 
• 
A rating of 7 (extreme) refers to the most serious level of psychopathology, whereby the 
manifestations drastically interfere in most or all major life functions, typically necessitating 
close supervision and assistance in many areas. 
 
Each item is rated in consultation with the definitions and criteria provided in this manual. The 
ratings are rendered on the PANSS rating form overleaf by encircling the appropriate number 
following each dimension. 
 
 


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PANSS RATING FORM 
 
Absent 
Minimal 
Mild 
Moderate 
Moderate 
severe 
Severe 
Extreme 
 
P1 
Delusions 
1 
2 
3 
4 
5 
6 
7 
P2 
Conceptual disorganization 
1 
2 
3 
4 
5 
6 
7 
P3 
Hallucinatory behaviour 
1 
2 
3 
4 
5 
6 
7 
P4 
Excitement 
1 
2 
3 
4 
5 
6 
7 
P5 
Grandiosity 
1 
2 
3 
4 
5 
6 
7 
P6 
Suspiciousness/persecution 
1 
2 
3 
4 
5 
6 
7 
P7 
Hostility 
1 
2 
3 
4 
5 
6 
7 
 
N1 
Blunted affect 
1 
2 
3 
4 
5 
6 
7 
N2 
Emotional withdrawal 
1 
2 
3 
4 
5 
6 
7 
N3 
Poor rapport 
1 
2 
3 
4 
5 
6 
7 
N4 
Passive/apathetic social 
withdrawal 
1 
2 
3 
4 
5 
6 
7 
N5 
Difficulty in abstract thinking 
1 
2 
3 
4 
5 
6 
7 
N6 
Lack of spontaneity & flow 
of conversation 
1 
2 
3 
4 
5 
6 
7 
N7 
Stereotyped thinking 
1 
2 
3 
4 
5 
6 
7 
 
G1 
Somatic concern 
1 
2 
3 
4 
5 
6 
7 
G2 
Anxiety 
1 
2 
3 
4 
5 
6 
7 
G3 
Guilt feelings 
1 
2 
3 
4 
5 
6 
7 
G4 
Tension 
1 
2 
3 
4 
5 
6 
7 
G5 
Mannerisms & posturing 
1 
2 
3 
4 
5 
6 
7 
G6 
Depression 
1 
2 
3 
4 
5 
6 
7 
G7 
Motor retardation 
1 
2 
3 
4 
5 
6 
7 
G8 
Uncooperativeness 
1 
2 
3 
4 
5 
6 
7 
G9 
Unusual thought content 
1 
2 
3 
4 
5 
6 
7 
G10 
Disorientation 
1 
2 
3 
4 
5 
6 
7 
G11 
Poor attention 
1 
2 
3 
4 
5 
6 
7 
G12 
Lack of judgment & insight 
1 
2 
3 
4 
5 
6 
7 
G13 
Disturbance of volition 
1 
2 
3 
4 
5 
6 
7 
G14 
Poor impulse control 
1 
2 
3 
4 
5 
6 
7 
G15 
Preoccupation 
1 
2 
3 
4 
5 
6 
7 
G16 
Active social avoidance 
1 
2 
3 
4 
5 
6 
7 


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SCORING INSTRUCTIONS 
 
Of the 30 items included in the PANSS, 7 constitute a Positive Scale, 7 a Negative Scale, and the 
remaining 16 a General Psychopathology Scale. The scores for these scales are arrived at by 
summaries of ratings across component items. Therefore, the potential ranges are 7 to 49 for the 
Positive and Negative Scales, and 16 to 112 for the General Psychopathology Scale. In addition 
to these measures, a Composite Scale is scored by subtracting the negative score from the 
positive score. This yields a bipolar index that ranges from -42 to +42, which is essentially a 
difference score reflecting the degree of predominance of one syndrome in relation to the other. 
 
 
POSITIVE SCALE (P) 
P1. 
DELUSIONS – Beliefs which are unfounded, unrealistic, and idiosyncratic. 
 
Basis for rating – Thought content expressed in the interview and its influence on social relations and 
behaviour. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Presence of one or two delusions which are vague, uncrystallised and not tenaciously held. 
Delusions do not interfere with thinking, social relations or behaviour. 
 
4 
Moderate – Presence of either a kaleidoscopic array of poorly formed, unstable delusions or a few well-
formed delusions that occasionally interfere with thinking, social relations or behaviour. 
 
5 
Moderate Severe – Presence of numerous well-formed delusions that are tenaciously held and 
occasionally interfere with thinking, social relations and behaviour. 
 
6 
Severe – Presence of a stable set of delusions which are crystallised, poss bly systematized, tenaciously 
held and clearly interfere with thinking, social relations and behaviour. 
 
7 
Extreme – Presence of a stable set of delusions which are either highly systematized or very numerous, 
and which dominate major facets of the patient’s life. This frequently results in inappropriate and 
irresponsible action, which may even jeopardise the safety of the patient or others. 
 
 
 
P2. 
CONCEPTUAL DISORGANISATION – Disorganised process of thinking characterized by disruption of goal-directed 
sequencing, e.g., circumstantiality, loose associations, tangentiality, gross illogicality or thought block. 
 
Basis for rating – Cognitive-verbal processes observed during the course of interview. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Thinking is circumstantial, tangential or paralogical. There is some difficulty in directing thoughts 
towards a goal, and some loosening of associations may be evidenced under pressure. 
 
4 
Moderate – Able to focus thoughts when communications are brief and structured, but becomes loose or 
irrelevant when dealing with more complex communications or when under minimal pressure. 
 
5 
Moderate Severe – Generally has difficulty in organizing thoughts, as evidenced by frequent irrelevancies, 
disconnectedness or loosening of associations even when not under pressure. 
 
