Clinical trial NCT04951076
Conditions: Post-Traumatic Stress Disorder
Sponsor: Bionomics Limited
Start date: 2021-07-27; Completion date: 2023-08-14
Enrollment: 212 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the effects of BNC210 compared to placebo on Post-Traumatic Stress Disorder (PTSD) symptom severity as measured by the Clinician Administered PTSD scale for The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (CAPS-5) Total Symptom Severity Scores.

Detailed description:
This is a randomized, double-blind, placebo-controlled, parallel group, multi-center study with a 12 week, 2-arm treatment period. Participants will attend a Screening visit within 3 weeks before randomization to confirm eligibility. Approximately 200 participants will be randomized using a 1:1 ratio to receive either BNC210 900 mg twice daily (b.i.d.) or matched placebo. Participants will then complete 12 weeks of treatment with their allocated study intervention. Participants will return to their study site at 2-weekly intervals to complete study assessments. Participants are then requested to attend a Follow-up visit at Week 15 (i.e., 3 weeks after their last study intervention is administered).

Arms: arm 1: None arm 2: None
Interventions: intervention 1: BNC210 intervention 2: Placebo
Intervention descriptions: intervention 1: BNC210 900 mg twice daily (b.i.d.) for 12 weeks intervention 2: Placebo twice daily (b.i.d.) for 12 weeks

Protocol documents:
Prot_000.pdf: 
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        Protocol BNC210.012             Version 4.0 (US), 17-Nov-2022 
 
 
1 
Title Page 
Protocol Title:  
A Phase 2b, Randomized, Double Blind, Two Arm Study to Investigate the Effects of BNC210 
Tablet Formulation Compared to Placebo in Adults with Post-Traumatic Stress Disorder (PTSD)  
Protocol Number: BNC210.012 
Amendment Number: 5 
Compound: BNC210 
Brief Title: A Phase 2b Study of BNC210 Tablet Formulation in Adults with Post-Traumatic 
Stress Disorder (PTSD) 
Study Phase: 2b 
Sponsor Name: Bionomics Limited  
Legal Registered Address: 200 Greenhill Road, Eastwood, SA, 5063, AUSTRALIA 
Regulatory Agency Identifier Number(s): 
Registry 
ID 
IND 
135,696 
NCT 
04951076 
 
Approval Date: 17-Nov-2022 
Confidentiality Statement 
This document contains the confidential information of Bionomics Limited.  It is provided to you 
as an Investigator or consultant for review by you, your personnel, and the applicable Institutional 
Review Board (IRB). Your acceptance of this document constitutes an agreement that you will not 
disclose the information contained herein to others without the prior written consent of Bionomics 
Limited, unless it is necessary to obtain informed consent from potential study participants.  No 
other use or reproduction is authorized by Bionomics Limited, nor does Bionomics Limited 
assume any responsibility for unauthorized use of this protocol. 
 
 
 
 
 


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Sponsor Signatory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17 Nov 2022  
 
 
Bionomics Limited 
 
Date 
 
 
 
 
 
 
 
 
Medical Monitor Name and Contact Information  
 
 
  
  
 
 
 
 


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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Rationale for Amendment 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
1. 
Protocol Summary ..........................................................................................................7 
1.1. 
Synopsis ............................................................................................................................7 
1.2. 
Schema ............................................................................................................................11 
1.3. 
Schedule of Activities (SoA) ..........................................................................................12 
2. 
Introduction ...................................................................................................................14 
2.1. 
Study Rationale ...............................................................................................................14 
2.2. 
Background .....................................................................................................................15 
2.2.1. 
Disease Background........................................................................................................15 
 
 
 
 
 
 
 
 
2.3. 
Benefit/Risk Assessment ................................................................................................17 
3. 
Objectives, Endpoints, and Estimands .......................................................................18 
4. 
Study Design ..................................................................................................................21 
4.1. 
Overall Design ................................................................................................................21 
4.2. 
Scientific Rationale for Study Design ............................................................................21 
 
 
4.4. 
End of Study Definition ..................................................................................................22 
5. 
Study Population ...........................................................................................................23 
5.1. 
Inclusion Criteria ............................................................................................................23 
5.2. 
Exclusion Criteria ...........................................................................................................24 
5.3. 
Lifestyle Considerations .................................................................................................27 
5.4. 
Screen Failures ................................................................................................................27 
5.5. 
Criteria for Temporarily Delaying Randomization or 
Administration of Study Intervention .............................................................................27 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................28 
6.1. 
Study Intervention(s) Administered................................................................................28 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................29 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................30 
 
 
 
 
 
 
 
 
6.5. 
Dose Modification ..........................................................................................................32 
6.6. 
Continued Access to Study Intervention After the End of the 
Study ...............................................................................................................................32 
6.7. 
Treatment of Overdose ...................................................................................................32 
6.8. 
Concomitant Therapy .....................................................................................................32 
6.8.1. 
Rescue Medications for Insomnia ...................................................................................33 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................34 


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7.1. 
Discontinuation of Study Intervention ............................................................................34 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................34 
7.1.2. 
QTc Stopping Criteria .....................................................................................................35 
7.1.3. 
Suicidal Behavior Stopping Criteria ...............................................................................35 
7.1.4. 
Temporary Discontinuation ............................................................................................35 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................35 
7.3. 
Lost to Follow up ............................................................................................................36 
8. 
Study Assessments and Procedures.............................................................................37 
8.1. 
Efficacy Assessments .....................................................................................................38 
8.1.1. 
Clinician-Administered PTSD Scale for the DSM-5 (CAPS-5) .....................................38 
8.1.2. 
PTSD Checklist for DSM-5 (PCL-5) ..............................................................................39 
8.1.3. 
Clinical Global Impression Scales – Severity and Improvement 
(CGI-S/I) .........................................................................................................................39 
8.1.4. 
Patient Global Impression Scales – Severity and Improvement 
(PGI-S/I) .........................................................................................................................39 
8.1.5. 
Hamilton Anxiety Rating Scale (HAM-A) .....................................................................39 
8.1.6. 
Montgomery-Åsberg Depression Rating Scale (MADRS).............................................39 
8.1.7. 
Sheehan Disability Scale (SDS)......................................................................................39 
8.1.8. 
Insomnia Severity Index (ISI) .........................................................................................39 
8.2. 
Safety Assessments .........................................................................................................40 
8.2.1. 
Physical Examinations ....................................................................................................40 
8.2.2. 
Vital Signs .......................................................................................................................40 
8.2.3. 
Electrocardiograms .........................................................................................................40 
8.2.4. 
Clinical Safety Laboratory Assessments ........................................................................41 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring ...........................................................41 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and 
Other Safety Reporting ...................................................................................................42 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................42 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................43 
8.3.3. 
Follow-up of AEs and SAEs ...........................................................................................43 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................43 
8.3.5. 
Pregnancy ........................................................................................................................43 
8.4. 
Pharmacokinetics ............................................................................................................44 
8.5. 
Genetics ..........................................................................................................................44 
8.6. 
Biomarkers ......................................................................................................................44 
8.7. 
Immunogenicity Assessments.........................................................................................44 
8.8. 
Health Economics OR Medical Resource Utilization and Health 
Economics .......................................................................................................................44 
9. 
Statistical Considerations .............................................................................................45 
9.1. 
Statistical Efficacy Hypotheses ......................................................................................45 
9.1.1. 
Multiplicity Adjustment ..................................................................................................46 
9.2. 
Analysis Sets ...................................................................................................................47 
9.3. 
Statistical Analyses .........................................................................................................47 
9.3.1. 
General Considerations ...................................................................................................47 


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9.3.3. 
Primary and Key Secondary Endpoint/Estimand Analyses ............................................48 
9.3.4. 
Supportive Analyses for Primary and Key Secondary Efficacy 
Endpoints ........................................................................................................................49 
9.3.5. 
Multiple Imputation Methods .........................................................................................49 
9.3.6. 
Other Secondary Endpoints Analyses .............................................................................50 
9.3.7. 
Safety Analyses ...............................................................................................................50 
 
 
9.4. 
Population Pharmacokinetic (PK) Analysis ...................................................................50 
9.5. 
Interim Analysis ..............................................................................................................50 
9.6. 
Sample Size Determination ............................................................................................50 
10. 
Supporting Documentation and Operational Considerations ..................................52 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................52 
10.1.1. Regulatory and Ethical Considerations ...........................................................................52 
10.1.2. Financial Disclosure........................................................................................................52 
10.1.3. Informed Consent Process ..............................................................................................53 
10.1.4. Data Protection................................................................................................................53 
10.1.5. Independent Safety Review ............................................................................................54 
10.1.6. Data Quality Assurance ..................................................................................................54 
10.1.7. Source Documents ..........................................................................................................55 
10.1.8. Study and Site Closure ....................................................................................................55 
10.1.9. Publication Policy ...........................................................................................................56 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................57 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................59 
10.3.1. Definition of AE .............................................................................................................59 
10.3.2. Definition of SAE ...........................................................................................................60 
10.3.3. Recording and Follow-Up of AE and/or SAE ................................................................61 
10.3.4. Reporting of SAEs ..........................................................................................................64 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................66 
10.4.1. Definitions.......................................................................................................................66 
10.4.2. Contraception Guidance..................................................................................................67 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................68 
10.6. 
Appendix 6: Abbreviations .............................................................................................71 
11. 
References ......................................................................................................................74 


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1. 
 Protocol Summary 
1.1. 
Synopsis 
Protocol Title: A Phase 2b, Randomized, Double Blind, Two Arm Study to Investigate the 
Effects of BNC210 Tablet Formulation Compared to Placebo in Adults with 
Post-Traumatic Stress Disorder (PTSD)  
Brief Title: 
A Phase 2b Study of BNC210 Tablet Formulation in Adults with Post-
Traumatic Stress Disorder (PTSD) 
Rationale: 
This Phase 2b study will assess the potential effect of BNC210 in the treatment of Post-
Traumatic Stress Disorder (PTSD), a condition which is classified in the Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) as a Trauma and Stressor-Related 
Disorder.  
Previous human studies with BNC210 have established its safety and tolerability and 
demonstrated effects in a panic model in healthy volunteers. In a Phase 2a study in generalized 
anxiety disorder (GAD) patients (BNC210.006) using functional magnetic resonance imaging 
(fMRI), BNC210 reduced bilateral amygdala reactivity to fearful faces in an Emotional Faces 
Task and connectivity between the left amygdala and anterior cingulate cortex (ACC). In both 
anxiety and PTSD patients, significant arousal of the amygdala occurs in response to viewing 
fearful faces. Reduction of this response has been demonstrated by first line therapeutics for 
anxiety. In addition, anxious patients have a strong connection between the ACC and the 
amygdala. The reduction of connectivity in this circuit, and of amygdala hyperactivity, 
demonstrate BNC210 efficacy on two validated biomarkers of anxiety-induced brain changes. In 
the same study, BNC210 caused a significant reduction in defensive behavior (threat avoidance), 
demonstrating the positive effect of BNC210 on modulating hypothalamic pituitary adrenal axis 
behavior. These human data demonstrate proof-of-biology for BNC210 and potential for efficacy 
in the treatment of anxiety disorders and PTSD. 
Furthermore, based on preclinical data demonstrating BNC210’s positive effects on fear 
extinction, BNC210 is being studied in PTSD patients where deficits in fear extinction are 
thought to contribute to the pathology of this disorder.   
BNC210 has previously been evaluated in patients with PTSD in a randomized, double-blind, 
placebo-controlled trial over 12 weeks (BNC210.007). BNC210 was administered orally as a 
suspension and was well tolerated with no pattern of drug-related adverse effects becoming 
apparent. However, improvements in the efficacy measurement of Clinician-Administered PTSD 
Scale for the DSM-5 (CAPS-5) Total Symptom Severity scores were not statistically different 
between BNC210 and placebo. Using population pharmacokinetics, exposure to BNC210 was 
modelled in the trial participants and was substantially less than that expected when compared to 
pharmacokinetic (PK) data from a healthy volunteer study with the same suspension formulation 
(BNC210.005). This may be attributed in part to the unsuitability of the suspension formulation 
for an out-patient study, in particular, its dependence on food for optimal absorption.  A 
pharmacometric exposure-response relationship was modelled based on the population PK and 




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• To assess the effects of BNC210 on 
Investigator-rated symptoms of 
anxiety and depression in participants 
with PTSD 
• To assess the effects of BNC210 on 
patient-reported symptoms of PTSD  
• To assess the effects of BNC210 on 
patient-reported global functioning 
and sleep quality in participants with 
PTSD 
• To assess the safety and tolerability of 
BNC210 in participants with PTSD 
• Proportion of participants who achieve 
remission in PTSD symptoms with a 
score of <11 on CAPS-5 Total 
Symptom Severity Scores 
• The difference between BNC210 and 
placebo in endpoint scores (Week 12) 
in Clinical Global Impression – 
Improvement Scale (CGI-I) 
• The difference between BNC210 and 
placebo in change from Baseline to 
endpoint (Week 12) in Hamilton 
Anxiety Rating Scale (HAM-A) 
• The difference between BNC210 and 
placebo in change from Baseline to 
endpoint (Week 12) in Montgomery-
Åsberg Depression Rating Scale 
(MADRS) 
• The difference between BNC210 and 
placebo in change from Baseline to 
endpoint (Week 12) in PTSD 
Checklist for DSM-5 (PCL-5) 
• The difference between BNC210 and 
placebo in change from Baseline to 
endpoint (Week 12) in Patient Global 
Impression – Severity and 
Improvement Scales (PGI-S/I) 
• The difference between BNC210 and 
placebo in change from Baseline to 
endpoint (Week 12) in Insomnia 
Severity Index (ISI) 
• The following assessments will be 
used to monitor safety and tolerability 
from Baseline to Week 15: vital signs, 
electrocardiogram (ECG), hematology 
and blood chemistry, urinalysis, 
physical examination, and Columbia 
Suicide Severity Rating Scale (C-
SSRS). Reporting of continuous 
Adverse Events (AE). 
 
 


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Overall Design: 
This is a randomized, double-blind, placebo-controlled, parallel group, multi-center study with a 
12 week, 2-arm treatment period.  Participants will attend a Screening visit within 3 weeks 
before randomization to confirm eligibility. Approximately 200 participants who fulfill the 
inclusion criteria and none of the exclusion criteria will be randomized using a 1:1 ratio to 
receive either BNC210 900 mg twice daily (b.i.d.) or matched placebo. Participants will then 
complete 12 weeks of treatment with their allocated study intervention.  Participants will  
complete study visits every 2 weeks during the treatment period and a Follow-up visit at Week 
15 (i.e., 3 weeks after their last study intervention is administered). In the event that a participant 
cannot be physically present at the study site for a specified visit due to coronavirus disease 2019 
(COVID-19) related restrictions, quarantine or positive test, or a natural disaster, a 
telehealth/remote visit may be completed instead if appropriate. 
Brief Summary: 
The purpose of this study is to assess the effects of BNC210 compared to placebo on PTSD s
ymptom severity as measured by CAPS-5 Total Symptom Severity Scores.  
Number of Participants: 
Approximately 400 participants will be screened to achieve a total enrollment of approximately 
200 randomly assigned participants. 
Intervention Groups and Duration: 
The total duration for each participant enrolled in the study is expected to be up to 18 weeks 
following the sequence below: 
• Screening period: Up to 3 weeks 
• Treatment period: 12 weeks 
• Follow up visit: 3 weeks after the last study intervention is administered 
The visit frequency during the treatment period will be every 2 weeks.  Details of study 
assessments to be conducted at each visit are included in the Schedule of Activities (SoA). 
Each participant will be randomized in a 1:1 ratio to receive b.i.d. doses of BNC210 900 mg OR 
placebo over the 12-week treatment period.  Treatment assignments will be double-blinded.   
Dose adjustments are not permitted during the study. Dose interruptions are only allowed for 
safety purposes in line with Section 7.1.4 of the study protocol.  Discontinuation of study 
intervention for safety purposes is described in Section 7.1. 
 
 
 
 
 
 


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Data Monitoring/Other Committee:  
An independent Safety Review Committee will be established to monitor participant safety 
throughout the study. The meetings will occur approximately every 3 months and will review all 
safety data including vital signs, ECG, pathology results, physical examinations, C-SSRS and 
continuous AE reporting. 
 
