Clinical trial NCT06107803
Conditions: Negative Symptoms in Schizophrenia
Sponsor: Minerva Neurosciences
Start date: 2023-10-13; Completion date: 2024-01-12
Enrollment: 17 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The goal of this clinical trial is to evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of the Co-Administration of Roluperidone and Olanzapine in Adult Subjects with Moderate to Severe Negative Symptoms of Schizophrenia.

The main question this clinical trial aims to answer are the pharmacodynamic and pharmacokinetic effects and safety of the concomitant therapy of Roluperidone with an established and widely used antipsychotic, such as olanzapine in order to provide further guidance to clinical practitioners that may prescribe off-label use of these drugs concomitantly in clinical practice.

Eligible Participants will undergo the following study phases in the clinic:

* Screening Phase: Between 2 and up to 28 days during which study eligibility will be established and subjects receiving psychotropics will be washed out. Subjects will remain inpatient at the clinical site at least through the end of Treatment Phase 2.
* Treatment Phase 1: After the Baseline Visit, Roluperidone 64 mg/day will be administered as a monotherapy for 7 days (Days 1-7).
* Treatment Phase 2: Concomitant administration of Olanzapine 10 mg/day and Roluperidone 64 mg/day for 10 days, starting on Day 8 (Days 8-17). Subjects may be discharged from the clinic at least 48 hours after the last administration of the study drugs and after the collection of the last plasma sample; however, the inpatient period may be extended at the discretion of the investigator.

End of Study (EOS): Will take place at least 14 days after the last dose of the study.

Detailed description:

Arms: arm 1: Roluperidone 64 mg monotherapy administered as an oral dose daily for 7 days on Days 1-7. arm 2: Roluperidone 64 mg oral and olanzapine 10 mg oral administered at the same time daily for 10 days on Days 8-17.
Interventions: intervention 1: Roluperidone 64 mg intervention 2: Olanzapine 10 MG
Intervention descriptions: intervention 1: 64 mg/day oral intervention 2: 10 mg/day oral

Protocol documents:
Prot_000.pdf: 
Minerva Neurosciences, Inc. 
NCT06107803
Protocol MIN-101C18 
Confidential 
___________________________________________________________________________ 
Original Protocol v.1.5– 02 November 2023 
1
Minerva Neurosciences, Inc. 
Clinical Protocol 
A Phase 1b, In-Patient Study to Evaluate the Safety, Tolerability, 
Pharmacodynamics, and Pharmacokinetics of the Co-Administration of 
Roluperidone and Olanzapine in Adult Subjects with Moderate to Severe 
Negative Symptoms of Schizophrenia 
Protocol MIN-101C18 
Phase 1b 
Roluperidone 
Sponsor: 
Minerva Neurosciences, Inc. 
Protocol Version 
Issue Date 
Original Protocol Version 1.5 
02 November 2023 
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. 


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TABLE OF CONTENTS 
SYNOPSIS ................................................................................................................................. 5 
TIME AND EVENTS SCHEDULE ........................................................................................... 12 
ABBREVIATIONS ................................................................................................................... 14 
1.
INTRODUCTION ......................................................................................................... 16
1.1. 
Background on the Disease ........................................................................................ 16 
1.2. 
Background on the Study Drugs ................................................................................. 16 
1.3. 
Overall Rationale for the Study ................................................................................... 17 
2.
OBJECTIVES AND ENDPOINTS .............................................................................. 18 
3.
OVERVIEW OF STUDY DESIGN ............................................................................... 18 
3.1. 
Study Design ............................................................................................................... 18 
3.2. 
Study Design Rationale............................................................................................... 19 
4.
STUDY POPULATION ............................................................................................... 19 
4.1. 
General Considerations .............................................................................................. 19 
4.2. 
Inclusion Criteria ......................................................................................................... 19 
4.3. 
Exclusion Criteria ........................................................................................................ 21 
5.
STUDY TREATMENT ................................................................................................. 23 
5.1. 
Randomization and Blinding ....................................................................................... 23 
5.2. 
Dosage and Administration ......................................................................................... 23 
5.3. 
Compliance ................................................................................................................. 23 
5.4. 
Labeling ....................................................................................................................... 23 
5.5. 
Storage Conditions ...................................................................................................... 23 
5.6. 
Drug Accountability ..................................................................................................... 23 
5.7. 
Retrieval of Treatment and/or Destruction .................................................................. 24 
5.8. 
Concomitant Therapy .................................................................................................. 24 
6.
STUDY EVALUATIONS ............................................................................................. 25 
6.1. 
Study Procedures ........................................................................................................ 25 
6.1.1. 
Screening Phase ........................................................................................ 25 
6.1.2. 
Admission to Clinical Site ........................................................................... 25 
6.1.3. 
Baseline Visit .............................................................................................. 25 
6.1.4. 
Treatment Phase 1 ..................................................................................... 25 
6.1.5. 
Treatment Phase 2 ..................................................................................... 26 
6.1.6. 
End of Study/Early Termination .................................................................. 26 
6.2. 
Collection of Blood ...................................................................................................... 26 
6.3. 
Pharmacokinetic Evaluations ...................................................................................... 27 
6.3.1. 
Sample Collection and Handling................................................................. 27 
6.3.2. 
Analytical Procedures ................................................................................. 27 
6.3.3. 
Pharmacokinetic Parameters ...................................................................... 27 
6.4. 
Pharmacodynamic Evaluations ................................................................................... 28 
6.5. 
Safety Evaluations ...................................................................................................... 28 
7.
SUBJECT COMPLETION/WITHDRAWAL ................................................................ 32 
7.1. 
Completion .................................................................................................................. 32 
7.2. 
Stopping Criteria ......................................................................................................... 32 
7.3. 
Withdrawal from the Study and Replacement............................................................. 33 
8.
STATISTICAL METHODS .......................................................................................... 33 
8.1. 
Sample Size Determination ........................................................................................ 34 
8.2. 
General Methodology .................................................................................................. 34 




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ATTACHMENT 4: CLINICAL GLOBAL IMPRESSION – SEVERITY RATING (CGI-S) ........ 70 
ATTACHMENT 5: ABNORMAL INVOLUNTARY MOVEMENT SCALE (AIMS) ................... 71 
ATTACHMENT 6: BARNES AKATHISIA RATING SCALE (BARS) ..................................... 72 
ATTACHMENT 7: COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) ................ 74 
INVESTIGATOR AGREEMENT .............................................................................................. 76 
 
LIST OF IN-TEXT FIGURES 
 
Figure 1:  Study Design Diagram ...................................................................................................... 19 
LIST OF IN-TEXT TABLES 
 
Table 1:  Volume of Blood to be Collected from Each Subject ...................................................... 27 
 


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SYNOPSIS 
Name of Sponsor/Company:  Minerva Neurosciences, Inc. 
Name of Investigational Product:  Roluperidone (MIN-101) 
Study Title:  A Phase 1b, In-Patient Study to Evaluate the Safety, Tolerability, 
Pharmacodynamics, and Pharmacokinetics of the Co-Administration of Roluperidone and 
Olanzapine in Adult Subjects with Moderate to Severe Negative Symptoms of Schizophrenia 
Study Phase:  Phase 1b 
Study Period: October 2023 – February 2024 
Objectives and Endpoints: 
Objectives 
Endpoints 
To evaluate the pharmacodynamics (PD), 
including safety and tolerability of the 
coadministration of roluperidone 64 mg and 
olanzapine 
Safety assessments, including adverse events 
(AEs), clinical laboratory, electrocardiogram 
(ECG), vital signs, extrapyramidal symptoms 
(assessed by Abnormal Involuntary Movement 
Scale [AIMS] and Barnes Akathisia Rating Scale 
[BARS]), and suicidal ideation (assessed by the 
Columbia Suicide Severity Rating Scale 
[C-SSRS]) 
To evaluate the effect of the coadministration of 
roluperidone and olanzapine on the 
pharmacokinetics (PK) of roluperidone in subjects 
with moderate to severe negative symptoms of 
schizophrenia 
• The plasma pharmacokinetic parameters of 
roluperidone and its metabolite, BFB-520, 
following single dose and at steady state (Cmax, 
Tmax, AUC0-24, AUC∞) 
• Plasma pharmacokinetic parameters of 
roluperidone and BFB-520 when administered 
concomitantly with olanzapine 
• The plasma pharmacokinetic parameters of 
olanzapine administered concomitantly with 
roluperidone compared to its pharmacokinetic 
profile based on monotherapy administration 
from published literature 
 
  
 
 
 Clinical 
Global Impression - Severity Rating (CGI-S) 
Methodology: 
This is a prospective, open-label, one-sequence, inpatient, clinical study of CYP2D6 normal 
metabolizer (NM) subjects with moderate to severe negative symptoms of schizophrenia. 
Olanzapine, a commonly used antipsychotic having dopaminergic antagonistic activities, will 
be coadministered to subjects already being administered roluperidone to determine its effect 
on the PD and PK of roluperidone. Eligible subjects will undergo 3 study phases as follows: 
• Screening Phase: Between 2 and up to 28 days during which study eligibility will be 
established and subjects receiving psychotropics will be washed out. Discontinuation 
of psychotropics must occur at least 2 days prior to the start of Treatment Period 1 
(Day 1). Subjects will be admitted to the site on Day -2 and complete a Baseline Visit 
on Day -1. 


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• Treatment Phase 1: After the Baseline Visit (Day -1), roluperidone 64 mg/day will 
be administered as a monotherapy for 7 days (Days 1-7). 
• Treatment Phase 2: Concomitant administration of olanzapine 10 mg/day and 
roluperidone 64 mg/day for 10 days, starting on Day 8 (Days 8-17). Subjects may be 
discharged from the clinic at least 48 hours after the last administration of the study 
drugs and after the collection of the last plasma sample; however, the inpatient period 
may be extended at the discretion of the investigator. 
An End of Study (EOS) visit will take place at least 14 days after the last dose of study 
treatment. After the EOS visit, the medications and clinical care of the subject will be managed 
as per the judgement of the investigator/clinician. 
Number of Subjects (planned): Approximately 18 subjects may be enrolled in the study to 
ensure that at least 12 subjects complete the study. 
Diagnosis and Main Criteria for Inclusion/Exclusion:  Male and female CYP2D6 NM 
subjects, 18 to 55 years of age, inclusive, with moderate to severe negative symptoms of 
schizophrenia and no history of any clinically significant conditions that, in the opinion of the 
investigator, would jeopardize the safety of the subject or impact the validity of the study. 
Inclusion Criteria: 
Subjects must satisfy all the following inclusion criteria during screening to be enrolled in the 
study: 
1. 
Subject and/or subject's legal representative, if applicable, provided informed consent 
prior to the initiation of any study related procedures, and the subject is judged by the 
investigator as being capable of understanding the study requirements. 
2. 
Male or female subject, 18 to 55 years of age, inclusive, and body mass index (BMI) < 35 
kg/m2 at Screening.  
3. 
Subject 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)1. 
4. 
Has a caregiver or family member or health care personnel who can provide information 
towards assessment and support the subject in terms of compliance with the protocol.   
5. 
Has documented diagnosis of schizophrenia for at least 1 year before screening into the 
trial. 
6. 
Subject is stable in terms of both positive and negative symptoms of schizophrenia over 
the last 3 months according to his or her clinician and/or a caregiver who knows the patient 
like the responsible person at the patient residence, a social worker, rehabilitation therapist 
or a caregiver/ family member or based on documentation in the clinical chart or medical 
records. Subjects with or without positive symptoms are allowed if these symptoms are 
stable for the last 3 months and they do not meet exclusion criterion 2. 
7. 
Subject is currently an outpatient and has not been hospitalized for the last 3 months for 
acute exacerbation or symptoms worsening. Subjects who have been hospitalized for 
 
1 Current version for DSM-5. 


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social reasons for any time period during the last 3 months or are currently hospitalized 
for social reasons can be included only with Sponsor’s Responsible Medical Officer’s 
approval. The social reasons must be documented in the case report form (CRF). 
8. 
Subject with a score of > 20 on the PANSS original negative symptoms subscale score 
(sum of N1+N2+N3+N4+N5+N6+N7) at Screening and Baseline (Day -1) AND < 4 
points absolute difference between the 2 visits. 
9. 
Subject has discontinued psychotropic medications without risk to their clinical status or 
safety by Baseline (Day -1). Subjects receiving treatment with long-acting or depot 
antipsychotic medication must have discontinued the depot antipsychotic for a full cycle 
of the drug (ie, 1-6 months depending on formulation). 
10. No history of violence against self or others during the last 1 year.    
11. Female subject, if not of childbearing potential, must be a woman who is 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 (eg, tubal occlusion, hysterectomy, bilateral salpingectomy). 
12. Female subject, if of childbearing potential, must test negative for pregnancy and must be 
using 2 methods of contraception for at least 30 days after the completion of the study, 
one of which must be a highly effective method. The following highly effective 
contraception methods acceptable for this study are: 
• 
Surgical sterilization (for example, bilateral tubal ligation/salpingectomy, 
hysterectomy for female subjects or vasectomy for her male partner provided that the 
partner is the sole sexual partner of the female subject and that the vasectomized 
partner has received medical assessment of the surgical success). 
• 
Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
• 
Hormonal contraception (oral, implantable, patch, injectable). 
• 
True sexual abstinence when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (for example, calendar ovulation, sympto-thermal, 
post-ovulation methods), declaration of abstinence for the duration of the study, and 
withdrawal are NOT acceptable methods of contraception). 
The following acceptable methods can be used as a second form of contraception during 
the study: 
• 
Barrier methods for a female subject include use of an occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam, gel, film, cream, or suppository. 
• 
A male subject who has been sterilized (with medical assessment of the surgical 
success) or have partners of non-childbearing potential (including homosexual men) 
is required to use a condom with spermicide. This is to prevent unintended exposure 
of the partner to the study drug via seminal fluid. 
• 
A male subject who has partners of childbearing potential must be willing to use a 
condom with spermicide. Because a condom alone is not adequate contraception for 
this study, male subjects are strongly recommended to discuss the potential risks to a 
fetus with all female partners and advise them of the need to high effective 
contraception for up to 90 days after completion of the study. A male subject whose 
partner is pregnant is not allowed in the study. 


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• 
A female subject who is post-menopausal (defined as spontaneous amenorrhea for at 
least 1 year without an alternative medical cause) is eligible for this study. Hormone 
replacement therapy (HRT) is allowed during the study. 
13. Subject must be normal metabolizer for P450 CYP2D6, defined as a subject that has at 
least one functional allele (eg, *1, *2 or *35), as determined by study-specific genotyping 
test before the first drug dose is administered.  
14. Subject and the caregiver are considered by the investigator to be reliable and likely to 
cooperate with the assessment procedures.  
Exclusion Criteria: 
Subjects meeting any of the following exclusion criteria are not to be enrolled 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. 
Subject with PANSS item score of > 4 on: 
• P4 Excitement/Hyperactivity 
• 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 BARS.  
5. 
Subjects with known hypersensitivity to olanzapine.  
6. 
Subject’s condition is due to direct physiological effects of a substance (eg, a drug of 
abuse, or medication) or a general medical condition. 
7. 
Has a current or recent history of serious suicidal behavior within the past 1 year.  
8. 
Subject has a history of substance use disorder within 3 months of the Screening visit 
(excluding caffeine and cigarette smoking).  
9. 
Positive urine drug screen for drugs of abuse (cocaine, methadone, amphetamines,  
opiates, benzodiazepines, and barbiturates), tricyclic antidepressants (TCA), and alcohol 
(except for prescription benzodiazepines). Recreation cannabinoids are allowed if the 
clinician determines that the subject does not meet criteria for cannabis use disorder as 
defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the 
clinician can ensure that the subject is not using cannabis during days -2 to 17.  
10. Subject cannot be discontinued from psychotropic medication(s). 
11. Subject who received clozapine within 3 months of the Screening visit. 
12. Subject is currently taking proton pump inhibitors (PPI). 


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13. Subject with a history of significant other major or unstable neurological, neurosurgical 
(eg, head trauma), metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, 
metabolic, gastrointestinal, or urological disorder. 
14. Subject with a history of seizures (subject with a history of a single childhood febrile 
seizure may be enrolled in this study). 
15. Subject 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. 
16. Subject 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. 
17. Current systemic infection (eg, Hepatitis B, Hepatitis C, human immunodeficiency virus 
[HIV], tuberculosis). Subjects 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 [ALT] and aspartate aminotransferase [AST]) do not 
exceed 2 times upper limit of normal (ULN). 
18. Positive for COVID-19 virus. 
19. Subject who requires or may require concomitant treatment with any other medication 
likely to increase QT interval (eg, paroxetine, fluoxetine, duloxetine, amiodarone; a non-
exhaustive list is provided in ATTACHMENT 1:  Prohibited Concomitant Medications). 
20. Subject who requires medication inhibiting CYP2D6.  
21. Subject with a clinically significant ECG abnormality that could be a safety risk 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. 
22. Subject with a myocardial infarction within 6 months of Screening based on medical 
history or significant ECG findings at Screening. 
23. Familial or personal history of long QT syndrome or with additional risk factors for 
Torsade de Pointes.  
24. Subject 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. 
25. Subjects with unexplained syncope.   
26. Woman of child-bearing potential, or man, who is unwilling or unable to use accepted 
methods of birth control.  
27. Woman with a positive pregnancy test, who is lactating, or who is planning to become 
pregnant during the study. 
28. Subject who participated in another clinical study within 3 months prior to Screening, or 
received roluperidone previously, or has previously participated in > 3 clinical studies with 
experimental medication within the past 2 years. 