6 
Severe – Thinking is seriously derailed and internally inconsistent, resulting in gross irrelevancies and 
disruption of thought processes, which occur almost constantly. 
 
7 
Extreme – Thoughts are disrupted to the point where the patient is incoherent. There is marked loosening 
of associations, which result in total failure of communication, e.g., “word salad” or mutism. 
 
 


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P3. 
HALLUCINATORY BEHAVIOR – Verbal report or behavior indicating perceptions which are not generated by 
external stimuli. These may occur in the auditory, visual, olfactory or somatic realms. 
 
Basis for rating – Verbal report and physical manifestations during the course of interview as well as reports of 
behaviour by primary care workers or family. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – One or two clearly formed but infrequent hallucinations, or else a number of vague abnormal 
perceptions which do not result in distortions of thinking or behaviour. 
 
4 
Moderate – Hallucinations occur frequently but not continuously, and the patient’s thinking and behaviour 
are only affected to a minor extent. 
 
5 
Moderate Severe – Hallucinations occur frequently, may involve more than one sensory modality, and 
tend to distort thinking and/or disrupt behaviour. Patient may have a delusional interpretation of these 
experiences and respond to them emotionally and, on occasion, verbally as well. 
 
6 
Severe – Hallucinations are present almost continuously, causing major disruption of thinking and 
behaviour. Patient treats these as real perceptions, and functioning is impeded by frequent emotional and 
verbal responses to them. 
 
7 
Extreme – Patient is almost totally preoccupied with hallucinations, which virtually dominate thinking and 
behaviour. Hallucinations are provided a rigid interpretation and provoke verbal and behavioural 
responses, including obedience to command hallucinations. 
 
 
 
P4. 
EXCITEMENT – Hyperactivity as reflected in accelerated motor behaviour, heightened responsivity to stimuli, 
hypervigilance or excessive mood lability. 
 
Basis for rating – Behavioural manifestations during the course of interview as well as reports of behaviour by 
primary care workers or family. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Tends to be slightly agitated, hypervigilant or mildly overaroused throughout the interview, but 
without distinct episodes of excitement or marked mood lability. Speech may be slightly pressured. 
 
4 
Moderate – Agitation or overarousal is clearly evident throughout the interview, affecting speech and 
general mobility, or episodic outbursts occur sporadically. 
 
5 
Moderate Severe – Significant hyperactivity or frequent outbursts of motor activity are observed, making it 
difficult for the patient to sit still for longer than several minutes at any given time. 
 
6 
Severe – Marked excitement dominates the interview, delimits attention, and to some extent affects 
personal functions such as eating or sleeping. 
 
7 
Extreme – Marked excitement seriously interferes in eating and sleeping and makes interpersonal 
interactions virtually impossible. Acceleration of speech and motor activity may result in incoherence and 
exhaustion. 
 
 
 
P5. 
GRANDIOSITY – Exaggerated self-opinion and unrealistic convictions of superiority, including delusions of 
extraordinary abilities, wealth, knowledge, fame, power and moral righteousness. 
 
Basis for rating – Thought content expressed in the interview and its influence on behaviour. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Some expansiveness or boastfulness is evident, but without clear-cut grandiose delusions. 
 
4 
Moderate – Feels distinctly and unrealistically superior to others. Some poorly formed delusions about 
special status or abilities may be present but are not acted upon. 
 
5 
Moderate Severe – Clear-cut delusions concerning remarkable abilities, status or power are expressed 
and influence attitude but not behaviour. 
 
6 
Severe – Clear-cut delusions of remarkable superiority involving more than one parameter (wealth, 
knowledge, fame, etc.) are expressed, notably influence interactions and may be acted upon. 
 
7 
Extreme – Thinking interactions and behaviour are dominated by multiple delusions of amazing ability, 
wealth, knowledge, fame, power and/or moral stature, which may take on a bizarre quality. 
 
 


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P6. 
SUSPICIOUSNESS/PERSECUTION – Unrealistic or exaggerated ideas of persecution, as reflected in guardedness, 
and distrustful attitude, suspicious hypervigilance or frank delusions that others mean harm. 
 
Basis for rating – Thought content expressed in the interview and its influence on behaviour. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Presents a guarded or even openly distrustful attitude, but thoughts, interactions and behaviour are 
minimally affected. 
 
4 
Moderate – Distrustfulness is clearly evident and intrudes on the interview and/or behaviour, but there is 
no evidence of persecutory delusions. Alternatively, there may be indication of loosely formed persecutory 
delusions, but these do not seem to affect the patient’s attitude or interpersonal relations. 
 
5 
Moderate Severe – Patient shows marked distrustfulness, leading to major disruption of interpersonal 
relations, or else there are clear-cut persecutory delusions that have limited impact on interpersonal 
relations and behaviour. 
 
6 
Severe – Clear-cut pervasive delusions of persecution which may be systematized and significantly 
interfere in interpersonal relations. 
 
7 
Extreme – A network of systematized persecutory delusions dominates the patient’s thinking, social 
relations and behaviour. 
 
 
 
P7. 
HOSTILITY – Verbal and nonverbal expressions of anger and resentment, including sarcasm, passive-aggressive 
behaviour, verbal abuse and assaultiveness. 
 
Basis for rating – Interpersonal behaviour observed during the course of interview and reports by primary care 
workers or family. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Indirect or restrained communication of anger, such as sarcasm, disrespect, hostile expressions 
and occasional irritability. 
 
4 
Moderate – Presents an overtly hostile attitude, showing frequent irritability and direct expression of anger 
or resentment. 
 
5 
Moderate Severe – Patient is highly irritable and occasionally verbally abusive or threatening. 
 
6 
Severe – Uncooperativeness and verbal abuse or threats notably influence the interview and seriously 
impact upon social relations. Patient may be violent and destructive but is not physically assaultive towards 
them. 
 