1.2. 
Schema 
Section not applicable. 
 


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1.3. 
Schedule of Activities (SoA) 
 
Assessment1 
Screening 
<-21 days 
Treatment Period 
Week 15 / 
Follow-up 
(+5 days)  
Baseline2 
(+3 days) 
Week 23 
(+3 days) 
Week 4 
(+3 days) 
Week 6 
(+3 days) 
Week 8 
(+3 days) 
Week 10 
(+3 days) 
Week 12 / Early 
Termination 
(+3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria4 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Medical history including current & prior medications 
X 
 
 
 
 
 
 
 
 
Structured Clinical Interview for DSM-5 disorders – Clinical 
Trials Version (SCID-5-CT) and Personality Disorders (SCID-
5-PD) Borderline Personality Disorder section only 
X 
 
 
 
 
 
 
 
 
Human immunodeficiency virus (HIV), Hepatitis B surface 
antigen (HBsAg) and Hepatitis C virus (HCV) antibody screen 
X 
 
 
 
 
 
 
 
 
Serum pregnancy test (if applicable) 
X 
 
 
 
 
 
 
 
 
Urine pregnancy test (if applicable) 
 
X 
 
 
 
 
 
X 
 
Urine drug screen5 
X 
X 
 
X 
 
X 
 
X 
 
12-lead electrocardiogram (ECG)6  
X 
 
 
X 
 
X 
 
X 
 
Vital signs7  
X 
X 
 
X 
 
X 
 
X 
X 
Physical examination (including height only at Screening; 
weight only at Screening and Week 12 / Early Termination)8 
X 
X 
 
X 
 
X 
 
X 
X 
Clinical labs (hematology, biochemistry, urinalysis) 
X 
X 
 
X 
X9 
X 
X9 
X 
X 
 
1 See Section 8 for guidance on the order of assessments to be completed at each visit 
2 All baseline assessments to be completed pre-dose 
3 Visit can be performed at the study site, or remotely via phone/video call 
4 Recheck eligibility and clinical status before randomization 
5 Screening assessment to be performed by the central laboratory. Subsequent assessments to be performed locally by study site using urine dip stick test 
6 ECGs to be completed in triplicate with an approximate 2-minute break between tests.  Participants must be resting in a semi-supine or supine position for at least 5 minutes prior to performing 
the ECG.  The same ECG machine should be used for all recordings from an individual participant, where possible.  Single triplicate repeat during Screening allowed in the event of a clinically 
significant abnormality including prolonged Fridericia corrected QT interval (QTcF). 
7 Blood pressure and heart rate will be measured in a sitting position after resting for 5 minutes 
8 Full physical examination at Screening & W12 / Early Termination. Abbreviated physical examination at Baseline, Week 4, Week 8, and Follow-up 
9 Blood biochemistry testing only for Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Bilirubin (direct and total) 


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Assessment1 
Screening 
<-21 days 
Treatment Period 
Week 15 / 
Follow-up 
(+5 days)  
Baseline2 
(+3 days) 
Week 23 
(+3 days) 
Week 4 
(+3 days) 
Week 6 
(+3 days) 
Week 8 
(+3 days) 
Week 10 
(+3 days) 
Week 12 / Early 
Termination 
(+3 days) 
Columbia Suicide Severity Rating Scale (C-SSRS)10 
X 
X 
 
X 
 
X 
 
X 
X 
Life Events Checklist for DSM-5 (LEC-5)11 
X 
 
 
 
 
 
 
 
 
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)12 
X 
X 
 
X 
 
X 
 
X 
 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
X 
X 
 
X 
 
X 
 
X 
 
Randomization13 
 
X 
 
 
 
 
 
 
 
Hamilton Anxiety Rating Scale (HAM-A) 
 
X 
 
X 
 
X 
 
X 
 
Clinical Global Impressions Severity and Improvement scales 
(CGI-S/I)14 
 
X 
 
X 
 
X 
 
X 
 
Patient Global Impression – Severity and Improvement scales 
(PGI-S/I)14 
 
X 
 
X 
 
X 
 
X 
 
PTSD Checklist (PCL-5) 
 
X 
 
 
 
 
 
X 
 
Sheehan Disability Scale (SDS) 
 
X 
 
X 
 
X 
 
X 
 
Insomnia Severity Index (ISI) 
 
X 
 
X 
 
X 
 
X 
 
Study Intervention dispensing 
 
X15 
 
X 
 
X 
 
 
 
Concomitant medications recording 
 
X 
X 
X 
 
X 
 
X 
X 
Adverse Event (AE) recording16 
 
 
X 
X 
 
X 
 
X 
X 
Blood sample collection for concentration of BNC210  
 
 
 
X 
 
X 
 
X 
 
 
10 “Screening C-SSRS” to be used at Screening. “C-SSRS Since Last Visit” to be used at every other visit 
11 To be completed prior to CAPS-5 assessment at Screening 
12 Past month version to be used at every visit and should be audio recorded at every visit using the provided iPhone.  
13 Once eligibility has been confirmed 
 
14 Improvement scale at Week 12 only 
15 Participants to administer one PM dose on day of completing Baseline assessments and randomization 
16 See Appendix 3 for definitions 
 
 


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2. 
Introduction 
Bionomics Limited is developing BNC210 for the treatment of anxiety, and trauma- and stressor-
related, disorders.  BNC210 is a negative allosteric modulator of the alpha-7 nicotinic 
acetylcholine receptor (alpha-7 nAChR), which represents a novel target for the treatment of 
these disorders.  BNC210 is a new chemical entity which has exhibited potent anxiolytic activity 
in a range of animal models at low doses with a wide therapeutic window.  There is an absence 
of the adverse effects particularly associated with standard-of-care treatments for acute disorders, 
such as benzodiazepines, and the antidepressants used in first line therapy for chronic disorders. 
2.1. 
Study Rationale 
This Phase 2b study will assess the potential effect of BNC210 in the treatment of PTSD, a 
condition which is classified in the Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (DSM-5) as a Trauma and Stressor-Related Disorder.  
Previous human studies with BNC210 have established its safety and tolerability and 
demonstrated effects in a panic model in healthy volunteers. In a Phase 2a study in generalized 
anxiety disorder (GAD) patients (BNC210.006) using functional magnetic resonance imaging 
(fMRI), BNC210 reduced bilateral amygdala reactivity to fearful faces in an Emotional Faces 
Task and connectivity between the left amygdala and anterior cingulate cortex (ACC). In both 
anxiety and PTSD patients, significant arousal of the amygdala occurs in response to viewing 
fearful faces. Reduction of this response has been demonstrated by first line therapeutics for 
anxiety. In addition, anxious patients have a strong connection between the ACC and the 
amygdala. The reduction of connectivity in this circuit, and of amygdala hyperactivity, 
demonstrate BNC210 efficacy on two validated biomarkers of anxiety-induced brain changes. In 
the same study, BNC210 caused a significant reduction in defensive behavior (threat avoidance), 
demonstrating the positive effect of BNC210 on modulating hypothalamic pituitary adrenal axis 
behavior. These human data demonstrate proof-of-biology for BNC210 and potential for efficacy 
in the treatment of anxiety disorders and PTSD. 
Furthermore, based on preclinical data demonstrating BNC210’s positive effects on fear 
extinction, BNC210 is being studied in PTSD patients where deficits in fear extinction are 
thought to contribute to the pathology of this disorder.   
BNC210 has previously been evaluated in patients with PTSD in a randomized, double-blind, 
placebo-controlled trial over 12 weeks (BNC210.007). BNC210 was administered orally as a 
suspension and was well tolerated with no pattern of drug-related adverse effects becoming 
apparent. However, improvements in the efficacy measurement of Clinician-Administered PTSD 
Scale for the DSM-5 (CAPS-5) Total Symptom Severity scores were not statistically different 
between BNC210 and placebo. Using population pharmacokinetics, exposure to BNC210 was 
modelled in the trial participants and was substantially less than that expected when compared to 
pharmacokinetic (PK) data from a healthy volunteer study with the same suspension formulation 
(BNC210.005). This may be attributed in part to the unsuitability of the suspension formulation 
for an out-patient study, in particular, its dependence on food for optimal absorption.  A 
pharmacometric exposure-response relationship was modelled based on the population PK and 


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CAPS-5 scores from the study and suggests potential for BNC210 to have clinical efficacy in 
PTSD provided that adequate plasma exposures are achieved.   
A spray-dried dispersion tablet formulation of BNC210 has since been developed and when 
evaluated in single and multiple dose PK studies in healthy adult volunteers has demonstrated 
that it can safely and reliably achieve the exposure predicted by the pharmacometric model for 
potential clinical efficacy in PTSD patients, without the dependence on food, and hence justifies 
further evaluation of BNC210 as a potential treatment for adults with PTSD. 
2.2. 
Background 
2.2.1. 
Disease Background 
PTSD may result from exposure to a traumatic event during which an individual experienced, 
witnessed, or was confronted with the actual threat of death or serious injury, or the threat to 
physical integrity to self or others. PTSD symptoms can be divided into four clusters: (1) 
persistent re-experiencing of the trauma, (2) avoidance behavior associated with feelings of 
detachment and emotional numbness, (3) negative alterations in cognitions and mood, and (4) 
symptoms of increased autonomic arousal. 
The lifetime prevalence of PTSD in the general population is approximately 8% making PTSD 
the fifth most prevalent mental disorder in the United States (Krystal et al., 2017). People with 
PTSD continue to experience adverse effects of their exposure to trauma for years afterwards, 
when the trauma is no longer present, and this inability to return to the pre-trauma state 
differentiates PTSD from other stressor-related disorders.  
Treatment is based on early interventions, psychotherapy and pharmacotherapy. Only two 
pharmacological agents, the antidepressants Paxil® (paroxetine) and Zoloft® (sertraline), 
belonging to the selective serotonin reuptake inhibitors class (SSRIs), are Food and Drug 
Administration (FDA)-approved for the treatment of PTSD, but they have not been shown to 
ameliorate the full range of PTSD symptoms, and complete remission of symptoms is rare. It has 
been estimated that no more than 20 to 30% of people with PTSD are effectively treated, and a 
high percentage of those who begin PTSD treatment eventually drop out (Alexander, 2012; 
VA/DOD Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder and 
Acute Stress Disorder, 2017). The use of benzodiazepines are contraindicated for PTSD based on 
their unproven efficacy and their risks for abuse and dependence in a population at risk of co-
morbid substance use disorder. 
There is a need for improved therapeutics for PTSD with greater clinical benefit, fewer side 
effects and a faster onset of action, something that might be achieved by targeting a different 
mechanism of action. 
 
 
 
 
 
 
 


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• To assess the effects of BNC210 on 
patient-reported symptoms of PTSD  
• To assess the effects of BNC210 on 
patient-reported global functioning 
and sleep quality in participants with 
PTSD 
• To assess the safety and tolerability of 
BNC210 in participants with PTSD 
• The difference between BNC210 and 
placebo in endpoint scores (Week 12) 
in Clinical Global Impression – 
Improvement Scale (CGI-I) 
• The difference between BNC210 and 
placebo in change from Baseline to 
endpoint (Week 12) in Hamilton 
Anxiety Rating Scale (HAM-A) 
• The difference between BNC210 and 
placebo in change from Baseline to 
endpoint (Week 12) in Montgomery-
Åsberg Depression Rating Scale 
(MADRS) 
• The difference between BNC210 and 
placebo in change from Baseline to 
endpoint (Week 12) in PTSD 
Checklist for DSM-5 (PCL-5) 
• The difference between BNC210 and 
placebo in change from Baseline to 
endpoint (Week 12) in Patient Global 
Impression – Severity and 
Improvement Scales (PGI-S/I) 
• The difference between BNC210 and 
placebo in change from Baseline to 
endpoint (Week 12) in Insomnia 
Severity Index (ISI) 
• The following assessments will be 
used to monitor safety and tolerability 
from Baseline to Week 15: vital signs, 
electrocardiogram (ECG), hematology 
and blood chemistry, urinalysis, 
physical examination, and Columbia 
Suicide Severity Rating Scale (C-
SSRS). Reporting of continuous 
Adverse Events (AE). 
 
 
 
 
 




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4. 
Study Design 
4.1. 
Overall Design 
This is a randomized, double-blind, placebo-controlled, parallel group, multi-center study with a 1
2 week, 2-arm treatment period.  Participants will attend a Screening visit within 3 weeks before 
randomization to confirm eligibility. Approximately 200 participants who fulfill the inclusion 
criteria and none of the exclusion criteria will be randomized using a 1:1 ratio to receive either 
BNC210 900 mg b.i.d. or matched placebo. Participants will then complete 12 weeks of 
treatment with their allocated study intervention.  Participants will complete study visits every 2 
weeks during the treatment period and a Follow-up visit at Week 15 (i.e., 3 weeks after their last 
study intervention is administered). In the event that a participant cannot be physically present at 
the study site for a specified visit due to coronavirus disease 2019 (COVID-19) related 
restrictions, quarantine or positive test, or a natural disaster, a telehealth/remote visit may be 
completed instead if appropriate (see Section 8). 
Details are included in the Schedule of Activities (SoA). 
4.2. 
Scientific Rationale for Study Design 
This study evaluates as its primary endpoint, the effects of BNC210 compared to placebo on 
PTSD symptom severity using the CAPS-5. CAPS-5 is the universally accepted scale for 
diagnosis of PTSD as well as for assessment of PTSD symptom severity. It can monitor 
worsening or improvement in a participant’s symptoms by applying a well-defined scoring 
system according to specific criteria. It is therefore an appropriate tool for measuring the primary 
endpoint of this study and clinically meaningful changes in PTSD symptom severity.  
The primary and secondary endpoints in this study will utilize clinician-administered scales as 
well as patient-reported scales.  A double blind, placebo-controlled study design has been chosen 
as a well-established and appropriate study design to minimize the potential for bias in study 
assessments or in reporting of AEs. Clinic staff and participants are blinded to treatment 
assignments to ensure objective reporting.  In addition, participants will be randomized 1:1 to 
receive either BNC210 or placebo to ensure there are no order effects and to further minimize 
bias. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study.  
 


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5. 
Study Population 
Investigators will be responsible for evaluating potential participants against the study eligibility 
criteria during the Screening period.  At the initial Screening visit, each participant will 
participate in the informed consent process and sign and date the ICF before any procedures 
specified in this protocol are performed. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be 18 to 75 years of age inclusive, at the time of signing informed 
consent 
Type of Participant and Disease Characteristics 
2. Current diagnosis of PTSD as defined by the CAPS-5, with a CAPS-5 Total Symptom S
everity Score of >30 at Screening and Baseline and no >25% decrease in Score from 
Screening to Baseline 
3. The index trauma event must have occurred in adulthood, i.e., when the participant was 
≥18 years of age 
4. In the opinion of the Investigator the participant has a high probability for adherence 
with and completion of the study 
5. Ability to swallow tablets 
6. Fluent in English and able to understand and comply with written and verbal protocol-
related requirements 
Sex and Contraceptive/Barrier Requirements 
 
7. Contraceptive use by participants should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
a. Male participants are eligible to participate if they agree to the following during the 
study intervention period and for at least 60 days after the last dose of study 
intervention: 
• Refrain from donating sperm PLUS, either: 
o Be abstinent from heterosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 
OR 
o Must agree to use a male condom with female partner using an additional 
highly effective contraceptive method with a failure rate of < 1% per year as 
described in Appendix 4 Contraceptive and Barrier Requirements, when 


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having sexual intercourse with a woman of childbearing potential (WOCBP) 
who is not currently pregnant 
b. Female participants are eligible to participate if they are not pregnant or 
breastfeeding and the following conditions applies: 
o Is a woman of nonchildbearing potential (WONCBP) as defined in Appendix 4 
Contraception and Barrier Guidance.  
OR 
o Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of < 1% per year), preferably with low user dependency, as 
described in Appendix 4 Contraception and Barrier Guidance during the study 
intervention period and for at least 60 days after the last dose of study 
intervention and agrees not to donate eggs (ova, oocytes) for the purpose of 
reproduction during this period. The Investigator should evaluate the potential 
for contraceptive method failure (e.g., noncompliance, recently initiated) in 
relationship to the first dose of study intervention. 
• A WOCBP must have a negative serum pregnancy test at Screening and a 
negative urine test at Baseline (within 24 hours before the first dose of study 
intervention). 
The Investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy. 
Informed Consent 
8. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. A period of less than 6 months since the index trauma event occurred 
2. Current and ongoing exposure to the trauma that caused the PTSD 
3. Complex PTSD, defined as a condition that may develop following exposure to an 
event or series of events of an extreme and prolonged or repetitive nature, which the 
participant experienced as extremely threatening or horrific and from which escape was 
difficult or impossible (e.g., torture, slavery, genocide campaigns, prolonged domestic 
violence, repeated childhood sexual or physical abuse). If affect dysregulation and 
interpersonal dysfunction are primary over other core PTSD symptoms, in the 
Investigator’s opinion, participants should be excluded.  
4. Severe depression as measured by a score of ≥ 35 on the Montgomery-Åsberg 
Depression Rating Scale (MADRS) at Screening 