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Test Product, Dosage, and Route of Administration: 
Roluperidone will be available in a tablet form at a strength of 64 mg per day.   
Oral olanzapine 10 mg will be available in a tablet form as marketed formulations. 
Reference Therapy, Dosage and Mode of Administration:  Not applicable 
Duration of Subject Participation/Duration of Study/Duration of Treatment:   
• Screening:  Up to 28 days prior to admission to the clinical site 
• Inpatient admission: Day -2 
• Baseline Visit: Day -1  
• Treatment Phase 1: Day 1 to Day 7 
• Treatment Phase 2: Day 8 to Day 19 
• End-of-study visit:  14 (+ 2 days) days after the last dose 
Total possible study length:  Up to 63 days 
EVALUATION CRITERIA 
Pharmacodynamics: Safety assessments, including adverse events, clinical laboratory, ECG, 
vital signs, extrapyramidal symptoms (assessed by AIMS and BARS), and suicidal ideation 
(assessed by the C-SSRS). The incidence of adverse events and clinically significant abnormal 
laboratory, vital signs, and ECGs values will be recorded based upon Investigator observation, 
central assessments as appropriate, and subject reporting. 
Pharmacokinetics: The following plasma PK parameters after roluperidone single dose, at 
steady state, and when administered concomitantly with olanzapine will be calculated for 
roluperidone and its metabolites using non-compartmental methods: Cmax, Tmax, AUC24, and 
AUC∞. Additional PK parameters may be included if deemed appropriate. 
  
 
 CGI-S. 
STATISTICAL CONSIDERATIONS 
Sample Size Determination:  The planned sample size is approximately 18 subjects dosed 
with 64 mg roluperidone in Treatment Phase 1 such that at least 12 subjects can complete 
dosing with 64 mg roluperidone and 10 mg olanzapine during Treatment Phase 2. The selected 
sample size is sufficient to calculate the 90% confidence interval of the estimated ratio of Cmax 
and AUC of roluperidone with and without coadministration of olanzapine for a true 
within-subject standard deviation of 0.25 or 0.40 with maximum imprecision of 20.5% or 
30.8%, respectively. 
Statistical Methods: A detailed description of subject accountability including count of 
subjects included, exposed, completed (ie, subjects who complete the study treatment period) 
and discontinued along with the main reason for discontinuation, will be generated for all 
subjects.  
All subjects who are exposed to study treatment, regardless of the amount of treatment 
administered, will be included in the safety population. 


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All subjects with no major deviations related to study drug intake (eg, vomiting), for whom the 
primary pharmacokinetic data are considered sufficient and interpretable, will be included in 
the pharmacokinetic population. 
Demographic characteristics will be listed and summarized using descriptive statistics. 
 
 CGI-S
 
 
  
Pharmacodynamic Analysis: Safety will be evaluated by an analysis of adverse events, vital 
signs, ECG, physical examination results, and clinical laboratory tests (including blood and 
urine analyses), AIMS, BARS, and C-SSRS, at specified time-points during the study.  
Standard descriptive statistics for all safety variables will be tabulated for each treatment group 
and measuring time, as appropriate.   
Laboratory data (hematology, clinical chemistry, and urine analysis) will be compared to the 
normal ranges given by the laboratory. Vital signs and ECG data will be compared to normal 
ranges as well as predefined change ranges. Frequencies of potentially clinically significant 
abnormalities will be tabulated. 
Pharmacokinetic Analysis:  The plasma pharmacokinetic parameters after roluperidone single 
dose, at steady state, and when administered concomitantly with olanzapine (Cmax, Tmax, AUC0-
24, and AUC∞) of roluperidone and its metabolite BFB-520 will be determined from plasma 
concentration data using non-compartmental methods. Pharmacokinetic parameters will be 
summarized by arithmetic mean, SD, geometric mean, coefficient of variation (CV%, both 
arithmetic and geometric), median, minimum and maximum. 
Plasma concentration data will be summarized by treatment group (roluperidone alone, 
roluperidone + olanzapine). Nominal timepoints will be used for the presentation of tables and 
figures. 
Treatment ratios (roluperidone + olanzapine versus roluperidone alone) for Cmax, AUC0-24, and 
AUC∞, following at steady state, will be summarized using the same descriptive statistics as 
above. LS means (±90% confidence interval [CI]) for log transformed Cmax, AUC0 24, and 
AUC∞ will be evaluated by a linear mixed effects model with a fixed term for treatment and a 
random term for subject, fit by estimated generalized least squares with restricted maximum 
likelihood estimates of random effects.  If deemed relevant to test for a treatment difference in 
Tmax, a Wilcoxon signed rank test will be used. 
The plasma pharmacokinetic parameters of olanzapine from Day 17 will be compared with its 
pharmacokinetic profiles available in published literature. 
 
 
 CGI-S 
 
. 


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TIME AND EVENTS SCHEDULE  
Period 
SCR 
Admis-
sion 
BL 
Treatment Phase 1 
Treatment Phase 2 
EOS/ 
ET 
Study Day 
-28 to -3 
-2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
31 (+2) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion & exclusion criteria 
X 
 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/update 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Institutionalization 
 
 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • → 
 
Roluperidone administration 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Olanzapine administration 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital signsb 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Triplicate ECGc 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CYP2D6 genotype 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry & hematology 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Urinalysise 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Drug screen, alcohol test, and 
COVID-19 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samplesf 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
FSH test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
CGI-S 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
BARS 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
AIMS 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Prior & Concomitant 
medications 
X 
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ABBREVIATIONS  
5-HT2A 
5-hydroxytryptamine-2A  
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve  
BARS 
Barnes Akathisia Rating Scale 
BMI 
body mass index 
BNSS 
Brief Negative Symptoms Scale 
BUN 
blood urea nitrogen 
 
 
CGI-S 
Clinical Global Impression of Severity Score 
CI 
confidence interval 
Cmax 
maximum drug concentration (in plasma or serum) 
CPK 
creatine phosphokinase 
CRF 
case report form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV 
coefficient of variation 
DA 
dopamine/dopaminergic 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders- Fifth Edition 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECT 
electroconvulsive therapy 
EOS 
End-of-Study 
ET 
Early Termination 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
HDL 
high density lipoprotein 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IRB 
Institutional Review Board 
LDH 
lactic acid dehydrogenase 
LDL 
low density lipoprotein 
MIN-101 
roluperidone 
MINI 
Mini International Neuropsychiatric Interview 
NM 
normal metabolizer 
 
 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPI 
proton pump inhibitor 
QTcF 
QT interval value corrected for heart rate using Fridericia’s formula 
RBC 
red blood cell 
r-TMS 
repetitive trans-cranial magnetic stimulation 
SAE 
serious adverse event 
SUSAR 
Suspected unexpected serious adverse reaction 
TCA 
tricyclic antidepressants 
Tmax 
time to maximum drug concentration (in plasma or serum) 


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ULN 
upper limit of normal 
US 
United States 
VNS 
vagal nerve stimulation 
WBC 
white blood cell 


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1. 
 INTRODUCTION 
1.1. 
Background on the Disease 
Worldwide, the overall lifetime prevalence of schizophrenia is around 1% of the general 
population and the majority of patients with schizophrenia have moderate to severe negative 
symptoms at different times during their life (Simeone 2015; Error! Reference source not 
found. 2010).  
Negative symptoms are an integral feature of schizophrenia and often emerge during the 
prodromal phase, before the full-blown manifestation of positive (psychotic) symptoms that 
lead to the diagnosis of schizophrenia (Piskulic 2012; Yung 2019; Sauvé 2019; Carpenter WT 
Jr, Buchanan RW. Negative symptom therapeutics. Schizophr Bull. 2017;43:681-682. 
Cohen AS, Schwartz E, Le TP, et al. Digital phenotyping of negative symptoms: the relationship to 
clinician ratings. Schizophr Bull. 2021;47:44-53. 
Devoe 2021). Negative symptoms thus constitute a major burden on patients, their families, and 
society (Foussias 2014; Strauss 2010; Galderisi 2018). 
Negative symptoms include emotional experiences such as avolition, asociality, and anhedonia 
as well as abnormal expression such as blunted affect and poverty of speech (Giordano GM, 
Caporusso E, Pezzella P, et al. Updated perspectives on the clinical significance of negative symptoms 
in patients with schizophrenia. Exp Review Neurother. 2022. 
Kirkpatrick B, Strauss GP, Nguyen L, et al. The brief negative symptom scale: psychometric properties. 
Schizophr Bull. 2011;37(2):300-5. 
Kirkpatrick B. Developing concepts in negative symptoms: primary vs secondary and apathy vs 
expression. J Clin Psychiatry. 2014;75:3-7. 
Kirkpatrick 2017). Avolition or the lack of will to start and continue pleasurable or essential 
daily activities is a central feature of primary negative symptoms (Error! Reference source 
not found. 2020; Trémeau 2012; Kirschner M, Aleman A, Kaiser S. Secondary negative 
symptoms-a review of mechanisms, assessment and treatment. Schizophr Res. 2017;186:29-38. 
Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia 
derived by factor analysis: combined results of the North American trials. J Clin Psychiatry. 
1997;58(12):538-46. 
Messinger 2011) and reducing its severity probably drives the overall improvements in negative 
symptoms (Strauss 2020; Strauss 2021). Simply put, negative symptoms encompass a 
reduction or absence of the normal range of emotions and behaviors.  
Negative symptoms are categorized by researchers and clinicians into primary negative 
symptoms, that are intrinsic to the schizophrenic illness, and secondary negative symptoms, 
that manifest as the adverse effect of antipsychotic drugs or can be the result of avoiding social 
interactions in response to threatening delusions and hallucinations (Artaloytia 2006; 
Kirschner 2017; Carpenter 2017; Giordano GM, Caporusso E, Pezzella P, et al. Updated 
perspectives on the clinical significance of negative symptoms in patients with schizophrenia. Exp 
Review Neurother. 2022. 
Kirkpatrick B, Strauss GP, Nguyen L, et al. The brief negative symptom scale: psychometric properties. 
Schizophr Bull. 2011;37(2):300-5. 
Kirkpatrick 2014). The current instruments used to measure the severity and therapeutic induced 
changes in negative symptoms comprise Positive and Negative Symptom Score- (PANSS-) 


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derived constructs (White 1997; Marder 1997), other scales focused exclusively on negative 
symptoms such as the Brief Negative Symptoms Scale (BNSS) (Giordano GM, Caporusso E, 
Pezzella P, et al. Updated perspectives on the clinical significance of negative symptoms in patients 
with schizophrenia. Exp Review Neurother. 2022. 
Kirkpatrick 2011) and NSA-16 (Axelrod 1993), and remote digital measurements 
(Cohen 2021). However, opinions about which instrument is best to measure changes in these 
manifestations continue to evolve (Error! Not a valid bookmark self-reference. 2022; 
Giordano 2022). 
Unfortunately, there are no approved treatments for negative symptoms of schizophrenia in the 
United States (US). Therefore, the treatment of primary negative symptoms of schizophrenia 
and the resulting functional deficits remains a serious unmet need and meets the criteria for a 
serious or life-threatening disease or condition. 
1.2. 
Background on the Study Drugs 
Roluperidone is a novel cyclic amido derivative, with affinity and antagonistic activity at the 
5-hydroxytryptamine-2A (5-HT2A), sigma2, α1A-adrenergic, and, to a lesser extent, α1B-
adrenergic receptors. Its metabolite, BFB-520, has a comparable profile to roluperidone, with 
lower affinity for sigma2 receptors, and lower affinity for 5-HT2A receptors. Roluperidone has 
very low or no affinity to, or antagonistic activities on, dopaminergic, muscarinic, cholinergic, 
and histaminergic receptors. Hence, roluperidone mainly targets 5-HT2A, sigma2, α1A- and 
α1B-adrenergic pathways without direct blockade of dopaminergic pathways/receptors and, in 
particular, the D2 dopaminergic receptor sub-type, which is the main target of most available 
antipsychotics to alleviate psychotic symptoms of patients afflicted by schizophrenia.  
Because roluperidone lacks antagonistic activity at the D2 receptors, it exerts its pharmacologic 
effect without blocking the brain’s dopamine- (DA-) driven reward systems. Therefore, 
roluperidone does not induce secondary negative symptoms such as sedation and 
Parkinsonism. Unlike most antipsychotics, it does not, at therapeutic doses, increase prolactin 
levels or cause weight gain or akathisia.  
Nevertheless, it is possible that roluperidone modulates both dopaminergic and glutamatergic 
pathways without blocking DA receptors, in addition to its effects on neuroplasticity and brain 
cholesterol metabolism (data on file). The various effects of roluperidone in the different brain 
areas can be explained by the complexity of the mesolimbic and mesocortical pathways and 
their role in schizophrenia. Moreover, the antagonist properties of roluperidone on its main 
targets (5‑HT2A, sigma2, α1A-adrenergic, and α1B-adrenergic receptors) can contribute to the 
regulation of the imbalance between DA, glutamate, and serotonin. Indeed, these targets are 
involved in the modulation of the different pathways involved in positive and negative 
symptoms of schizophrenia.  
Roluperidone is intended for the treatment of negative symptoms of schizophrenia. 
Roluperidone should be used as monotherapy, ie, non-adjunctively with antipsychotics. Due to 
a risk of QT prolongation that is known to be partly related to the CYP2D6 metabolism of 
metabolite BFB-520, roluperidone is only intended for patients who have at least 1 CYP2D6 
allele with normal function.  
Additional information about roluperidone is provided in the Investigator’s Brochure. 
Olanzapine is among the most frequently used drugs to treat acute exacerbation of psychosis 
in schizophrenia. Once psychosis ameliorates or stabilizes, olanzapine is used as maintenance 


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treatment to reduce the risk of recurrence of psychosis. Olanzapine has affinities for 
dopaminergic, cholinergic, serotonergic, and histaminergic receptors. As such it can produce 
extrapyramidal, parkinsonian effects, sedation, constipation, blurry vision, and weight gain.  
1.3. 
Overall Rationale for the Study 
The efficacy of roluperidone monotherapy in the treatment of negative symptoms of 
schizophrenia has been established in two adequate and well-controlled multinational clinical 
trials (MIN-101C03 and MIN-101C07). These effects have been demonstrated across both 
psychometric (PANSS, Negative Symptom Factor Score, BNSS, etc.) and global and 
functional outcomes (CGI-S and Personal and Social Performance, respectively). Since there 
exists the possibility that roluperidone might be prescribed off-label in concomitance with 
antipsychotics, the rationale of this clinical trial is to evaluate the pharmacodynamic and 
pharmacokinetic effects of the concomitant therapy of roluperidone with an established and 
widely used antipsychotic, such as olanzapine in order to provide further guidance to clinical 
practitioners that may prescribe off-label these drugs concomitantly in clinical practice.  


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2. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
To evaluate the pharmacodynamics (PD), 
including safety and tolerability of the 
coadministration of roluperidone 64 mg and 
olanzapine 
Safety assessments, including adverse events 
(AEs), clinical laboratory, electrocardiogram 
(ECG), vital signs, extrapyramidal symptoms 
(assessed by Abnormal Involuntary Movement 
Scale [AIMS] and Barnes Akathisia Rating Scale 
[BARS]), and suicidal ideation (assessed by the 
Columbia Suicide Severity Rating Scale 
[C-SSRS]) 
To evaluate the effect of the coadministration of 
roluperidone and olanzapine on the 
pharmacokinetics (PK) of roluperidone in subjects 
with moderate to severe negative symptoms of 
schizophrenia 
• The plasma pharmacokinetic parameters of 
roluperidone and its metabolite, BFB-520, 
following single dose and at steady state (Cmax, 
Tmax, AUC0-24, AUC∞) 
• Plasma pharmacokinetic parameters of 
roluperidone and BFB-520 when administered 
concomitantly with olanzapine 
• The plasma pharmacokinetic parameters of 
olanzapine administered concomitantly with 
roluperidone compared to its pharmacokinetic 
profile based on monotherapy administration 
from published literature 
 
  
 
 
Clinical Global Impression- Severity Rating 
(CGI-S) 
 
3. 
OVERVIEW OF STUDY DESIGN 
3.1. 
Study Design 
This is a prospective, open-label, one-sequence, inpatient, clinical study of CYP2D6 normal 
metabolizer (NM) subjects with moderate to severe negative symptoms of schizophrenia. be 
coadministered to subjects already being administered roluperidone to determine its effect on 
the PD and PK of roluperidone. Eligible subjects will undergo 3 study phases as follows: 
• Screening Phase: Between 2 and up to 28 days during which study eligibility will be 
established and subjects receiving psychotropics will be washed out. Discontinuation 
of psychotropics must occur at least 2 days prior to the start of Treatment Period 1 
(Day 1). Subjects will be admitted to the site on Day -2 and complete a Baseline Visit 
on Day -1. 
• Treatment Phase 1: After the Baseline Visit (Day -1), roluperidone 64 mg/day will 
be administered as a monotherapy for 7 days (Days 1-7). 
• Treatment Phase 2: Concomitant administration of olanzapine 10 mg/day and 
roluperidone 64 mg/day for 10 days, starting on Day 8 (Days 8-17). Subjects may be 
discharged from the clinic at least 48 hours after the last administration of the study 
drugs and after the collection of the last plasma sample; however, the inpatient period 
may be extended at the discretion of the investigator. 


