Clinical trial NCT02933606
Conditions: Post-Traumatic Stress Disorder
Sponsor: Bionomics Limited
Start date: 2016-06-30; Completion date: 2018-07-25
Enrollment: 193 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled study, evaluating the effects of BNC210 versus placebo on the symptoms of Post-Traumatic Stress Disorder, as measured by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5).

The secondary objectives of the study are to evaluate the effects of BNC210 on anxiety, depression, global functioning and patient reported outcomes in patients with PTSD. Safety and tolerability of BNC210 will also be assessed. Study participants will receive 12 weeks of blinded treatment followed by a 3 week follow-up period.

Detailed description:

Arms: arm 1: Suspension administered orally for 12 weeks. arm 2: Suspension administered orally for 12 weeks. arm 3: Suspension administered orally for 12 weeks. arm 4: Suspension administered orally for 12 weeks.
Interventions: intervention 1: BNC210 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Bionomics Limited 
Version 4.0 
Protocol No.: BNC210.007 
 Date: 30-May-2018 
CONFIDENTIAL  
Page 1 of 62 
 
 
 
CLINICAL STUDY PROTOCOL  
 
A Randomized, Double-blind, Placebo-controlled Phase II Study of BNC210 
in Adults with Post-Traumatic Stress Disorder (PTSD) 
 
 
 
Protocol Number: 
BNC210.007 
 
Investigational Product: 
BNC210 
 
 
 
 
 
 
 
Sponsor:  
BIONOMICS LIMITED 
31 Dalgleish Street 
Thebarton SA 5031 
AUSTRALIA 
 
Date and version: 
Version 4.0, 30 May 2018 
 
 
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 
Human Research Ethics Committee (HREC) / 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. 
 
 


Bionomics Limited 
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Protocol No.: BNC210.007 
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CONFIDENTIAL  
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PROTOCOL SYNOPSIS 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled Phase II Study of 
BNC210 in Adults with Post-Traumatic Stress Disorder (PTSD). 
Rationale for the Study: 
BNC210 acts through negative allosteric modulation (NAM) of the 
alpha 7 nicotinic acetylcholine receptor and is under development for 
the treatment of anxiety, and trauma and stressor-related disorders. 
 
 
 
 
 
 
 
 
 
 
 
. This study will assess the safety and efficacy of BNC210 in 
subjects with a diagnosis of PTSD, a stress and trauma related 
disorder with limited pharmacotherapy treatment options. 
Objectives: 
Primary Objectives 
• 
To assess the effects of BNC210 on Investigator-rated 
symptoms of PTSD measured by Clinician-Administered 
PTSD Scale for the Diagnostic and Statistical Manual of 
Mental Disorders, 5th Edition (DSM-5) (CAPS-5) scores.  
Secondary Objectives 
• 
To assess the effects of BNC210 on Investigator-rated 
symptoms of PTSD measured by each of the four symptom 
clusters (Intrusion; Avoidance; Negative Alterations in 
Cognition and Mood; Arousal and Reactivity) of the CAPS-5. 
• 
To assess the effects of BNC210 on other psychiatric outcomes 
in subjects with PTSD including anxiety and depression. 
• 
To assess the effects of BNC210 on global functioning and 
Quality of Life in subjects with PTSD. 
• 
To assess the effects of BNC210 on patient-reported outcomes 
in subjects with PTSD. 
• 
To assess the safety and tolerability of BNC210 in subjects with 
PTSD. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Endpoints 
Primary Efficacy Endpoint 
The effect of BNC210 compared to placebo on baseline to endpoint 
change in CAPS-5 total symptom severity scores after 12 weeks of 
treatment. 
Secondary Efficacy Endpoints 
The effect of BNC210 on Investigator-rated and self-reported PTSD 


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symptom severity, depression, anxiety, cognitive function, global 
function, quality of life, social functioning, and sleep quality after 12 
weeks of treatment, when compared to placebo using the following 
instruments: 
• 
Symptom cluster severity score for CAPS-5 Criterion B: 
Intrusion. 
• 
Symptom cluster severity score for CAPS-5 Criterion C: 
Avoidance. 
• 
Symptom cluster severity score for CAPS-5 Criterion D: 
Negative Alterations in Cognition and Mood. 
• 
Symptom cluster severity score for CAPS-5 Criterion E: 
Arousal and Reactivity. 
• 
PTSD Checklist for DSM-5 (PCL-5). 
• 
Montgomery- Åsberg Depression Rating Scale (MADRS). 
• 
Hamilton Anxiety Rating Scale (HAM-A). 
• 
CANTAB Cognitive Assessment.  
• 
Clinical Global Impressions – Severity and Improvement 
Scale (CGI-S/CGI-I). 
• 
Patient Global Impression – Severity and Improvement Scale 
(PGI-S/PGI - I). 
• 
Assessment of Quality of Life (AQoL-8D). 
• 
Sheehan Disability Scale (SDS). 
• 
Pittsburgh Sleep Quality Index (PSQI). 
Safety Analyses 
Suicidal ideation, self-injurious non-suicidal and suicidal behavior 
will be monitored from Baseline to week 15 using the Columbia 
Suicide Severity Rating Scale (C-SSRS).  
Other 
safety 
parameters 
(e.g. 
vital 
sign 
measurements, 
electrocardiogram (ECG) readings, physical examination, and 
laboratory tests) will be monitored from Baseline to week 15 and 
described using descriptive statistics by treatment group when 
applicable, and by visit otherwise.  
All adverse events (AEs) will be listed and summarized by treatment 
group, organ class and preferred term with:  
• 
The number of subjects with at least one AE and number of 
AEs for each treatment group and overall. 
• 
Analyses taking into account intensity and drug relationship to 
treatment could also be carried out. 
Description of potentially clinically significant values will be 
performed for vital signs, ECG parameters, blood chemistry and 
hematology parameters. All these parameters will be listed by subject 
and measurement time. The data outside of normal ranges will be 
flagged. 
 