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5. Bipolar, Borderline Personality and other psychotic disorders as identified at Screening 
using the Structured Clinical Interview for DSM-5 Disorders – Clinical Trials Version 
(SCID-5-CT) and Personality Disorders (SCID-5-PD). 
6. History of moderate to severe traumatic brain injury 
7. History of seizure disorders, uncontrolled sleep apnoea or severe neurologic disease 
8. Any moderate or severe substance use disorder according to DSM-5 in the 12 months 
prior to Screening  
9. Increased risk of suicide, defined as: 
• Any suicide attempt in the 12 months prior to Screening disclosed by the 
participant using the Columbia Suicide Severity Rating Scale (C-SSRS) 
• Any suicidal ideation with intent (yes to item 4 and/or 5) or suicidal behavior in the 
past 12 months, as captured at Screening using the C-SSRS 
• A score > 4 on item 10 of the MADRS at Screening. 
10. History or presence of impaired renal function, as indicated by clinically significant 
abnormal creatinine, blood urea nitrogen (BUN) or plasma urea, or moderate to severe 
renal dysfunction as defined by the Cockcroft-Gault equation (estimated glomerular 
filtration rate (eGFR) <50 mL/min) 
11. Alanine transaminase (ALT), aspartate transaminase (AST) or alkaline phosphatase 
(ALP) > 2.0 x upper limit of normal (ULN) 
12. Total bilirubin > 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if total 
bilirubin is fractionated and direct bilirubin < 35%) 
13. Current or chronic history of liver disease. This includes but is not limited to hepatitis 
virus infections, drug- or alcohol-related liver disease, nonalcoholic steatohepatitis, 
autoimmune hepatitis, hemochromatosis, Wilson’s disease, α-1 antitrypsin deficiency, 
primary biliary cholangitis, primary sclerosing cholangitis, or any other liver disease 
considered clinically significant by the Investigator 
14. Any clinically significant abnormalities in laboratory test results (biochemistry, 
hematology or urinalysis) as assessed by the Investigator 
15. Blood Pressure systolic >160 mmHg or diastolic >90 mmHg. Two repeat measures are 
allowed at the discretion of the Investigator 
16. Fridericia-corrected QT interval (QTcF) >450 msec for males and QTcF >470 msec for 
females, or QTc >480 msec in participants with bundle branch block, as measured by 
ECG at Screening 
17. Any clinically significant ECG abnormality as determined by the Investigator at 
Screening 
18. A family history of congenital long QT syndrome, Brugada syndrome or unexplained 
sudden cardiac death 
 


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 Prior/Concomitant Therapy 
19. The use of antidepressant medications within 30 days (fluoxetine within 90 days) of 
Screening.  The use of alprazolam, flunitrazepam and chronic daily use of other 
benzodiazepines within 90 days of Screening. The use of other psychotropic active 
medications within 5 days of Screening. 
20. Failed more than three trials of antidepressant medication(s) prescribed for the 
treatment of PTSD. Each trial must have lasted at least 6 weeks to be considered a 
failed attempt. A trial that was terminated due to intolerability or side effects does not 
constitute a failed attempt. 
21. Receiving concurrent trauma-based psychotherapy such as Cognitive Behavior 
Therapy, Prolonged Exposure Therapy, Eye Movement Desensitization and 
Reprocessing Therapy. Participants may continue to receive supportive counseling that 
has been in place for a minimum of three months prior to Screening. 
22. The use of cytochrome P450 3A4 inducers within 30 days of Screening 
23. The use of moderate-strong cytochrome P450 3A4 inhibitors within 2 weeks of 
Screening.  This includes but is not limited to, grapefruit or grapefruit-containing 
products. 
Prior/Concurrent Clinical Study Experience 
24. Current enrolment OR past participation in another investigational study in which an 
investigational intervention (e.g., drug, vaccine, invasive device) was administered 
within 30 days before signing of consent in this clinical study. 
25. Previously participated in Bionomics’ Phase 2 PTSD study BNC210.007 (RESTORE 
study) 
Diagnostic Assessments 
26. Positive result for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C (HCV) at Screening  
27. Positive urine test for an illicit substance, excluding cannabis, at Screening or Baseline 
Other Exclusions 
28. History of allergies, allergic reactions or hypersensitivity to BNC210 or excipients 
29. A member of the United States military currently serving on active duty 
30. In the process of litigating for compensation for a psychiatric disorder. Participants 
who are in the process of applying for medical or Veterans Affairs benefits and/or 
those who have settled a disability claim prior to enrollment in the trial are eligible.  
31. Participants that, in the opinion of the Investigator, are not suitable to participate in the 
study due to clinically significant findings from medical history that could interfere 
with the objectives of the study or put the participant at risk or any other reason the 
Investigator deems applicable 
 
 


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5.3. 
Lifestyle Considerations 
There are no specific lifestyle considerations or restrictions applicable to this study outside of the 
criteria detailed in Sections 5.1, 5.2 and 6.8.  However, over the course of the study, participants 
should be counseled on the importance of maintaining consistent behaviors. This includes 
limiting any change to alcohol, cannabis or tobacco use, dietary intake, and sleep patterns when 
compared to Baseline. Participants will also be encouraged to attend study visits at the same time 
of day to avoid possible diurnal variation in measurement responses.  
5.4. 
Screen Failures 
Participants who sign and date the ICF but who fail to meet the inclusion and exclusion criteria 
are considered screen failures. Reason(s) for screen failure must be documented by the 
Investigator and provided to the Sponsor in a timely fashion. 
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAEs. 
In the event that a participant fails a clinical laboratory or ECG screening assessment, that 
assessment can be repeated once only during the screening period. The repeat assessment must 
be completed within the allowed screening period (21 days + 3 days of Baseline) for eligibility 
purposes. If the repeat assessment cannot be completed within the screening period, the 
participant must be re-screened in entirety. Participants who fail any other screening assessment 
must be screen-failed.  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened, if deemed appropriate by the Investigator and with prior approval from the 
Sponsor/Medical Monitor. However, individuals who do not meet the criterion for CAPS-5 Total 
Symptom Severity Score in line with inclusion criterion #2, will not be eligible for rescreening. 
Rescreened participants should be reconsented and assigned a new participant number (Subject 
ID) for every screening/rescreening event. 
5.5. 
Criteria for Temporarily Delaying Randomization or Administration 
of Study Intervention 
Section not applicable 
 


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6. 
Study Intervention(s) and Concomitant Therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
Detailed information related to the composition of the study interventions to be used in this study 
can be found in the study Investigational Product Manual and the Investigator’s Brochure. 
Participants will administer study intervention b.i.d. for 12 weeks. 
 
 
 
 
 
 
6.1. 
Study Intervention(s) Administered 
 
Table 1.  Study Intervention(s) Administered 
Intervention Label 
BNC210 900 mg 
Placebo 
Intervention Name 
BNC210 
Placebo 
Intervention Description 
BNC210 900 mg b.i.d. for 12 
weeks 
Placebo b.i.d. for 12 weeks 
Type  
Drug 
Drug 
Dose Formulation 
Tablet 
Tablet 
Unit Dose Strength 
225 mg 
N/A 
 
 
 
Route of Administration 
Oral 
Oral 
Use 
Experimental  
Placebo Comparator  
Investigational Medicinal 
Product (IMP) 
IMP 
IMP 
Sourcing 
Provided centrally by Sponsor  Provided centrally by Sponsor  


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Packaging and Labeling 
4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2.  Study Arm(s) 
 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention, and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
Arm Title 
BNC210  
Placebo 
Arm Type 
Experimental 
Placebo Comparator 
Associated Intervention Labels 
BNC210 900 mg 
Placebo 


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4. Further guidance and information on the handling, storage, accountability, dispensing and 
for the final disposition of unused study interventions are provided in the Investigational 
Product Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
 
IWRS 
After a participant signs the ICF at Screening, site personnel will register 
the participant in the interactive web response system (IWRS). 
Upon successful completion of the Screening module the system will 
assign the participant a unique participant number (Subject ID).  
Randomization will be performed as double blind, Central 
Randomization.    
Upon successful completion of randomization in the IWRS the system 
will determine the correct study intervention kit type to dispense. Once a 
participant is randomized to a treatment arm, the randomization will 
remain documented as such. The system will never reuse the same 
randomization number. 
The system will then determine which study intervention kit of that type 
is available for dispensing and inform the study site to dispense that kit. 
The kit assigned will correspond to the correct treatment for the 
participant. 
Study intervention will be dispensed at the study visits as summarized in 
the SoA.  
 
Blind break 
(IWRS) 
This is a double-blind study in which participants/Investigators/raters, etc. 
are blinded to study intervention. The IWRS will be programmed with 
blind-breaking instructions. In case of an emergency, the Investigator has 
the sole responsibility for determining if unblinding of a participant’s 
intervention assignment is warranted. Participant safety must always be 
the first consideration in making such a determination. If the Investigator 
decides that unblinding is warranted, the Investigator should make every 
effort to contact the Medical Monitor and/or Sponsor prior to unblinding a 
participant’s intervention assignment unless this could delay emergency 
treatment for the participant. If a participant’s intervention assignment is 
unblinded, the Sponsor must be notified within 24 hours of this 
occurrence. The date and reason that for the unblinding must be recorded. 


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6.5. 
Dose Modification 
Dose reductions or increases will not be allowed in this study. 
6.6. 
Continued Access to Study Intervention After the End of the Study 
Participants will not have access to study interventions after completion of their participation in 
the study.  Participants should be directed to receive standard of care treatments as directed by 
the Investigator or their primary care physician. 
6.7. 
Treatment of Overdose 
For this study, any dose of BNC210/placebo greater than 1,800 mg within a 24-hour time period 
will be considered an overdose. 
In the event of an overdose, the Investigator should: 
• Contact the Medical Monitor immediately. 
• Evaluate the participant to determine, in consultation with the Medical Monitor, whether 
study intervention should be interrupted. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until they 
have resolved or stabilized.  
• Document the quantity of the excess dose as well as the duration of the overdose. 
6.8. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) or other specific categories of interest that the 
participant is receiving at the time of Screening or receives during the study must be recorded 
along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Use of any investigational drug, vaccine or invasive device within 30 days prior to Screening and 
at any point during the study is prohibited. 
Inducers of cytochrome P450 3A4 should not be used within 30 days of Screening and their use 
is prohibited during the study. This includes, but is not limited to: carbamazepine, phenytoin, 
oxcarbazepine, barbiturates, phenobarbital, butalbital, St. John's wort, rifampicin, rifabutin, 
efavirenz, nevirapine, pioglitazone, troglitazone, corticosteroids by the systemic route (see 
Appendix 6 for a more extensive list).   
 


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Moderate to strong inhibitors of cytochrome P450 3A4 should not be used within two weeks of 
Screening and their use is prohibited during the study.  These include grapefruit juice, verapamil, 
diltiazem, fluvoxamine, fluconazole and itraconazole and HIV antivirals (refer to the following 
website for a more extensive list https://drug-interactions.medicine.iu.edu/MainTable.aspx).  
Participants that are under consideration for the study and are being treated with an 
antidepressant medication, must have discontinued the medication for at least 30 days prior to 
Screening (as per exclusion criterion #19) and be titrated off their medication in accordance with 
current prescribing guidelines. Participants must also have discontinued the use of alprazolam, 
flunitrazepam and chronic daily use of other benzodiazepines for at least 90 days prior to 
Screening. The use of other psychotropic medications must have been discontinued for at least 5 
days prior to Screening.  The withdrawal of these medications is at the discretion of the 
participant in consultation with their primary physician and falls outside the scope of this study 
protocol. 
The use of antidepressants and psychotropic medications are also prohibited during all stages of 
the study. This includes, but is not limited to, mood stabilizers, stimulants, antipsychotics, 
anticonvulsant drugs (including gabapentinoids), hypnotics, benzodiazepines, methylphenidate, 
doxazosin, prazosin, clonidine, first generation sedating H1 antihistamines, quetiapine, 
eszopiclone, zolpidem extended-release and acetylcholinesterase inhibitors.  
The use of non-prescription medications (including herbal medications) will be discouraged 
during the course of the study. Prescription medications should be limited and avoided if 
possible, but will be allowed where clinically indicated, e.g., for treatment of AEs or pre-existing 
medical conditions documented at Screening.   
Ongoing long-term supportive counseling is allowed only if the participant commenced therapy 
> 3 months prior to Screening and is willing to continue therapy at the same frequency 
throughout the study. 
If a medication or treatment is administered that is in breach of these restrictions, the Medical 
Monitor must be promptly notified in order to assess the participant’s suitability for continued 
study participation. 
6.8.1. 
Rescue Medications for Insomnia 
Only the use of certain nonbenzodiazepine sleep inducers (e.g., zolpidem immediate-release [up 
to 10 mg at bedtime], zaleplon [up to 20 mg at bedtime]), melatonin, or ramelteon for sleep are 
allowed. The date and time of rescue medication administration as well as the name and dosage 
regimen of the rescue medication must be recorded. 
 


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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
The process for discontinuation of specific sites or the study as a whole are detailed in Appendix 
1. 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will not remain in 
the study. See the SoA for evaluations that need to be completed at the time of discontinuation of 
study intervention (Early Termination visit). 
7.1.1. 
Liver Chemistry Stopping Criteria 
Discontinuation of study intervention for abnormal liver tests is required by the Investigator 
when a participant meets one of the conditions outlined in the algorithm or in the presence of 
abnormal liver chemistries not meeting protocol-specified stopping rules if the Investigator 
believes that it is in best interest of the participant.  Study intervention restart or rechallenge after 
liver chemistry stopping criteria are met by any participant in this study is not allowed. 
Phase 2 Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm 
 
Abbreviations: ALT = alanine transaminase; AST = aspartate transaminase, INR = international normalized ratio; 
SAE = serious adverse event; Tbili = total bilirubin, ULN = upper limit of normal. 
Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix 5.  


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7.1.2. 
QTc Stopping Criteria 
A participant who meets the bulleted criterion based on the average of triplicate ECG readings 
will be withdrawn from study intervention. 
• QTc > 500 msec OR change from Baseline of QTc > 60 msec 
For participants with underlying bundle branch block, follow the discontinuation criteria listed 
below: 
Baseline QTc with Bundle Branch Block 
Discontinuation QTc Threshold with 
Bundle Branch Block 
< 450 msec 
> 500 msec 
450 to 480 msec 
≥ 530 msec 
If a clinically significant finding is identified (including, but not limited to changes from 
Baseline in QT interval corrected using Fridericia’s formula [QTcF]) after enrollment, the 
Investigator or qualified designee will determine if the participant can continue in the study and 
if any change in participant management is needed. This review of the ECG printed at the time of 
collection must be documented. Any new clinically relevant finding should be reported as an AE. 
7.1.3. 
Suicidal Behavior Stopping Criteria 
A participant who meets any of the bulleted criteria below will be withdrawn from study 
intervention. 
• Any new suicidal behavior since Screening, as disclosed by the participant during 
administration of the C-SSRS 
• Any suicidal ideation with intent (yes to item 4 and/or 5) since Screening, as disclosed by 
the participant during administration of the C-SSRS 
• A score > 4 on item 10 of the MADRS 
7.1.4. 
Temporary Discontinuation 
Dose interruptions will be allowed following the onset of AEs if deemed appropriate by the 
Investigator. However, should an interruption of 3 or more days occur, approval from the 
Medical Monitor and Sponsor must be obtained prior to re-commencing study intervention. Dose 
reductions will not be allowed. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an Early Termination visit should 
be conducted, as shown in the SoA.  
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 


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• If the participant withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
7.3. 
Lost to Follow up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the study site for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  


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8. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Medical Monitor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
 
 
 
 
 
   
• As a guide, diagnostic and efficacy assessment scales such as CAPS-5, PCL-5, SCID-5-
CT and SCID-PD (Screening only) and LEC-5 (Screening only) should be administered 
first, followed by depression, anxiety and suicidality scales (i.e., MADRS, HAM-A, C-
SSRS). Other efficacy scales such as CGI-S/I, PGI-S/I, SDS, and ISI should then be 
administered prior to remaining safety and diagnostic assessments such as clinical labs, 
physical examinations and ECGs. This order of procedures should be followed 
throughout the study where possible. 
• At the Week 2 visit, assessment of AEs and recording of concomitant medications should 
be performed, as well as a general assessment of how the participant is managing their 
dosing with the study intervention.  The Week 2 visit can be performed either at the study 
site or via phone/video call with the study participant. 
• At the Week 6 and Week 10 visits, the only assessments required are routine safety blood 
laboratory testing for ALT, AST, ALP, and bilirubin (direct and total).  Participants can 
have this testing performed at the study site for analysis at the central laboratory or 
testing can be performed at a local laboratory.  There is no requirement for the participant 
to attend the study site to have this testing performed if a suitable alternative arrangement 
has been agreed with the study site (e.g., home health visit). 
• All Investigator-rated assessments and Patient Recorded Outcomes (PROs) will be 
completed using paper assessment scales. 
• Where possible, study assessments will be made available for remote administration in 
cases where restrictions, as a consequence of COVID-19 or other natural disasters, 
prevent participants from attending clinic visits.  PROs will be provided to participants as 
paper versions to be completed at the appropriate time point and returned to the study site 
upon completion.  Laboratory assessments, inclusive of samples for concentration of 


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BNC210 as well as physical examinations and vital signs assessments, may be collected 
per site COVID-19 protocols or as an unscheduled assessment upon lifting of any 
restrictions. Any procedures that are missed or cannot be performed within the allowed 
study visit window due these restrictions being in place will not be considered protocol 
deviations. 
• Where restrictions due to COVID-19 or other natural disasters, prevent participants from 
performing study visits in person, a participant or verified representative of the 
participant, may attend the study site to return/obtain study intervention. If Sponsor 
approved procedures are in place at a study site, study intervention may also be delivered 
to a participant’s home.   
• Analyte results that could unblind the study will not be reported to study sites or other 
blinded personnel. 
• The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, should not exceed 110 mL. 
• On days where study visits occur, participants should continue to take their morning dose 
of study intervention at their scheduled time, even if prior to attending the study site for 
the scheduled visit. If the scheduled time of dosing coincides with a study visit, 
participants can take their dose of study intervention during the study visit.   
• Dispensing of study intervention should occur last, after all study tests and assessments 
have been completed for a specified study visit. All visits should be scheduled to occur at 
approximately the same time of day. 
• Participants may attend an unscheduled visit at any time. All assessments completed 
during an unscheduled visit must be captured in the eCRF. This includes the results of all 
pathology tests scheduled by the Investigator. 
• Visits scheduled due to increased safety monitoring in line with Section 7.1 must be 
captured as an unscheduled visit.  
• A visit with a participant’s primary physician (i.e., not a study Investigator) is not 
considered an unscheduled visit. Similarly, hospital admissions due to SAEs are also not 
considered unscheduled visits. Assessments completed by external institutions should not 
be entered into the eCRF. 
8.1. 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA. 
8.1.1. 
Clinician-Administered PTSD Scale for the DSM-5 (CAPS-5) 
The CAPS-5 is a 30-item structured interview used to diagnose PTSD and assess PTSD 
symptoms over the past month. Information about the frequency and intensity of each item is 
combined into a severity rating, and the CAPS-5 total symptom severity score is calculated by 
adding the severity scores for the 20 PTSD symptoms in the DSM-5 (National Centre for PTSD).  
The CAPS-5 interview should be audio recorded using the provided iPhone at every study visit. 