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An End of Study (EOS) visit will take place at least 14 days after the last dose of study 
treatment. After the EOS visit, the medications and clinical care of the subject will be managed 
as per the judgement of the investigator/clinician. 
Figure 1:  Study Design Diagram 
 
3.2. 
Study Design Rationale 
The objectives of this clinical trial are to evaluate the safety and tolerability, 
pharmacodynamics, 
and 
pharmacokinetics 
of 
treatment 
with 
roluperidone 
when 
co-administered with an established and widely used antipsychotic such as olanzapine. An 
open-label design serves the needs of identifying potential safety signals to guide further 
clinical development and will provide guidance to clinical practitioners who may prescribe in 
clinical practice non-prohibited antipsychotics concomitantly with roluperidone. 
4. 
STUDY POPULATION 
4.1. 
General Considerations 
Male and female CYP2D6 NM subjects, 18 to 55 years of age, inclusive, with moderate to 
severe negative symptoms of schizophrenia and no history of any clinically significant 
conditions that, in the opinion of the investigator, would jeopardize the safety of the subject 
or impact the validity of the study. 
4.2. 
Inclusion Criteria 
Subjects must satisfy all the following inclusion criteria during screening to be enrolled in the 
study: 
1. 
Subject and/or subject's legal representative, if applicable, provided informed consent 
prior to the initiation of any study related procedures, and the subject is judged by the 
investigator as being capable of understanding the study requirements. 
2. 
Male or female subject, 18 to 55 years of age, inclusive, and body mass index (BMI) < 35 
kg/m2 at Screening.  
3. 
Subject 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 subject in terms of compliance with the protocol.   
5. 
Has 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. 
Subject is stable in terms of both positive and negative symptoms of schizophrenia over 
the last 3 months according to his or her clinician and/or a caregiver who knows the patient 
like the responsible person at the patient residence, a social worker, rehabilitation therapist 
or a caregiver/ family member or based on documentation in the clinical chart or medical 
records. Subjects with or without positive symptoms are allowed if these symptoms are 
stable for the last 3 months and they do not meet exclusion criterion 2. 
7. 
Subject is currently an outpatient and has not been hospitalized for the last 3 months for 
acute exacerbation or symptoms worsening. Subjects who have been hospitalized for 
social reasons for any time period during the last 3 months or are currently hospitalized 
for social reasons can be included only with Sponsor’s Responsible Medical Officer’s 
approval. The social reasons must be documented in the case report form (CRF). 
8. 
Subject with a score of > 20 on the PANSS original negative symptoms subscale (Sum of 
N1+N2+N3+N4+N5+N6+N7) at Screening and Baseline (Day -1) AND < 4 points 
absolute difference between the 2 visits. 
9. 
Subject has discontinued psychotropic medications without risk to their clinical status or 
safety by Baseline. Subjects receiving treatment with long-acting or depot antipsychotic 
medication must have discontinued the depot antipsychotic for a full cycle of the drug (ie, 
1-6 months depending on formulation).  
10. No history of violence against self or others during the last 1 year.    
11. Female subject, if not of childbearing potential, must be a woman who is 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 (eg, tubal occlusion, hysterectomy, bilateral salpingectomy). 
12. Female subject, if of childbearing potential, must test negative for pregnancy and must be 
using a 2 methods of contraception for at least 30 days after the completion of the study, 
one of which must be a highly effective method. The following highly effective 
contraception methods acceptable for this study are: 
• 
Surgical sterilization (for example, bilateral tubal ligation/salpingectomy, 
hysterectomy for female subjects or vasectomy for her male partner provided that the 
partner is the sole sexual partner of the female subject and that the vasectomized 
partner has received medical assessment of the surgical success). 
• 
Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
• 
Hormonal contraception (oral, implantable, patch, injectable). 
• 
True sexual abstinence when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (for example, calendar ovulation, sympto-thermal, post-
ovulation methods), declaration of abstinence for the duration of the study, and 
withdrawal are NOT acceptable methods of contraception). 
The following acceptable methods can be used as a second form of contraception during 
the study: 
• 
Barrier methods for a female subject include use of an occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam, gel, film, cream, or suppository. 
• 
A male subject who has been sterilized (with medical assessment of the surgical 
success) or have partners of non-childbearing potential (including homosexual men) is 


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required to use a condom with spermicide. This is to prevent unintended exposure of 
the partner to the study drug via seminal fluid. 
• 
A male subject who has partners of childbearing potential must be willing to use a 
condom with spermicide. Because a condom alone is not adequate contraception for 
this study, male subjects are strongly recommended to discuss the potential risks to a 
fetus with all female partners and advise them of the need to high effective 
contraception for up to 90 days after completion of the study. A male subject whose 
partner is pregnant is not allowed in the study. 
• 
A female subject who is post-menopausal (defined as spontaneous amenorrhea for at 
least 1 year without an alternative medical cause) is eligible for this study. Hormone 
replacement therapy (HRT) is allowed during the study. 
13. Subject must be normal metabolizer for P450 CYP 2D6, defined as a subject that has at 
least one functional allele (eg, *1, *2 or *35), as determined by study-specific genotyping 
test before the first drug dose is administered.  
14. Subject and the caregiver are considered by the investigator to be reliable and likely to 
cooperate with the assessment procedures.  
4.3. 
Exclusion Criteria 
Subjects meeting any of the following exclusion criteria are not to be enrolled 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. 
Subject with PANSS item score of > 4 on: 
• P4 Excitement/Hyperactivity 
• 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. 
Subjects with known hypersensitivity to olanzapine.  
6. 
Subject’s condition is due to direct physiological effects of a substance (eg, a drug of abuse 
or medication) or a general medical condition. 
7. 
Has a current or recent history of serious suicidal behavior within the past 1 year.  
8. 
Subject has a history of substance use disorder within 3 months of the Screening visit 
(excluding caffeine and cigarette smoking).  
9. 
Positive urine drug screen for drugs of abuse (cocaine, methadone, amphetamines,  
opiates, benzodiazepines, and barbiturates), tricyclic antidepressants (TCA), and alcohol 
(except for prescription benzodiazepines). Recreation cannabinoids are allowed if the 


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clinician determines that the subject does not meet criteria for cannabis use disorder as 
defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the 
clinician can ensure that the subject is not using cannabis during days -2 to 17. 
10. Subject cannot be discontinued from psychotropic medication(s). 
11. Subject who received clozapine within 6 months of the Screening visit  
12. Subjects is currently taking proton pump inhibitors (PPI)  
13. Subject with a history of significant other major or unstable neurological, neurosurgical 
(eg, head trauma), metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, 
metabolic, gastrointestinal, or urological disorder. 
14. Subject with a history of seizures (subject with a history of a single childhood febrile 
seizure may be enrolled in this study). 
15. Subject 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. 
16. Subject 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. 
17. Current systemic infection (eg, Hepatitis B, Hepatitis C, human immunodeficiency virus 
[HIV], tuberculosis). Subjects 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 [ALT] and aspartate aminotransferase [AST]) do not 
exceed 2 times upper limit of normal (ULN). 
18. Positive for COVID-19 virus. 
19. Subject who requires or may require concomitant treatment with any other medication 
likely to increase QT interval (eg, paroxetine, fluoxetine, duloxetine, amiodarone; a non-
exhaustive list is provided in ATTACHMENT 1:  Prohibited Concomitant Medications). 
20. Subject who requires medication inhibiting CYP2D6.  
21. Subject with a clinically significant ECG abnormality that could be a safety risk 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. 
22. Subject with a myocardial infarction within 6 months of Screening based on medical 
history or significant ECG findings at Screening. 
23. Familial or personal history of long QT syndrome or with additional risk factors for 
Torsade de Pointes.  
24. Subject 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. 
25. Subjects with unexplained syncope.   
26. Woman of child-bearing potential, or man, who is unwilling or unable to use accepted 
methods of birth control.  


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27. Woman with a positive pregnancy test, who is lactating, or who is planning to become 
pregnant during the study. 
28. Subject who participated in another clinical study within 3 months prior to Screening, or 
received roluperidone previously, or has previously participated in > 3 clinical studies with 
experimental medication within the past 2 years. 
5. 
STUDY TREATMENT 
5.1. 
Randomization and Blinding 
This is an open-label, one-sequence study; therefore, randomization and blinding will not be 
performed. Eighteen (18) subjects will be enrolled in the study to ensure 12 subjects complete 
the study. Eligible subjects will be assigned a subject identification number in sequential order.  
 
5.2. 
Dosage and Administration 
A daily dose of 64 mg roluperidone will be orally administered in the clinic by the investigator 
or other trained designee during Treatment Period 1.  
Daily doses of 64 mg roluperidone and 10 mg olanzapine will be orally administered at the 
same time in the clinic by the investigator or other trained designee during Treatment Period 2. 
Under all conditions, roluperidone tablets must be swallowed whole and not chewed, divided, 
dissolved, or crushed. Roluperidone and olanzapine, as applicable, must be administered at 
approximately the same time of day for each subject. 
5.3. 
Compliance 
Roluperidone and olanzapine will be administered in the controlled setting of a clinical study 
center. Study center staff will directly observe the administration of roluperidone and 
olanzapine, as applicable, during both treatment periods to ensure compliance with study 
requirements. Mouth and hand checks will be conducted after dosing to ensure the tablets have 
been swallowed.  
The exact date and time of each dose of roluperidone and olanzapine will be recorded in the 
CRF.  
5.4. 
Labeling 
The cases containing the roluperidone tablets will have a product and study-specific label with 
all the information that meets the applicable regulatory requirements. Dispensing instructions 
will be provided separately in the investigational medicinal product manual.  
Oral olanzapine 10 mg will be available in a tablet form as marketed formulations 
(ZYPREXA 2019) and will be used with no further modifications. 
5.5. 
Storage Conditions 
All study drugs must be stored in a controlled environment at room temperature.  
5.6. 
Drug Accountability 
The clinical 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 subject 


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must be documented on the drug accountability form. Unused or partially used study drug will 
be stored and disposed of according to the sponsor’s instructions. Contents of the study drug 
containers must not be combined. 
Study drug must be handled strictly in 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 must not be disposed of until the sponsor’s site monitor has 
completed drug accountability during an on-site monitoring visit. The return to the sponsor or 
destruction on site of used and unused study drug will 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 subjects participating in the study. Study drug may not be relabeled or reassigned for use by 
other subjects. The investigator agrees to store and dispense the study drug only at the site 
agreed upon with the sponsor. 
5.7. 
Retrieval of Treatment and/or Destruction 
All partially used or unused study drugs will be retrieved by the Sponsor. A detailed treatment 
log of the returned Investigational Product will be established with the Investigator (or the 
Pharmacist) and countersigned by the Investigator and the Monitoring Team. 
The Investigator will not destroy the unused Investigational Product unless the Sponsor 
provides written authorization to the contrary. 
A potential defect in the quality of Investigational Product may be subject to initiation by the 
Sponsor of a recall procedure. In this case, the Investigator will be responsible for promptly 
addressing any request made by the Sponsor in order to recall Investigational Product and 
eliminate potential hazards. 
5.8. 
Concomitant Therapy 
Throughout the study, prescription or nonprescription medications (including vitamins and 
herbal supplements) other than the study drugs are prohibited, except for the following: 
• The use of acetaminophen/antihistamines is allowed until 3 days before treatment 
period 1. Throughout the study, a maximum of 3 doses per day of 500 mg 
acetaminophen, and no more than 3 grams per week, will be allowed for the treatment 
of headache or other pain. If acetaminophen is used, the dose and dosage regimen and 
reason for use will be recorded in the CRF. 
• Rescue medication for agitation (lorazepam) and sleep (zolpidem) is allowed at any 
time during screening and throughout the study. 
Women using hormonal contraceptives as a means of birth control must continue to use the 
same hormonal contraceptives throughout the study. Women using hormone replacement 
therapy (HRT) must continue to use the same HRT throughout the study. 
The sponsor must be notified immediately if prohibited therapies are administered. 
All medications taken by a subject (prescription or nonprescription) other than roluperidone 
will be documented in the CRF. This includes medications taken before and during the study 
through the end-of-study visit. 


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6. 
STUDY EVALUATIONS 
The TIME AND EVENTS SCHEDULE summarizes the frequency and timing of 
pharmacokinetic, safety, and other measurements. Prior to engaging in any study procedure, 
each subject must sign and date an informed consent form. 
6.1. 
Study Procedures 
Adverse event assessment will be recorded on the CRF throughout the study from the time of 
informed consent form signature. Concomitant medication and AE assessments will be 
recorded on the CRF throughout the study.  
6.1.1. Screening Phase 
During the screening phase subjects and their legal representatives must provide written 
informed consent before any study evaluations are performed or any laboratory samples are 
collected. After written informed consent is obtained, subjects will be evaluated for study 
eligibility during the screening period. A complete medical history will be documented, and a 
complete physical examination will be conducted, including measurement of vital signs, 
electrocardiogram (triplicate ECG), body weight, and height. Hematology, clinical chemistry, 
serology, and urinalysis will be performed for all subjects, as well as verification of CYP2D6 
genotype (confirmed by study-specific testing). AIMS, 
CGI-S, BARS, 
, and 
C-SSRS will also be administered. All psychotropic drugs must be discontinued by Day -2; the 
time and rate of psychotropic discontinuation will be at the discretion of the investigator. 
6.1.2. Admission to Clinical Site 
Subjects will be admitted to the research site on Day -2. Patients will remain inpatient at the 
clinical site at least through the end of Treatment Phase 2. 
6.1.3. Baseline Visit 
At the Baseline visit on Day -1, subjects will complete admission procedures and confirm 
eligibility for enrollment. Vital signs, electrocardiogram (3 sets of triplicate ECG), body 
weight, and height will be measured. Laboratory samples for hematology, clinical chemistry, 
and urinalysis (by dipstick) will be performed for all subjects. AIMS, 
 CGI-S, BARS, 
 and C-SSRS will also be administered.  
6.1.4. Treatment Phase 1 
In Treatment Phase 1, beginning on Day 1, subjects will receive 64 mg roluperidone each day 
at approximately the same time (between approximately 7:00 and 10:00 AM), followed by 
sequential collection of blood samples for measurement of plasma concentrations of 
roluperidone and ECG assessments, until Day 7. On Days 1 and 7, subjects will receive the 
study drug after fasting for at least 9 hours starting the night before. Subjects will receive 
standardized light meals approximately 2 hours after dosing. Vital signs, ECGs (in triplicate), 
and PK samples at specified time points will be collected throughout Treatment Phase 1. AIMS, 
 CGI-S, BARS, 
C-SSRS will be administered on Day 7. Subjects will remain 
at the clinic after Day 7 to continue Treatment Phase 2. 


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6.1.5. Treatment Phase 2 
In Treatment Phase 2, beginning on Day 8 subjects will receive study drugs (roluperidone and 
olanzapine) each day at approximately the same time followed by sequential collection of blood 
samples for measurement of plasma concentrations of both drugs and ECG assessments until 
Day 17. On Day 17, subjects will receive the study drug after fasting for at least 9 hours starting 
the night before. Subjects will receive standardized light meals approximately 2 hours after 
dosing. Vital signs, ECGs (in triplicate), and PK samples at specified time points will be 
collected throughout Treatment Phase 2. AIMS, BARS, and 
will be administered on 
Day 8, and AIMS, 
CGI-S, BARS, 
 C-SSRS will be administered on Day 17. 
Subjects may be released from the clinic after the collection of the last plasma sample (at least 
48 hours after the last administration of the study drugs); however the inpatient period may be 
extended at the discretion of the investigator. 
6.1.6. End of Study/Early Termination 
All subjects will return to the site for subsequent EOS assessments 14 (+ 2) days after receiving 
their last dose in Treatment Phase 2.  
If a subject is terminated early from the study, a PK sample and a blood sample for chemistry 
and hematology will be drawn as soon as possible together with any relevant safety 
assessments. 
6.2. 
Collection of Blood 
The maximum amount of blood drawn per subject in this study will not exceed 500 mL for 
subjects who complete the study. Repeat or unscheduled samples may be taken for safety 
reasons. 