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Criteria for evaluation: 
Efficacy: Response to treatment will be assessed using the CAPS-5, 
PCL-5, CGI-I/CGI-S, HAM-A, MADRS, CANTAB Cognitive 
Assessment, SDS, PSQI, PGI-I/PGI-S and AQoL-8D. 
Safety: Vital signs, ECG, hematology and blood chemistry, urinalysis, 
physical examinations, C-SSRS and continuous AE reporting. 
Adherence: This will be assessed via blood sampling for 
determination of BNC210 plasma concentrations and counts of 
returned medication bottles. 
  
 
Nicotine intake: The average daily number of tobacco products 
smoked and the use of nicotine replacement products will be recorded. 
Overall Design: 
This is a randomized, double-blind, parallel, placebo-controlled, 
multi-centre study with a 12-week, 4-arm treatment phase (placebo 
and 150mg bid, 300mg bid and 600mg bid BNC210).  Subjects will 
attend a Screening visit within 3 weeks of randomization to confirm 
eligibility.  Approximately 192 subjects who fulfill the inclusion 
criteria and none of the exclusion criteria will be randomized on Day 1 
using a 1:1:1:1 ratio. Subjects will then complete 12 weeks of their 
allocated treatment. The Investigational Product or Placebo will be 


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taken twice daily (bid) with food.  Subjects will return to the clinical 
site at weekly or 2-weekly intervals to receive study medication, 
complete safety assessments and questionnaires.  Subjects are then 
requested to attend a post-study visit at 15 weeks (i.e., 3 weeks after 
the last treatment). Subjects will undergo assessments for efficacy and 
safety during the study as per the schedule of assessments. 
Study Duration: 
Screening evaluation within 3 weeks of randomization 
Treatment phase: 12 weeks of treatment, bid (weekly or fortnightly 
visits to the clinic). 
Post-study visit:   3 weeks after the last treatment (i.e. 15 weeks after 
the first treatment). 
Recruitment timeframe estimate is 2 years. 
Study Centers: 
Approximately 20-30 centers located in Australia and the United 
States.  
Number of Planned 
Subjects: 
A total of 192 male and female patients with PTSD will be enrolled 
in the study at a 1:1:1:1 ratio (about 48 subjects per treatment arm). 
 
 
 
 
 
 
 
 
 
 
 
Investigational Product: 
BNC210 (150 mg, 300 mg, and 600 mg) administered bid with food 
from a prefilled single-use bottle for 12 weeks (BNC210 will be 
suspended in a vehicle solution). 
Reference Therapy: 
Placebo administered bid from a prefilled single-use bottle for 
12 weeks in a vehicle solution matching the Investigational Product. 
Inclusion Criteria: 
Subjects must satisfy all of the following inclusion criteria before 
being allowed to participate in the study: 
1. Signed and dated informed consent 
2. Male or female between 18 and 70 years of age, inclusive. 
3. Diagnosed with current PTSD as defined by the CAPS-5 for 
DSM-5. 
4. Currently not using any psychiatric medications except for: 
• No more than one selective serotonin reuptake inhibitor 
(SSRI) (fluvoxamine is excluded) or serotonin noradrenaline 
reuptake inhibitor (SNRI) within the licensed prescribing dose 
range.  Subjects must have been on a stable dose for at least 3 
months prior and through Screening, with the intent to remain 
on the same dose through to Week 15.  
• As needed (PRN) use of benzodiazepines (BZD) at a 
frequency not exceeding 2 days per week in the 3 months prior 
to Screening. The total dose must not exceed 30 mg/day in 
diazepam equivalents 
5. Subjects not currently receiving psychotherapy except long term 
supportive counseling or subjects that have received intensive 
regular psychotherapy for a minimum of three months prior to 
Screening. 
6. Females of childbearing potential must have a negative serum 
pregnancy test at Screening and a negative urine test at Day 1. 
Females not of childbearing potential must be postmenopausal 
(defined as cessation of regular menstrual periods for at least 