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8.1.2. 
PTSD Checklist for DSM-5 (PCL-5) 
The PCL-5 is a 20-item self-report assessment of the 20 DSM-5 symptoms of PTSD (National 
Centre for PTSD). Each symptom is rated on a scale from 0 (not at all) to 4 (extremely).  
8.1.3. 
Clinical Global Impression Scales – Severity and Improvement (CGI-S/I) 
The CGI-S is a rating scale designed to assess the severity of the participant’s symptoms, and the 
CGI-I is designed to assess the change in the participant’s condition since the initial assessment. 
Severity is rated on the CGI-S from 1 (normal, not at all ill) to 7 (among the most extremely ill 
of participants). The changes in the participant’s condition are rated on the CGI-I from 1 (very 
much improved) to 7 (very much worse). 
8.1.4. 
Patient Global Impression Scales – Severity and Improvement (PGI-S/I) 
The PGI-S is a self-rating scale designed to assess the severity of the participant’s symptoms, 
and the PGI-I is designed to assess the change in the participant’s condition since the initial 
assessment. Severity is rated on the CGI-S from 1 (normal) to 4 (severe). The changes in the 
participant’s condition are rated on the CGI-I from 1 (very much better) to 7 (very much worse). 
8.1.5. 
Hamilton Anxiety Rating Scale (HAM-A) 
The HAM-A is an interview questionnaire that measures severity of anxiety symptoms based on 
14 parameters, including anxious mood, tension, fears, insomnia, somatic complaints and 
behavior during the interview (Hamilton, 1959). Each parameter is rated on a scale of 0 (not 
present) to 4 (very severe). 
8.1.6. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item self-diagnostic and clinician-rated questionnaire to measure the 
presence and severity of depressive episodes and includes the following symptoms: 1) apparent 
sadness; 2) reported sadness; 3) inner tension; 4) reduced sleep; 5) reduced appetite; 6) 
concentration difficulties; 7) lassitude; 8) inability to feel; 9) pessimistic thoughts; and 10) 
suicidal thoughts (Williams and Kobak, 2008). The rater must decide whether the rating lies on 
defined scale steps (0, 2, 4, 6) or between them (1, 3, 5). 
8.1.7. 
Sheehan Disability Scale (SDS) 
The SDS is a rating scale designed to measure impairment in three domains: work/school, social 
life, and family life/home responsibilities. Each item is rated on a scale of 0 (not at all) to 10 
(extremely), for a total score of 0 to 30.  
8.1.8. 
Insomnia Severity Index (ISI) 
The ISI is a brief self-report instrument measuring both nocturnal and diurnal symptoms of 
insomnia (Morin 1993).  The ISI comprises seven items, each scored from 0 to 4, assessing the 
perceived severity of difficulties initiating sleep, staying asleep, and early morning awakenings, 
satisfaction with current sleep pattern, interference with daily functioning, noticeability of 
impairment attributed to the sleep problem, and degree of distress or concern caused by the sleep 
problem.  The scores from each of the 7 questions are added up to get a total score of 0 to 28.  
 
 


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8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the general 
appearance, skin and lymphatics, eyes, ears, nose, throat, cardiovascular system, 
respiratory system, abdomen/gastrointestinal system, musculoskeletal and neurological 
systems.  Other body systems may also be examined as required. Height and weight will 
also be measured and recorded at the time points specific in the SoA. 
• An abbreviated physical examination will include, at a minimum, assessments of the 
eyes, ears, nose, throat, cardiovascular system, respiratory system, and 
abdomen/gastrointestinal system. Other body systems may also be examined as required. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Clinically significant changes from first dose of study intervention will be recorded as 
AEs. 
8.2.2. 
Vital Signs 
• Body temperature, pulse rate, respiratory rate, and systolic and diastolic blood pressure 
will be assessed. 
• Blood pressure and pulse measurements will be assessed in a sitting position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
in a seated position for the participant in a quiet setting without distractions (e.g., 
television, cell phones). 
8.2.3. 
Electrocardiograms 
• Triplicate 12-lead ECGs will be obtained as outlined in the SoA using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. Refer to Section 7.1.2 for QTc withdrawal criteria and any additional QTc 
readings that may be necessary. 
• At each time point, 3 individual ECG tracings should be obtained in succession, 
approximately 2 minutes apart. 
• One repeat is allowed for screening purposes if abnormal findings are observed. The 
repeat must also be completed in triplicate. 
• Participants must be resting in a semi-supine or supine position for at least 5 minutes 
prior to obtaining ECG.   
• The same ECG machine should be used for all recordings from an individual participant, 
where possible.   


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• ECGs will be read by the Investigator or designated physician at the unit.   
• QTcF values will be derived from the data available and the average QTcF will be used 
when assessing eligibility and treatment withdrawal. 
For safety monitoring purposes, the Investigator or designee must review, sign and date all ECG 
tracings.  Paper copies will be kept at the study center with the participant's clinical file as part of 
the permanent record.  The ECG intervals and interpretation will be recorded on the appropriate 
eCRF. 
Paper ECG recordings should be photocopied and maintained as a permanent source document.  
The Sponsor reserves the right to request copies of paper ECG recordings for independent 
cardiology review. 
8.2.4. 
Clinical Safety Laboratory Assessments 
• See Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents.  
• Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the Investigator to be more severe than expected 
for the participant's condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 3 weeks after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the Investigator or Medical Monitor. 
o If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the Investigator, the etiology should be identified, and the 
Medical Monitor/Sponsor notified. 
o All protocol-required laboratory tests, as defined in Appendix 2, must be conducted in 
accordance with the Laboratory Manual and the SoA. 
o If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (e.g., SAE or AE or dose 
interruption), then the results must be recorded. 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring 
BNC210 is considered to be a Central Nervous System (CNS) active intervention. Patients with 
PTSD may occasionally develop suicidal ideation or behavior. 
Participants being treated with study intervention should be monitored appropriately and 
observed closely for suicidal ideation and behavior or any other unusual changes in behavior, 
especially at the beginning and end of the course of intervention. Participants who experience 


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signs of suicidal ideation or behavior, should undergo a risk assessment. All factors contributing 
to suicidal ideation or behavior should be evaluated and consideration should be given to 
discontinuation of the study intervention.  
When informed consent or assent has been given, families and caregivers of participants being 
treated with study intervention should be alerted about the need to monitor participants for the 
emergence of unusual changes in behavior, as well as the emergence of suicidal ideation and 
behavior and to report such symptoms immediately to the study Investigator. 
Baseline assessment of suicidal ideation and behavior/ intervention emergent suicidal ideation 
and behavior will be monitored during the study using the C-SSRS. 
The C-SSRS is a suicidal ideation rating scale designed to identify behaviors that may be 
indicative of a patient’s intent to commit suicide. The scale is administered via a semi-structured 
interview and measures both passive and active suicidal ideation and the intensity and duration 
of the ideation. Both suicidal and non-suicidal self-injurious behavior is also assessed. 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting 
The definitions of AEs and SAEs can be found in Appendix 3. 
The definitions of unsolicited and solicited AEs can be found in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs/SAEs. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the signing of the ICF until the Follow-up visit at the time points 
specified in the SoA. 
All AEs will be collected from the start of intervention until the Follow-up visit at the time 
points specified in the SoA. Medical occurrences that begin before the start of study intervention 
but after obtaining informed consent will be recorded as Medical History/Current Medical 
Conditions, not as AEs. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 


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8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the participant is lost to follow-up (as defined in Section 
7.3). Further information on follow-up procedures is provided in Appendix 3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Board (IRB) 
and Investigators. 
• An Investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the IRB, if 
appropriate according to local requirements. 
8.3.5. 
Pregnancy 
• Details of all pregnancies in female participants and female partners of male participants w
ill be collected after the start of study intervention and until 3 weeks after the last dose of 
study intervention is administered. 
• If a pregnancy is reported in a female participant or female partner of male participant 
(after obtaining the necessary signed informed consent from the female partner), the 
Investigator will record pregnancy information on the appropriate form and submit it  
promptly, within 24 hours of learning of the pregnancy, signing and dating the Pregnancy 
Data Collection Form, verifying the accuracy of the information recorded in the form 
with the source documents and eCRF.  Pregnancy reporting contact information can be 
found in Appendix 3, Section 10.3.4. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 


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• The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the 
participant/pregnant female partner and the neonate and the information will be 
forwarded to the Sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants/pregnant female partner, he or she may learn of an SAE through 
spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and be withdrawn from the study. 
8.4. 
Pharmacokinetics 
• Whole blood samples of approximately 4 mL will be collected for measurement of 
plasma concentrations of BNC210 as specified in the SoA. Samples will be used to 
evaluate the pharmacokinetics of BNC210. 
• As the study is double-blind, samples will be collected from all participants but only 
those allocated to the BNC210 treatment arm will have their samples analyzed at the 
appropriate time. 
• Instructions for the collection and handling of biological samples will be provided by the 
Sponsor in the study specific Laboratory Manual.  
8.5. 
Genetics 
Genetics are not evaluated in this study. 
8.6. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.7. 
Immunogenicity Assessments 
Not applicable. 
8.8. 
Health Economics OR Medical Resource Utilization and Health 
Economics 
Health economics OR Medical resource utilization and health economics parameters are not 
evaluated in this study. 


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9. 
Statistical Considerations 
9.1. 
Statistical Efficacy Hypotheses 
The primary objective of the current study is to evaluate the efficacy of BNC210 on Investigator-
rated total symptom severity of PTSD in adult participants with PTSD. 
• The null hypothesis for the primary efficacy endpoint of equality of BNC210 and placebo is: 
H01: Mean change in CAPS-5 Total Symptom Severity Scores between Baseline and 
Week 12 in the two treatment groups are equal. 
The key secondary objectives of the current study and their respective null hypotheses of the 
equality of BNC210 and placebo are: 
• To evaluate the efficacy of BNC210 on Investigator-rated global functioning in adult 
participants with PTSD. 
H02: Mean change in CGI-S between Baseline and Week 12 in the two treatment groups 
are equal. 
• To evaluate the efficacy of BNC210 on patient-reported social functioning in adult 
participants with PTSD. 
• H03: Mean change in SDS between Baseline and Week 12 in the two treatment groups are 
equal. 
Other secondary objectives of the current study and their respective null hypotheses of the 
equality of BNC210 and placebo are: 
• To evaluate the efficacy of BNC210 on Investigator-rated symptom clusters of PTSD in adult 
participants with PTSD. 
H04: Mean change in CAPS-5 Intrusion Severity Scores (Cluster B) between Baseline and 
Week 12 in the two treatment groups are equal. 
H05: Mean change in CAPS-5 Avoidance Severity Scores (Cluster C) between Baseline 
and Week 12 in the two treatment groups are equal. 
H06: Mean change in CAPS-5 Negative Alterations in Cognitions and Mood Severity 
Scores (Cluster D) between Baseline and Week 12 in the two treatment groups are equal. 
H07: Mean change in CAPS-5 Arousal and Reactivity Severity Scores (Cluster E) 
between Baseline and Week 12 in the two treatment groups are equal. 
• To evaluate the response rate and remission rate of BNC210 on Investigator-rated total 
symptom severity of PTSD in adult participants with PTSD. 
H08: Proportion of participants who achieve a ≥30% improvement in CAPS-5 Total 
Symptom Severity Scores between Baseline and Week 12 in the two treatment groups are 
equal. 
H09: Proportion of participants who achieve a ≥50% improvement in CAPS-5 Total 
Symptom Severity Scores between Baseline and Week 12 in the two treatment groups are 
equal. 


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H10: Proportion of participants who achieve a score ≤11 on the CAPS-5 Total Symptom 
Severity Score between Baseline and Week 12 in the two treatment groups are equal. 
• To evaluate the efficacy of BNC210 on Investigator-rated global functioning in adult 
participants with PTSD. 
     
H11: Mean scores of the CGI-I at Week 12 in the two treatment groups are equal. 
• To evaluate the efficacy of BNC210 on Investigator-rated symptoms of anxiety in adult 
participants with PTSD. 
H12: Mean change in HAM-A Total Scores between Baseline and Week 12 in the two 
treatment groups are equal. 
• To evaluate the efficacy of BNC210 on Investigator-rated symptoms of depression in adult 
participants with PTSD. 
H13: Mean change in MADRS Total Scores between Baseline and Week 12 in the two 
treatment groups are equal. 
• To evaluate the efficacy of BNC210 on patient-reported symptoms of PTSD in adult 
participants with PTSD. 
H14: Mean change in PCL-5 Total Scores between Baseline and Week 12 in the two 
treatment groups are equal. 
• To evaluate the efficacy of BNC210 on patient-reported global functioning in adult 
participants with PTSD. 
   
H15: Mean change in PGI-S between Baseline and Week 12 in the two treatment groups 
are equal. 
     
H16: Mean scores of the PGI-I at Week 12 in the two treatment groups are equal. 
• To evaluate the efficacy of BNC210 on patient-reported sleep quality in adult participants 
with PTSD. 
H17: Mean change in ISI between Baseline and Week 12 in the two treatment groups are 
equal. 
9.1.1. 
Multiplicity Adjustment 
Because this is a Phase 2 study, the level of significance will be set at 0.05 for primary and 
secondary endpoints with no adjustment for multiple comparisons. 
 
 
 
 
 


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9.2. 
Analysis Sets 
The following analysis populations are planned for this study: 
• Safety Population (SAF): The safety population includes all participants who receive any 
amount of the study intervention. The safety population will be used for the analysis of 
the safety endpoints. Participants will be analyzed by actual treatment received. 
• Intent-to-Treat Population (ITT): The ITT population includes all randomized 
participants. Participants will be analyzed by randomized treatments. 
• Modified Intent-to-Treat Population (mITT): The mITT population includes all 
participants in the ITT population who receive any amount of the study intervention and 
have at least one post-baseline efficacy assessment.  Participants will be analyzed by 
randomized treatment. 
• Per-Protocol Population (PP): The per-protocol population will include participants from 
the mITT population who have no major protocol deviations. Before data are released for 
statistical analysis, a blinded review of all data will be performed in conjunction with the 
Sponsor to identify protocol deviations that may potentially affect the results. At this 
time, it will be determined if participants and/or data should be excluded from the PP 
population. The list of participants or observations to be excluded from the PP population 
will be provided in the Clinical Study Report. Participants will be analyzed by 
randomized treatments. 
• PK Population (PK): The PK population will include all participants from the safety 
population who have a valid concentration measurement. 
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
This section presents a summary of the planned statistical analyses. A Statistical Analysis Plan 
(SAP) that describes the details of the analyses to be conducted will be written prior to the study 
database being locked. 
Unless otherwise indicated, all testing of statistical significance will be two-sided and a 
difference resulting in a p value of ≤0.05 will be considered statistically significant. 
Summary statistics will be provided for the variables described below. For continuous variables, 
these statistics will typically include the number of participants, mean, standard deviation (SD), 
median, minimum, and maximum. For categorical variables, these statistics will typically include 
the number and percentage of participants in each category. 
9.3.2. 
 Study Participant and Demographics 
9.3.2.1. 
  Disposition and Withdrawals 
The number of participants randomized, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of participants in each 
analysis population will be reported. 
 