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Table 1:  Volume of Blood to be Collected from Each Subject 
Type of Sample 
Volume per 
Sample 
(mL) 
No. of 
Samples 
per 
Subject 
Total 
Volume of 
Blooda 
(mL) 
Safety (including screening and post-treatment 
assessments) 
 
 
 
- Hematology 
4 
5 
20 
- Clinical chemistryb 
8.5 
5 
42.5 
- Genotyping 
4 
1 
4 
Pharmacokinetic samples (roluperidone / BFB-520)  
2.5 
70 
175 
Pharmacokinetic samples (olanzapine) 
3 
35 
105 
Loss by use of indwelling intravenous cannula 
2 
1 
2 
Total: 
348.5 
a Calculated as number of samples multiplied by amount of blood per sample. 
b Clinical chemistry includes lipids, serology, serum -hCG pregnancy tests & FSH, as applicable. 
Note: An indwelling intravenous cannula may be used for blood sample collection. If a mandarin (obturator) 
is used, blood loss due to discard is not expected. 
 
If blood samples are collected via an indwelling cannula, an appropriate amount (ie, 1 mL) of 
fluid slightly more than the dead space volume of the lock will be removed from the cannula 
and discarded before each blood sample is taken. After blood sample collection, the cannula 
will be flushed with 0.9% pharmaceutical grade for injection sodium chloride, or sodium 
heparin of 100 U/mL (where applicable) and charged with a volume equal to the dead space 
volume of the lock.  
6.3. 
Pharmacokinetic Evaluations 
6.3.1. Sample Collection and Handling 
Blood samples for determination of roluperidone and its metabolite, BFB-520, as well as 
olanzapine plasma concentrations will be collected at the time points indicated in the TIME 
AND EVENTS SCHEDULETIME AND EVENTS SCHEDULE. The exact dates and times 
of blood sample collection must be recorded in the CRF. 
6.3.2. Analytical Procedures 
Plasma samples will be stored at -80C until analysis. Plasma samples will be analyzed to 
determine concentrations of roluperidone and its metabolite, BFB-520, as well as olanzapine 
using validated, specific, and sensitive liquid chromatography/mass spectrometry methods 
under the supervision of the sponsor’s bioanalytical facility or designee.  
Plasma samples will be disposed of after the clinical study report is finalized. 
6.3.3. Pharmacokinetic Parameters 
Pharmacokinetic analysis will be the responsibility of the sponsor in accordance with the 
current Clinical Pharmacokinetics Guideline. The following key plasma PK parameters will be 
calculated using non-compartmental methods: 
Cmax 
observed maximum plasma concentration (ng/mL) 
Tmax 
time to reach the observed maximum plasma concentration (h) 




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Adverse Events 
Adverse events will be reported by the subject for the duration of the study. Adverse events 
will be followed by the investigator as specified in Section 9. 
Clinical Laboratory Tests  
Blood samples for serum chemistry (collected after an overnight fast) and hematology and 
urine samples for urinalysis will be collected according to the TIME AND EVENTS 
SCHEDULE.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the adverse event section of the CRF. 
The following tests will be performed by the designated laboratory. 
• 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 
 
If dipstick result is abnormal, the sediment will be examined microscopically. 
• Hematology: 
- hemoglobin 
- platelet count 
- hematocrit 
- red blood cell (RBC) count 
- white blood cell (WBC) count 
 with differential 
 
• Serum Chemistry: 
 
- sodium 
-  lactic acid dehydrogenase (LDH) 
- potassium 
-  uric acid 
- chloride 
-  calcium  
- magnesium 
-  prolactin 
- blood urea nitrogen (BUN) 
-  phosphorous (inorganic) 
- creatinine 
-  albumin  
- glucose (fasting) 
-  total protein  
- aspartate aminotransferase (AST) 
-  cholesterol (total) 
- alanine aminotransferase (ALT) 
-  triglycerides  
-  total bilirubin 
-  high density lipoprotein (HDL) 
- alkaline phosphatase 
-  low density lipoprotein (LDL) 
- gamma-glutamyl transferase (GGT) 
 
- creatine phosphokinase (CPK)   
 


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• In women of childbearing potential, a serum pregnancy will be performed at Screening, 
Day -1, Day 17 and the EOS visit (refer to the TIME AND EVENTS SCHEDULE). 
Additional urine pregnancy tests may be conducted throughout the study, as determined by 
the investigator, to establish the absence of pregnancy during the study. 
• Women of non-childbearing potential and post-menopausal as defined by spontaneous 
amenorrhea for at least 6 months but less than 1 year will provide a blood sample for FSH 
testing as screening. 
• Serology (HBsAg, HBcAg, hepatitis C antibody, and HIV antibodies 1 and 2) at Screening.  
• Tuberculosis testing will occur at Screening. 
• Urine drug screen and alcohol breath test: potential subjects will be tested for drugs of 
abuse (cocaine, methadone, amphetamines, cannabinoids, opiates, benzodiazepines, 
barbiturates, tricyclic antidepressants) and alcohol according to the TIME AND EVENTS 
SCHEDULE. If the results of the urine drug screen or the alcohol breath test are positive 
at Screening or Baseline, the subject will not be enrolled.  
Vital Signs  
Vital signs will include supine blood pressure, pulse, oral/tympanic temperature, and 
respiratory rate. 
Standing and supine blood pressure and pulse will be taken after the subject has been resting 
quietly for 5 minutes. Blood pressure and pulse should be taken in the arm with the 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. After blood 
pressure has been assessed in the supine position, blood pressure will be re-measured within 3 
minutes of standing). 
Electrocardiogram 
ECG will be recorded in triplicate (1 minute apart within 5 minutes). During the collection of 
ECG data, subjects should be in a quiet setting without distractions (eg, television, cell phones). 
Subjects should rest in a supine position for at least 10 minutes before ECG collection and 
should refrain from talking or moving arms or legs. If blood sampling or vital sign measurement 
is scheduled for the same time point as ECG recording, the ECG should be performed first, 
followed by vital sign measurements, and blood draws.  
Three 12-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, reasonableness and online safety assessment.  
ECGs will be overread by an ECG central reader. The following ECG intervals will be 
measured: RR, PR, QRS, and QT. Electrocardiogram monitoring will include the evaluation of 
lengthening of QTcF. A qualitative assessment of the T-wave morphology will be made by the 
central reader. 
If a significant prolongation in QT is observed, a PK sample should be obtained. 
Physical Examination 
Physical examinations as well as anthropomorphic measurements (height and weight) will be 
performed at the times specified in the TIME AND EVENTS SCHEDULE. 
Any abnormalities present at Baseline, or subsequent changes, will be documented in the 


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appropriate sections of the CRF. 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. 
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 SCHEDULE. 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 
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 5: Abnormal Involuntary Movement Scale (AIMS) for an example of the 
AIMS. 
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 SCHEDULE. 
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-


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patients on maintenance medication.  Subsequently, its validity and reliability have been 
established, and it has been used extensively in clinical studies worldwide. 
See ATTACHMENT 6: Barnes Akathisia Rating Scale (BARS) for an example of the BARS. 
C-SSRS is a measure used to identify and assess individuals at risk for suicide. Questions are 
phrased for use in an interview format but can be completed as a self‐report measure if 
necessary. The C‐SSRS measures four constructs: the severity of ideation, the intensity of 
ideation, behavior, and lethality. It includes “stem questions,” which if endorsed, prompt 
additional follow‐up questions to obtain more information. 
See ATTACHMENT 7: Columbia Suicide Severity Rating Scale (C-SSRS) for an example of 
the C-SSRS. 
7. 
SUBJECT COMPLETION/WITHDRAWAL 
7.1. 
Completion 
A subject will be considered to have completed the study if he or she completed all required 
assessments at Day 19. Subjects who prematurely discontinue for any reason before completion 
of Day 19 will not be considered to have completed the study.  
7.2. 
Stopping Criteria 
Subjects who meet any of the following stopping criteria will be discontinued from the study: 
1. 
 
 
 
 
 
 
 
 
 
  
2. CGI-S worsening of more than 2 points.  
3. Suicidal ideations or behavior.  
4. Occurrence of an AE, which could jeopardize the subject’s health as per investigator 
opinion.  
5. Worsening of psychotic symptoms or occurrence of any dangerous behavior against 
self or others as per investigator opinion.  
6. Significant increase in ALT (ie, > 5 × ULN).  
7. Abnormal laboratory results with simultaneous increases of total bilirubin (> 2 × ULN), 
ALT or AST (> 3 × ULN) with AP (< 1.5 × ULN).  
8. Sustained mean QTcF value > 500 msec (confirmed by a second ECG under strict 
resting position and at minimum at 30-minute duration from the first measurement). 
The subject’s treatment must be discontinued until mean QTcF values are obtained 
from the ECG central reader. If values are confirmed, the subject must be discontinued 
from the study; if not, the study treatment may be restarted at the discretion of the 
investigator.  
9. 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 30-minute duration 
from the first measurement). The subject’s treatment must be discontinued until mean 
QTcF values are obtained from the ECG central reader. If values are confirmed, the 
subject must be discontinued from the study; if not, the study treatment may be restarted 
at the discretion of the investigator. 


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10. The subject requires treatment with another therapeutic agent that had been 
demonstrated to increase the QT interval or inhibit CYP2D6. In this case, 
discontinuation from the study should occur prior to the introduction of the new agent.  
11. The subject experiences a syncope or severe dizziness not explained by other known 
causes, eg, documented orthostatic hypotension, Ménière disease.  
12. The subject has an overt seizure or reports seizure-like activity (loss of consciousness, 
uncontrollable tremor not due to extrapyramidal symptoms).  
The study will be stopped if 4 or more subjects are discontinued due to any of the criteria, 
except stopping criterion 4 if the AE is considered to be definitely not related to study drug and 
stopping criteron 10. 
7.3. 
Withdrawal from the Study and Replacement 
The subjects have the right to withdraw from the study at any time for any reason, without the 
need to justify. Additionally, the investigator may withdraw the subject acording to clinical 
judjment. 
A subject will be withdrawn from the study for any of the following reasons: 
• Subject withdraws consent 
• Lost to follow-up 
• Termination of the study 
• The investigator believes that for safety reasons (eg, adverse event) it is in the best interest 
of the subject to stop treatment 
• The subject becomes pregnant 
• Failure to use an acceptable method of birth control  
• Significant deviation from the protocol  
• Occurrence of a treatment-related SAE 
• Concurrent illness and requirement of a prohibited medication 
• The subject meets any of the stopping criteria listed in Section 7.2. 
If a subject is lost to follow-up, every possible effort will be made by study center staff to 
contact the subject and determine the reason for discontinuation; this information will be 
recorded on the subject’s CRF. 
If a subject withdraws before completing the study, the reason for withdrawal will be 
documented on the subject’s CRF and in the source document. Study drug assigned to the 
withdrawn subject may not be assigned to another subject. 
Should the sponsor elect to replace subjects who withdraw before they complete all study 
procedures, the replacement subjects will be of the same gender as the subjects they are 
replacing. A replacement subject will be assigned a new identification number which will be 
equal to the identification number of the subject being replaced plus 500. Replacement subjects 
will be assigned to the same treatment-sequence as the subjects they are replacing. 
Replacement subjects will start with Treatment Period 1. 
8. 
STATISTICAL METHODS  
This statistical plan may be revised during the study to accommodate protocol amendments 
and to make changes to adapt to unexpected issues in study execution and data that could affect 






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product, whether or not related to that medicinal (investigational or non-investigational) 
product (Definition per International Council for 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. 
Serious Adverse Event 
An SAE is defined as any AE that results in any of the following: 
• Death:  The subject died as the result of the event. 
• Life-threatening event:  Any AE that places the subject, in the view of the Investigator 
or Sponsor, at immediate risk of death from the AE as it occurred, ie, 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 subject 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 subject 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 subject or may require intervention to prevent one of the outcomes listed in 
the definition above (eg, suspected transmission of an infectious agent by a medicinal product 
is considered a serious adverse event). Any adverse event is considered a serious adverse event 
if it is associated with clinical signs or symptoms judged by the investigator to have a 
significant clinical impact. 
Adverse Event of Special Interest 
AESIs are defined as the any of the following events: 
• Syncope 
• Sudden death, cardiac death 
• TdP, QT/QTc prolongation, long QT syndrome 
• ECG T wave and U wave abnormalities 
• Ventricular arrhythmia, tachycardia, fibrillation / flutter 


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Suspected Unexpected Serious Adverse Reactions (SUSARs) Event/Reference Safety 
Information 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are believed to be 
related to the study drug and are both unexpected (ie, the nature or severity is not expected 
from the information provided in the Investigator’s Brochure) and serious. SUSARs are subject 
to expedited reporting to the appropriate competent authorities.  
Adverse Drug Reaction 
An adverse drug reaction is any AE where a causal relationship with the study drug is at least 
a reasonable possibility (possibly, probably or definitely related as by the definitions listed 
below). 
9.1.2. Assessment of Causality 
Every effort should be made by the investigator to try to explain each AE and assess its 
relationship, if any, to the study drug. The temporal relationship of the event to study drug 
administration should be considered in the causality assessment (ie, if the event starts soon 
after study drug administration and resolves when the study drug is stopped). 
Causality should be assessed using the following categories. 
Unrelated: An adverse event that is not related to the use of the drug. 
Possibly/probably related: An adverse event that might be due to the use of the drug. An 
alternative explanation, eg, 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 adverse event that cannot be reasonably explained by an alternative explanation, 
eg, concomitant drug(s), concomitant disease(s). The relationship in time is very suggestive. 
9.1.3. 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 subject (eg, laboratory abnormalities).  


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9.1.4. Action Taken and Outcome  
For all AEs reported, the following will also be specified: 
• Actions taken: none, medication required, tests required, hospitalization required or 
prolonged, study drug withdrawn, other-specify   
• Outcome and date of outcome according to the following definitions: 
• Recovered/resolved 
• Recovering/resolving 
• Not recovered/not resolved 
• Recovered with sequelae/resolved with sequelae 
• Fatal 
• Unknown 
• Seriousness: yes or no (criteria for SAE see above) 
9.2. 
Procedures 
9.2.1. All Adverse Events 
All adverse events, 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). Serious adverse events, including those 
spontaneously reported to the investigator within 30 days after the last dose of study drug, must 
be reported using the Serious Adverse Event 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 serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments.  
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
therapy, must be recorded using medical terminology in the source document and the CRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported 
as “upper respiratory infection”). Investigators must record in the CRF their opinion concerning 
the relationship of the adverse event 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 adverse events to the 
regulatory authorities. The sponsor will also report to the investigator all serious adverse events 
that are SUSARs. The investigator (or sponsor where required) must report these events to the 
appropriate Institutional Review Board (IRB) that approved the protocol unless otherwise 
required and documented by the IRB.  
Subjects 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. 
9.2.2. Serious Adverse Events 
All serious adverse events occurring during clinical studies must be reported to the appropriate 
sponsor contact person and pharmacovigilance provider by investigational staff within 
24 hours of their knowledge of the event. 