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12 months prior to Screening and confirmed by follicle-
stimulating hormone (FSH) levels in menopausal range at 
Screening). Sterilized male patients must be at least 1 year post-
vasectomy to be considered of non-child bearing potential.  
Acceptable forms of sterilization include bilateral tubal ligation, 
bilateral oophorectomy, and hysterectomy for women or 
vasectomy for men. 
Females and males of childbearing potential must agree to use 
two effective methods of contraception (double barrier 
contraception or hormonal contraceptive along with a barrier 
contraceptive) during the study and for 16 weeks following last 
study treatment.  Contraception that is deemed acceptable in this 
study includes the following:  
• 
Condoms.  
• 
Hormonal (includes oral, injected, intrauterine, transdermal, 
or implanted).  Females must be using hormonal 
contraceptives for at least 3 months prior to randomization 
and not change the contraceptive during the trial. 
• 
Rhythm methods will not be considered as an effective 
method of birth control, however, abstinence may be allowed 
based on the opinion of the Investigator. 
o Requirement for contraception can be waived in certain 
circumstances (i.e. same sex relationships) if approved by 
the Sponsor. 
o Males must agree to not donate sperm for at least 16 weeks 
following last study treatment. 
7. In the opinion of the Investigator the participant has a high 
probability for adherence with and completion of the study, and 
willing and able to withdraw and refrain from specific therapies. 
8. Fluent in English and able to understand and comply with written 
and verbal protocol-related requirements. 
Exclusion Criteria: 
If any of the following exclusion criteria apply, the subject will not be 
allowed to participate in the study: 
1. Current and ongoing exposure to the trauma that caused the 
PTSD. 
2. 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. 
3. The use of psychiatric medications within 2 weeks of Screening 
except for SSRIs, SNRIs or limited PRN BZD use as per 
inclusion criterion 4. Restricted psychiatric medications include 
(but are not limited to) antidepressants not allowed by inclusion 
criterion 4, antianxiety drugs (except limited BZD use per 
inclusion criterion 4), mood stabilizers, stimulants, antipsychotics, 
hypnotics and acetylcholinesterase inhibitors. 
4. History of significant traumatic brain injury. 
5. Depression as measured by Montgomery-Äsberg depression scale 


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(MADRS) rating > 23. 
6. Bipolar and psychotic disorders as identified at Screening using 
the MINI International Neuropsychiatric Interview (V7.0) 
(M.I.N.I). 
7. A score > 7 on the McLean Screening Instrument for Borderline 
Personality Disorder (MSI-BPD) at Screening. 
8. History of seizure disorders, uncontrolled sleep apnoea or severe 
neurologic disease. 
9. Increased risk of suicide, defined as: 
• 
Any previous suicide attempt disclosed by the participant at 
Screening 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 year, as captured at Screening 
using the C-SSRS. 
• 
A score > 4 on item 10 of the MADRS at Screening. 
10. The use of cytochrome P450 3A4 inducers within 30 days of 
Screening. 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, 
grapefruit or grapefruit-containing products. 
11. The use of alprazolam or flunitrazepam within 3 months of 
Screening. 
12. 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). 
13. Liver disease or liver injury as indicated by abnormal liver 
function tests (LFTs), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (ALP), or serum 
bilirubin (>2x upper limit of normal [ULN]) or history of hepatic 
cirrhosis. 
14. Any clinically significant abnormalities in laboratory test results 
at Screening (biochemistry, hematology or urinalysis) as assessed 
by an Investigator. 
15. Fridericia-corrected QT interval (QTcF) >460 msec for males and 
QTcF >480 msec for females as measure by ECG at Screening. 
16. Any clinically significant ECG abnormality as determined by the 
Investigator at Screening. 
17. A family history of congenital long QT syndrome, Brugada 
syndrome or unexplained sudden cardiac death.  
18. Positive result for human immunodeficiency virus (HIV), 
hepatitis B surface antigen (HBsAg), or hepatitis C (HCV) at 
Screening. 
19. Any moderate to severe substance use disorder (any type) in the 
12 months prior to Screening as identified by the DSM-5 using 
the M.I.N.I (V7.0). 


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20. Participation in an investigational study within 30 days of 
Screening. 
21. Current Australian serving Defense personnel or any member of 
the US military currently serving on active duty. 
22. Participants involved with ongoing insurance or workplace claims 
that in the opinion of the Investigator are likely to have an impact 
on the mental health, presentation or capacity of the patient to 
engage in the study. 
23. Females who are pregnant, nursing, or intend to become pregnant 
during the study or within 16 weeks of last dose of Investigational 
Product, or any males who plan to father/conceive a child within 
16 weeks of last dose of Investigational Product. 
24. Blood or plasma donation or significant blood loss within 60 days 
of Day 1. 
25. Known to have poor peripheral venous access. 
26. Subjects 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 subject at risk or any other reason the investigator 
deems applicable. 
27. History of allergies, allergic reactions or hypersensitivity to 
BNC210 or excipients. 
28. Blood Pressure (BP) systolic >160 mmHg or diastolic >90 
mmHg. Allow two repeat measures at the discretion of the 
Investigator. 


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Table 1: Schedule of Assessments 
Visit 
Screening 
Baseline1  
V1 
V2 
V3 
V4 
V5 
V6 
V7 / Early 
Term 
Post-
study 
Study Days: Investigational Product to be administered 
pre-visit except at Baseline 
<-21 
Day 1 
(+ 2 days) 
Week 1 
Day 8 
(+ 2 days) 
Week 2 
Day15 
(+ 2 days) 
Week 4 
Day 29 
(+ 2 days) 
Week 6 
Day 43 
(+ 2 days) 
Week 8 
Day 57 
(+ 2 days) 
Week 10 
Day 71 
(+ 2 days) 
Week 12 
Day 85 
(+ 2 days) 
Week 15 
Day 106 
(+ 5 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Register subject in Interactive Web Response System 
(IWRS) 
X 
 
 
 
 
 
 
 
 
 
Medical history including current & prior medications 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Physical examination3 
X4 
 
 
X 
 
X 
 
 
X 
X 
Human immunodeficiency virus (HIV), Hepatitis B surface 
antigen (HBsAg) and Hepatitis C virus (HCV) antibody 
screen 
X 
 
 
 
 
 
 
 
 
 
The M.I.N.I. International Neuropsychiatric Interview 
(V7.0)5 
X 
 
 
 
 
 
 
 
 
 