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Completers will be recorded as Week 12 completers and Week 15 completers. Week 12 
completers will be defined as all participants who complete the randomized treatment period, 
while Week 15 completers will be defined as those who complete the randomized treatment 
period as well as the Follow-up visit. 
9.3.2.2. 
 Protocol Deviations 
Protocol deviations will be identified and classified as important or non-important for statistical 
analysis purposes before unblinding and will be summarized or listed as appropriate. Important 
protocol deviations that might affect efficacy data will be used to exclude participants from the 
per protocol analysis. 
9.3.2.3. 
 Demographics and Other Baseline Characteristics 
The following analyses will be conducted for all analysis populations: 
• Demographic variables will include age, sex, height, and weight. Information on race and 
ethnicity will be collected for any eventual analysis of differences in response to the 
study intervention in accordance with local regulatory requirements.  
• Baseline participant characteristics will include medical history including confirmation of 
PTSD diagnosis, index trauma event and time since index trauma event. Baseline 
evaluation of the CAPS-5 Total Severity Score, PCL-5 total score, CGI-S score, PGI-S 
score, MADRS total score, HAM-A total score, SDS total score, and ISI total score will 
also be reported. 
• Prior and concomitant medications will be summarized by treatment group, by the 
number and percentage of participants taking each medication, classified using World 
Health Organization Drug Dictionary (WHO-DD) Anatomical Therapeutic Chemical 
(ATC) classes and preferred terms. 
9.3.3. 
Primary and Key Secondary Endpoint/Estimand Analyses 
The primary efficacy endpoint for the current study will be the change in CAPS-5 Total Sy
mptom Severity Scores from Baseline to Week 12 for participants receiving BNC210 compared 
to participants receiving placebo. The analysis of the primary efficacy endpoint will be evaluated 
for the mITT population according to the planned treatment. 
Taking into consideration the potential for missing data, the primary and key secondary 
endpoints will be assessed for the mITT population according to the planned treatment with a 
Mixed Model for Repeated Measures (MMRM) with multiple imputation (MI). Each model will 
include fixed effects for treatment, interaction between treatment and visit, center, and covariate 
for Baseline score. MMRM with no MI will be used as a supportive analysis for the primary and 
key secondary endpoints for the mITT and PP populations according to the planned treatment. 
Additionally, a figure with the Least Squares (LS) means ± Standard Error (SE) of change from 
Baseline in the CAPS-5 Total Symptom Severity Score in the mITT population will be presented 
by treatment group and visit. 


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9.3.4. 
Supportive Analyses for Primary and Key Secondary Efficacy Endpoints 
Supportive analyses will be performed on the primary and key secondary efficacy endpoints to  
demonstrate the robustness of the conclusions.   Supportive analyses will be conducted using 
MMRM with no MI on the mITT and PP populations. 
Summary statistics on the endpoints by treatment group and visit, including the end of treatment 
visit (Week 12), will also be presented.  
9.3.5. 
 Multiple Imputation Methods 
Although the assumption of missing at random (MAR) is often reasonable in clinical trials, the 
possibility of missing not at random (MNAR) data cannot be ruled out. Therefore, analysis valid 
under MNAR will be performed as the primary analysis. Both MNAR- and MAR-based analyses 
using MI methods will be the basis upon which sensitivity of the analysis to missing data are 
assessed.  
Any participants who withdraws or is discontinued from the study or who misses a scheduled 
visit or assessments up through Week 12 will have their primary and key secondary efficacy 
missing data analyzed as imputed using MI techniques. This analysis will be presented as the 
primary analysis. 
Multiple imputation is a simulation-based approach where missing values are replaced using an 
appropriate stochastic model given the observed data and covariates, creating multiple completed 
data sets. These completed datasets are then analyzed using standard analysis methods (MMRM 
for this study), and the different parameter estimates across the datasets are then combined to 
produce unique point estimates, standard errors, and confidence intervals taking into account the 
uncertainty of the imputation process. 
In most randomized clinical trials that collect data over time, the great majority of missing data 
follow a monotone pattern. That is, once a participant has a missing data for some visit, data will 
be missing for all subsequent visits. Typically, there is also a small amount of non-monotone 
missing data (i.e., some participants have missing values for intermediate visits, but have non-
missing data at subsequent visits).  
The following MI analysis model, based on the MNAR approach, will be used as the primary 
analysis. 
MI with Placebo-Based Imputation 
A placebo-based (jump to control) multiple imputation for missing primary and key secondary 
endpoints will be carried out for participants who withdraw from the study or have missing data 
at a scheduled visit through Week 12, as indicated previously. The imputation has three broad 
components; i) the multiple imputation process for the placebo data; ii) the multiple imputation 
process for the BNC210 data; and iii) the analysis model that will be used to draw inference 
regarding the primary causal estimands along with the method for combining the results across 
the multiply-imputed datasets. Specific steps for this imputation will be outlined in the SAP. 


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9.3.6. 
Other Secondary Endpoints Analyses 
All other secondary efficacy endpoints will be conducted with MMRM with no MI on the mITT 
population only. Summary statistics on the endpoints by treatment group and visit, including the 
end of treatment visit (Week 12), will also be presented.  
For the binary outcomes of the proportion of participants who achieve a) ≥30% improvement; b) 
≥50% improvement; c) remission of PTSD symptoms, the number and proportion will be 
summarized by treatment group and visit. A Pearson’s Chi-squared test or Fisher’s exact test will 
be used to calculate the p-value for the difference between treatment groups. 
9.3.7. 
Safety Analyses 
Safety analyses will be conducted using data from the safety population. Safety variables include 
C-SSRS, AEs, physical examination findings, ECGs, vital signs, and clinical laboratory test 
results (hematology, biochemistry, urinalysis). No formal inferential analyses will be conducted 
for safety variables unless otherwise noted.  
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 22.1 or higher. 
TEAEs are defined as AEs that are newly occurring or worsening after the first dose of study 
intervention. The incidence of TEAEs will be summarized by treatment group, by system organ 
class (SOC) and preferred term (PT), by severity, and by relationship to study intervention. 
Serious TEAEs and TEAEs leading to study termination will also be summarized by SOC, PT, 
and treatment group. 
 
 
 
 
 
 
 
 
9.4. 
Population Pharmacokinetic (PK) Analysis 
Systemic concentrations of BNC210 will be determined at Weeks 4, 8, and 12. Plasma 
concentration data will be presented nominally. A data dependent population PK analysis will be 
outlined under a separate analytical plan. 
9.5. 
Interim Analysis 
No interim analysis is planned for this study. 
9.6. 
Sample Size Determination 
A sample size of approximately 200 participants (100 participants per treatment arm) is 
calculated to provide ≥80% power to detect a 6-point difference between BNC210 and placebo 
groups in change from Baseline to Week 12 for the CAPS-5 Total Symptom Severity Scores, 


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with an expected SD of 12.5. These assumptions are based on data from the previous BNC210 
Phase 2 PTSD study and pharmacometric analysis. In a two-sample t-test using a two-sided 
significance level of 0.05 and power of 80%, 70 participants per treatment group would be 
needed to demonstrate a 6-point difference between treatment groups, and assuming 30% drop-
out over the 12-week treatment period leads to a planned sample size of 100 per group. 
 


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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable International Conference on Harmonization (ICH) Good Clinical Practice 
(GCP) Guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB by the Investigator and 
reviewed and approved by the IRB before the study is initiated. 
• The protocol cannot be altered or changed except through a formal protocol amendment, 
which requires written approval from the Sponsor.  Any amendments to the protocol will 
require IRB approval and health authority approval where applicable and must be signed 
by the Investigator before implementation of changes, except for changes necessary to 
eliminate an immediate hazard to study participants.  
• The Investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB 
o Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, European regulation 536/2014 for 
clinical studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
 


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10.1.3. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study, including 
the risks and benefits, to the participant and answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB or study center. 
• The rights and welfare of the participants will be protected by emphasizing to them that 
the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant. 
• Informed consent will be obtained before the participant can participate in the study. 
• The Investigator or his/her representative must also explain to the participant that they are 
completely free to refuse to enter the study or to withdraw from it at any time. 
• Participants who are rescreened are required to sign a new ICF. 
• Participants who are rescreened will not need to repeat routine clinical laboratory 
assessments or ECGs if an eligible result from the prior screening period has been 
obtained within 21 (+3 days) of randomization into the study.  
• The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. 
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier as part of their study participation. Any 
participant records or datasets that are transferred to the Sponsor will contain the 
identifier and information collected as part of the study only; participant names or any 
information which would make the participant identifiable will not be transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data to 
be used as described in the ICF.  
• The study data entry and study management systems used by clinical sites and by the 
Sponsor/designee will be secured and password protected.  


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• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB members, and by inspectors from regulatory authorities. 
10.1.5. 
Independent Safety Review 
An independent Safety Review Committee will be established to monitor participant safety 
throughout the study. The meetings will occur approximately every 3 months and will review all 
safety data including vital signs, ECG, pathology results, physical examinations, C-SSRS and 
continuous AE reporting. 
10.1.6. 
Data Quality Assurance 
• All participant data relating to the study will be recorded in the eCRF unless transmitted 
to the Sponsor or designee electronically (e.g., laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
• Guidance on completion of eCRFs will be provided in the study specific eCRF 
completion guidelines. 
• The Investigator must permit study-related monitoring, audits, IRB review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Quality tolerance limits (QTLs) will be predefined in the study specific Risk Log to 
identify systematic issues that can impact participant safety and/or reliability of study 
results. These predefined parameters will be monitored during the study, and important 
deviations from the QTLs and remedial actions taken will be summarized in the Clinical 
Study Report. 
• Monitoring details describing strategy, including definition of study critical data items 
and processes (e.g., risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring), methods, 
responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the 
Clinical Monitoring Plan. 
• The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor. 


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10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents, or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
• Examples of acceptable source documentation include, but are not limited to, hospital 
records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. The Investigator must 
maintain accurate documentation (source data) that supports the information entered in 
the eCRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.8. 
Study and Site Closure 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants 
by the Investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IRBs, the regulatory authorities, and any contract research organization(s) used 
in the study of the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 


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10.1.9. 
Publication Policy 
The publication policy is outlined in the study site specific Clinical Trial Agreement. 
 
 
 




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Pregnancy 
testing 
• Highly sensitive serum human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)3 
Other 
Screening 
Tests 
• Follicle-stimulating hormone and estradiol (as needed in women of 
non-childbearing potential only) 
• Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody) 
• All study-required laboratory tests will be performed by a central 
laboratory, with the exception of: 
o Urine drug test and pregnancy test at Baseline, Week 4, Week 8 and 
Week 12 
o ALT, AST, ALP, and bilirubin (direct and total) at Week 6 and 
Week 10 
NOTES: 
1. Details of liver chemistry stopping criteria and required actions and follow-up are given in 
Section 7.1.1 Liver Chemistry Stopping Criteria and Appendix 5: Liver Safety: Suggested 
Actions and Follow-up Assessments.  All events of ALT or AST 3 × upper limit of normal 
(ULN) and total bilirubin 2 × ULN (>35% direct bilirubin) which may indicate severe liver 
injury (possible Hy’s Law), must be reported to the Medical Monitor in an expedited manner 
(excluding studies of hepatic impairment or cirrhosis). 
2. If alkaline phosphatase is elevated, consider fractionating. 
3. Local urine testing will be standard for the protocol unless serum testing is required by local 
regulation or IRB. 
 
Investigators must document their review of each laboratory safety report. 
 
 










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• The Investigator will also consult the Investigator’s Brochure and/or product 
information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to the Sponsor or designee. 
However, it is very important that the Investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data to the Sponsor 
or designee. 
• The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
The Investigator will use clinical judgment to determine the relationship following the below 
definitions: 
• Not Related: This category applies to an AE that is clearly not related to the 
investigational agent/procedure, beyond a reasonable doubt. That is, another cause of 
the event is most plausible; and/or a clinically plausible temporal sequence is 
inconsistent with the onset of the event and the administration of study intervention 
and/or a causal relationship is considered biologically implausible. 
 
• Unlikely Related: This category applies to an AE that could reasonably be considered 
caused by something else, and where there is no known or expected response pattern to 
the suspected study intervention. 
 
• Possibly Related: This category applies to an AE that follows a reasonable temporal 
sequence from administration of the study intervention and that follows a known or 
expected response pattern to the suspected study intervention, but that could readily 
have been produced by a number of other factors 
 
• Probably Related: This category applies to an AE that follows a reasonable temporal 
sequence from administration of the study intervention; that follows a known response 
pattern to the suspected study intervention; that is confirmed by an improvement on 
stopping the study intervention; and that cannot be reasonably explained by the 
participant’s clinical state.  
• Definitely Related: This category applies to an AE that is plausible, and concurrent 
disease or other drugs or chemicals cannot explain event. The response to withdrawal 
of the study intervention (dechallenge) should be clinically plausible. The event must 
be definitive pharmacologically or phenomenologically, using a satisfactory 
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• Date of occurrence of the event 
• Severity of the SAE term 
• A brief description of the event, treatment, outcome to date, and any actions taken with 
study intervention 
• The seriousness criteria(on) that were met 
• Investigator causality assessment 
• Concomitant medications being taken within 30 days of onset of the event 
• Relevant medical history information 
• Relevant laboratory test findings 
• Whether and when the Investigator was unblinded as to the participant’s treatment 
assignment 
Any missing or additional relevant follow-up information concerning the SAE should be sent 
to the 
 via the same contact details above as 
soon as possible on a follow-up SAE Report Form, together with the following minimal 
information; initial report, adverse event, date of occurrence, study participant identifier, and 
site number. This will allow the follow-up information to be linked to the initial SAE report.  
Specific information may be requested by the 
 
 using a follow-up request form or via email communication. 
The Investigator is required to comply with applicable regulations (including local laws and 
guidances) regarding the notification of his or her health authorities, IRB, Principal and 
Coordinating Investigators, Study Investigators, and institutions. Each Investigator is obligated 
to learn about the reporting requirements for Investigators in his/her country. The study 
monitor may be able to assist with this. 
 
 
 


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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming postmenopausal unless permanently sterile 
(see below) 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement and FSH levels 
within the institutional postmenopausal range is required.  
o Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
• Permanent sterilization methods (for the purpose of this study) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
o For individuals with permanent infertility due to an alternate medical cause other than 
the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
• If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
 
 
 
 
 


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10.4.2. 
Contraception Guidance 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency  
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of 
the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview. 
Highly Effective Methodsb That Are User Dependent  
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
o 
oral 
o 
intravaginal 
o 
transdermal 
o 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
o 
oral 
o 
injectable 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b) Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c) Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode of action.  
Note: Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception for this 
study.  Male condom and female condom should not be used together (due to risk of failure from friction). 
 
 


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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Phase 2 liver chemistry stopping criteria are designed to assure participant safety and to evaluate 
liver event etiology. 
 
 
Liver Chemistry Stopping Criteria 
ALT or AST-absolute ALT or AST  5 x ULN 
ALT or AST Increase ALT or AST  3 x ULN persists for  4 weeks 
Bilirubin1,2 
ALT or AST  3 x ULN and total bilirubin  2 x ULN (> 35% 
direct bilirubin) 
INR2 
ALT or AST  3 x ULN and international normalized ratio (INR) 
> 1.5 
Cannot Monitor 
ALT or AST  3 x ULN and cannot be monitored weekly for 4 
weeks 
Symptomatic3 
ALT or AST  3 x ULN associated with symptoms (new or 
worsening) believed to be related to liver injury or hypersensitivity 
Suggested Actions, Monitoring, and Follow-up Assessments  
Actions 
Follow-Up Assessments 
• Immediately discontinue study 
intervention.  
• Report the event to the Medical Monitor 
within 24 hours. 
• Complete a Serious Adverse Event Report 
Form if the event also met the criteria for 
an SAE.2 
• Perform follow-up assessments as 
described in the Follow Up Assessment 
column.  
• Monitor the participant until liver 
chemistry test abnormalities resolve, 
stabilize, or return to baseline. 
MONITORING: 
If ALT or AST  3 x ULN AND total 
bilirubin  2 x ULN or INR > 1.5:  
• Viral hepatitis serology4 
• Obtain serum creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), 
gamma-glutamyltransferase [GGT], 
glutamate dehydrogenase [GLDH], and 
serum albumin. 
• Fractionate bilirubin, if total bilirubin 
 2 x ULN. 
• Obtain complete blood count with 
differential to assess eosinophilia. 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity. 
• Record use of concomitant medications 
(including acetaminophen, herbal 
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• Repeat liver chemistry tests (include ALT, 
AST, ALP, total bilirubin, and INR) and 
perform liver event follow up assessments 
within 24 hours. 
• Monitor participant twice weekly until 
liver chemistry test abnormalities resolve, 
stabilize, or return to baseline. 
• A hepatology consultation is 
recommended. 
If ALT or AST  3 x ULN AND total 
bilirubin < 2 x ULN and INR  1.5:  
• Repeat liver chemistry tests (include ALT, 
AST, alkaline phosphatase, total bilirubin, 
and INR) and perform liver chemistry 
follow-up assessments within 24 to 72 
hours. 
• Monitor participants weekly until liver 
chemistry abnormalities resolve, stabilize, 
or return to baseline. 
 