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Information regarding serious adverse events will be transmitted to the sponsor using the 
Serious Adverse Event 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 serious adverse event should be made by facsimile (fax) or e-mail. 
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject’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 (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts) 
The cause of death of a subject in a clinical study, whether or not the event is expected or 
associated with the investigational agent, is considered a serious adverse event. Suspected 
transmission of an infectious agent by a medicinal product should be reported as a serious 
adverse event.  
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a subject’s participation in a clinical study must be reported as a serious adverse 
event, except hospitalizations for surgery or procedure planned before entry into the study 
(must be documented in the CRF).  
9.2.3. 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 serious adverse events and must be 
reported using the Serious Adverse Event Form. Any subject 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 
subjects 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. 
9.3. 
Reporting 
9.3.1. Reporting Serious Adverse Events to the Sponsor 
The investigator is required to notify the study sponsor and pharmacovigilance provider within 
24 hours of becoming aware of the occurrence of an SAE. In accordance with ICH guidelines 
for Good Clinical Practice (GCP), a copy of the written report of the event should promptly be 
sent to the study sponsor and pharmacovigilance provider by email. The names and contact 
details of the individuals who should be contacted regarding safety issues or questions 
regarding the study as well as the email address/fax number that must be used to send SAE 


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report form, are listed on the Contact Information page(s), which will be provided as a separate 
document. 
9.3.2. Reporting of Suspected Unexpected Serious Adverse Reactions 
(SUSARs) 
It is the responsibility of the sponsor, with the pharmacovigilance provider, to determine 
whether a reported SAE fits the classification of a SUSAR. 
9.3.3. Expedited Reporting of Events 
Where expedited reporting is required, the following procedures should be followed. 
Fatal or life-threatening SUSARs  
It is the responsibility of the sponsor, via the pharmacovigilance provider, to report fatal or life-
threatening SUSARs to the appropriate competent authorities, IRB/EC as soon as possible, but 
no later than 7 calendar days after they first became aware of the reaction. 
The investigator is required to notify the EC of any fatal or life-threatening SUSAR as soon as 
possible, but no later than 7 calendar days after they first became aware of the reaction.  
Any additional relevant information should be sent within 8 days of the report. 
Other SUSARs 
It is the responsibility of the sponsor, via the pharmacovigilance provider, to report other 
SUSARs to the appropriate competent authorities, and IRB/Ethics Committee (EC) as soon as 
possible, but no later than 15 calendar days after they first became aware of the reaction. 
The investigator is required to notify the EC of any other SUSAR as soon as possible, but no 
later than 15 calendar days after they first became aware of the reaction. 
9.4. 
Reporting of Urgent Safety Issues 
The sponsor is required to inform the appropriate competent authorities, investigators, and ECs 
within 3 calendar days of the urgent safety issue. 
10. 
SERIOUS BREACHES 
It is the responsibility of the sponsor to notify the competent/licensing authority of any serious 
breach that is likely to affect, to a significant degree, the safety or mental integrity of the 
subjects in the study or the scientific value of the study. 
All serious breaches will be communicated to the appropriate competent authorities within 7 
days. The reporting will be performed by the party who suspects the serious breach.  


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11. 
STUDY-SPECIFIC MATERIALS 
The investigator will be provided with the following supplies: 
• Investigator Brochure 
• Pharmacy manual 
• Laboratory manual 
• CRF and infrastructure 
• Pharmacokinetic blood sampling supplies 
• Subject education material 
12. 
ETHICAL ASPECTS 
12.1. 
Study-Specific Design Considerations 
This study is being conducted to evaluate the pharmacokinetics, pharmacodynamics, safety, 
and tolerability of roluperidone and olanzapine. 
This study will be performed in subjects with schizophrenia who will receive no benefit from 
participation in the study.  Subjects will be exposed to an investigational drug that may have 
adverse effects, such as headache, nausea, postural hypotension and somnolence. In addition 
they will be exposed to a marketed drug olanzapine which may induce well known adverse 
effects such as EPS, sedation, constipation, blurry vision, weight gain. In this and all clinical 
pharmacokinetic studies, there are risks associated with the collection of multiple blood 
samples. 
Potential subjects will be fully informed of the risks and requirements of the study and, during 
the study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study may be withdrawn 
at any time with no reason given and without penalty or loss of benefits to which they would 
otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled. No 
undue incentives will be provided. 
Safety of Dose 
The potential risks to subjects in this study include exposure to study drugs, with a potential 
for side effects, and the inherent risks associated with venipuncture and multiple blood sample 
collection. Multiple dose, chronic exposure studies with 64 mg roluperidone have been 
conducted (Study MIN-101C03 and Study MIN-101C07), and 64 mg roluperidone was overall 
well tolerated. Rare instances of QTc prolongation were noted in the 64 mg dose group in the 
MIN-101C03 and MIN-101C07 studies. In a recently completed study in healthy subjects, 
doses up to 256 mg of the GR formulation were well-tolerated. Non-clinically significant 
increase in QTcF were observed from the 160 mg dose onwards. Subjects in this study will 
receive a single dose of 64 mg, which was found to be well-tolerated in healthy volunteers and 
in subjects with schizophrenia. All subjects will be closely monitored for adverse events 
throughout the study. In addition, expert investigators will be chosen to conduct the study. 
Measures will be taken to ensure that all subjects will be closely supervised for anticipated side 
effects known to occur in healthy subjects, such as those cited in Section 0. Subjects will be 
confined to the study center with close ECG monitoring. 
Pharmacokinetic Blood Sampling 


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To avoid multiple venipunctures, which cause additional discomfort and other potentially toxic 
effects, the use of intravenous indwelling catheters is permitted in this study. The blood sample 
collection scheme was designed to collect the minimum number of blood samples that 
accurately and completely describe the pharmacokinetics of the study drug. This minimizes the 
number of venipunctures and the total volume of blood collected from each subject during the 
study. The total amount of blood to be drawn is less than of what is collected during a routine 
blood donation (500 mL) and, thus, is an acceptable amount of blood to be collected over this 
time period from the population in this study. 
Capacity to Provide Informed Consent 
Only subjects who are fully able to understand the risks, benefits, potential adverse events, and 
alternatives to participation, provide their consent voluntarily, and are not hospitalized 
involuntarily will be enrolled. Subjects may withdraw their consent at any time without having 
to give a reason. 
Risk Assessment for SAR-CoV2 
This study will enroll healthy subjects between the ages of 18-55 years who are not at an 
increased risk for developing the symptoms of SAR-CoV2 infection. Subjects will be tested 
for the virus at Screening and prior to the institutionalization. If a subject is positive for the 
virus at Screening or prior to admission, he/she will not be permitted to enroll in the study.  
12.2. 
Regulatory Ethics Compliance 
12.2.1. Investigator Responsibilities 
The investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH guidelines on GCP, and applicable regulatory and country-
specific requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being 
of study subjects are protected, consistent with the principles that originated in the Declaration 
of Helsinki and that the clinical study data are credible. 
12.2.2. Institutional Review Board (IRB) / Ethics Committee (EC) 
Before the start of the study, the investigator (or sponsor where required) will provide the 
IRB/EC 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 subjects) 
• Investigator’s Brochure (or equivalent information) and amendments 
• Sponsor-approved subject recruiting materials 
• Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable 
• Investigator’s curriculum vitae or equivalent information (unless not required, as 
documented by IRB/EC) 


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• Information regarding funding, name of the sponsor, institutional affiliations, other 
potential conflicts of interest, and incentives for subjects 
• Any other documents that the IRB/EC requests to fulfill its obligation. 
This study will be undertaken only after the IRB/EC has given full approval of the final 
protocol, amendments (if any), the informed consent form, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IRB/EC and the documents being 
approved. 
During the study, the investigator (or sponsor, where required) will send the following 
documents and updates to the IRB/EC for their review and approval, where appropriate:  
• Protocol amendments 
• Revision(s) to informed consent form and any other written materials to be provided to 
subjects 
• If applicable, new or revised subject recruiting materials approved by the sponsor 
• Revisions to compensation for study-related injuries or payment to subjects 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 IRB/EC (at 
least annually) 
• Reports of adverse events that are serious, unexpected, and related with the investigational 
drug 
• New information that may adversely affect the safety of the subjects or the conduct of the 
study 
• Deviations from or changes to the protocol to eliminate immediate hazards to the subjects 
• Report of deaths of subjects 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 IRB/EC 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data, or trial conduct), the amendment and applicable informed 
consent form revisions must be submitted promptly to the IRB/EC 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 IRB/EC 
about the study completion. 
12.2.3. Informed Consent 
Each subject 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 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. 


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Before enrollment in the study, the investigator or an authorized member of the investigational 
staff must explain to potential subjects the aims, methods, reasonably anticipated benefits, and 
potential hazards of the study, and any discomfort participation in the study may entail. Subjects 
will be informed that their participation is voluntary and that they may withdraw consent to 
participate at any time. Finally, they will be told that the investigator will maintain a subject 
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 subject) is authorizing such access and agrees to allow his or her 
study physician to re-contact the subject for the purpose of obtaining consent for additional 
safety evaluations, if needed, or to obtain information about his or her survival status. 
The subject 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 the subject's personally dated signature. After having 
obtained the consent, a copy of the informed consent form must be given to the subject. 
If the subject 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 subject 
is obtained. 
12.2.4. Privacy of Personal Data 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to investigate 
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 whose responsibilities require access to personal data agree 
to keep the identity of study subjects confidential. 
The informed consent obtained from the subject 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, IRB review, and regulatory inspection. This 
consent also addresses the transfer of the data to other entities and to other countries. 
The subject 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 
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. 
12.2.5. Country Selection 
This study is being conducted in the US. 
13. 
ADMINISTRATIVE REQUIREMENTS 
13.1. 
Protocol Amendments 
Neither the investigator nor the sponsor will modify this protocol without a formal amendment. 


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All protocol amendments must be issued by the sponsor and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the subjects, in which case the amendment must 
be promptly submitted to the IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IRB must be provided to the sponsor or its 
designee.  
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. 
13.2. 
Regulatory Documentation 
13.2.1. 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. 
13.2.2. 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 
• A copy of the dated and signed written IRB/EC 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 IRB/EC, including a current list of the IRB/EC 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 IRB/EC, a general statement may be substituted for this list. If an investigator or 
a member of the investigational staff is a member of the IRB/EC, 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 (eg, 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 
subject: 


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• Documentation of subinvestigator qualifications (eg, 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 
(eg, accreditation/license), if applicable. 
13.3. 
Subject Identification, Enrollment, and Screening Logs 
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by 
the sponsor site contact for completeness. 
The subject identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file. To ensure subject confidentiality, no copy will be made. 
All reports and communications relating to the study will identify subjects by initials and 
assigned number only. 
The investigator must also complete a subject-screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study. 
13.4. 
Source Documentation 
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: subject identification, eligibility, and study identification; study 
discussion and date of informed consent; dates of visits; results of safety 
 
parameters as required by the protocol; record of all adverse events; and follow-up of adverse 
events; 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.  
It is recommended that the author of an entry in the source documents be identifiable. 
At a minimum, the type and level of detail of source data available for a study subject 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). 
13.5. 
Case Report Form Completion 
Case report forms are provided in electronic format for each subject who was randomized and 
received at least one dose of study drug. Screen failures will not be entered.  
Data must be entered into CRFs in English. The investigator must verify that all data entries in 
the CRFs are accurate and correct. All CRF entries, corrections, and alterations must be made 
by the investigator or other authorized study-site personnel. 
13.6. 
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.  


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Guidelines for CRF completion will be provided and reviewed with study personnel before the 
start of the study.  
The sponsor will review CRFs 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 the upload of the data into the clinical study database they 
will be verified for accuracy.  
13.7. 
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 subject, 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. 
13.8. 
Monitoring 
On-site monitoring visits will be performed 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 after enrollment has begun. At these visits, the monitor 
will compare the data entered into the CRFs 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 CRF 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 CRF are consistent with the original source data. Findings 
from this review of CRF 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 


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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. 
13.9. 
Study Completion/Termination 
13.9.1. Study Completion 
The study is considered completed with the last visit of the last subject participating in the 
study. The final data from the investigational site will be sent to the sponsor (or designee) after 
completion of the final subject visit at that site. The investigational site will be closed upon 
study completion. The investigational site is considered closed when all required documents 
and study supplies have been collected and a site closure visit has been performed. 
13.9.2. 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. The 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 subjects by the investigator 
• Discontinuation of further drug development. 
13.10. 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 CRF. Subject 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. 
13.11. Use of Information and Publication 
All information, including but not limited to information regarding roluperidone or the 
sponsor’s operations (eg, 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. 


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The investigator understands that the information developed in the clinical study will be used 
by the sponsor in connection with the continued development of roluperidone, 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 CRF 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 
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.  
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. 
13.12. 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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14. 
REFERENCES 
Ahmed AO, Kirkpatrick B, Granholm E, et al. Two factors, five factors, or both? External validation 
studies of negative symptom dimensions in schizophrenia. Schizophr Bull. 2022;48(3):620-630. 
Artaloytia JF, Arango C, Lahti A, et al. Negative signs and symptoms secondary to antipsychotics: a 
double-blind, randomized trial of a single dose of placebo, haloperidol, and risperidone in healthy 
volunteers. Am J Psychiatry. 2006;163:488-493. 
Axelrod BN, Goldman RS, Alphs LD. Validation of the 16-item negative symptom assessment. J Psych 
Res. 1993;27:253-258. 
Barnes TRE. A Rating Scale for Drug-Induced Akathisia.  Brit J Psychiatry. 1989;154(5):672-676.  
Bègue I, Kaiser S, Kirschner M. Pathophysiology of negative symptom dimensions of schizophrenia - 
current developments and implications for treatment. Neurosci Biobehav Rev. 2020;116:74-88. 
Bobes J, Arango C, Garcia-Garcia M, Rejas J, CLAMORS Study Collaborative Group. Prevalence of 
negative symptoms in outpatients with schizophrenia spectrum disorders treated with antipsychotics in 
routine clinical practice: Findings from the CLAMORS study. J Clin Psychiatry. 2010;71:280-286. 
Carpenter WT Jr, Buchanan RW. Negative symptom therapeutics. Schizophr Bull. 2017;43:681-682. 
Cohen AS, Schwartz E, Le TP, et al. Digital phenotyping of negative symptoms: the relationship to 
clinician ratings. Schizophr Bull. 2021;47:44-53. 
Devoe DJ, Lu L, Cannon TD, et al. Persistent negative symptoms in youth at clinical high risk for 
psychosis: a longitudinal study. Schizophrenia Res. 2021;227:28-37. 
Foussias G, Agid O, Fervaha G, et al. Negative symptoms of schizophrenia: clinical features, relevance 
to real world functioning and specificity versus other CNS disorders. Eur Neuropsychopharmacol. 
2014;24:693-709. 
Galderisi S, Mucci A, Buchanan R, et al. Negative symptoms of schizophrenia: new developments and 
unanswered research questions. Lancet Psychiatry. 2018;5:664-677. 
Giordano GM, Caporusso E, Pezzella P, et al. Updated perspectives on the clinical significance of 
negative symptoms in patients with schizophrenia. Exp Review Neurother. 2022. 
Kirkpatrick B, Strauss GP, Nguyen L, et al. The brief negative symptom scale: psychometric properties. 
Schizophr Bull. 2011;37(2):300-5. 
Kirkpatrick B. Developing concepts in negative symptoms: primary vs secondary and apathy vs 
expression. J Clin Psychiatry. 2014;75:3-7. 
Kirkpatrick B, Mucci A, Galderisi S. Primary, enduring negative symptoms: an update on research. 
Schizophr Bull. 2017;43:730-736. 
Kirschner M, Aleman A, Kaiser S. Secondary negative symptoms-a review of mechanisms, assessment 
and treatment. Schizophr Res. 2017;186:29-38. 
Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia 
derived by factor analysis: combined results of the North American trials. J Clin Psychiatry. 
1997;58(12):538-46. 
Messinger JW, Trémeau F, Antonius D, et al. Avolition and expressive deficits capture negative 
symptom phenomenology: implications for DSM-5 and schizophrenia research. Clin Psychol Rev. 
2011;31(1):161-8. 
ZYPREXA (olanzapine) Tablet for Oral Use Package Insert. Eli Lilly and Company. Rev. 2019. 


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Piskulic D, Addington J, Cadenhead KS, et al. Negative symptoms in individuals at clinical high risk 
of psychosis. Psychiatry Res. 2012;196:220-224. 
Simeone JC, Ward AJ, Rotella P, et al. An evaluation of variation in published estimates of 
schizophrenia prevalence from 1990─2013: a systematic literature review. BMC Psychiatry. 
2015;15:193. 
Sauvé G, Brodeur MB, Shah JL, et al. The prevalence of negative symptoms across the stages of the 
psychosis continuum. Harv Rev Psychiatry. 2019;27:15-32. 
Strauss GP, Harrow M, Grossman LS, et al. Periods of recovery in deficit syndrome schizophrenia: a 
20-year multi-follow-up longitudinal study. Schizophr Bull. 2010;36:788-799. 
Strauss GP, Zamani Esfahlani F, Sayama H, et al. Network analysis indicates that avolition is the most 
central domain for the successful treatment of negative symptoms: evidence from the roluperidone 
randomized clinical trial. Schizophr Bull. 2020;46(4):964-970. 
Strauss GP, Bartolomeo LA, Harvey PD. Avolition as the core negative symptom in schizophrenia: 
relevance to pharmacological treatment development. NPJ Schizophr. 2021;7(1):16. 
Trémeau F, Nolan KA, Malaspina D, Javitt DC. Behavioral validation of avolition in schizophrenia. 
Schizophr Res. 2012;138(2-3):255-61. 
White L, Harvey PD, Opler L, Lindenmayer JP. Empirical assessment of the factorial structure of 
clinical symptoms in schizophrenia. A multisite, multimodel evaluation of the factorial structure of the 
Positive and Negative Syndrome Scale. The PANSS Study Group. Psychopathology. 1997;30(5):263-
74. 
Yung AR, Nelson B, McGorry PD, et al. Persistent negative symptoms in individuals at ultra high risk 
for psychosis. Schizophr Res. 2019;206:355-361. 
 