McLean Screening Instrument for Borderline Personality 
Disorder (MSI-BPD) 
X 
 
 
 
 
 
 
 
 
 
Clinical labs (hem, biochem, C-reactive protein [CRP], 
urinalysis) 
X 
 
 
X 
 
X 
 
 
X 
 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
X 
 
 
 
 
 
 
X 
 
Follicle stimulating hormone (FSH) for females of non-child 
bearing potential only 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Blood sample collection for concentration of BNC210 
X 
 
 
X 
 
X 
 
 
X 
 
Vital signs 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead Electrocardiogram (ECG) 8 
X9 
 
 
X 
 
X 
 
 
X 
 
 
1 All baseline assessments to be completed pre-dose. Subjects to administer one PM dose with food on Day 1. 
 
 
3 Full physical examination at Screening & V7 / Early Termination. Abbreviated physical examination at V2, V4, and Post Study. 
4 Include height and weight measurements. 
5 Modules C, I, J, K, and O are required for eligibility purposes. Other modules may be completed at the discretion of the Investigator. All diagnoses to be included in the subject’s medical history. 
 
 
7 Blood pressure and heart rate will be measured in a sitting position after resting for 5 minutes. 
8 All ECGs are to be completed in triplicate with at least a 2-minute break between tests.  Repeat ECGs must also be completed in triplicate. The subject 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 subject, where possible.   


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Visit 
Screening 
Baseline1  
V1 
V2 
V3 
V4 
V5 
V6 
V7 / Early 
Term 
Post-
study 
Study Days: Investigational Product to be administered 
pre-visit except at Baseline 
<-21 
Day 1 
(+ 2 days) 
Week 1 
Day 8 
(+ 2 days) 
Week 2 
Day15 
(+ 2 days) 
Week 4 
Day 29 
(+ 2 days) 
Week 6 
Day 43 
(+ 2 days) 
Week 8 
Day 57 
(+ 2 days) 
Week 10 
Day 71 
(+ 2 days) 
Week 12 
Day 85 
(+ 2 days) 
Week 15 
Day 106 
(+ 5 days) 
Standard Life Events Checklist for DSM-5 (LEC-5) 
X10 
 
 
 
 
 
 
 
 
 
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)11 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Columbia Suicide Severity Rating Scale (C-SSRS)12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Montgomery- Åsberg depression rating scale (MADRS) 
X 
X 
 
 
X 
 
X 
 
X 
X 
Hamilton anxiety rating scale (HAM-A) 
 
X 
 
 
X 
 
X 
 
X 
X 
CANTAB Cognitive Assessment13 
X14 
X 
 
 
X 
 
 
 
X 
 
Clinical Global Impressions Improvement & Severity (CGI-
I/CGI-S) 
 
 
X15 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Patient Global Impression – Improvement & Severity (PGI-
I/PGI-S). 
 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of Quality of Life (AQoL-8D) 
 
X 
 
 
X 
 
X 
 
X 
X 
PTSD Checklist (PCL-5)17 
 
X 
 
 
X 
 
X 
 
X 
X 
Social functioning (Sheehan Disability Scale, SDS) 
 
X 
 
 
X 
 
X 
 
X 
X 
Sleep monitoring (Pittsburgh Sleep Quality Index, PSQI) 
 
X 
X 
 
X 
 
X 
 
X 
X 
Randomization via Interactive Web Response System 
(IWRS) 
 
X 
 
 
 
 
 
 
 
 
Investigational Product (IP) dispensing 
 
X 
 
X 
X 
X 
X 
X 
 
 
Subject dosing diary 
 
X 
 
X 
X 
X 
X 
X 
 
 
Adverse event (AE) recording 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nicotine use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
9 Single triplicate repeat allowed in the event of a clinically significant abnormality including prolonged QTcF. 
10 “Standard” LEC-5 to be completed prior to CAPS-5. 
11 “Past month” version used at Screening. “Past week” version used at all other visits. 
12 “Screening C-SSRS” to be used at Screening. “C-SSRS Since Last Visit” to be used at every other visit. 
13  All CANTAB cognitive assessments to be completed within + 1hr of baseline assessment start time (excluding the test completed during the screening period). 
14 A single practice session on the CANTAB Cognitive Assessment to be completed > 7 days prior to baseline visit 
15 Severity scale only. 
16 Severity scale only. 
17 “Standard” PCL-5 used at all visits. 


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TABLE OF CONTENTS 
1 
INTRODUCTION AND RATIONALE .......................................................................................... 19 
1.1 
DISEASE BACKGROUND ................................................................................................................. 19 
1.2 
INVESTIGATIONAL PRODUCT .......................................................................................................... 19 
 
 
 
 
1.3 
RATIONALE ................................................................................................................................. 23 
 
 
 
 
2 
STUDY OBJECTIVES ............................................................................................................... 24 
2.1 
PRIMARY OBJECTIVES ................................................................................................................... 24 
2.2 
SECONDARY OBJECTIVES ............................................................................................................... 24 
 
 
3 
INVESTIGATIONAL PLAN ....................................................................................................... 25 
3.1 
DESCRIPTION OF OVERALL STUDY DESIGN AND PLAN ......................................................................... 25 
3.2 
DISCUSSION OF STUDY DESIGN INCLUDING CHOICE OF CONTROL GROUPS ............................................ 25 
3.3 
SELECTION OF STUDY POPULATION ................................................................................................. 25 
3.3.1 
Inclusion Criteria .............................................................................................................. 26 
3.3.2 
Exclusion Criteria ............................................................................................................. 27 
4 
TREATMENTS ........................................................................................................................ 29 
 