7 
Extreme – Marked anger results in extreme uncooperativeness, precluding other interactions, or in 
episode(s) of physical assault towards others. 
NEGATIVE SCALE (N) 
N1. 
BLUNTED AFFECT – Diminished emotional responsiveness as characterized by a reduction in facial expression, 
modulation of feelings and communicative gestures. 
 
Basis for rating – Observation of physical manifestations of affective tone and emotional responsiveness 
during the course of interview. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Changes in facial expression and communicative gestures seem to be stilted, forced, artificial or 
lacking in modulation. 
 
4 
Moderate – Reduced range of facial expression and few expressive gestures result in a dull appearance. 
 
5 
Moderate Severe – Affect is generally ‘flat’ with only occasional changes in facial expression and a paucity 
of communicative gestures. 
 
6 
Severe – Marked flatness and deficiency of emotions exhibited most of the time. There may be 
unmodulated extreme affective discharges, such as excitement, rage or inappropriate uncontrolled 
laughter. 
 
7 
Extreme – Changes in facial expression and evidence of communicative gestures are virtually absent. 
Patient seems constantly to show a barren or ‘wooden’ expression. 
 
 
 


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N2. 
EMOTIONAL WITHDRAWAL – Lack of interest in, involvement with, and affective commitment to life’s events. 
 
Basis for rating – Reports of functioning from primary care workers or family and observation of interpersonal 
behaviour during the course of the interview. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Usually lack initiative and occasionally may show deficient interest in surrounding events. 
 
4 
Moderate – Patient is generally distanced emotionally from the milieu and its challenges but, with 
encouragement, can be engaged. 
 
5 
Moderate Severe – Patient is clearly detached emotionally from persons and events in the milieu, resisting 
all efforts of engagement. Patient appears distant, docile, and purposeless, but can be involved in 
communication at least briefly and tends to personal needs, sometimes with assistance. 
 
6 
Severe – Marked deficiency of interest and emotional commitment results in limited conversation with 
others and frequent and frequent neglect of personal functions, for which the patient requires supervision. 
 
7 
Extreme – Patient is almost totally withdrawn, uncommunicative and neglectful of personal needs as a 
result of profound lack of interest and emotional commitment. 
 
 
 
N3. 
POOR RAPPORT – Lack of interpersonal empathy, openness in conversation and sense of closeness, interest or 
involvement with the interviewer. This is evidenced by interpersonal distancing and reduced verbal and 
nonverbal communication. 
 
Basis for rating – Interpersonal behaviour during the course of interview. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Conversation is characterized by a stilted, strained or artificial tone. It may lack emotional depth or 
tend to remain on an impersonal, intellectual plane. 
 
4 
Moderate – Patient typically is aloof, with interpersonal distance quite evident. Patient may answer 
questions mechanically, act bored or express disinterest. 
 
5 
Moderate Severe – Disinvolvement is obvious and clearly impedes the productivity of the interview. 
Patient may tend to avoid eye or face contact. 
 
6 
Severe – Patient is highly indifferent, with marked interpersonal distance. Answers are perfunctory, and 
there is little nonverbal evidence of involvement. Eye and face contact are frequently avoided. 
 
7 
Extreme – Patient is totally uninvolved with the interviewer. Patient appears to be completely indifferent 
and consistently avoids verbal and nonverbal interactions during the interview. 
 
N4. 
PASSIVE/APATHETIC SOCIAL WITHDRAWAL – Diminished interest and initiative in social interactions due to passivity, 
apathy, anergy or avolition. This leads to reduced interpersonal involvements and neglect of activities or daily 
living. 
 
Basis for rating – Reports on social behaviour from primary care workers or family. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Shows occasional interest in social activities but poor initiative. Usually engages with others only when 
approached first by them. 
 
4 
Moderate – Passively goes along with most social activities but in a disinterested or mechanical way. Tends 
to recede into the background. 
 
5 
Moderate Severe – Passively participates in only a minority of activities and shows virtually no interest or 
initiative. Generally spends little time with others. 
 
6 
Severe – Tends to be apathetic and isolated, participating very rarely in social activities and occasionally 
neglecting personal needs. Has very few spontaneous social contacts. 
 
7 
Extreme – Profoundly apathetic, socially isolated and personally neglectful. 
 


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N5. 
DIFFICULTY IN ABSTRACT THINKING – Impairment in the use of abstract-symbolic mode of thinking, as evidence 
by difficulty in classification, forming generalisations and proceeding beyond concrete or egocentric thinking in 
problem-solving tasks. 
 
Basis for rating – Responses to questions on similarities and proverb interpretation, and use of concrete vs. 
abstract mode during the course of the interview. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Tends to give literal or personalized interpretations to the more difficult proverbs and may have 
some problems with concepts that are fairly abstract or remotely related. 
 
4 
Moderate – Often utilizes a concrete mode. Has difficulty with most proverbs and some categories. Tends 
to be distracted by functional aspects and salient features. 
 
5 
Moderate Severe – Deals primarily in a concrete mode, exhibiting difficulty with most proverbs and many 
categories. 
 
6 
Severe – Unable to grasp the abstract meaning of any proverbs or figurative expressions and can 
formulate classifications for only the most simple of similarities. Thinking is either vacuous or locked into 
functional aspects, salient features and idiosyncratic interpretations. 
 
7 
Extreme – Can use only concrete modes of thinking. Shows no comprehension of proverbs, common 
metaphors or similes, and simple categories. Even salient and functional attributes do not serve as a basis 
for classification. This rating may apply to those who cannot interact even minimally with the examiner due 
to marked cognitive impairment. 
 
 
 
N6. 
LACK OF SPONTANEITY AND FLOW OF CONVERSATION – Reduction in the normal flow of communication 
associated with apathy, avolition, defensiveness or cognitive deficit. This is manifested by diminished fluidity 
and productivity of the verbal interactional process. 
 