 


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ATTACHMENT 1:  PROHIBITED CONCOMITANT MEDICATIONS 
 
A list of CYP2D6 substrates can be found at:  
https://www.drugbank.ca/categories/DBCAT002623 
 
 
Please note that the following lists of drugs inducing QT prolongation and CYP2D6 
inhibitors are not exhaustive.  
 


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Drugs Inducing QT Prolongation 
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  
hydroxychloroquine 
Levofloxacin 
norfloxacin 
Metronidazole 
Moxifloxacin 
Ofloxacin 
Quinine 
Roxithromycin 
Telavancin 
Telithromycin 
Antifungal 
Amphotericin B 
Fluconazole  
Itraconazole 
Ketoconazole 
Pentamidine 
Posaconazole 
Voriconazole 
Antiviral 
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  
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  
paliperidone 
Pimavanserin 
Pipamperone 
Pimozide 
Promethazine 
Prothipendyl 
Perphenazine  
Quetiapine  
Risperidone 
Sertindole 
Sulpiride 
sultopride 
Thioridazine 
ziprasidone 
Zotepine 
  Antimanic 
Lithium 
  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 
Pasireotide 
Romidepsin 
Solifenacin 
Tacrolimus 
Tamoxifen 
Terlipressin 
Terolidine  
Tetrabenazine 
Tiapride 
Tizanidine  
Tolterodine 
Toremifene 
Vandetanib 
Vardenafil 
Vemurafenib 
Vorinostat 
Underlined: known risk of TdP;  
Highlighted grey: possible risk of TdP;  
Otherwise: conditional risk of TdP: eg, in case of overdose, DDI or electrolytes imbalance. 
 


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55 
CYP2D6 Inhibitors 
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 
Dextropropoxyphene 
Diltiazem 
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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71 
ATTACHMENT 
 CLINICAL GLOBAL IMPRESSION – SEVERITY RATING (CGI-
S) 
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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72 
ATTACHMENT 5: 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 
 
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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73 
ATTACHMENT 6: 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  
1 
Questionable. Non-specific inner tension and fidgety movements  


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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 7: COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) 
 


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INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this 
study. I will conduct the study as outlined herein and will complete the study within the time 
designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible 
to me who assist in the conduct of this study. I will discuss this material with them to ensure 
that they are fully informed regarding the study drug, the conduct of the study, and the 
obligations of confidentiality. 
Coordinating Investigator (where required): 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
 
Principal (Site) Investigator: 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Telephone Number: 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Sponsor’s Responsible Medical Officer: 
 
Name (typed or printed): 
 
 
Institution: 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Note 
If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be 
required. 
 
 

SAP_001.pdf: 
Minerva Neurosciences, Inc. 
MIN-101C18 
Statistical Analysis Plan     
 Final Version 1.0 
STATISTICAL ANALYSIS PLAN 
Study Title: 
A Phase 1b, In-Patient Study to Evaluate the Safety, 
Tolerability, Pharmacodynamics, and Pharmacokinetics of the 
Co-Administration of Roluperidone and Olanzapine in Adult 
Subjects with Moderate to Severe Negative Symptoms of 
Schizophrenia 
Phase: 
1 
Protocol No.: 
MIN-101C18 
Protocol Version and Date 
MIN-101C18 v1.5, 02 November 2023 
Analysis Plan Version and 
Date 
Final v1.0, 07 February 2024 
Prepared By: 
  
 
  
 
Prepared For: 
Minerva Neurosciences, Inc. 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION
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Statistical Analysis Plan                                                                                                          Final Version 
 
 
 
 
CONFIDENTIAL 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL ............................. 2 
TABLE OF CONTENTS ......................................................................................... 3 
1. 
INTRODUCTION ............................................................................................ 5 
1.1. 
Study Overview ...................................................................................................................... 5 
1.2. 
Study Measurements and Visit Schedule ................................................................................. 6 
1.3. 
Glossary of Abbreviation ........................................................................................................ 8 
2. 
OBJECTIVES ................................................................................................ 10 
3. 
GENERAL STATISTICAL CONSIDERATIONS ........................................... 11 
3.1. 
Sample Size and Power ......................................................................................................... 11 
3.2. 
Randomization and Blinding ................................................................................................ 11 
3.2.1. 
Examination of Subject Subsets ...................................................................................... 11 
3.2.2. 
Multiple Testing and Comparisons .................................................................................. 11 
3.2.3. 
Missing Data and Outliers ................................................................................................... 11 
3.2.3.1. 
Missing Dates ...................................................................................................................... 11 
3.2.3.2. 
Imputation of Alphanumeric Data ....................................................................................... 12 
3.2.4. 
Presentations by Time Point............................................................................................ 13 
3.2.5. 
Definitions and Terminology ............................................................................................ 13 
3.3. 
Timing of Analysis ................................................................................................................ 15 
4. 
ANALYSIS POPULATIONS .......................................................................... 16 
4.1. 
Full Set ................................................................................................................................. 16 
4.2. 
Safety Set (SAF) .................................................................................................................... 16 
4.3. 
PK Set .................................................................................................................................. 16 
4.4. 
PK Completer Set ................................................................................................................. 16 
5. 
STATISTICAL METHODS ........................................................................... 16 
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1. 
INTRODUCTION 
This document describes the statistical methods and data presentations to be used in the summary 
and analysis of data from Protocol MIN-101C18. Background information is provided for the overall 
study design and objectives. The reader is referred to the study protocol and electronic case report 
forms (eCRFs) for details of study conduct and data collection. 
1.1. 
STUDY OVERVIEW 
This is a prospective, open-label, one-sequence, inpatient, clinical study of CYP2D6 normal 
metabolizer (NM) subjects with moderate to severe negative symptoms of schizophrenia. be 
coadministered to subjects already being administered roluperidone to determine its effect on the 
PD and PK of roluperidone. Eligible subjects will undergo 3 study phases as follows: 
 
 
Screening Phase: Between 2 and up to 28 days during which study eligibility will be 
established and subjects receiving psychotropics will be washed out. Discontinuation of 
psychotropics must occur at least 2 days prior to the start of Treatment Phase 1 (Day 1). 
Subjects will be admitted to the site on Day -2 and complete a Baseline Visit on Day -1. 
 
Treatment Phase 1: After the Baseline Visit (Day -1), roluperidone 64 mg/day will be 
administered as a monotherapy for 7 days (Days 1-7). 
 
Treatment Phase 2: Concomitant administration of olanzapine 10 mg/day and roluperidone 
64 mg/day for 10 days, starting on Day 8 (Days 8-17). Subjects may be discharged from 
the clinic at least 48 hours after the last administration of the study drugs and after the 
collection of the last plasma sample; however, the inpatient period may be extended at the 
discretion of the investigator. 
 
An End of Study (EOS) visit will take place at least 14 days after the last dose of study treatment. 
After the EOS visit, the medications and clinical care of the subject will be managed as per the 
judgement of the investigator/clinician. 
 
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1.2. 
STUDY MEASUREMENTS AND VISIT SCHEDULE  
Phase 
SCR 
Admis-
sion 
BL 
Treatment Phase 1 
Treatment Phase 2 
EOS/ 
ET 
Study Day 
-28 to -3 
-2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
31 (+2) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion & exclusion criteria 
X 
 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/update 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Institutionalization 
 
 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •  
 
Roluperidone administration 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Olanzapine administration 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital signsb 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Triplicate ECGc 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CYP2D6 genotype 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry & hematology 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Urinalysise 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Drug screen, alcohol test, and 
COVID-19 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samplesf 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
FSH test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
CGI-S 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
BARS 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
AIMS 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
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Phase 
SCR 
Admis-
sion 
BL 
Treatment Phase 1 
Treatment Phase 2 
EOS/ 
ET 
Study Day 
-28 to -3 
-2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
31 (+2) 
Prior & Concomitant 
medications 
X 
 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •  
Adverse events 
X 
 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •  
NOTE: There is no washout period between Treatment Phases. 
Abbreviations: AIMS = abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; BL = baseline; 
; 
CGI-S = Clinical Global Impression – Severity C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EOS = end-of-study; ET = early termination; 
PK = pharmacokinetics; SCR = screening; 
 SCR = screening. 
a Verify eligibility. 
b Vital signs include blood pressure (standing and supine), pulse, oral/tympanic temperature, and respiratory rate. During Treatment Phase 1, vital signs are assessed 
prior to PK sampling at pre-dose and 6 hours post-dose on Days 1-7. During Treatment Phase 2, vital signs are assessed prior to PK sampling at pre-dose and 6 hours 
post-dose on Days 8-17 and 24 hours and 48 hours after last dose of study drug is administered (eg, Days 18 and 19). 
c Three sets of triplicate ECGs (1 minute apart within 5 minutes; total of 9 ECGs are recorded at Baseline (Day -1). Other ECG assessments are recorded in triplicate 
prior to PK sampling. During Treatment Phase 1, ECGs are recorded at pre-dose and 6 hours post-dose on Days 1-7. During Treatment Phase 2, ECGs are recorded 
pre-dose and 6 hours post-dose on Days 8-17 and 24 hours and 48 hours after last dose of study drug is administered (eg, Days 18 and 19). 
d CYP2D6 genotyping to be performed. 
e Urinalysis will be performed by dipstick. Urine will be sent to the laboratory for microscopic analysis only in the event that the dipstick results are abnormal. 
f After vital signs and triplicate ECG. During Treatment Phase 1, PK samples for roluperidone will be obtained at time 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, and 
24 hours post-dose on Days 1 and 7, at 6 hours post dose on Day 2, and at pre-dose and 6 hours post-dose on Days 3-6. During Treatment Phase 2, PK samples for 
roluperidone and olanzapine will be obtained at 6 hours post-dose on Day 8, time 0 (pre-dose) and 6 hours post-dose on Days 9-16, and starting on Day 17 at time 0 (pre-
dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24, 28, 32, 36, and 48 hours post-dose. If a significant prolongation in QT is observed, a PK sample should be obtained. 
 
 
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1.3. 
GLOSSARY OF ABBREVIATION 
AE 
 
Adverse event 
AESI  
Adverse event of special interest 
AIMS  
Abnormal involuntary movement scale 
ALT 
 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST  
 
Aspartate aminotransferase 
ATC 
 
Anatomical Therapeutic Class  
AUC 
 
Area under the plasma concentration-time curve (ng.h/mL) 
AUC0-24 
Area under the plasma concentration-time curve from time 0 to 
concentration C24 at the 24-hour time point (ng.h/mL) 
AUC∞ 
Area under the plasma concentration-time curve from time zero to infinity 
(ng.h/mL) 
BARS 
Barnes akathisia rating scale 
BFB-520 
Metabolite of roluperidone 
BLQ 
 
Below limit of quantitation 
BMI 
 
Body mass index 
BUN 
 
Blood urea nitrogen 
  
 
CGI-S  
Clinical global impression - severity rating 
CI 
 
Confidence interval 
Clast 
 
Last measurable concentration (ng/mL) 
Cmax 
 
Maximum drug concentration (ng/mL) 
CSR 
 
Clinical study report 
C-SSRS 
Columbia suicide severity rating scale 
CV 
 
Coefficient of variation 
CYP2D6 
Cytochrome P450 2D6 enzyme 
ECG 
 
Electrocardiogram 
eCRF  
Electronic case report form 
EOS 
 
End-of-study 
LLN 
 
Lower limit of normal laboratory reference range 
MedDRA 
Medical dictionary for regulatory activities 
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NA 
 
Not applicable 
NM 
 
Normal metabolizer 
  
 
PCS 
 
Potentially clinically significant 
PD 
 
Pharmacodynamic 
PK 
 
Pharmacokinetic 
PT 
 
Preferred term 
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 
SAE 
 
Serious adverse event 
SAF 
 
Safety set  
SARS-CoV 
Severe acute respiratory syndrome coronavirus 2 
SCR 
 
Screening 
SD 
 
Standard Deviation 
SEM 
 
Standard Error of Mean 
SI 
 
Le Système International d'Unités (International System of Units) 
SOC 
 
System Organ Classification 
TEAE  
Treatment-emergent adverse event 
t1/2 
 
Terminal elimination half-life 
Tmax 
 
Time to maximum drug concentration (h) 
UNL 
 
Upper normal limit of laboratory reference range 
WHO  
World Health Organization 
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2. 
OBJECTIVES 
Primary Objective: 
To evaluate the pharmacodynamics (PD), including safety and tolerability of the coadministration of 
roluperidone 64 mg and olanzapine. 
 
 
Adverse events (AEs) 
 
Laboratory evaluations 
 
Physical examination (including weight, baseline height and BMI) 
 
Vital signs (including blood pressure, heart rate, respiratory rate, pulse, temperature)  
 
12-Lead electrocardiograms (ECGs) 
 
Extrapyramidal symptoms (assessed by Abnormal Involuntary Movement Scale (AIMS) and 
Barnes Akathisia Rating Scale (BARS)) 
 
Suicidal ideation (assessed by the Columbia Suicide Severity Rating Scale (C-SSRS)) 
 
Secondary Objective: 
To evaluate the effect of the coadministration of roluperidone and olanzapine on the 
pharmacokinetics (PK) of roluperidone in subjects with moderate to severe negative symptoms of 
schizophrenia. The secondary endpoint, PK, will include the following parameters: 
 
 
PK parameters of roluperidone and its metabolite, BFB-520, following single dose and at 
steady state. 
 
PK parameters of roluperidone and BFB-520 when administered concomitantly with 
olanzapine. 
 
PK parameters of olanzapine administered concomitantly with roluperidone compared to its 
pharmacokinetic profile based on monotherapy administration from published literature. 
 
PK parameters are included but are not limited to the variables given below: 
− Cmax: observed maximum plasma concentration (ng/mL). 
− tmax: time to reach the observed maximum plasma concentration (h). 
− AUC0-24: area under the plasma concentration-time curve from time 0 to 
concentration C24 (ng.h/mL) at the 24-hour time point. 
− AUC∞: area under the plasma concentration-time curve from time 0 to infinite 
time, calculated according to the following equation AUC∞ = AUClast + Clast / λz 
(ng.h/mL), where Clast is the last measurable plasma concentration and λz is the 
terminal elimination rate constant. 
 
 
 
 Clinical Global Impression- Severity 
Rating (CGI-S). 
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3. 
GENERAL STATISTICAL CONSIDERATIONS 
3.1. 
SAMPLE SIZE AND POWER 
The planned sample size is approximately 18 subjects dosed with 64 mg roluperidone in Treatment 
Phase 1 such that at least 12 subjects can complete dosing with 64 mg roluperidone and 10 mg 
olanzapine during Treatment Phase 2. The selected sample size is sufficient to calculate the 90% 
confidence interval of the estimated ratio of Cmax and AUC of roluperidone with and without 
coadministration of olanzapine for a true within subject standard deviation of 0.25 or 0.40 with 
maximum imprecision of 20.5% or 30.8%, respectively. 
3.2. 
RANDOMIZATION AND BLINDING 
This is an open-label, one-sequence study; therefore, randomization and blinding will not be 
performed. Eighteen (18) subjects will be enrolled in the study to ensure 12 subjects complete the 
study. Eligible subjects will be assigned a subject identification number in sequential order. 
 
3.2.1. Examination of Subject Subsets 
Select PK summaries will be presented by sex, as detailed in Section 5.2.4. 
3.2.2. Multiple Testing and Comparisons  
All analyses will be conducted without adjustments for multiple comparisons. 
3.2.3. Missing Data and Outliers 
Every effort will be made to obtain required data at each scheduled evaluation from all subjects who 
have been treated. For analysis purposes, imputation of dates may be necessary and is described 
below in Section 3.2.3.1. Additionally, some results may be reported as alphanumeric. For the 
purposes of calculating summary statistics, these values may be imputed as described in Section 
3.2.3.2. No other imputation of values for missing data will be performed for this study. 
3.2.3.1. 
Missing Dates 
An incomplete date is any date for which either the day, month or year is unknown, but all three 
fields are not unknown. An incomplete date occurs when the exact date an event occurred or ended 
cannot be obtained from a subject.  
For many of the analyses, a complete date is necessary in order to determine if the event should be 
included in the analysis (i.e., if the event is treatment-emergent) or to establish the duration of an 
event. In such cases, incomplete dates will be imputed. 
For the purposes of handling partially reported start and stop dates for an event the following 
algorithm will be applied: 
 
Missing start day, but month and year present: 
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If the event occurs in the same month and year as the dosing of the study drug, then the 
start day of the study drug will be assigned to the day of first dose of the study drug. 
Otherwise, the start day will be set to the first day of the month. 
 
Missing start day and month, but year present: 
If event occurs in the same year as the study drug dosing, then the start date of the 
event will be assigned to Day 1 of Treatment Phase 1. 
Otherwise, the start day and month will be set to 01 January. 
 
Missing all components of a start date:  
Assign the date of Day 1 of Treatment Phase 1. 
 
Missing end day, but month and year present: 
The day will be set to the last day of the month. 
 