 
4.2 
IDENTITY OF INVESTIGATIONAL PRODUCT ......................................................................................... 29 
4.3 
METHODS OF ASSIGNING SUBJECTS TO TREATMENT .......................................................................... 29 
4.4 
SELECTION OF DOSE IN THE STUDY ................................................................................................. 29 
4.5 
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT ........................................................................ 30 
4.6 
DOSE INTERRUPTIONS AND REDUCTIONS ......................................................................................... 30 
4.7 
BLINDING ................................................................................................................................... 30 
4.8 
EMERGENCY UNBLINDING OF STUDY SUBJECTS ................................................................................. 30 
4.9 
SUPPLY, PACKAGING AND LABELING OF THE INVESTIGATIONAL PRODUCT .............................................. 30 
4.10 STORAGE OF THE INVESTIGATIONAL PRODUCT .................................................................................. 31 
4.11 ACCOUNTABILITY, RECONCILIATION AND RETURN OF THE INVESTIGATIONAL PRODUCT ............................ 31 
4.12 PRIOR AND CONCOMITANT THERAPY .............................................................................................. 31 
4.13 TREATMENT COMPLIANCE ............................................................................................................. 32 
4.14 MEASURES TO MINIMIZE BIAS ....................................................................................................... 33 
4.14.1 
Randomization Procedures ......................................................................................... 33 
4.14.2 
Maintenance of Consistent Behaviors ........................................................................ 33 
5 
STUDY ASSESSMENTS AND PROCEDURES .............................................................................. 34 
5.1 
SCREENING EVALUATION .............................................................................................................. 34 
5.2 
BASELINE VISIT (DAY 1 +2 DAYS) ................................................................................................... 34 
5.3 
VISIT 1 (WEEK 1, DAY 8 ±2 DAYS) .................................................................................................. 35 
5.4 
VISIT 2 (WEEK 2, DAY 15 ±2 DAYS) ................................................................................................ 36 
5.5 
VISIT 3 (WEEK 4, DAY 29 ±2 DAYS) ................................................................................................ 36 
5.6 
VISIT 4 (WEEK 6, DAY 43 ±2 DAYS) ................................................................................................ 37 
5.7 
VISIT 5 (WEEK 8, DAY 57 ±2 DAYS) ................................................................................................ 37 
5.8 
VISIT 6 (WEEK 10, DAY 71 ±2 DAYS).............................................................................................. 38 
5.9 
VISIT 7 (WEEK 12, DAY 85 ±2 DAYS / EARLY TERMINATION) .............................................................. 38 


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5.10 POST-STUDY (WEEK 15, DAY 106 ± 5 DAYS) .................................................................................. 39 
5.11 UNSCHEDULED VISITS ................................................................................................................... 39 
5.12 RE-SCREENING OF STUDY SUBJECTS. ............................................................................................... 39 
6 
WITHDRAWAL OF SUBJECTS OR TERMINATION OF THE STUDY ............................................... 40 
7 
EFFICACY VARIABLES ............................................................................................................. 42 
7.1 
DEFINITIONS OF VARIABLES ........................................................................................................... 42 
7.1.1 
Clinician-Administered PTSD Scale for the DSM-5 (CAPS-5) ............................................ 42 
7.1.2 
PTSD Checklist for DSM-5 (PCL-5) .................................................................................... 42 
7.1.3 
Clinical Global Impression scales – Improvement and Severity (CGI-I/CGI-S) ................. 42 
7.1.4 
Patient Global Impression Scales – Improvement and Severity (PGI-I/PGI-S) ................. 42 
7.1.5 
Assessment of Quality of Life (AQoL-8D) ......................................................................... 42 
7.1.6 
Hamilton Anxiety Rating Scale (HAM-A) ......................................................................... 42 
7.1.7 
Montgomery-Asberg Depression Rating Scale (MADRS) ................................................ 43 
7.1.8 
CANTAB Cognitive Assessment ........................................................................................ 43 
7.1.9 
Sheehan Disability Scale (SDS) ........................................................................................ 44 
7.1.10 
Pittsburgh Sleep Quality Index (PSQI) ......................................................................... 44 
8 
COMPLIANCE, 
 ............................................... 45 
8.1 
BLOOD SAMPLING FOR PLASMA BNC210 CONCENTRATIONS ............................................................. 45 
 
 
 
 
9 
SAFETY VARIABLES ................................................................................................................ 46 
9.1 
SAFETY ENDPOINT(S) ................................................................................................................... 46 
9.2 
PHYSICAL EXAMINATION ............................................................................................................... 46 
9.3 
VITAL SIGNS ................................................................................................................................ 46 
9.4 
12-LEAD ECGS ............................................................................................................................ 46 
9.5 
CLINICAL LABORATORY TESTS ........................................................................................................ 47 
9.6 
COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) ...................................................................... 48 
9.7 
ADVERSE EVENTS (AES) ................................................................................................................ 48 
9.7.1 
Definitions ....................................................................................................................... 48 
9.7.2 
Grading of Adverse Events .............................................................................................. 48 
9.7.3 
Causal Relationship to Investigational Product ............................................................... 49 
9.7.4 
Documentation of Adverse Events by the Investigator ................................................... 49 
9.7.5 
Laboratory Test and other Test Abnormalities as Adverse Events .................................. 49 
9.8 
SERIOUS ADVERSE EVENTS (SAE) ................................................................................................... 50 
9.8.1 
Reporting for Serious Adverse Events (24 Hours) ............................................................ 50 
9.9 
SAFETY REVIEW COMMITTEE ......................................................................................................... 51 
10 DATA MANAGEMENT AND STATISTICS .................................................................................. 52 
10.1 DATA COLLECTION ....................................................................................................................... 52 
10.2 DATA MANAGEMENT AND QUALITY CONTROL ................................................................................. 52 
10.3 STATISTICAL CONSIDERATIONS ....................................................................................................... 52 
10.4 SAMPLE SIZE ............................................................................................................................... 53 
 