Basis for rating – Cognitive-verbal processes observed during the course of interview. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Conversation shows little initiative. Patient’s answers tend to be brief and unembellished, requiring 
direct and leading questions by the interviewer. 
 
4 
Moderate – Conversation lacks free flow and appears uneven or halting. Leading questions are frequently 
needed to elicit adequate responses and proceed with conversation. 
 
5 
Moderate Severe – Patient shows a marked lack of spontaneity and openness, replying to the 
interviewer’s questions with only one or two brief sentences. 
 
6 
Severe – Patient’s responses are limited mainly to a few words or short phrases intended to avoid or 
curtail communication. (e.g., “I don’t know”, “I’m not at liberty to say”). Conversation is seriously impaired 
as a result and the interview is highly unproductive. 
 
7 
Extreme – Verbal output is restricted to, at most, an occasional utterance, making conversation not 
possible. 
 
N7. 
STEREOTYPED THINKING – Decreased fluidity, spontaneity and flexibility of thinking, as evidenced in rigid, repetitious 
or barren thought content. 
 
Basis for rating – Cognitive-verbal processes observed during the interview. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Some rigidity shown in attitude or beliefs. Patient may refuse to consider alternative positions or have 
difficulty in shifting from one idea to another. 
 
4 
Moderate – Conversation revolves around a recurrent theme, resulting in difficulty in shifting to a new topic. 
 
5 
Moderate Severe – Thinking is rigid and repetitious to the point that, despite the interviewer’s efforts, 
conversation is limited to only two or three dominating topics. 
 
6 
Severe – Uncontrolled repetition of demands, statements, ideas or questions which severely impairs 
conversation. 
 
7 
Extreme – Thinking, behaviour and conversation are dominated by constant repetition of fixed ideas or limited 
phrases, leading to gross rigidity, inappropriateness and restrictiveness of patient’s communication. 
 
 


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GENERAL PSYCHOPATHOLOGY SCALE (G) 
G1. 
SOMATIC CONCERN – Physical complaints or beliefs about bodily illness or malfunctions. This may range from a 
vague sense of ill being to clear-cut delusions of catastrophic physical disease. 
 
Basis for rating – Thought content expressed in the interview. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Distinctly concerned about health or bodily malfunction, but there is no delusional conviction and 
overconcern can be allayed by reassurance. 
 
4 
Moderate – Complaints about poor health or bodily malfunction, but there is no delusional conviction, and 
overconcern can be allayed by reassurance. 
 
5 
Moderate Severe – Patient expresses numerous or frequent complaints about physical illness or bodily 
malfunction, or else patient reveals one or two clear-cut delusions involving these themes but is not 
preoccupied by them. 
 
6 
Severe – Patient is preoccupied by one or a few clear-cut delusions about physical disease or organic 
malfunction, but affect is not fully immersed in these themes, and thoughts can be diverted by the 
interviewer with some effort. 
 
7 
Extreme – Numerous and frequently reported somatic delusions, or only a few somatic delusions of a 
catastrophic nature, which totally dominate the patient’s affect or thinking. 
 
 
 
G2. 
ANXIETY – Subjective experience of nervousness, worry, apprehension or restlessness, ranging from excessive 
concern about the present or future to feelings of panic. 
 
Basis for rating – Verbal report during the course of the interview and corresponding physical manifestations. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Expresses some worry, overconcern or subjective restlessness, but no somatic and behavioural 
consequences are reported or evidenced. 
 
4 
Moderate – Patient reports distinct symptoms of nervousness, which are reflected in mild physical 
manifestations such as fine hand tremor and excessive perspiration. 
 
5 
Moderate Severe – Patient reports serious problems of anxiety which have significant physical and 
behavioural consequences, such as marked tension, poor concentration, palpitations or impaired sleep. 
 
6 
Severe – Subjective state of almost constant fear associated with phobias, marked restlessness or 
numerous somatic manifestations. 
 
7 
Extreme – Patient’s life is seriously disrupted by anxiety, which is present almost constantly and at times 
reaches panic proportion or is manifested in actual panic attacks. 
 
G3. 
GUILT FEELINGS – Sense of remorse or self-blame for real or imagined misdeeds in the past. 
 
Basis for rating – Verbal report of guilt feelings during the course of interview and the influence on attitudes and 
thoughts. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Questioning elicits a vague sense of guilt or self-blame for a minor incident, but the patient clearly is 
not overly concerned. 
 
4 
Moderate – Patient expresses distinct concern over his responsibility for a real incident in his life but is not 
pre-occupied with it and attitude and behaviour are essentially unaffected. 
 
5 
Moderate Severe – Patient expresses a strong sense of guilt associated with self-depreciation or the belief 
that he deserves punishment. The guilt feelings may have a delusional basis, may be volunteered 
spontaneously, may be a source of preoccupation and/or depressed mood, and cannot be allayed readily by 
the interviewer. 
 
6 
Severe – Strong ideas of guilt take on a delusional quality and lead to an attitude of hopelessness or 
worthlessness. The patient believes he should receive harsh sanctions such as punishment. 
 
7 
Extreme – Patient’s life is dominated by unshakable delusions or guilt, for which he feels deserving of drastic 
punishment, such as life imprisonment, torture, or death. There may be associated suicidal thoughts of 
attribution of others’ problems to one’s own past misdeeds. 


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G4. 
TENSION – Overt physical manifestations of fear, anxiety, and agitation, such as stiffness, tremor, profuse 
sweating and restlessness. 
 
Basis for rating – Thought content expressed in the interview. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Posture and movements indicate slight apprehensiveness, such as minor rigidity, occasional 
restlessness, shifting of positions, or fine rapid hand tremor. 
 