Missing end day and month, but year present: 
The end day and month will be set to the date of study completion (EOS Visit Date). 
However, if the study completion year is greater than the year of the event, then the 
day and month will be set to 31 December. 
 
In the event of a completely missing end date (year not present and ongoing not 
checked), the end date will be imputed as the date of study completion or 
discontinuation. If the imputed date is later than the date of study withdrawal, then the 
date of study withdrawal will be imputed for the date. 
If any imputed date causes the end date to occur prior to the start date of the event, the start date of 
the event will be used for the imputation of the end date. If any imputed date causes the start date of 
the event to occur after the end date of the event, the end date of the event will be used for the 
imputation of the start date. In subject data listings, start and stop date of events will be displayed as 
reported on the eCRF (i.e., imputed values will not be listed).  
3.2.3.2. 
Imputation of Alphanumeric Data 
Should there be instances where a clinical laboratory parameter is reported with imbedded non-
numeric characters, as for example, “<0.1” or “>10”, the data will be imputed for the purpose of 
quantitative summaries. The actual values as reported in the database will be presented in data 
listings.  
For incorporation in quantitative summaries, the following imputation rules will be employed: 
The limit of quantitation will be increased by one level of precision in the direction of the symbol 
that precedes the value. For example, “<0.1” will be imputed to “0.09”, while “>0.1” will be imputed 
to “0.11”, and “>10” will be imputed to “10.1”. Values reported as “≤” or “≥” will be imputed 
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similarly. For example, “≤0.1” will be imputed to “0.09”. For PK values, values reported as “BLQ” 
will be imputed to 0. BLQ values will not be presented on graphs for plots of semi-log values. 
3.2.4. Presentations by Time Point 
Subjects are institutionalized from washout phase to Day 19 (+2 days after the last dose on Day 17). 
See Section 1.2 for specifics regarding when assessments are measured within a phase. The timeline 
of assessment measurements is repeated for each treatment phase. Assessments after screening and 
occurring on Day -1 after a washout period will be attributed to the following treatment phase. 
Nominal Time Points as obtained from the eCRF or laboratory will be utilized for summary displays. 
Unscheduled visits will not be windowed and be excluded from summary tables and figures but will 
be listed.  
If assessments are collected multiple times within a given nominal time point, the result closest to 
the scheduled time will be used for summary presentations. If two measurements have the same 
distance to the expected time, the earlier value will be used. If a scheduled assessment and an early 
termination assessment are collected within a given time point window, the value from the scheduled 
assessment will be chosen over the value from the early termination assessment. 
3.2.5. Definitions and Terminology  
Baseline Value 
For quantitative safety measures, Baseline will be defined as the last valid evaluation completed 
before the study drug administration on Day 1. For ECG measures, including QTcF, Baseline will 
be defined as the mean of the triplicate set (total of 3 ECGs) performed pre-dose on Day 1 in 
Treatment Phase 1. This will also be referred to as Study Baseline. 
A second Baseline will be used and will be referred to as the Treatment Phase 2 Baseline. For ECG, 
Treatment Phase 2 Baseline will be the mean of the triplicate ECGs (total of 3 ECGs) performed pre-
dose on Day 8.  
Study Day  
Study Day is defined relative to Day 1. Thus, the study day of an event occurring on or after Day 1 
is calculated as: 
Study Day = event date – date of Day 1 + 1. 
The study day of an event occurring prior to Day 1 is calculated as: 
Study Day = event date – date of Day 1. 
Days on Study 
Days on Study is calculated as Final Day on Study based on the EOS eCRF page – First Day on 
Study Drug + 1. 
Treatment Phase Day 
The study day within a treatment phase. Treatment Phase Day will be defined within each Treatment 
Phase 1 or 2. 
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Treatment Phase Day = event date – date of Day 1 of Treatment Phase X + 1. 
Study Time Point  
Study Time Point is the nominal time point as recorded on the CRF. 
Change from Baseline  
Change from Baseline for a given endpoint is defined as the Study Time Point X value minus the 
Baseline Value. Change from Baseline may be study-specific (i.e., across all study phases), or 
Treatment Phase-specific (within any specific Treatment Phase). In the latter case, Baseline will be 
Treatment Phase specific. 
Adverse Event 
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event 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.  
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. 
All adverse events will be recorded on the Adverse Event page of the CRF. 
Serious Adverse Event (SAE) 
An SAE is defined as any AE that results in any of the following:  
 
Death: The subject died as the result of the event.  
 
Life-threatening event: Any AE that places the subject, 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.  
 
 
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 
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 subject exposed to the Investigational Product.  
 
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 subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above.  
Treatment-emergent Adverse Event (TEAE) 
Any recorded Adverse Event that occurs on or after the initiation of study drug is considered 
treatment-emergent. TEAEs will be attributed to the most recent treatment group that was received 
prior to the start of the AE. For AEs with partial dates, the event will be attributed to the earliest 
period the event could have occurred in based on the date. AEs that occur on a Day 1 of any 
Treatment Phase with no time will be attributed to the treatment received on that day. 
Adverse Event of Special Interest (AESI) 
AESIs are defined as the any of the following events: 
 
Syncope 
 
Sudden death, cardiac death 
 
TdP, QT/QTc prolongation, long QT syndrome 
 
ECG T wave and U wave abnormalities 
 
Ventricular arrhythmia, tachycardia, fibrillation / flutter 
Treatment-emergent Clinically Significant Laboratory Abnormality 
A Treatment-emergent Clinically Significant Laboratory Abnormality is defined as any post-
Baseline laboratory assessment occurring from Day 1 to the EOS determined to be clinically 
significant by the investigator, and for which the Baseline is not considered clinically significant. If 
the Baseline value is missing, normal, or not clinically significant, any clinically significant 
abnormality that occurs following initiation of study drug is considered treatment-emergent.  
Concomitant Medications 
Concomitant medications are those medications taken on or after the initiation of roluperidone on 
Day 1 of Treatment Phase 1. This definition includes medications that started prior to the initiation 
of roluperidone and continued concomitantly with roluperidone.  
Prior Medications 
Prior medications are those medications taken and stopped prior to the initiation of roluperidone.  
 
3.3. 
TIMING OF ANALYSIS 
A final analysis will be conducted once the last subject completes or discontinues the study, and the 
resulting clinical database has been cleaned, quality checked, the pre-analysis meeting has occurred, 
and the final database lock has occurred. 
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4. 
ANALYSIS POPULATIONS 
The populations for analysis will include the full set, safety (SAF) set, the PK set, and the PK 
Completer set. 
4.1. 
FULL SET 
The full set is the population of all subjects who sign an informed consent form. 
4.2. 
SAFETY SET (SAF)  
 
The SAF set is the population of all subjects who receive at least one dose of roluperidone. Subjects 
in this population will be analyzed according to the treatment(s) they receive. All safety analyses will 
be based on this population and treatment assignment. 
4.3. 
PK SET 
The PK set will consist of all subjects who completed all the PK assessments of at least 1 study phase, 
up to and including the 48-hour PK blood sample collection, provided they have no major protocol 
violations that could affect the pharmacokinetics of roluperidone. The PK evaluations will be based 
on the PK set. 
4.4. 
PK COMPLETER SET 
The PK Completer set will consist of all subjects who completed all the PK assessments, up to and 
including the 48-hour PK blood sample collection, provided they have no major protocol violations 
that could affect the pharmacokinetics of roluperidone. Select PK evaluations (Cmax, AUC24, 
AUClast, and AUC∞) will be performed for the PK Completer set. 
5. 
STATISTICAL METHODS 
Descriptive statistical methods will be used to summarize the data from this study.. Unless stated 
otherwise, the term “descriptive statistics” refers to number of subjects (n), mean, median, standard 
deviation (SD), minimum and maximum for continuous data and frequencies and percentages for 
categorical data, and coefficient of variation (%CV) for PK analysis. All data collected during the 
study will be included in data listings. Unless otherwise noted, the data will be sorted first by 
treatment, subject number, and then by date within each subject number. For all other tables 
presenting data collected on-treatment, summaries will be presented by treatment group.  
The term ‘treatment group’ refers to the administration of roluperidone alone or concomitantly 
with olanzapine to yield 2 groups. 
The statistical analyses will be conducted with the SAS® System version 9.4 or higher. All analyses 
will be subject to formal verification procedures. Specifically, results will be verified utilizing 
independent programming prior to issuance of the draft statistical report. All documents will be 
verified by the lead statistician to ensure accuracy and consistency of analyses. 
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5.1. 
SUBJECT DISPOSITION, DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Subject disposition will be presented for all subjects and the following will be presented: the number 
of subjects who meet all eligibility criteria, the number of subjects included in the Full, SAF and PK 
sets (PK set, and PK Completer set), the number of subjects who completed the study and 
discontinued from the study, and the reasons for early discontinuation at any point.  
Demographic data and Baseline characteristics will be summarized using descriptive statistics for 
the SAF set. The following variables will be included in the tables:  
 
Age (years) 
 
Sex (male/female) 
 
Ethnicity (Hispanic or Latino/not Hispanic or Latino/ Not Reported) 
 
Race (American Indian or Alaska Native/Asian/Black or African American/ Native 
Hawaiian or Other Pacific Islander/White/Not Reported/Other) 
 
Height (cm) 
 
Weight (kg) 
 
Body Mass Index (kg/m2) 
 
Childbearing potential 
This information will be reviewed for Baseline differences, but no statistical testing will be 
performed. 
5.2. 
PHARMACOKINETIC ANALYSES 
The secondary objective of the statistical analysis will be to evaluate the effect of the 
coadministration of roluperidone and olanzapine on the pharmacokinetics (PK) of roluperidone in 
subjects with moderate to severe negative symptoms of schizophrenia. The PK parameters of interest 
will be the natural log-transformed estimated AUCs and Cmax. Only the data from subjects who 
completed all the PK assessments, up to and including the 48-hour PK blood sample collections (PK 
Completer set), will be included in the statistical analysis, but all available data will be analyzed as 
well (PK set). 
5.2.1. 
Pharmacokinetic Sampling 
During Treatment Phase 1, all subjects will have plasma PK samples will be drawn for roluperidone 
and its metabolite BFB-520 at 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, and 24 hours post-
dose on Days 1 and 7, at 6 hours post dose on Day 2, and at pre-dose and 6 hours post-dose on Days 
3-6. During Treatment Phase 2, PK samples for roluperidone and olanzapine will be obtained at 6 
hours post-dose on Day 8, time 0 (pre-dose) and 6 hours post-dose on Days 9-16, and starting on 
Day 17 at time 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24, 28, 32, 36, and 48 hours post-
dose. 
5.2.2. 
Assay Results Below the Lower Limit of Quantification 
For purposes of calculation, plasma concentration values below the limit of quantification (BLQ) 
will be treated as zero for the determination of summary and order statistics. For purposes of data 
presentation, individual values that are BLQ will be presented as “BLQ” in the concentration data 
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listing. If the minimum, median, or maximum concentration is BLQ, it will be presented as BLQ in 
the table. If the mean concentration is BLQ, it will be presented as BLQ and SD and % coefficient 
of variation (CV) will be presented as “NA” (not applicable). If 1/3 or more of subjects have values 
of BLQ at any time point, descriptive statistics will not be calculated at that time point. The 
Geometric mean will not be calculated at the pre-dose time point. For post-dose values, concentration 
values equal to one-half the lower level of quantification (i.e., 0.125 ng/mL) will be used for BLQ 
values for calculation of the geometric mean. 
5.2.3. 
Pharmacokinetic Methods 
Pharmacokinetic parameters to be estimated from plasma concentration-time data are listed in 
Table 1. 
Table 1. Pharmacokinetic Parameters 
Pharmacokinetic Parameter 
Definition 
Cmax 
Observed maximum plasma concentration (ng/mL) 
Tmax 
Time to reach the observed maximum plasma concentration (h) 
AUC0-24 
Area under the plasma concentration-time curve from time 0 to 
Concentration C24(h.ng/mL) at the 24-hour time point 
AUC∞ 
Area under the plasma concentration-time curve from time 0 to 
infinite time, calculated according to the following equation 
AUC = AUClast + Clast / λz (h.ng/mL) ), where Clast is the last 
measurable plasma concentration and λz is the terminal 
elimination rate constant 
 
AUC∞ will be reported if t1/2, λ is calculable and if Clast / λz 
represented 30% or less of the AUC value. AUC values where 
Clast / λz is less than 30% but greater than or equal to 20% of the 
AUC value will be flagged in the report.  
t1/2 
Elimination half-life  
5.2.4. 
Statistical Analyses of Pharmacokinetic Data 
Plasma concentration data for roluperidone, BFB-520 and olanzapine will be summarized by 
treatment group. Nominal time point will be used for presentation of tables and figures. Summaries 
will include mean, SD, %CV, minimum and maximum.  
All estimated PK parameters for roluperidone, BFB-520 and olanzapine will be summarized by 
treatment group, with summaries including arithmetic mean, median, geometric mean, minimum, 
maximum, SD, and %CV (arithmetic and geometric) for each treatment. For the calculation of 
geometric mean, observed values of 0 (BLQ) will be included as 0.0001 before the natural log 
transformation. 
Descriptive summaries of Tmax, Cmax, AUC0-24, and AUC∞ will also be summarized within each 
treatment group. 
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Treatment ratios (roluperidone + olanzapine versus roluperidone alone) for Cmax, AUC0-24, and 
AUC∞ at steady state will be summarized using the same descriptive statistics as above. LS 
means (±90% confidence interval [CI]) for log transformed Cmax, AUC0 24, and AUC∞ will be 
evaluated by a linear mixed effects model with a fixed term for treatment and a random term for 
subject, fit by estimated generalized least squares with restricted maximum likelihood estimates 
of random effects. If deemed relevant to test for a treatment difference in Tmax, a Wilcoxon 
signed rank test will be used. 
Results for roluperidone, BFB-520, olanzapine will also be presented graphically. Figures will 
include plasma concentration-time profiles for the mean ± standard error of mean (SEM), which will 
be presented by treatment group. Additionally, plasma concentration-time profiles for each subject 
by treatment group will be presented. All figures will be produced on both the natural log-linear and 
linear-linear scales. 
The plasma pharmacokinetic parameters of olanzapine from Day 17 will be compared with its 
pharmacokinetic profiles available in published literature. 
5.2.5. 
Other Analyses 
Other pharmacokinetic analyses may be performed as deemed appropriate. 
5.3. 
SAFETY ANALYSES 
5.3.1. 
Adverse Events 
Adverse events will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) version 
26.1 preferred term and system organ classification. If a subject experiences multiple events that map 
to a single preferred term during the same treatment phase, the greatest severity grade and strongest 
investigator assessment of relation to study medication will be assigned to the preferred term for the 
appropriate summaries. Should an event have a missing severity or relationship, it will be classified 
as having the highest severity and/or strongest relationship to study medication.  
The occurrence of TEAEs will be summarized by treatment group using preferred terms (PT), system 
organ classifications (SOC), severity, and/or relationship. A similar summary of (Serious) TEAEs 
related to study drug will be generated. Separate summaries of treatment-emergent SAE, events of 
special interest, events leading to the discontinuation of roluperidone, and events leading to death 
will be generated by SOC and PT. Additionally, an overall summary of the number of subjects 
experiencing each of these types of TEAEs, along with the overall number of events of each type 
will be presented. All adverse events reported will be listed for individual subjects showing both 
verbatim and preferred terms. All adverse events that occurred prior to the initiation of study 
treatment will be excluded from the tables but will be included in the listings. Any treatment-
emergent adverse events occurring after the EOS visit will not be summarized. 
The overall summary table will include following types: 
 
Any TEAE 
 
Any serious TEAE 
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 
Any drug related TEAE 
 