 
• Do not restart/rechallenge participant 
with study intervention. 
 
medications) on the concomitant 
medications eCRF. 
• Record alcohol use 
If ALT or AST  3 x ULN AND total 
bilirubin  2 x ULN or INR > 1.5 obtain the 
following in addition to the assessments listed 
above: 
• Antinuclear antibody, antismooth muscle 
antibody, Type 1 antiliver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG), or gamma 
globulins 
• Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
to evaluate liver disease 
• Liver biopsy may be considered and 
discussed with local specialist if available, 
for instance: 
o In participants when serology raises 
the possibility of autoimmune hepatitis 
(AIH) 
o In participants when suspected drug 
induced liver injury (DILI) progresses 
or fails to resolve on withdrawal of 
study intervention 
o In participants with acute or chronic 
atypical presentation 
• Report all assessments conducted to 
the Medical Monitor as they become 
available  
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation testing is unavailable, 
record the absence/presence of detectable urinary bilirubin on dipstick which is indicative of direct bilirubin elevations 
suggesting liver injury.  
2. All events of ALT or AST > 3 x ULN and total bilirubin > 2 x ULN (> 35% direct bilirubin) or ALT or AST > 3 x ULN and 
INR > 1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported to sponsor in an expedited manner 
and as an SAE if SAE criteria met (excluding studies of hepatic impairment or cirrhosis). The INR stated threshold value 
will not apply to participants receiving anticoagulants.  


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3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, or jaundice) or hypersensitivity (such as fever, rash, or eosinophilia). 
4. Includes: Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot testing); and 
hepatitis E IgM antibody.  
 


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10.6. 
Appendix 6: Abbreviations 
Abbreviation 
Definition 
AE 
Adverse Event 
ACC 
Anterior Cingulate Cortex 
ADL 
Activities of Daily Living 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
AUC90 
Exposure at 90% of maximal effect 
b.i.d. 
Twice Daily 
BUN 
Blood Urea Nitrogen 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CAPS-5 
Clinician-Administered PTSD Scale for the DSM-5 
CGI-I 
Clinical Global Impressions – Improvement 
CGI-S 
Clinical Global Impressions – Severity 
CNS 
Central Nervous System 
COVID-19 
Coronavirus disease 2019 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
fMRI 
Functional Magnetic Resonance Imaging 
FSH 
Follicle Stimulating Hormone 
GAD 
Generalized Anxiety Disorder 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HAM-A 
Hamilton Anxiety Rating Scale 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HRT 
Hormone Replacement Therapy 
 


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ICH 
International Conference on Harmonization 
ICF 
Informed Consent Form 
INR 
International Normalization Ratio 
IRB 
Institutional Review Board 
ISI 
Insomnia Severity Index 
ITT 
Intent-To-treat 
IWRS 
Interactive Web Response System 
LEC-5 
Life Events Checklist for DSM-5. 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MAR 
Missing at Random 
MI 
Multiple Imputation 
mITT 
Modified Intent-To-Treat 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing Not at Random 
NOAEL 
No Observed Adverse Effect Level 
PCL-5 
Standard PTSD Checklist for DSM-5 
PEER 
Pre-Enrollment Eligibility Review 
PGI-I 
Patient Global Impressions – Improvement 
PGI-S 
Patient Global Impressions – Severity 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
PTSD 
Post-Traumatic Stress Disorder 
QTcF 
Fridericia-corrected QT Interval 
QTL 
Quality Tolerance Limit 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCID-5-CT 
Structured Clinical Interview for DSM-5 Disorders – 
Clinical Trials Version 
SCID-5-PD 
Structured Clinical Interview for DSM-5 Disorders – 
Personality Disorders 
SD 
Standard Deviation 


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SDS 
Sheehan Disability Scale 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
ULN 
Upper Limit of Normal 
WOCBP 
Women of Child Bearing Potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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  Protocol BNC210.012              Version 4.0 (US), 17-Nov-2022 
 
 
74 
11. 
References 
Alexander W. Pharmacotherapy for Post-traumatic Stress Disorder. In: Combat Veterans Focus 
Pharmacy &Therapeutics. 2012; 371:32-8. 
Clinician Administered PTSD Scale for DSM-5 (CAPS-5). Accessed at 
http://www.ptsd.va.gov/professional/assessment/adult-int/caps.asp 
PTSD Checklist for DSM-5 (PCL-5). Accessed at 
https://www.ptsd.va.gov/professional/assessment/adult-sr/ptsd-checklist.asp 
Hamilton M. The assessment of anxiety states by rating. Br. J. Med. Psychol. 1959; 32:50–55. 
Krystal JH, Davis LL, Neylan TC, A Raskind M, Schnurr PP, Stein MB, et al. It Is Time to 
Address the Crisis in the Pharmacotherapy of Posttraumatic Stress Disorder: A Consensus 
Statement of the PTSD Psychopharmacology Working Group. Biol Psychiatry. 2017; 82(7):e51-
e59. 
Morin CM.  Insomnia:  Psychological assessment and management. Guilford Press, New York. 
1993. 
Veterans Affairs/Department of Defense Clinical Practice Guideline for the Management of 
Posttraumatic Stress Disorder and Acute Stress Disorder Prepared by: The Management of 
Posttraumatic Stress Disorder Work Group with Support From: The Office of Quality, Safety 
and Value, VA, Washington, DC & Office of Evidence Based Practice, U.S. Army Medical 
Command Version 3.0 – 2017 based On Evidence Reviewed Through March 2016. Accessed at: 
https://www.healthquality.va.gov/guidelines/MH/ptsd/VADoDPTSDCPGFinal012418.pdf 
Williams, J. B. and K. A. Kobak. Development and reliability of a structured interview guide for 
the Montgomery Åsberg Depression Rating Scale (SIGMA). Br. J. Psychiatry. 2008. 192.1:52-
58. 
 
 
 

SAP_001.pdf: 




 
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Table of Contents 
Approvals ........................................................................................................................................ 1 
Document History ........................................................................................................................... 2 
Table of Contents .......................................................................................................................... 10 
List of Tables ................................................................................................................................ 11 
List of Abbreviations .................................................................................................................... 12 
1. 
Overview ........................................................................................................................... 16 
2. 
Study Objectives and Endpoints ....................................................................................... 16 
2.1. 
Study Objectives ......................................................................................................... 16 
2.1.1. Primary Objective ....................................................................................................... 16 
2.1.2. Secondary Objectives.................................................................................................. 16 
 
 
2.2. 
Study Endpoints .......................................................................................................... 17 
2.2.1. Efficacy Endpoints ...................................................................................................... 17 
2.2.2. Safety Endpoints ......................................................................................................... 19 
2.2.3. Pharmacokinetics Endpoint ........................................................................................ 19 
3. 
Overall Study Design and Plan ......................................................................................... 19 
3.1. 
Overall Design ............................................................................................................ 19 
3.2. 
Sample Size and Power ............................................................................................... 19 
3.3. 
Study Population ......................................................................................................... 20 
3.4. 
Treatments Administered ............................................................................................ 20 
3.5. 
Method of Assigning Participants to Treatment Groups ............................................ 20 
3.6. 
Blinding and Unblinding............................................................................................. 20 
3.7. 
Schedule of Events ...................................................................................................... 21 
4. 
Statistical Analysis and Reporting .................................................................................... 27 
4.1. 
Introduction ................................................................................................................. 27 
4.2. 
Interim Analysis and Data Monitoring ....................................................................... 27 
5. 
Analysis Populations ......................................................................................................... 27 
6. 
General Issues for Statistical Analysis .............................................................................. 28 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 28 
6.1.1. Baseline ....................................................................................................................... 28 
6.1.2. Adjustments for Covariates......................................................................................... 28 
6.1.3. Multiple Comparisons ................................................................................................. 28 
6.1.4. Handling of Dropouts or Missing Data ....................................................................... 28 


 
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6.1.5. Analysis Visit Windows ............................................................................................. 32 
6.1.6. Pooling of Sites ........................................................................................................... 33 
6.1.7. Derived Variables ....................................................................................................... 33 
6.1.8. Data Adjustments/Handling/Conventions .................................................................. 34 
6.2. 
Special Handling for COVID-19 Disruptions............................................................. 35 
7. 
Study Patients/Participants and Demographics ................................................................ 36 
7.1. 
Disposition of Patients/Participants and Withdrawals ................................................ 36 
7.2. 
Protocol Violations and Deviations ............................................................................ 36 
7.3. 
Demographics and Other Baseline Characteristics ..................................................... 37 
7.4. 
Exposure and Compliance .......................................................................................... 37 
8. 
Efficacy Analysis .............................................................................................................. 38 
8.1. 
Primary Efficacy Analysis .......................................................................................... 38 
8.2. 
Secondary Efficacy Analysis ...................................................................................... 39 
 
 
9. 
Safety and Tolerability Analysis ....................................................................................... 41 
9.1. 
Adverse Events ........................................................................................................... 42 
9.1.1. Adverse Events Leading to Withdrawal ..................................................................... 42 
9.1.2. Deaths and Serious Adverse Events ........................................................................... 42 
9.2. 
Clinical Laboratory Evaluations ................................................................................. 43 
9.3. 
Vital Signs ................................................................................................................... 43 
9.4. 
Electrocardiograms ..................................................................................................... 43 
9.5. 
Physical Examinations ................................................................................................ 44 
9.6. 
Further Safety Evaluations .......................................................................................... 44 
9.6.1 Columbia Suicide Severity Rating Scale (C-SSRS) ................................................... 44 
9.7. 
Concomitant Medication ............................................................................................. 45 
10. 
Pharmacokinetic Analysis ................................................................................................. 45 
11. 
Changes from Planned Analysis ....................................................................................... 45 
12. 
References ......................................................................................................................... 45 
 
List of Tables 
Table 1: Schedule of Events ......................................................................................................... 21 
Table 2: Efficacy Variable Visit Windows ................................................................................... 32 
 
 
 










 
 
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1. 
Overview 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Bionomics 
Limited protocol number BNC210.012 (A Phase 2b, Randomized, Double Blind, Two Arm 
Study to Investigate the Effects of BNC210 Tablet Formulation Compared to Placebo in Adults 
with Post-Traumatic Stress Disorder (PTSD)), dated 17 Nov 2022 Version 4.0 (UK and US 
versions). Reference materials for this statistical plan include the protocol and the accompanying 
sample data collection documents. Operational aspects related to collection and timing of 
planned clinical assessments are not repeated in this SAP unless relevant to the planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials (ICH, 1998). All work planned and reported for this SAP will follow internationally 
accepted guidelines, published by the American Statistical Association (ASA, 2018) and the 
Royal Statistical Society (RSS, 2014), for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post-hoc 
or unplanned, exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be approved before any 
unblinded inferential or descriptive analysis of data pertaining to Bionomics Limited’s study 
BNC210.012. 
2. 
Study Objectives and Endpoints 
2.1. 
Study Objectives 
2.1.1. Primary Objective 
The primary objective is to assess the effects of BNC210 on investigator-rated symptoms of 
PTSD measured by Clinician-Administered PTSD Scale for the DSM-5 (CAPS-5) Total 
Symptom Severity Scores. 
2.1.2. Secondary Objectives 
The key secondary objectives are to: 
• Assess the effects of BNC210 on investigator-rated global functioning in participants 
with PTSD; 
• Assess the effects of BNC210 on patient-reported social functioning in participants with 
PTSD. 






 
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2.2.2. Safety Endpoints 
The safety endpoints of this study include the following from Baseline to Week 15: 
• Continuous adverse events (AEs) and serious adverse events (SAEs); 
• Electrocardiograms (ECGs); 
• Vital signs (body temperature, pulse rate, respiratory rate, systolic and diastolic blood 
pressure); 
• Clinical laboratory results (hematology, blood chemistry, and urinalysis); 
• Physical examination; 
• Columbia Suicide Severity Rating Scale (C-SSRS). 
2.2.3. Pharmacokinetics Endpoint 
A population PK analysis will be done under a separate analysis plan. 
3. 
Overall Study Design and Plan 
3.1. 
Overall Design 
This is a randomized, double-blind, placebo-controlled, parallel group, multi-center Phase 2b 
study in participants with PTSD, who are between the ages of 18 to 75 (inclusive), with a 12 
week, 2-arm treatment period. 
Approximately 200 participants will be enrolled and randomized using a 1:1 ratio to receive 
either BNC210 or matched placebo. Participants will complete 12 weeks of treatment with their 
allocated study intervention. Participants in the US will complete study visits every 2 weeks 
during the treatment period and a follow-up visit at Week 15 (3 weeks after final intervention). 
Participants in the UK will complete study visits every week for the first 2 weeks, then every 2 
weeks from Week 4 onwards during the treatment period, and a Follow-up visit at Week 15 (3 
weeks after final intervention). 
3.2. 
Sample Size and Power 
A sample size of approximately 200 participants (100 participants per treatment arm) is 


 
 
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calculated to provide ≥ 80% power to detect a 6-point difference between BNC210 and placebo 
groups in change from Baseline to Week 12 for the CAPS-5 Total Symptom Severity Scores, 
with an expected standard deviation (SD) of 12.5. These assumptions are based on data from the 
previous BNC210 Phase 2 PTSD study and pharmacometric analysis. In a two-sample t-test 
using a two-sided significance level of 0.05 and power of 80%, 70 participants per treatment 
group would be needed to demonstrate a 6-point difference between treatment groups, and 
assuming 30% drop-out over the 12-week treatment period leads to a planned sample size of 100 
per group. 
3.3. 
Study Population 
The study population is comprised of male and female participants who are 18 to 75 years of age, 
with a current diagnosis of PTSD as defined by the CAPS-5 and with the index trauma event 
occurring in adulthood (at least 18 years old), and a CAPS-5 Total Symptom Severity Score of ≥ 
30 at Screening and Baseline with no > 25% decrease in CAPS-5 Total Symptom Severity Score 
between Screening and Baseline. 
3.4. 
Treatments Administered 
Participants will be randomized to one of two treatment groups: 
• BNC210 900 mg 
• Placebo 
Participants will self-administer the study intervention twice daily (b.i.d.) for 12 weeks. 
 
 
 
 
 
3.5. 
Method of Assigning Participants to Treatment Groups 
Participants who meet inclusion criteria and none of the exclusion criteria will be randomly 
assigned in a 1:1 ratio to receive BNC210 900 mg or matching placebo. 
3.6. 
Blinding and Unblinding 
This is a double-blind study in which participants/Investigators/raters, etc. are blinded to study 
intervention. 
The Interactive Web Response System (IWRS) will be programmed with blind-breaking 
instructions. In case of an emergency, the Investigator has the sole responsibility for determining 
if unblinding of a participant’s intervention assignment is warranted. Participant safety must 
always be the first consideration in making such a determination. If the Investigator decides that 
unblinding is warranted, the Investigator should make every effort to contact the Medical 
Monitor and/or Sponsor prior to unblinding a participant’s intervention assignment unless this 
could delay emergency treatment for the participant. If a participant’s intervention assignment is 
unblinded, the Sponsor must be notified within 24 hours of this occurrence. The date and reason 
for the unblinding must be recorded. 