4 
Moderate – A clearly nervous appearance emerges from various manifestations, such as fidgety 
behaviour, obvious hand tremor, excessive perspiration, or nervous mannerisms. 
 
5 
Moderate Severe – Pronounced tension is evidenced by numerous manifestations, such as nervous 
shaking, profuse sweating and restlessness, but conduct in the interview is not significantly affected. 
 
6 
Severe – Pronounced tension to the point that interpersonal interactions are disrupted. The patient, for 
example, may be constantly fidgeting, unable to sit still for long, or show hyperventilation. 
 
7 
Extreme – Marked tension is manifested by signs of panic or gross motor acceleration, such as rapid 
restless pacing and inability to remain seated for longer than a minute, which makes sustained 
conversation not possible. 
 
 
 
G5. 
MANNERISMS AND POSTURING – Unnatural movements or posture as characterized by an awkward, stilted, 
disorganised, or bizarre appearance. 
 
Basis for rating – Verbal report during the course of the interview and corresponding physical manifestations. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Slight awkwardness in movements or minor rigidity of posture. 
 
4 
Moderate – Movements are notably awkward or disjointed, or an unnatural posture is maintained for brief 
periods. 
 
5 
Moderate Severe – Occasional bizarre rituals or contorted posture are observed, or an abnormal position 
is sustained for extended periods. 
 
6 
Severe – Frequent repletion of bizarre rituals, mannerisms or stereotyped movements, or a controlled 
posture is sustained for extended periods. 
 
7 
Extreme – Functioning is seriously impaired by virtually constant involvement in ritualistic, manneristic, or 
stereotyped movements or by an unnatural fixed posture which is sustained most of the time. 
 
G6. 
DEPRESSION – Feelings of sadness, discouragement, helplessness and pessimism. 
 
Basis for rating – Verbal report of depressed mood during the course of interview and its observed influence on 
attitudes and behaviour. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Expresses some sadness or discouragement only on questioning, but there is no evidence of 
depression in general attitude or demeanor. 
 
4 
Moderate – Distinct feelings of sadness or hopelessness, which may be spontaneously divulged, but 
depressed mood has no major impact on behaviour or social functioning and the patient usually can be 
cheered up. 
 
5 
Moderate Severe – Distinctly depressed mood is associated with obvious sadness, pessimism, loss of social 
interest, psychomotor retardation and some interference in appetite and sleep. The patient cannot be easily 
cheered up. 
 
6 
Severe – Markedly depressed mood is associated with sustained feelings of misery, occasional crying, 
hopelessness and worthlessness. In addition, there is major interference in appetite and/or sleep as well as in 
normal motor and social functions, with possible signs of self-neglect. 
 
7 
Extreme – Depressive feelings seriously interfere in most major functions. The manifestations include 
frequent crying, pronounced somatic symptoms, impaired concentration, psychomotor retardation, social 
disinterest, self neglect, possible depressive or nihilistic delusions and/or possible suicidal thoughts or action. 
 


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G7. 
MOTOR RETARDATION – Reduction in motor activity as reflected in slowing or lessening or movements and 
speech, diminished responsiveness of stimuli, and reduced body tone. 
 
Basis for rating – Manifestations during the course of interview as well as reports by primary care workers as 
well as family. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Slight but noticeable diminution in rate of movements and speech. Patient may be somewhat 
underproductive in conversation and gestures. 
 
4 
Moderate – Patient is clearly slow in movements, and speech may be characterized by poor productivity 
including long response latency, extended pauses or slow pace. 
 
5 
Moderate Severe – A marked reduction in motor activity renders communication highly unproductive or 
delimits functioning in social and occupational situations. Patient can usually be found sitting or lying down. 
 
6 
Severe – Movements are extremely slow, resulting in a minimum of activity and speech. Essentially the 
day is spent sitting idly or lying down. 
 
7 
Extreme – Patient is almost completely immobile and virtually unresponsive to external stimuli. 
 
 
 
G8. 
UNCOOPERATIVENESS – Activity refusal to comply with the will of significant others, including the interviewer, 
hospital staff or family, which may be associated with distrust, defensiveness, stubbornness, negativism, 
rejection of authority, hostility or belligerence. 
 
Basis for rating – Verbal report during the course of the interview and corresponding physical manifestations. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Complies with an attitude of resentment, impatience, or sarcasm. May offensively object to sensitive 
probing during the interview. 
 
4 
Moderate – Occasional outright refusal to comply with normal social demands, such as making own bed, 
attending scheduled programs, etc. The patient may project a hostile, defensive or negative attitude but 
usually can be worked with. 
 
5 
Moderate Severe – Patient frequently is incompliant with the demands of his milieu and may be 
characterized by others as an “outcast” or having “a serious attitude problem”. Uncooperativeness is 
reflected in obvious defensiveness or irritability with the interviewer and possible unwillingness to address 
many questions. 
 
6 
Severe – Patient is highly uncooperative, negativistic and possibly also belligerent. Refuses to comply with 
most social demands and may be unwilling to initiate or conclude the full interview. 
 
7 
Extreme – Active resistance seriously impacts on virtually all major areas of functioning. Patient may 
refuse to join in any social activities, tend to personal hygiene, converse with family or staff and participate 
even briefly in an interview. 
 
G9. 
UNUSUAL THOUGHT CONTENT – Thinking characterized by strange, fantastic or bizarre ideas, ranging from those 
which are remote or atypical to those which are distorted, illogical and patently absurd. 
 
Basis for rating – Thought content expressed during the course of interview. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Thought content is somewhat peculiar, or idiosyncratic, or familiar ideas are framed in an odd context. 
 