 
10.5 STATISTICAL METHODS ................................................................................................................. 53 
10.6 ANALYSIS POPULATIONS AND/OR SUBSETS ...................................................................................... 53 
10.6.1 
Description of the Populations .................................................................................... 54 
10.7 DEMOGRAPHICS AND BASELINE CHARACTERISTICS ............................................................................ 54 
10.8 PROTOCOL DEVIATIONS ................................................................................................................ 54 
10.9 EFFICACY ANALYSIS ...................................................................................................................... 54 
10.9.1 
Primary Efficacy Endpoint ........................................................................................... 54 


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10.9.2 
Secondary Efficacy Endpoints ..................................................................................... 55 
 
10.11 COMPLIANCE ANALYSIS ................................................................................................................ 56 
10.12 SAFETY ANALYSIS ......................................................................................................................... 57 
10.12.1 
Safety Analysis Criteria ............................................................................................... 57 
10.12.2 
Statistical Methodology .............................................................................................. 57 
10.12.3 
Columbia Suicide Severity Rating Scale Safety Analysis ............................................. 57 
10.12.4 
Adverse Event Analysis ................................................................................................ 57 
11 STUDY ADMINISTRATION ...................................................................................................... 58 
11.1 ETHICAL CONSIDERATIONS ............................................................................................................ 58 
11.1.1 
Ethical Principles ......................................................................................................... 58 
11.1.2 
Informed Consent ........................................................................................................ 58 
11.1.3 
Human Research Ethics Committee / Institutional Review Board Approval ............... 58 
11.2 DATA HANDLING AND RECORD KEEPING .......................................................................................... 58 
11.2.1 
Data Collection and Reporting .................................................................................... 58 
11.2.2 
Monitoring .................................................................................................................. 59 
11.2.3 
Audit ............................................................................................................................ 59 
11.2.4 
Study Records Retention ............................................................................................. 60 
11.3 DATA DISCLOSURE AND SUBJECT CONFIDENTIALITY ........................................................................... 60 
11.4 PUBLICATION POLICY .................................................................................................................... 60 
12 REFERENCES ......................................................................................................................... 61 
 
IN-TEXT TABLES 
Table 1: Schedule of Assessments ............................................................................................................................................. 9 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse Event 
 
 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase (SGPT) 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AQoL 
Assessment of Quality of Life 
AST 
Aspartate Aminotransferase (SGOT) 
 
 
BIC 
Bayesian Information Criterion 
bid 
Twice Daily 
BOCF 
Baseline Observation Carried Forward 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
BZD 
Benzodiazepines 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CAPS-5 
Clinician-Administered PTSD Scale for the DSM-5 
CBC 
Complete Blood Count 
CCK 
Cholecystokinin 
CGI-I 
Clinical Global Impressions – Improvement 
CGI-S 
Clinical Global Impressions – Severity 
CI 
Confidence Interval 
Cmax 
Maximal Observed Plasma Concentration 
CRO 
Clinical Research Organization 
CRP 
C-reactive Protein 
CTN 
Clinical Trial Notification 
DBP 
Diastolic Blood Pressure 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
 
 
EMDR 
Eye Movement Desensitization and Reprocessing 
ET 
Early Termination 
 
 


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Abbreviation 
Definition 
fMRI 
Functional Magnetic Resonance Imaging 
FSH 
Follicle Stimulating Hormone 
GAD 
Generalized Anxiety Disorder 
 
 
eGFR 
Estimated Glomerular Filtration Rate 
GGT 
Gamma Glutamyl Transferase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HAM-A 
Hamilton Anxiety Rating Scale 
HbsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C virus 
 
 
HIV 
Human Immunodeficiency Virus 
HREC 
Human Research Ethics Committee 
 
 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
LEC-5 
Life Events Checklist for DSM-5. 
LFT 
Liver Function Test 
LOCF 
Last Observation Carried Forward 
 
 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed Model for Repeated Measurements 
MSI-BPD 
McLean Screening Instrument for Borderline Personality 
Disorder 
 
 
NAM 
Negative Allosteric Modulation 
 
 
 
 


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Abbreviation 
Definition 
PAL 
Paired Associates Learning 
PCL-5 
Standard PTSD Checklist for DSM-5 
PD 
Pharmacodynamic 
PGI-I 
Patient Global Impressions – Improvement 
PGI-S 
Patient Global Impressions – Severity 
PICF 
Patient Informed Consent Form 
PK 
Pharmacokinetics 
PRN 
As Needed 
PSQI 
Pittsburgh Sleep Quality Index 
PTSD 
Post-Traumatic Stress Disorder 
QTcF 
Fridericia-corrected QT Interval 
RBC 
Red Blood Cell 
RVP 
Rapid Visual Information Processing 
 