 
 
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3.7. 
Schedule of Events 
A detailed schedule of events for participants enrolled in the US is provided in Table 1A. 
Table 1A: Schedule of Events (US participants) 
Assessment1 
Screening 
<-21 days 
Treatment Period 
Week 15 / 
Follow-
up 
(+5 days)  
Baseline2 
(+3 days) 
Week 23 
(+3 days) 
Week 4 
(+3 days) 
Week 6 
(+3 days) 
Week 8 
(+3 days) 
Week 10 
(+3 days) 
Week 12 / 
Early 
Termination 
(+3 days) 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria4 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Medical history including current & prior medications 
X 
 
 
 
 
 
 
 
 
Structured Clinical Interview for DSM-5 disorders – 
Clinical Trials Version (SCID-5-CT) and Personality 
Disorders (SCID-5-PD) Borderline Personality 
Disorder section only 
X 
 
 
 
 
 
 
 
 
Human immunodeficiency virus (HIV), Hepatitis B 
surface antigen (HBsAg) and Hepatitis C virus (HCV) 
antibody screen 
X 
 
 
 
 
 
 
 
 
Serum pregnancy test (if applicable) 
X 
 
 
 
 
 
 
 
 
Urine pregnancy test (if applicable) 
 
X 
 
 
 
 
 
X 
 
 
1 See Section 8 in the protocol for guidance on the order of assessments to be completed at each visit 
2 All baseline assessments to be completed pre-dose 
3 Visit can be performed at the study site, or remotely via phone/video call. 
4 Recheck eligibility and clinical status before randomization 


 
 
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Assessment1 
Screening 
<-21 days 
Treatment Period 
Week 15 / 
Follow-
up 
(+5 days)  
Baseline2 
(+3 days) 
Week 23 
(+3 days) 
Week 4 
(+3 days) 
Week 6 
(+3 days) 
Week 8 
(+3 days) 
Week 10 
(+3 days) 
Week 12 / 
Early 
Termination 
(+3 days) 
 
Urine drug screen5 
X 
X 
 
X 
 
X 
 
X 
 
12-lead electrocardiogram (ECG)6  
X 
 
 
X 
 
X 
 
X 
 
Vital signs7  
X 
X 
 
X 
 
X 
 
X 
X 
Physical examination (including height only at 
Screening; weight only at Screening and Week 12 / 
Early Termination)8 
X 
X 
 
X 
 
X 
 
X 
X 
Clinical labs (hematology, biochemistry, urinalysis)  
X 
X 
 
X 
X9 
X 
X9 
X 
X 
Columbia Suicide Severity Rating Scale (C-SSRS)10 
X 
X 
 
X 
 
X 
 
X 
X 
Life Events Checklist for DSM-5 (LEC-5)11 
X 
 
 
 
 
 
 
 
 
Clinician-Administered PTSD Scale for DSM-5 
(CAPS-5)12 
X 
X 
 
X 
 
X 
 
X 
 
Montgomery-Åsberg Depression Rating Scale 
(MADRS) 
X 
X 
 
X 
 
X 
 
X 
 
 
5 Screening assessment to be performed by the central laboratory. Subsequent assessments to be performed locally by study site using urine dip stick test 
6 ECGs to be completed in triplicate with an approximate 2-minute break between tests.  Participants must be resting in a semi-supine or supine position for at 
least 5 minutes prior to performing the ECG.  The same ECG machine should be used for all recordings from an individual participant, where possible.  Single 
triplicate repeat during Screening allowed in the event of a clinically significant abnormality including prolonged Fridericia corrected QT interval (QTcF). 
7 Blood pressure and heart rate will be measured in a sitting position after resting for 5 minutes 
8 Full physical examination at Screening & W12 / Early Termination. Abbreviated physical examination at Baseline, Week 4, Week 8, and Follow-up 
9 Blood biochemistry testing only for Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Bilirubin (direct and 
total) 
10 “Screening C-SSRS” to be used at Screening. “C-SSRS Since Last Visit” to be used at every other visit 
11 To be completed prior to CAPS-5 assessment at Screening 
12 Past month version to be used at every visit and should be audio recorded at every visit using the provided iPhone.  


 
 
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Assessment1 
Screening 
<-21 days 
Treatment Period 
Week 15 / 
Follow-
up 
(+5 days)  
Baseline2 
(+3 days) 
Week 23 
(+3 days) 
Week 4 
(+3 days) 
Week 6 
(+3 days) 
Week 8 
(+3 days) 
Week 10 
(+3 days) 
Week 12 / 
Early 
Termination 
(+3 days) 
 
Randomization13 
 
X 
 
 
 
 
 
 
 
Hamilton Anxiety Rating Scale (HAM-A) 
 
X 
 
X 
 
X 
 
X 
 
Clinical Global Impressions Severity and Improvement 
scales (CGI-S/I)14 
 
X 
 
X 
 
X 
 
X 
 
Patient Global Impression – Severity and Improvement 
scales (PGI-S/I)14 
 
X 
 
X 
 
X 
 
X 
 
PTSD Checklist (PCL-5) 
 
X 
 
 
 
 
 
X 
 
Sheehan Disability Scale (SDS) 
 
X 
 
X 
 
X 
 
X 
 
Insomnia Severity Index (ISI) 
 
X 
 
X 
 
X 
 
X 
 
Study Intervention dispensing 
 
X15 
 
X 
 
X 
 
 
 
Concomitant medications recording 
 
X 
X 
X 
 
X 
 
X 
X 
Adverse Event (AE) recording16 
 
 
X 
X 
 
X 
 
X 
X 
Blood sample collection for concentration of BNC210  
 
 
 
X 
 
 
X 
X 
 
 
13 Once eligibility has been confirmed 
 
 
14 Improvement scale at Week 12 only 
15 Participants to administer one PM dose on day of completing Baseline assessments and randomization 
16 See Appendix 3 in the protocol for definitions 
 


 
 
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A detailed schedule of events for participants enrolled in the UK is provided in Table 1B. 
Table 1B: Schedule of Events (UK participants) 
Assessment1 
Screening 
<-21 days 
Treatment Period 
Week 15 
/ Follow-
up 
(+5 days)  
Baseline2 
(+3 days) 
Week 13 
(+3 days) 
Week 2 
(+3 days) 
Week 4 
(+3 days) 
Week 6 
(+3 days) 
Week 8 
(+3 days) 
Week 10 
(+3 days) 
Week 12 / 
Early 
Termination 
(+3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria4 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Medical history including current & prior 
medications 
X 
 
 
 
 
 
 
 
 
 
Structured Clinical Interview for DSM-5 
disorders – Clinical Trials Version (SCID-5-
CT) and Personality Disorders (SCID-5-PD) 
Borderline Personality Disorder section only 
X 
 
 
 
 
 
 
 
 
 
Human immunodeficiency virus (HIV), 
Hepatitis B surface antigen (HBsAg) and 
Hepatitis C virus (HCV) antibody screen 
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (if applicable) 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (if applicable) 
 
X 
 
 
 
 
 
 
X 
 
Urine drug screen5 
X 
X 
 
 
X 
 
X 
 
X 
 
 
1 See Section 8 in the protocol for guidance on the order of assessments to be completed at each visit 
2 All baseline assessments to be completed pre-dose 
3 Visit can be performed at the study site, or remotely via phone/video call. 
4 Recheck eligibility and clinical status before randomization 
5 Screening assessment to be performed by the central laboratory. Subsequent assessments to be performed locally by study site using urine dip stick test 


 
 
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Assessment1 
Screening 
<-21 days 
Treatment Period 
Week 15 
/ Follow-
up 
(+5 days)  
Baseline2 
(+3 days) 
Week 13 
(+3 days) 
Week 2 
(+3 days) 
Week 4 
(+3 days) 
Week 6 
(+3 days) 
Week 8 
(+3 days) 
Week 10 
(+3 days) 
Week 12 / 
Early 
Termination 
(+3 days) 
12-lead electrocardiogram (ECG)6  
X 
X7 
 
X 
X 
 
X 
 
X 
 
Vital signs8  
X 
X9 
 
X 
X 
 
X 
 
X 
X 
Physical examination (including height only at 
Screening; weight only at Screening and Week 
12 / Early Termination)10 
X 
X 
 
 
X 
 
X 
 
X 
X 
Clinical labs (hematology, biochemistry, 
urinalysis)  
X 
X 
 
X 
X 
X11 
X 
X11 
X 
X 
Columbia Suicide Severity Rating Scale (C-
SSRS)12 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Life Events Checklist for DSM-5 (LEC-5)13 
X 
 
 
 
 
 
 
 
 
 
Clinician-Administered PTSD Scale for DSM-
5 (CAPS-5)14 
X 
X 
 
 
X 
 
X 
 
X 
 
Montgomery-Åsberg Depression Rating Scale 
X 
X 
 
 
X 
 
X 
 
X 
 
 
6 ECGs to be completed in triplicate with an approximate 2-minute break between tests.  Participants must be resting in a semi-supine or supine position for at 
least 5 minutes prior to performing the ECG.  The same ECG machine should be used for all recordings from an individual participant, where possible.  Single 
triplicate repeat during Screening allowed in the event of a clinically significant abnormality including prolonged Fridericia corrected QT interval (QTcF). 
7 ECG to be completed 2 hours post initial dose 
8 Blood pressure and heart rate will be measured in a sitting position after resting for 5 minutes 
9 At Baseline, Vital Signs to be collected pre-dose and 2 hours post initial dose. 
10 Full physical examination at Screening & W12 / Early Termination. Abbreviated physical examination at Baseline, Week 4, Week 8, and Follow-up 
11 Blood biochemistry testing only for Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Bilirubin (direct and 
total) 
12 “Screening C-SSRS” to be used at Screening. “C-SSRS Since Last Visit” to be used at every other visit 
13 To be completed prior to CAPS-5 assessment at Screening 
14 Past month version to be used at every visit and should be audio recorded at every visit using the provided iPhone.  


 
 
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Assessment1 
Screening 
<-21 days 
Treatment Period 
Week 15 
/ Follow-
up 
(+5 days)  
Baseline2 
(+3 days) 
Week 13 
(+3 days) 
Week 2 
(+3 days) 
Week 4 
(+3 days) 
Week 6 
(+3 days) 
Week 8 
(+3 days) 
Week 10 
(+3 days) 
Week 12 / 
Early 
Termination 
(+3 days) 
(MADRS) 
Randomization15 
 
X 
 
 
 
 
 
 
 
 
Hamilton Anxiety Rating Scale (HAM-A) 
 
X 
 
 
X 
 
X 
 
X 
 
Clinical Global Impressions Severity and 
Improvement scales (CGI-S/I)16 
 
X 
 
 
X 
 
X 
 
X 
 
Patient Global Impression – Severity and 
Improvement scales (PGI-S/I)16 
 
X 
 
 
X 
 
X 
 
X 
 
PTSD Checklist (PCL-5) 
 
X 
 
 
 
 
 
 
X 
 
Sheehan Disability Scale (SDS) 
 
X 
 
 
X 
 
X 
 
X 
 
Insomnia Severity Index (ISI) 
 
X 
 
 
X 
 
X 
 
X 
 
Study Intervention dispensing 
 
X17 
 
 
X 
 
X 
 
 
 
Concomitant medications recording 
 
X 
X 
X 
X 
 
X 
 
X 
X 
Adverse Event (AE) recording18 
 
 
X 
X 
X 
 
X 
 
X 
X 
Blood sample collection for concentration of 
BNC210  
 
 
 
 
X 
 
X 
 
X 
 
 
15 Once eligibility has been confirmed 
 
16 Improvement scale at Week 12 only 
17 Participants to administer one PM dose on day of completing Baseline assessments and randomization 
18 See Appendix 3 in the protocol for definitions 


 
 
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4. 
Statistical Analysis and Reporting 
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will primarily use SAS (release 9.4 or higher). If the use of other 
software is warranted, the final statistical methodology report will detail what software was used 
for what purposes. 
Continuous (quantitative) variable summaries will include the number of participants (n) with 
non-missing values, mean, SD, median, minimum, and maximum.  
Categorical (qualitative) variable summaries will include the frequency and percentage of 
participants who are in the particular category for each possible value. In general, the 
denominator for the percentage calculation will be based upon the total number of participants in 
the study population for the treatment groups, unless otherwise specified. The denominator for 
by-visit displays will be the number of participants in the relevant study population with non-
missing data at each visit. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and measures of spread (SD) will 
be reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
Unless otherwise indicated, all statistical tests will be conducted at the ≤0.05 significance level 
using 2-tailed tests. P values and corresponding 95% confidence intervals (CIs) will be presented 
for statistical tests.  
4.2. 
Interim Analysis and Data Monitoring 
No interim analyses are planned. 
5. 
Analysis Populations 
The following analysis populations are planned for this study:  
• Safety Population (SAF): The SAF population includes all participants who receive any 
amount of the study intervention. The SAF population will be used for the analysis of the 
safety endpoints. Participants will be analyzed by actual treatment received. 
• Intent-to-Treat Population (ITT): Based on the ITT principle that asserts that the effect 
of a treatment can be best assessed by evaluating on the basis of the intention to treat a 
participant (i.e., the planned treatment regimen) rather than the actual treatment given, the 
ITT population includes all randomized participants. Participants will be analyzed by 
randomized treatments.  


 
 
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• Modified Intent-to-Treat Population (mITT): The mITT population includes all 
participants in the ITT population who receive any amount of the study intervention and 
have at least one post-baseline primary efficacy assessment (CAPS-5). Participants will 
be analyzed by randomized treatment. This will be the primary/main population for 
analysis. 
• Per Protocol Population (PP): The PP population will include participants from the 
mITT population who have no major protocol deviations. Before data are released for 
statistical analysis, a blinded review of all data will be performed in conjunction with the 
Sponsor to identify protocol deviations that may potentially affect the results. At this 
time, it will be determined if participants and/or data should be excluded from the PP 
population. The list of participants or observations to be excluded from the PP population 
will be provided in the Clinical Study Report. Participants will be analyzed by 
randomized treatments. 
• Pharmacokinetic Population (PK): The PK population will include all participants 
from the SAF population who have a valid concentration measurement. 
 
6. 
 General Issues for Statistical Analysis 
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
The last non-missing observation recorded before receiving the first dose of study drug will be 
used as the baseline observation for all calculations of change from baseline.  
6.1.2. Adjustments for Covariates 
The primary and key secondary endpoints will each be assessed with a Mixed Model for 
Repeated Measures (MMRM) with and without multiple imputation (MI). Each model will 
include fixed effects for treatment, visit, interaction between treatment and visit, center, and a 
covariate for baseline score. See Section 8 for more details. 
6.1.3. Multiple Comparisons 
Because this is a Phase 2 study, the level of significance will be set at 0.05 for primary and 
secondary endpoints with no adjustment for multiple comparisons. 
6.1.4. Handling of Dropouts or Missing Data 
 
 
 


 
 
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All possible efforts will be made to ensure that participants stay in the study and all data are 
collected as scheduled however, the occurrence of missing data cannot be completely eliminated. 
The primary and key secondary endpoints will be analyzed using MMRM with MI using 
placebo-based (jump to control) imputation. These endpoints will also be analyzed using 
MMRM without MI as a supportive analysis. 
All other secondary efficacy data will be analyzed as observed (with missing data not imputed). 
Safety data will not be imputed and will be analyzed as observed. 
6.1.4.1. 
Multiple Imputation Methods 
Data are considered MAR (missing at random) if, conditional upon the independent variables in 
the analytic model, the missingness depends on the observed outcomes of the variable being 
analyzed but does not depend on the unobserved outcomes of the variable being analyzed. This 
assumption implies that the behavior of the post dropout observations can be predicted from the 
observed variables, and therefore that treatment effect can be estimated without bias using the 
observed data (European Medicines Agency, 2010). For studies of missing data in a controlled 
clinical trial setting, MAR is usually considered as a plausible underlying missing mechanism 
(Molenberghs and Kenward, 2007; Siddiqui et al., 2009; Mallinckrodt et al., 2008; Mallinckrodt 
et al., 2013). The assumption of MAR is often reasonable because, particularly in longitudinal 
studies wherein the evolution of treatment effects is assessed by design over time, the observed 
data and the models used to analyze them can explain much of the missingness (Little and Rubin, 
1987; Verbeke and Molenberghs, 2000). This point may be especially relevant in well-controlled 
studies, in which extensive efforts are made to observe all outcomes and factors that influence 
them while participants are following protocol-defined procedures. Thus, longitudinal clinical 
trials by their very design aim to reduce the amount of MNAR (missing not at random) data 
(missingness explained by unobserved responses), thereby increasing the plausibility of MAR 
(Mallinckrodt et al., 2008).  
Although the assumption of MAR is often reasonable in clinical trials, the possibility of MNAR 
data cannot be ruled out. Therefore, analysis valid under MNAR will be performed as the 
primary/main analysis.  
Any participant who withdraws or is discontinued from the study or who misses a scheduled visit 
or assessments up through Week 12 will have their primary and key secondary efficacy missing 
data analyzed as imputed using MI techniques. This analysis will be presented as the main 
analysis. 
Multiple imputation is a simulation-based approach where missing values are replaced using an 
appropriate stochastic model given the observed data and covariates, creating multiple completed 
data sets. These completed datasets are then analyzed using standard analysis methods (MMRM 
for this study), and the different parameter estimates across the datasets are then combined to 
produce unique point estimates, standard errors, and confidence intervals taking into account the 








 
Statistical Analysis Plan  
 
Sponsor Bionomics Limited  
 
Protocol Number BNC210.012  
 
PCN Number BION.1642 
 
 
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6.1.6. Pooling of Sites 
This is a multicenter study and there will be no pooling of a site factor. 
6.1.7. Derived Variables 
• Change from baseline = value at current time point – value at baseline. 
• PCL-5 = sum of 20 individual items with a score ranging from 0 (not at all) to 4 
(extremely) for a total severity score of 0 to 80. 
• SDS = sum of 3 individual questions scored on a scale of 0 (not at all) to 10 (extremely) 
for a total score of 0 to 30. 
• ISI = sum of 7 individual questions scored from 0 (none) to 4 (very much) for a total 
score of 0 to 28. 
• Body Mass Index (BMI) kg/m2 =  
(
𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
ℎ𝑒𝑖𝑔ℎ𝑡(𝑐𝑚)
100
∗ℎ𝑒𝑖𝑔ℎ𝑡(𝑐𝑚)
100
) 
 
• Treatment Emergent Adverse Event (TEAE) = any AE that starts or deteriorates on or 
after the first dose of study medication and reported through Follow-up Week 15/EOT 
visit. 
 