4 
Moderate – Ideas are frequently distorted and occasionally seem quite bizarre. 
 
5 
Moderate Severe – Patient expresses many strange and fantastic thoughts, (e.g., Being the adopted son of a 
king, being an escapee from death row), or some which are patently absurd (e.g., Having hundreds of 
children, receiving no radio message from outer space from a tooth filling). 
 
6 
Severe – Patient expresses many illogical or absurd ideas or some which have a distinctly bizarre quality 
(e.g., having three heads, being a visitor from another planet. 
 
7 
Extreme – Thinking is replete with absurd, bizarre and grotesque ideas. 
 
 
 


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G10. 
DISORIENTATION – Lack of awareness of one’s relationship to the milieu, including persons, place and time, 
which may be due to confusion or withdrawal. 
 
Basis for rating – Responses to interview questions on orientation. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – General orientation is adequate but there is some difficulty with specifics. For example, patient 
knows his location but not the street address, knows hospital staff names but not their functions, knows 
the month but confuses the day of the week with an adjacent day, or errs in the date by more than two 
days. There may be narrowing of interest evidenced by familiarity with the immediate but not extended 
milieu, such as ability to identify staff but not the mayor, governor, or president. 
 
4 
Moderate – Only partial success in recognizing persons, places, and time. For example, patient knows he 
is in a hospital but not its name, knows the name of the city but not the borough or distinct, knows the 
name of his primary therapist but not many other direct care workers, knows the year or season but not 
sure of the month. 
 
5 
Moderate Severe – Considerable failure in recognizing persons, place and time. Patient has only a vague 
notion of where he is and seems unfamiliar with most people in his milieu. He may identify the year 
correctly or nearly but not know the current month, day of week or even the season. 
 
6 
Severe – Marked failure in recognizing persons, place, and time. For example, patient has no knowledge 
of his whereabouts, confuses the date by more than one year, can name only one or two individuals in this 
current life. 
 
7 
Extreme – Patient appears completely disoriented with regard to persons, place, and time. There is gross 
confusion or total ignorance about one’s location, the current year and even the most familiar people, such 
as parents, spouse, friends, and primary therapist. 
 
 
 
G11. 
POOR ATTENTION – Failure in focused alertness manifested by poor concentration, distractibility for internal and 
external stimuli, and difficulty in harnessing, sustaining or shifting focus to new stimuli. 
 
Basis for rating – Manifestations during the course of interview. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Limited concentration evidenced by occasional vulnerability to distraction and faltering attention 
toward the end of the interview. 
 
4 
Moderate – Conversation is affected by the tendency to be easily distracted, difficulty in long sustaining 
concentration on a given topic, or problems in shifting attention to new topics. 
 
5 
Moderate Severe – Conversation is seriously hampered by poor concentration, distractibility, and difficulty 
in shifting focus appropriately. 
 
6 
Severe – Patient’s attention can be harnessed for only brief moments or with great effort, due to marked 
distraction by internal or external stimuli. 
 
7 
Extreme – Attention is so disrupted that even brief conversation is not possible. 
 
 
 


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G12. 
LACK OF JUDGMENT AND INSIGHT– Impaired awareness or understanding of one’s own psychiatric condition and life 
situation. This is evidenced by failure to recognize past or present psychiatric illness or symptoms, denial of need 
for psychiatric hospitalization or treatment, decisions characterized by poor anticipation or consequences, and 
unrealistic short-term and long-range planning. 
 
Basis for rating – Thought content expressed during the interview. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Recognises having a psychiatric disorder but clearly underestimates its seriousness, the implications 
for treatment, or the importance of taking measures to avoid relapse. Future planning may be poorly 
conceived. 
 
4 
Moderate – Patient shows only a vague or shallow recognition of illness. There may be fluctuations in 
acknowledgement of being ill or little awareness of major symptoms which are present, such as delusions, 
disorganised thinking, suspiciousness and social withdrawal. The patient may rationalize the need for 
treatment in terms of its relieving lesser symptoms, such as anxiety, tension and sleep difficulty. 
 
5 
Moderate Severe – Acknowledges past but not present psychiatric disorder. If challenged, the patient may 
concede the presence of some unrelated or insignificant symptoms, which tend to be explained away by 
gross misinterpretation or delusional thinking. The need for psychiatric treatment similarly goes unrecognized. 
 
6 
Severe – Patient denies ever having had a psychiatric disorder. He disavows the presence of any psychiatric 
symptoms in the past or present and, though compliant, denies the need for treatment and hospitalization. 
 
7 
Extreme – Emphatic denial of past and present psychiatric illness. Current hospitalization and treatment are 
given a delusional interpretation (e.g., as punishment for misdeeds, as persecution by tormentors, etc.), and 
the patient thus refuses to cooperate with therapists, medication or other aspects of treatment. 
 
G13. 
DISTURBANCE OF VOLITION – Disturbance in the willful initiation, sustenance and control of one’s thoughts, 
behaviour, movements, and speech 
 
Basis for rating – Thought content and behaviour manifested in the course of interview. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – There is evidence of some indecisiveness in conversation and thinking, which may impede verbal 
and cognitive processes to a minor extent. 
 
4 
Moderate – Patient is often ambivalent and shows clear difficulty in reaching decisions. Conversation may 
be marred by alteration in thinking, and in consequence, verbal and cognitive functioning is clearly 
impaired. 
 
5 
Moderate Severe – Disturbance of volition interferes in thinking as well as behaviour. Patient shows 
pronounced indecision that impedes the initiation and continuation of social and motor activities, and 
which also may be evidenced in halting speech. 
 
6 
Severe – Disturbance of volition interferes in the execution of simple automatic motor functions, such as 
dressing or grooming, and markedly affects speech. 
 
7 
Extreme – Almost complete failure of volition is manifested by gross inh bition of movement and speech 
resulting in immobility and/or mutism. 
 