 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SDS 
Sheehan Disability Scale 
SNRI 
Serotonin Noradrenaline Reuptake Inhibitor 
SOP 
Standard Operating Procedure 
SSID 
Study Subject Identification Number 
SSRI 
Selective Serotonin Reuptake Inhibitor 
SWM 
Spatial Working Memory 
 
 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHODRUG 
World Health Organization Drug Dictionary 
 
 


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PROTOCOL APPROVAL/SIGNATURES 
 
I herewith approve the following protocol entitled “A Randomized, Double-blind, Placebo-
controlled Phase II Study of BNC210 in Adults with Post-Traumatic Stress Disorder (PTSD)” 
Version 4.0 dated 30-May-2018 
 
SPONSOR SIGNATURE 
 
 Signature: 
_______________________________________________ 
Name: 
 
Date: 
____/____/2018 
 


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INVESTIGATOR SIGNATURE 
 
A Randomized, Double-blind, Placebo-controlled Phase II Study of BNC210 in Adults with 
Post-Traumatic Stress Disorder (PTSD) 
 
BNC210.007 
 
Version: 4.0 
 
Issue Date: 30-May-2018 
 
Investigator Agreement 
 
I have read the above-mentioned protocol and am aware of my responsibilities as Principal 
Investigator for this study. As such, I agree to: 
• Personally supervise the conduct of this trial; 
• Conduct the trial in accordance with International Conference on Harmonization 
(ICH) E6 Good Clinical Practice: Consolidated Guidance (GCP), applicable 
regulatory requirements, and the protocol; 
• Comply with the procedures for data recording and reporting as required by the 
regulatory authorities and the Sponsor; 
• Permit monitoring, auditing, and inspection of study records as required by ICH GCP; 
• Retain the essential clinical study documents as required by ICH GCP and the 
Sponsor. 
 
 
Principal Investigator Signature: 
_______________________________________________ 
Principal Investigator Name: 
_______________________________________________ 
Date: 
____/____/2018 
 
 


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1 INTRODUCTION AND RATIONALE 
1.1 
Disease Background 
According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
(DSM-5), Post-Traumatic Stress Disorder (PTSD) results 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. 
Treatment is based on early interventions, psychotherapies (cognitive behavioral therapy 
[Otis et al. 2009], exposure, eye movement desensitization and reprocessing [EMDR], etc.) 
and pharmacotherapy. For the latter, only two pharmacological agents, the antidepressants 
Paxil® (paroxetine) and Zoloft® (sertraline), belonging to the selective serotonin reuptake 
inhibitors class (SSRIs), are 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. Combat exposure, in particular, produces a virulent form of PTSD, which 
is highly resistant to current pharmacological interventions. Overall, antidepressants have (1) 
moderate efficacy (2) marginal efficacy on male military populations (3) rebound effect upon 
treatment discontinuation (worsening symptoms) (4) severe side effects upon initiation of 
treatment (depression, generalized anxiety, panic, substance abuse, suicidal ideation), (5) 
elevated risk of suicide in young adults (non-approved treatment for children) and (6) 
potential for sexual dysfunction. 
Benzodiazepines (BZD) use is not indicated for PTSD. Data on alprazolam show that it has a 
deleterious effect on PTSD recovery during exposure therapy (Rothbaum et al. 2014, Rosen 
et al. 2013) and it is now contraindicated in the Veterans Administration Guideline 
(Kobayashi et al. 2015). The 2008 World Federation of Societies of Biological Psychiatry 
conference have also cautioned against the use of BZDs in PTSD (Bandelow et al. 2008). In 
an epidemiological study, the concomitant use of BZD with an antidepressant increased the 
risk of hospitalization, both in psychiatric and non-psychiatric wards (Hawkins et al 2013). 
However, despite a reduction in prescriptions, 30% of PTSD patients still received BZD in 
2012 (Lund et al. 2012). 
Community-based epidemiologic studies indicate a lifetime prevalence of PTSD ranging 
from 8% to 12% (Kessler et al. 1995, Breslau et al. 1991), with at-risk individuals (victims of 
criminal violence, survivors of civilian disasters, combat veterans) showing a prevalence rate 
from 4% to 30% (Berger et al. 2012, Burri et al. 2014, Thomas et al. 2010, Winfield et al. 
1990, Shore et al. 1989, Jordan et al. 1991). 
1.2 
Investigational Product 
The investigational product (IP), BNC210, is a new chemical entity being developed by 
Bionomics Limited for the treatment of anxiety, and trauma and stressor-related, disorders. 
BNC210 is a negative allosteric modulator (NAM) of the alpha 7 nicotinic acetylcholine 
receptor, which represents a novel target for the treatment of these disorders. In vivo 
pharmacology has confirmed BNC210 efficacy in animal models of anxiety at low doses with 
a wide therapeutic index. There is an absence of the adverse effects particularly those 
associated with standard-of-care treatments for acute disorders, such as BZD and the 
antidepressants used as first line therapy for chronic disorders. 
 