• 
 
 
 
 
 
 
 
 
 


 
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6.1.8. Data Adjustments/Handling/Conventions 
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included in the data listings. 
All P values will be displayed in four decimals and rounded using standard scientific notation (e.g., 
0.XXXX). If a P value less than 0.0001 occurs it will be shown in tables as < 0.0001. 
Adverse Events and Concomitant Medication Coding 
An AE is any untoward medical occurrence in a clinical study participant, temporally associated 
with the use of the study medication, whether or not considered related to the study medication. 
All AEs that occur after any participant has received study treatment or within 21 (±5 days) days 
following the cessation of treatment, will be recorded. 
Adverse events will be coded using the MedDRA version 24.0 or higher thesaurus. Concomitant 
medications will be coded using the World Health Organization Drug Dictionary (WHO-DD 
Global B3 version March 2021). 
Concomitant Treatment Definition and Handling of Data 
A concomitant treatment refers to all treatment, including concomitant medications, vaccines, 
herbal supplements, vitamins, recreational drugs, and behavioral treatments such as counseling 
or regular psychotherapy, taken between the dates of the first dose of study medication and the 
end of the participant’s participation in the study (Follow-up Week 15), inclusive.  
Partial Date Imputation 
If partial dates occur, the convention for replacing missing dates for the purpose of statistical 
analysis is as follows: if just day is missing then the day assigned is the first day of the month or 
the date of first dose (if in the same month), whichever is later; if just month is missing then the 
month assigned is the month of the first dose, unless that results in a date prior to the first dose in 
which case the month after the first dose is used; and if both month and day are missing then the 
month assigned is the month of the first dose and the day assigned is either the first day of the 
month or the first dose date, whichever is later. 
If partial times occur, the convention is as follows: if the missing time occurs on the day of the 
first dose and both the hour and minute are missing then the time assigned is the time of the first 
dose, otherwise if both the hour and minute are missing and the date is not the date of first dose 
the time assigned is 12:00; if the date is the same as the date of the first dose and only hour is 
missing the hour assigned is 12 or the hour of first dose, whichever is later, and if the date is the 
same as the date of first dose and only the minute is missing the minute assigned is 30 or the 
minute of first dose, whichever is later. Otherwise the hour assigned is 12 if the hour is missing 






 
 
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Important protocol deviations may include: 
• Significant and/or persistent dosing error 
• Participant did not meet eligibility criteria  
• Error in randomization (i.e., received wrong drug) 
• Use of prohibited concomitant treatment during participation in the trial 
The final decision regarding inclusion and exclusion of participants from the analysis 
populations will be based on a final listing of protocol deviations. This will be determined during 
a (blinded) review meeting before any unblinding occurs or database freeze/lock, with input from 
the Clinical and Biostatistics team members and approval from the Sponsor. 
Protocol deviations will be summarized by type and by treatment group for the SAF population.   
7.3. 
Demographics and Other Baseline Characteristics 
The following analyses will be conducted for the SAF, mITT and PP populations: 
• Demographic variables will include age, sex, height, and weight. Information on race, 
ethnicity, and country will be collected for any eventual analysis of differences in 
response to the study intervention in accordance with local regulatory requirements. 
• Baseline participant characteristics will include medical history including confirmation of 
PTSD diagnosis, index trauma event (from CAPS-5 Criterion A), and time since index 
trauma event (as reported by the participant in months from the life events questionnaire). 
Baseline evaluation of the CAPS-5 Total Severity Score, PCL-5 total score, CGI-S score, 
PGI-S score, MADRS total score, HAM-A total score, SDS total score, and ISI total 
score will also be reported. 
A complete participant medical history will be summarized by MedDRA system organ class 
(SOC) and preferred term (PT), conducted on the SAF population. Prior and concomitant 
medications will be summarized by treatment group, by the number and percentage of 
participants taking each medication, classified using WHO-DD Anatomical Therapeutic 
Chemical (ATC) classes and preferred terms. 
7.4. 
Exposure and Compliance 
Treatment compliance (%) will be summarized by randomized treatment group and overall.  
 
 
 
 


 
 
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8. 
Efficacy Analysis 
Efficacy analyses will be performed on the mITT population. MMRM with no MI will be used 
as a supportive analysis for the primary and key secondary endpoints for the mITT and PP 
populations according to the planned treatment. The mITT will be considered the primary/main 
population for efficacy analyses.  
For all efficacy analyses, participants will be analyzed by the randomized treatment group 
assignment (BNC210 or placebo). All efficacy data will be presented in participant listings. 
8.1. 
Primary Efficacy Analysis 
For this study, the primary estimand is the difference between BNC210 and placebo in the mean 
change from Baseline to Week 12 in the CAPS-5 Total Symptom Severity score. In the course of 
the 12-week randomized treatment period, participants may be exposed to possible known or 
unknown inter-current events that could possibly impact the estimand, such as treatment 
discontinuation due to a specific adverse effect or perhaps lack of effect. The “Treatment Policy 
Strategy” will be adopted for handling all known or unknown inter-current events in this study. 
To this end, the ITT principle will serve as the analytical basis for interpreting the estimand. In 
other words, the difference between BNC210 and placebo in the mean change from Baseline to 
Week 12 in the CAPS-5 Total Symptom Severity Score will be evaluated regardless of the 
occurrence of any such inter-current event. 
The primary efficacy endpoint is the change from Baseline to Week 12 in the CAPS-5 Total 
Symptom Severity Score. A restricted maximum likelihood (REML)-based MMRM model with 
MI will be used as the primary/main analysis method. The repeated measures include post-
baseline visits (i.e., weeks 4, 8, 12) with change from baseline in the CAPS-5 Total Symptom 
Severity Score as the dependent variable. The MMRM model will include fixed effects for 
treatment, visit, interaction between treatment and visit, center, and covariate for baseline score, 
using an unstructured covariance structure. If the unstructured covariance model will not 
converge using the Newton-Raphson algorithm, the following alternatives will be tried in the 
order presented, stopping if convergence occurs:  
1) Fisher Scoring Algorithm 
2) Factor Analytic Structure 
3) Successive univariate analytic regression method as proposed in Lu and Mehrotra (2010) 
If still the mentioned methods fail, a more specific covariance structure, first the Toeplitz 
covariance structure (alternative 4) then the auto-regressive order 1 (AR[1]) (alternative 5) 
structures will be tested. A sandwich estimator will be used with structured covariance models to 
control Type I error. If still the model does not converge, additional covariance structures will be 
explored and the final decision will be documented in the CSR.  
The primary efficacy analysis will compare BNC210 and placebo using the contrast (difference 
in least squares [LS] means) between treatment groups through to Week 12. Significance tests 






 
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performed at Week 12 for the P/CGI-I, in which those with a rating of Very Much Improved or 
Much Improved (i.e., “Significant Improvement"). Odds ratios and corresponding 95% CIs for 
significant improvement versus all other categories (including missing values at that visit, where 
appropriate) will be presented. Additionally, for the binary outcomes of the proportion of 
participants who achieve a) ≥30% improvement; b) ≥50% improvement; c) a score ≤ 11 on the 
CAPS-5 Total Symptom Severity Score, the number and proportion will be summarized by 
treatment group and visit. Proportions will be compared between treatments using Pearson’s chi 
square or Fisher’s exact test as appropriate. All tests will be performed as 2-sided tests at the 
0.05 level of significance. 
 
 
 
 
 
 
 
  
 
 
9. 
Safety and Tolerability Analysis 
All safety analyses will be performed on the SAF population, defined as all participants who 
were randomized and received at least 1 dose of study medication. 
For all safety and tolerability analyses, participants will be analyzed by the treatment received 
(BNC210 or placebo) and, if applicable, overall, for all participants receiving the study 
medication. 
Safety data collected at the baseline visit (Day 0) or the last preceding visit if not collected at 
Baseline will be used as the baseline value for safety analyses. 
Safety measures including AEs, C-SSRS, physical examination findings, ECGs, vital signs, and 
clinical laboratory test results (hematology, biochemistry, urinalysis) will be summarized 
descriptively. For quantitative variables, descriptive statistics including number of observations, 
mean, median, SD, minimum, and maximum will be presented for observed and change from 
baseline values at each study visit. Qualitative variables will be summarized using counts and 
percentages. No formal inferential analyses will be conducted for safety variables unless 
otherwise noted. 
All safety and tolerability data will be presented in participant listings. 


 
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9.1. 
Adverse Events 
In general, TEAEs are defined as AEs that start or deteriorate on or after the first dose of study 
medication and reported through the Follow-up Day Week 15. For any participants who die 
during the study and the date of death is between the date of first dose of study medication and 
the date of study discontinuation (as entered by the site), inclusive, all AEs (including those 
resulting in death) that occur during the study will be considered as TEAEs irrespective of the 
last dose and will be included in the TEAE summaries. All summaries of AEs will be based on 
TEAEs unless specified otherwise. All SAEs will be collected from the signing of the ICF until 
the Follow-up visit at the time points specified in the SoA. 
All AEs, TEAEs, and SAEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), Version 22.1 or higher. 
The incidence of TEAEs will be summarized by treatment group, by system organ class (SOC) 
and preferred term (PT), by severity, and by relationship to study intervention. 
The number and percent of participants reporting TEAEs, grouped by MedDRA SOC and PT 
(coded using MedDRA v. 22.1 or higher), will be tabulated by severity and treatment group. In 
the case of multiple occurrences of the same TEAE within the same participant, each participant 
will only be counted once for each preferred term. 
In the summaries showing severity and relationship to study medication the event with the 
maximum severity (severe) or strongest relationship (probably related) will be reported. If a 
particular event is missing the severity and/or relationship, then the strongest possible severity or 
relationship will be assumed for analysis (severity = severe, relationship = definitely related). 
In the AE data listings, all AEs will be displayed. AEs that are treatment-emergent will be 
flagged. 
9.1.1. Adverse Events Leading to Withdrawal 
A summary of incidence rates (frequencies and percentages) of TEAEs leading to withdrawal of 
study drug, by treatment group, SOC, and PT will be prepared for the SAF population. No 
inferential statistical tests will be performed. 
A data listing of AEs leading to withdrawal of study drug will also be provided, displaying 
details of the event(s) captured on the CRF. 
9.1.2. Deaths and Serious Adverse Events 
Any deaths that occur during the study will be listed. 
Serious adverse events (SAEs) will be listed and also tabulated by SOC and PT and presented by 
treatment group, severity, and relationship to study drug. 




 
 
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Descriptive summaries will be presented for ECG measures of PR interval, QRS interval, QT 
interval, QTCF interval, and heart rate (HR). These summaries will be presented by study visit 
and treatment group. 
The number and percentage of patients/participants with normal and abnormal ECG results will 
be summarized for the SAF population by treatment group at each visit. Summary statistics for 
all collected visits will be displayed for QT and the QTC correction method by treatment group. 
Fridericia’s correction for QTC will be applied as follows: 
 
Fridericia’s Correction 
(QTCF) 
3
sec
RR
QT
QTc
m
f =
 
where: Relative Rate: RR = 60 / HR. HR = Heart Rate obtained from the ECG. 
9.5. 
Physical Examinations 
The number and percentage of participants with normal and abnormal findings in the physical 
examination at screening, baseline and each post-baseline visit will be displayed for each 
treatment group. Full physical examination will be done at Screening and at Week 12/Early 
Termination and abbreviated physical exams will be completed at Baseline, Week 4, Week 8, 
Week 15 (Follow-Up). A listing of physical examination findings will be provided for complete 
and brief examinations. 
Complete physical examinations will include assessments of the general appearance, skin and 
lymphatics, eyes, ears, nose, throat, cardiovascular system, respiratory system, 
abdomen/gastrointestinal system, musculoskeletal and neurological systems, and other body 
systems as required. Height will be measured at Screening and weight will be measured at 
Screening and Week 12/Early Termination. 
Abbreviated physical examinations will include assessments of the eyes, ears, nose, throat, 
cardiovascular system, respiratory system, abdomen/gastrointestinal system, and other body 
systems as required. 
9.6. 
Further Safety Evaluations 
9.6.1 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is an instrument to assess both suicidal behavior and ideation. The Screening 
version will be administered at Screening and the Since Last Visit version of the scale will be 
administered at Baseline, Week 4, Week 8, Week 12/Early Termination, and Follow-Up Week 
15. Participants enrolled in the UK will additionally have C-SSRS administered at Week 1 and 
Week 2. Results will be summarized by treatment group and study visit. C-SSRS data will also 
be listed. 


  
 
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9.7. 
Concomitant Medication 
Prior and concomitant treatments will be summarized descriptively by treatment group using the 
number and proportion of participants by PT and ATC Class Level 4. Prior treatments will be 
flagged separately from concomitant treatments. Treatments that started before the first dose of 
study medication will be considered prior treatments, whether or not they were stopped before 
the first dose of study medication. Any treatments continuing or starting after the first dose of 
study medication will be considered to be concomitant. If a treatment starts before the first dose 
of study medication and continues after the first dose of study medication, it will be considered 
both prior and concomitant. 
10. Pharmacokinetic Analysis 
Systemic concentrations of BNC210 will be determined at Weeks 4, 8, and 12. Plasma 
concentration data will be presented nominally. A data dependent population PK analysis will be 
outlined under a separate analytical plan. 
11. Changes from Planned Analysis 
ANCOVA has been added in this version to analyze the difference in the mean CGI-I and mean 
PGI-I scores between BNC210 and placebo at Week 12. 
 
12. References 
1. US Federal Register. (1988) International Conference on Harmonization; Guidance on 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food 
and Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 
179, pages 79583-49598. September 16, 1998. 
2. ASA. (2018) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2018. http://www.amstat.org/about/ethicalguidelines.cfm 
3. ICH (1998). ICH Harmonised Tripartite Guideline. Statistical Principles for Clinical 
Trials E9; 1998. https://database.ich.org/sites/default/files/E9_Guideline.pdf 
4. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014. 
https://rss.org.uk/about/policy-and-guidelines/code-of-conduct/. 
5. Mallinckrodt C.H., Lane P.W., Schnell D., Peng Y., Mancuso J.P. 2008. 
Recommendations for the Primary Analysis of Continuous Endpoints in Longitudinal 
Clinical Trials. Drug Information Journal, 42, 303-319. 
6. Molenberghs G., Kenward M.G. 2007. Missing Data in Clinical Studies. New York: 
Wiley. 
7. Cnaan, A., Laird, N.M., & Slasor, P. (1997). Using the General Linear Mixed Model to 
Analyse Unbalanced Repeated Measures and Longitudinal Data. Statistics in Medicine. 
16, 2349-2380. 


 
 
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8. Moelnberghs, G., Thijs, H., Jansen, I., Beunckens, C., Kenward, M.G., Mallinckrodt, C., 
& Carrol, R.J. (2004). Analyzing incomplete longitudinal clinical trial data. Biostatistics. 
5, 445-464. 
9. Mallinckrodt C. H., Clark W. S., David S. R. (2001). Accounting for dropout bias using 
mixed-effects models. Journal of Biopharmaceuticals Statistics. 11, 9-21. 
10. European Medicines Agency. 2010. Guideline on Missing Data in Confirmatory Clinical 
Trials. 
11. Siddiqui O., Hung H.M., O’Neil R. 2009. MMRM vs. LOCF a comprehensive 
comparison based on simulation study and 25 NDA datasets. Journal of 
Biopharmaceuticals Statistics, 19(2), 227-246. 
12. Mallinckrodt C.H., Roger J., Chuang-Stein C., Molenberghs G., O’Kelly M., Ratitch B., 
Jannsens M., Bunouf P. 2013. Recent Developments in the Prevention and Treatment of 
Missing Data. Drug Information Journal, 48, 68-80. 
13. Little R., Rubin D. 1987. Statistical Analysis with Missing Data. New York: John Wiley. 
14. Verbeke G., Molenberghs, G. 2000. Linear Mixed Models for Longitudinal Data. New 
York: Springer. 
15. Lu, K., Mehrotra, D.V. 2010. Specification of covariance structure in longitudinal data 
analysis for randomized clinical trials. Statistics in Medicine, 29, 474-488.