 


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G14. 
POOR IMPULSE CONTROL – Disordered regulation and control of action on inner urges, resulting in sudden, 
unmodulated, arbitrary or misdirected discharge of tension and emotions without concern about consequences. 
 
Basis for rating – Behaviour during the course of interview and reported by primary care workers or family. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Patient tends to be easily angered and frustrated when facing stress or denied gratification but 
rarely acts on impulse. 
 
4 
Moderate – Patient gets angered and verbally abusive with minimal provocation. May be occasionally 
threatening, destructive, or have one or two episodes involving physical confrontation or a minor brawl. 
 
5 
Moderate Severe – Patient exh bits repeated impulsive episodes involving verbal abuse, destruction of 
property, or physical threats. There may be one or two episodes involving serious assault, for which the 
patient requires isolation, physical restraint, or PRN sedation. 
 
6 
Severe – Patient frequently impulsive aggressive, threatening, demanding, and destructive, without any 
apparent consideration of consequences. Shows assaultive behaviour and may also be sexually offensive 
and possibly respond behaviourally to hallucinatory commands. 
 
7 
Extreme – Patient exhibits homicidal, sexual assaults, repeated brutality, or self-destructive behaviour. 
Requires constant direct supervision or external constraints because of inability to control dangerous 
impulses. 
G15. 
PREOCCUPATION – Absorption with internally generated thoughts and feelings and with autistic experiences to the 
detriment of reality orientation and adaptive behaviour. 
 
Basis for rating – Interpersonal behaviour observed during the course of interview. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Excessive involvement with personal needs or problems, such that conversation veers back to 
egocentric themes and there is diminished concern exhibited toward others. 
 
4 
Moderate – Patient occasionally appears self-absorbed, as if daydreaming or involved with internal 
experiences, which interferes with communication to a minor extent. 
 
5 
Moderate Severe – Patient often appears to be engaged in autistic experiences, as evidence by behaviours 
that significantly intrude on social and communicational functions, such as the presence of a vacant stare, 
muttering or talking to oneself, or involvement with stereotyped motor patterns. 
 
6 
Severe – Marked preoccupation with autistic experiences, which seriously delimits concentration, ability to 
converse, and orientation to the milieu. The patient frequently may be observed smiling, laughing, muttering, 
talking, or shouting to himself. 
 
7 
Extreme – Gross absorption with autistic experiences, which profoundly affects all major realms of behaviour. 
The patient constantly may be responding verbally or behaviourally to hallucinations and show little 
awareness of other people or the external milieu. 
G16. 
ACTIVE SOCIAL AVOIDANCE – Diminished social involvement associated with unwarranted fear, hostility, or distrust. 
 
Basis for rating – Reports of social functioning from primary care workers or family. 
 
1 
Absent – Definition does not apply 
 
2 
Minimal – Questionable pathology; may be a the upper extreme of normal limits 
 
3 
Mild – Patient seems ill at ease in the presence of others and prefers to spend time alone, although he 
participates in social functions when required. 
 
4 
Moderate – Patient begrudgingly attends all or most social activities but may need to be persuaded or may 
terminate prematurely on account of anxiety, suspiciousness, or hostility. 
 
5 
Moderate Severe – Patient fearfully or angrily keeps away from many social interactions despite others’ 
efforts to engage him. Tends to spend unstructured time alone. 
 
6 
Severe – Patient participates in very few social activities because of fear, hostility, or distrust. When 
approached, the patient shows a strong tendency to break off interactions, and generally he tends to isolate 
himself from others. 
 
7 
Extreme – Patient cannot be engaged in social activities because of pronounced fears, hostility, or 
persecutory delusions. To the extent possible, he avoids all interactions and remains isolated from others. 
 
 
 
 


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Amendment 2, 26 September 2018 
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ATTACHMENT 6: PERSONAL AND SOCIAL PERFORMANCE SCALE 
Please rate the patient on his/her level of functioning during the reference period (e.g., past month or 
last 7 days). Consider what the person is doing, taking into account if she needs help or prompting by 
others. 
The four main domains of functioning considered in this scale are (a) personal and social relationships; 
(b) socially useful activities, including work and study; (c) self-care; and (d) disturbing and aggressive 
behaviors. 
In each area, consider the worst behavior observed in the reference period. One difficulty is that areas 
a, b, and c include more subareas. In this case, give the score corresponding to the subarea where the 
worst functioning would be rated with the lowest degree of severity score 0–6 (see below). For area a, 
subareas are work or study and other socially useful activities (e.g., housework, voluntary work, “useful” 
hobbies as gardening); for area b, subareas are relationship with partner (only if the patient has a 
partner and usually lives with him/her, otherwise ignore), family relationships, and social relationships; 
for area c, subareas are personal hygiene, care of one’s appearance, and attire. 
Other areas (different from the main four areas) (e.g., self-management of the disorder; having interests 
and being informed about social, political, or even sport issues; instrumental activities as managing 
money, using the phone, travelling) may be taken into account to define the score inside each ten-point 
interval. 
If there was a recent crisis, you may want to give two scores, one for the crisis period (e.g., last 7 days) 
and one for the month before the beginning of the crisis. 
 