Any drug related serious TEAE 
 
Any AESI TEAE 
 
TEAEs by maximum severity 
 
TEAEs by maximum relationship  
 
Any TEAE leading to drug discontinuation 
 
Any TEAE leading to death 
Missing onset dates will be imputed as previously outlined in Section 3.2.3.1 as required to determine 
treatment-emergent events. 
5.3.2. Clinical Laboratory Assessments 
All laboratory parameters collected at each center’s local laboratory will be standardized by 
converting values in original units to values in standard units and classified as normal, low, or high 
based on normal ranges supplied by the local laboratories and upon employing standardization.  
Laboratory evaluations (including hematology, biochemistry, and urinalysis) will be listed by 
Treatment Phase and time point. Descriptive summaries of selected (quantitative) clinical laboratory 
results, and changes from Study Baseline (for Treatment Phase 1) and from Treatment Phase 2 
Baseline (for Treatment Phase 2), will be presented by time point and treatment group. 
The number and percentage of subjects experiencing treatment-emergent clinically significant 
laboratory abnormalities will be summarized by treatment group. See Table 2 for parameter specific 
criteria. All abnormalities that occur post-baseline, regardless of Baseline status will be included. 
Additionally, shifts in laboratory values with reference to the normal range from Baseline to 48 hours 
post-dose and from Baseline to EOS will be summarized by treatment. 
Listings will be provided for subjects with any laboratory results outside the reference ranges, as 
well as for subjects with any potentially clinically significant (PCS) laboratory results as defined in 
Table 2. 
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Table 2. Criteria For Potentially Clinically Significant Laboratory Tests 
Laboratory Parameter SI Units Conversion 
Factora 
Traditional 
Units 
PCS Criteriab 
Low Values 
PCS Criteriab 
High Values 
Hematology 
Hemoglobin 
g/L 
0.1 
g/dL 
< 0.9 × LLN 
— 
Hematocrit 
ratio 
100 
% 
< 0.9 × LLN 
— 
White cell count 
109/L 
1 
103/µL 
≤ 2.5 
≥ 15 
Eosinophils absolute 
cell count 
109/L 
1 
103/µL 
— 
≥ 1.5  
Neutrophils absolute 
cell count (not Black) 
109/L 
1 
103/µL 
< 1.5 
> 15.0 
Neutrophils absolute 
cell count (Black) 
109/L 
1 
103/µL 
< 1.1 
> 15.0 
Lymphocyte absolute 
cell count 
109/L 
1 
103/µL 
< 0.75 
≥ 5.0 
Platelet count 
109/L 
1 
103/µL 
< 125.000 
≥ 700 
Chemistry 
Albumin 
g/L 
0.1 
g/dL 
< 27  
— 
Alkaline phosphatase 
U/L 
1 
U/L 
— 
≥ 2 × UNL 
ALT 
U/L 
1 
U/L 
— 
≥ 3 × UNL 
AST 
U/L 
1 
U/L 
— 
≥ 3 × UNL 
Blood urea nitrogen 
mmol/L 
2.8011 
mg/dL 
— 
> 1.3 × UNL 
Calcium 
mmol/L 
4.008 
mg/dL 
< 1.97 
> 2.77 
Cholesterol 
mmol/L 
38.6698 
mg/dL 
— 
> 7.75 
Creatinine 
µmol/L 
0.0113 
mg/dL 
— 
> 1.3 × UNL 
Glucose, fasting 
mmol/L 
18.015 
mg/dL 
< 3.4 
> 6.16 
Potassium 
mmol/L 
1 
mEq/L 
< 3.4 
> 5.3 
Sodium 
mmol/L 
1 
mEq/L 
< 131 
> 146 
Total bilirubin 
µmol/L 
0.0585 
mg/dL 
— 
> 2 × UNL 
Urinalysis 
Protein 
— 
— 
— 
— 
≥ 2 + 
Glucose 
— 
— 
— 
— 
≥ 1 + 
a 
Conversion factor is the multiplication factor to convert from SI units to traditional units.  
b 
Criteria refer to SI units. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; LLN = lower limit of normal of 
laboratory reference range; PCS = potentially clinically significant; SI = Le Système International d'Unités 
(International System of Units); UNL = upper normal limit of laboratory reference range. 
 
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All laboratory abnormalities that occurred before dosing for a given treatment phase will be excluded 
from the tables but will be included in the listings. This includes any unscheduled laboratory 
assessments. 
5.3.3. Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
dictionary version WHODrug Global b3 September 2023 release. Concomitant medications will be 
summarized by ATC Classification, preferred name, and treatment group. Prior and concomitant 
medications will be presented in a data listing. 
5.3.4. Other Safety Analyses 
Descriptive summaries of vital signs and their respective change from Baseline values will be 
presented by time point and treatment group. The number and percentage of subjects with PCS vital 
signs occurring post-baseline will also be summarized by time point and treatment group. All 
abnormalities that occur post-baseline, regardless of Baseline status will be included. All vital signs 
will be listed with PCS vital signs flagged.  
Table 3. Criteria For Potentially Clinically Significant Vital Signs 
Vital Sign Parameter 
Flag 
Criteria 
Systolic Blood Pressure 
(mmHg) 
High 
 150 mmHg 
Low 
 80 mmHg 
Diastolic Blood Pressure 
(mmHg) 
High 
100 mmHg 
Low 
 45 mmHg 
Heart Rate (bpm) 
High 
> 115 bpm 
Low 
< 45 bpm 
Temperature (oC) 
High 
 38 oC 
Low 
< 35 oC 
ECG parameters and their change from Baseline (using both Study Baseline and Treatment Phase 2 
Baseline) will be summarized with descriptive statistics by time point and treatment group. ECG 
parameters will include heart rate, PR interval, RR interval, QRS interval, QT interval, and QTc 
interval corrected for heart rate using QTcB and QTcF. QTcF values will also be tabulated for their 
absolute values and tabulated relative to Baseline measurements in order to detect individual QTcF 
changes.  
Additionally, the number and percentage of subjects with post-baseline QTcF interval > 450 - 480 
milliseconds (msec), > 480 - 500 msec, or > 500 msec will be summarized, as will the number and 
percentage of subjects with QTcF interval increases from Baseline of >30 – 60 msec or > 60 msec. 
For these summaries, worst-case assignments will be made to ensure subjects with such values are 
not counted more than once. For example, a subject with QTc interval > 500 msec will count once 
in the > 500 msec category and will not appear in the > 450 - 480 or > 480 - 500 msec categories. 
Similar conventions will be used for the >30 - 60 and >60 msec categories. 
All ECG assessments and abnormalities in ECG waveform that are changes from Baseline readings 
will also be reported in a listing. 
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Table 4. Potentially Clinically Significant Criteria for ECG 
Variable 
Units 
PCS Criteria 
Low Values 
PCS Criteria High 
Values 
Change from 
Baseline or 
Observed Value 
Heart Rate 
beats/min 
<45 
>115 
- 
QTcF Interval 
msec 
- 
>450 Males 
>470 Females 
>30-60, > 60,  
> 450-480,  
> 480-500, > 500 
QRS Interval 
msec 
- 
>120 
- 
PR Interval 
msec 
- 
>220 
- 
All physical examination results will be listed. 
Extrapyramidal symptoms will be assessed by AIMS and BARS. Observed and change from baseline 
(both Study Baseline and Treatment Phase 2 Baseline) in AIMS and BARS will be summarized by 
treatment group and time point for Safety Set. Separate listings will be provided for AIMS and BARS 
for Safety Set. 
Suicidal ideation will be assessed by C-SSRS. Observed and change from baseline (both Study 
Baseline and Treatment Phase 2 Baseline) in C-SSRS will be summarized by treatment group and 
time point for Safety Set. Separate listings will be provided for C-SSRS for Safety Set. 
Tuberculosis, FSH, Pregnancy Test, Drug Screen and Alcohol Breath Test, SARS-CoV2 Test, and 
Serology Test will be listed for the Safety Set. 
 
 
 CGI-S 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 CGI-S 
   
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6. 
PROTOCOL VIOLATIONS 
Possible protocol deviations will be identified and displayed in a data listing and sorted by Treatment-
Phase, subject, and study day (where applicable). The following deviations may be identified as 
protocol deviations from the database: 
 
Missing ECG or PK assessments 
 
Violations of inclusion/exclusion criteria 
 
Non-compliance with roluperidone and/or olanzapine 
 
7. 
CHANGES IN THE PLANNED ANALYSES 
No deviations in the conduct of the study or the planned analysis are anticipated. Should any 
deviations from the analyses specified in the authorized statistical analysis plan arise, such deviations 
will be documented in the final clinical study report (CSR). 
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8. 
PROGRAMMING CONVENTIONS 
 
Page orientation, margins, and fonts: Summary tables, listings, and figures will appear in 
landscape orientation. There should be a minimum of a 1.0” boundary on the left and right edges. 
The top and bottom margins are 1.0” for tables and listings but may vary for figures. The output 
should be printed in Courier New with point size of 8. 
 
Identification of analysis population: Every summary table and figure should clearly specify the 
analysis population being summarized. Listings will be prepared for all subjects. 
 
Group headers: In the summary tables, the group headers will identify the summary group and 
the sample size for the indicated analysis population. Of note, the header’s sample size does not 
necessarily equal the number of subjects actually summarized within any given summary 
module; some subjects in the analysis population may have missing values and thus may not be 
summarized. 
 
Suppression of percentages corresponding to null categories: When count data are presented as 
category frequencies and corresponding percentages, the percentage should be suppressed when 
the count is zero in order to draw attention to the non-zero counts. 
 
Presentation of sample sizes: Summary modules should indicate, in one way or another, the 
number of subjects contributing to the summary statistics presented in any given summary 
module. As mentioned above, this may be less than the number of subjects in the analysis 
population due to missing data. 
 In the quantitative modules describing continuous variables (and thus presenting sample size, 
means, and standard deviations), the sample size should be the number of non-missing 
observations. The number of missing observations, if any, will be noted. 
 For categorical variables that are presented in frequency tables, the module should present 
the total count in addition to the count in each category. Percentages should be calculated 
using this total as the denominator, and the percentage corresponding to the sum itself (that 
is, 100%) should be presented so as to indicate clearly to a reviewer the method of 
calculation. The number of missing observations, if any, will be noted. 
 
Sorting: Listings will be sorted by treatment group, subject number, and date, if applicable. If a 
listing is sorted in a different manner, a footnote will indicate as such.  
 
General formatting rules: Rounding for all variables will occur only as the last step, immediately 
prior to presentation in listings, tables, and figures. No intermediate rounding will be performed 
on derived variables. The standard rounding practice of rounding numbers ending in 0-4 down 
and numbers ending in 5-9 up will be employed.  
 
The presentation of numerical values will adhere to the following guidelines:  
 Raw measurements will be reported to the number of significant digits as captured 
electronically or on the CRFs.  
 Standard deviations will be reported to one decimal place beyond the number of decimal 
places the original parameter is presented. 
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 Means and medians will be reported to the same number of significant digits as the 
parameter.  
 Calculated percentages will be reported with no decimals. 
 
Dates will be formatted as DDMMMYYYY. Partial dates will be presented on data listings as 
recorded on CRFs. 
 
Time will be presented according to the 24-hour clock (HH:MM). 
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9. 
PROPOSED TABLES, LISTINGS, AND FIGURES 
Summary Tables 
Accountability and Baseline Characteristics 
14.1.1.1  
Subject Disposition, Full Set 
14.1.1.2 
Analysis Sets, Full Set 
14.1.2  
Demographics and Baseline Characteristics, Safety Set 
14.1.3  
Medical and Psychiatric History, Safety Set 
14.1.4  
Concomitant Medications, Safety Set 
 
 
  
 
 
  
 
 
14.2.1.3 
Clinical Global Impression- Severity Rating (CGI-S) by Treatment Phase, Safety 
Set 
 
Pharmacokinetics 
14.2.3.1.1  
Plasma Concentrations of Roluperidone, PK Set 
14.2.3.1.2  
Plasma Concentrations of Roluperidone Metabolite BFB-520, PK Set 
14.2.3.1.3  
Plasma Concentrations of Olanzapine, PK Set 
14.2.3.2.1  
Plasma PK Parameters for Roluperidone, PK Set 
14.2.3.2.2  
Plasma PK Parameters for Roluperidone Metabolite BFB-520, PK Set 
14.2.3.2.3 
Plasma PK Parameters for Olanzapine, PK Set 
14.2.3.2.4 
Plasma PK Parameters for Roluperidone, PK Completer Set 
14.2.3.2.5 
Plasma PK Parameters for Roluperidone Metabolite BFB-520, PK Completer Set 
14.2.3.2.6 
Plasma PK Parameters for Olanzapine, PK Completer Set 
 
Safety 
14.3.1.1  
Overall Summary of Treatment-Emergent Adverse Events, Safety Set 
14.3.1.2  
Treatment-Emergent Adverse Events by System Organ Classification and 
Preferred Term, Safety Set 
14.3.1.3  
Treatment-Emergent Adverse Events by System Organ Classification, Preferred 
Term, and Maximum Severity, Safety Set 
14.3.1.4  
Treatment-Emergent Adverse Events by System Organ Classification, Preferred 
Term, and Maximum Relationship, Safety Set 
14.3.1.5  
Treatment-Emergent Adverse Events Related to Study Drug by System Organ 
Classification, Preferred Term, and Maximum Severity, Safety Set 
14.3.1.6  
Treatment-Emergent Serious Adverse Events by System Organ Classification and 
Preferred Term, Safety Set 
14.3.1.7  
Treatment-Emergent Serious Adverse Events Related to Study Drug by System 
Organ Classification, Preferred Term, and Maximum Severity, Safety Set 
14.3.1.8  
Treatment-Emergent Adverse Events of Special Interest by System Organ 
Classification and Preferred Term, Safety Set 
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14.3.1.9  
Treatment-Emergent Adverse Events Leading to Discontinuation of Study Drug by 
System Organ Classification and Preferred Term, Safety Set 
14.3.1.10  
Treatment-Emergent Adverse Events Leading to Death by System Organ 
Classification and Preferred Term, Safety Set 
14.3.5.1  
Clinical Laboratory Hematology Parameters by Time Point, Safety Set 
14.3.5.2  
Clinical Laboratory Chemistry Parameters by Time Point, Safety Set 
14.3.5.3  
Clinical Laboratory Urinalysis Parameters by Time Point, Safety Set 
14.3.5.4  
Potentially Clinically Significant Laboratory Values Occurring Post-Baseline, 
Safety Set 
14.3.5.5 
Clinical Laboratory Parameter Post-Baseline Shifts, Safety Set 
14.3.6.1 
Vital Signs by Time Point, Safety Set 
14.3.6.2 
Potentially Clinically Significant Vital Signs Occurring Post-Baseline, Safety Set 
14.3.7.1 
12-Lead ECG Assessments by Time Point, Safety Set 
14.3.7.2  
Potentially Clinically Significant ECG Abnormalities Occurring Post-Baseline, 
Safety Set 
14.3.7.3 
Clinically Significant Change from Baseline QTcF Values, Safety Set 
14.3.8  
Extrapyramidal Symptoms by Time Point, Safety Set 
14.3.9  
Suicidal Ideation by Time Point, Safety Set 
 
Figures 
14.2.3.1.4 
Plasma Concentration (Roluperidone/BFB-520/Olanzapine) by Subject, Log-
Linear Scale, PK Set 
14.2.3.1.5  
Plasma Concentration (Roluperidone/BFB-520/Olanzapine) by Subject, Linear-
Linear Scale, PK Set 
14.2.3.2.7 
Mean (SEM) Plasma Concentration (Roluperidone/BFB-520/Olanzapine), Log-
Linear Scale, PK Completer Set 
14.2.3.2.8 
Mean (SEM) Plasma Concentration (Roluperidone/BFB-520/Olanzapine), Linear-
Linear Scale, PK Completer Set 
14.2.3.2.9 
Mean (SEM) Plasma Concentration (Roluperidone/BFB-520/Olanzapine), Log-
Linear Scale, PK Set 
14.2.3.2.10 
Mean (SEM) Plasma Concentration (Roluperidone/BFB-520/Olanzapine), Linear-
Linear Scale, PK Set 
 
Data Listings 
16.2.1  
Subject Disposition 
16.2.2.1 
Protocol Deviations 
16.2.2.2 
Inclusion/Exclusion Criteria 
16.2.3  
Study Populations 
16.2.4.1  
Demographics 
16.2.4.2  
CYP2D6 Genotype 
16.2.4.3  
Medical and Psychiatric History 
16.2.4.4 
SARS-CoV2 Testing  
16.2.5.1  
Study Drug Administration 
16.2.5.2  
Prior and Concomitant Medications 
16.2.5.3.1  
Pharmacokinetic Plasma Concentrations 
16.2.5.3.2  
Pharmacokinetic Plasma Parameters 
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16.2.6.3  
Clinical Global Impression - Severity Rating (CGI-S) 
16.2.7.1  
Adverse Events 
16.2.7.2  
Serious Adverse Events 
16.2.8.1.1  
Laboratory Data – Chemistry 
16.2.8.1.2  
Laboratory Data – Hematology  
16.2.8.1.3  
Laboratory Data – Urinalysis  
16.2.8.1.4  
Laboratory Data – Other  
16.2.8.1.5  
Laboratory Results Outside Reference Range 
16.2.8.1.6  
Laboratory Abnormalities 
16.2.8.1.7 
Drug Screen and Alcohol Breath Test 
16.2.8.1.8 
Serum Pregnancy Test 
16.2.8.1.9 
Tuberculosis Test 
16.2.8.1.10 
FSH Test 
16.2.8.2  
Vital Signs, Weight, Height and BMI 
16.2.8.3 
Potentially Clinically Significant Vital Signs 
16.2.8.4  
Physical Examinations 
16.2.8.5  
12-Lead ECG Findings 
16.2.8.6 
Potentially Clinically Significant 12-Lead ECG Findings 
16.2.8.7  
12-Lead ECG Waveform Findings 
16.2.8.8  
Extrapyramidal Symptoms 
16.2.8.9  
Suicidal Ideation 
 
 
 
 
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