There are two different sets of operational criteria to judge the degree of difficulties: 
One for areas a–c and one for area d  
Degrees of severity areas a – c 
Degrees of severity area d 
0. Absent 
0. Absent 
1. Mild: difficulties that are known only by someone who is 
very familiar with the person 
1. Mild: corresponding to mild 
rudeness, unsociability, or whining 
2. 
Manifest, but not marked (equivalent to moderate): 
difficulties clearly noticeable by everyone, but not 
interfering substantially with the person’s ability to 
perform his/her role in that area, given the person’s 
sociocultural context, age, gender, and educational 
levels; rate area a as “manifest” if the person has a 
sheltered work and the performance is good 
2. 
Manifest or moderate: such as 
speaking too loudly or speaking to 
others in a too familiar manner or 
eating in a socially unacceptable 
manner 
3. 
Marked: difficulties interfering severely with role 
performance in that area; however, the person is still 
able to do something without professional or social help, 
although inadequately and/or occasionally; if helped by 
someone, he/she may be able to reach the previous 
level of functioning 
3. 
Marked: insulting others in public, 
breaking or wrecking objects, acting 
frequently in a socially inappropriate 
but not dangerous way (e.g., 
stripping or urinating in public) not 
occasionally  
4  
Severe: the person is unable to perform any role in that 
area without help or has a harmful influence; the 
person’s health, bur not his/her life, may be at risk 
4  
Severe: frequent verbal threats or 
frequent physical assaults, without 
intention or possibility of severe 
injuries not occasionally  
 
 
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There are two different sets of operational criteria to judge the degree of difficulties: 
One for areas a–c and one for area d 
Degrees of severity areas a – c 
Degrees of severity area d 
5. 
Very severe: impairments and difficulties of such 
intensity to endanger the person’s survival. Suicide risk 
should be taken into account only as much as suicide 
ideation and rumination interferes with social functioning 
5. 
Very severe: defined as aggressive 
acts, aimed at or likely to cause 
severe injuries not occasionally  
For a disturbing behavior to be considered as “occasional,” it must have taken place only once in the 
preceding week or 1–2 times in the preceding month, and in the judgment of mental health 
professionals and caregivers, it is unlikely to happen again in the next 6 months. If a behavior meets 
this definition of “occasional,” the rating should be decreased by one point (e.g., severe to marked, 
moderate to mild). An injury has to be considered “severe” if it would need to be treated in an emergency 
department, if available. 
The following table may be used to score the severity of problems in each main area 
  
Absent Mild Manifest Marke  Seve e 
Very 
severe 
1) Soc lly useful activities, including 
ork 
and study 
€ 
 
 
f 
” 
… 
2) Personal and social relationships 
€ 
 
’ 
f 
” 
… 
3) Self-care 
€ 
 
’ 
f 
” 
… 
4) Disturbing and aggressive behaviors 
€ 
 
’ 
f 
” 
… 
Overall score instructions on the basis of the four main areas’ scores 
100–
91 
Excellent functioning in all four main areas. He/she is held in high consideration for his/her good qualities, 
copes adequately with life problems and is involved in a wide range of interests and activities 
90–
81 
Good functioning in all four areas, presence of only common problems and difficulties 
80–
71 
Mild difficulties in one or more of the areas a–c 
70–
61 
Manifest, but not marked, difficulties in one or more areas a–c or mild difficulties in d. For area a, include 
here sheltered work, if the performance is good 
60–
51 
Marked difficulties in only one area a–c or manifest difficulties in d 
50–
41 
Marked difficulties in two or three of the areas a–c or severe difficulties in only one area a–c without 
marked difficulties in the other two; no marked difficulties in d 
40–
31 
Severe difficulties only in one area a–c and marked difficulties in at least one of the other two; or marked 
difficulties in d 
30–
21 
Severe difficulties in two areas a–c or severe difficulties in d, even if severe and marked difficulties in the 
areas a–c are absent 
20–
11 
Severe difficulties in all areas a–c or very severe difficulties in d, even if severe difficulties in area –-c are 
absent. If the person reacts to external prompts, the suggested scores are 20–16; if not, they are 15–11 
 
 
 
 
1
 
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Amendment 2, 26 September 2018 
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10–1 
Lack of autonomy in basic functioning with extreme behaviors but without survival risk (scores 10–6) or 
with survival risk, e.g., death risk due to malnutrition, dehydration, infections, and inability to recognize 
situations of marked danger (scores 5–1) 
  
 
5) Overall score |___|___|___| 
Summary meaning of PSP total score 
71–
00 
These ratings reflect absence of disability or only mild difficulties 
31–
70 
These ratings reflect varying degrees of disability 
–30 These ratings reflect functioning so poor that the patient requires intensive support or supervision 
 
 
 
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Amendment 2, 26 September 2018 
138 
ATTACHMENT 7: CLINICAL GLOBAL IMPRESSION – SEVERITY RATING 
Severity of illness 
Considering your total clinical experience with this particular patient, how mentally ill is the patient at this time?  
0 = Not assessed 
1 = Normal, not at all ill 
2 = Borderline mentally ill 
3 = Mildly ill 
4 = Moderately ill 
5 = Markedly ill 
6 = Severely ill 
7 = Among the most extremely ill patients 
 


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Amendment 2, 26 September 2018 
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ATTACHMENT 8: 
  
 
 
  
 
 
 
 
 
 
 
 
 
 


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Amendment 2, 26 September 2018 
140 
ATTACHMENT 9: COGNITIVE TESTING 
It is imperative that personnel who will be testing patients practice administering and scoring the entire 
test battery at their institutions in order to become familiar with the materials. Some tests require 
simultaneous administration and scoring; in others, additional attention must be paid to scoring details. 
All the tests require specific and rigorous adherence to instructions to preserve standardization.  
There are alternate forms for the tests that may be sensitive to practice effect or learning due to previous 
test administration. Patients should not receive the same forms or versions two times consecutively.  
Verbal Fluency 
Letter Fluency. In two separate trials, patients will be given 60 seconds to generate as many words 
as possible.  
Measures: number of words generated 


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© Dr. Donald Addington and Dr. Jean Addington.  
 


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ATTACHMENT 11: SHEEHAN SUICIDALITY TRACKING SCALE 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
  
  
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
    
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol MIN-101C07 
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SAP_001.pdf: 
ClinicalTrials.gov ID:   
  NCT03397134