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1.3 
Rationale 
 
 
This Phase II study is intended to assess the potential effect of BNC210 on the treatment of 
PTSD, a condition which is now classified in the DSM-5 as a Trauma and Stressor-Related 
Disorder rather than an Anxiety Disorder. Previous human studies have established safety, 
tolerability and demonstrated a reduction of CCK-induced anxiety in healthy subjects, as well 
as cognitive profiling. A Phase II imaging (fMRI) study 
 
 showed significant effects of 
BNC210 on anxiety-related brain activity and defensive behavior in drug-free GAD patients. 
In line with preclinical data demonstrating BNC210’s positive effects on fear extinction, and 
in order to expand the usefulness of BNC210 to other disorders related to anxiety, this 
molecule will be studied in PTSD patients where deficits in fear extinction are thought to 
contribute to the pathology of this disorder. Thus, PTSD is a condition with unmet medical 
needs, for which BNC210 may be of benefit. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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2 STUDY OBJECTIVES 
2.1 
Primary Objectives 
• To assess the effects of BNC210 on Investigator-rated symptoms of PTSD measured 
by Clinician-Administered PTSD Scale for the Diagnostic and Statistical Manual of 
Mental Disorders, 5th Edition (DSM-5) (CAPS-5) scores.  
2.2 
Secondary Objectives 
• To assess the effects of BNC210 on Investigator-rated symptoms of PTSD measured by 
each of the four symptom clusters (Intrusion; Avoidance; Negative Alterations in 
Cognition and Mood; Arousal and Reactivity) of the CAPS-5. 
• To assess the effects of BNC210 on other psychiatric outcomes in subjects with PTSD 
including anxiety and depression. 
• To assess the effects of BNC210 on global functioning and Quality of Life in subjects 
with PTSD. 
• To assess the effects of BNC210 on patient-reported outcomes in subjects with PTSD.  
• To assess the safety and tolerability of BNC210 in subjects with PTSD. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3 INVESTIGATIONAL PLAN 
3.1 
Description of Overall Study Design and Plan 
This is a randomized, double-blind, parallel, placebo-controlled, multi-center study with a 
12-week, 4-arm treatment phase (placebo and BNC210).  Subjects will attend a Screening 
visit within 3 weeks before randomization to confirm eligibility. Approximately 192 subjects 
who fulfill the inclusion criteria and none of the exclusion criteria will be randomized on 
Day 1 using a 1:1:1:1 ratio. Subjects will then complete 12 weeks of their allocated treatment. 
The IP (total daily dose 300 mg, 600 mg or 1200 mg) or Placebo will be taken bid with food.  
Subjects will return to the clinical site at weekly or 2-weekly intervals to receive study 
medication, complete safety assessments and questionnaires.  Subjects are then requested to 
attend a post-study visit at 15 weeks (i.e., 3 weeks after the last treatment). 
The details are included in the Schedule of Assessments (Table 1). 
3.2 
Discussion of Study Design Including Choice of Control Groups 
This randomized, double-blind, placebo-controlled, Phase II study design was chosen to 
investigate whether BNC210 causes a decrease in symptoms of PTSD, as assessed by the 
CAPS-5 (National Centre for PTSD) compared to placebo. Subjects will be randomized to 
ensure that there are no order effects and to minimize bias. The study will be double-blind to 
ensure that the patients and clinic staff are unaware of the dosing assignment and to minimize 
the potential for bias in study assessments or in reporting of AEs.  
Subjects will still receive standard of care, even if randomized to placebo as their wellbeing 
will be monitored through application of various questionnaires and safety assessments.  
Subjects who received psychotherapy on a regular basis in the previous 3 months before 
inclusion into the study may continue to receive this care. A stable as needed (PRN) dose of 
benzodiazepine use will still be allowed during the study. 
3.3 
Selection of Study Population 
Each Investigator will identify potentially suitable patients from their active caseload.  A 
recruitment campaign may also be implemented to facilitate recruitment.  The campaign may 
consist of radio, print, and web based advertisements approved by the Human Research 
Ethics Committee (HREC) / Independent Review Board (IRB). The Principal or Co-
Investigator will be responsible for enrolling patients who are referred by an external clinician 
or respond to an advertisement.  All patients will be evaluated against the study eligibility 
criteria at Screening.  Only eligible patients will proceed through to the treatment phase. 
Patients must complete all protocol defined visits at study centers listed on the Clinical Trial 
Notification (CTN) form (Australia) and the Investigational New Drug (IND) application 
(USA).  
At the Screening visit, each patient will participate in the informed consent process and sign 
and date the patient informed consent form (PICF) before any procedures specified in this 
protocol are performed. 
 
 


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3.3.1 
Inclusion Criteria 
Subjects must satisfy all of the following inclusion criteria before being allowed to participate 
in the study: 
1. Signed and dated informed consent. 
2. Male or female between 18 and 70 years of age, inclusive. 
3. Diagnosed with current PTSD as defined by the CAPS-5 for DSM-5. 
4. Currently not using any psychiatric medications, except for: 
• No more than one selective serotonin reuptake inhibitor (SSRI) (fluvoxamine is 
excluded) or serotonin noradrenaline reuptake inhibitor (SNRI) within the licensed 
prescribing dose range.  Subjects must have been on a stable dose for at least 3 
months prior and through Screening, with the intent to remain on the same dose 
through to week 15.  
• As needed (PRN) use of benzodiazepines (BZD) at a frequency not exceeding 2 
days per week in the 3 months prior to Screening. The total dose must not exceed 
30 mg/day in diazepam equivalents  
5. Subjects not currently receiving psychotherapy except long term supportive 
counseling or subjects that have received intensive regular psychotherapy for a 
minimum of three months prior to Screening. 
6. Females of childbearing potential must have a negative serum pregnancy test at 
Screening and a negative urine test at Day 1. Females not of childbearing potential 
must be postmenopausal (defined as cessation of regular menstrual periods for at least 
12 months prior to Screening and confirmed by follicle-stimulating hormone [FSH] 
levels in menopausal range at Screening). Sterilized male patients must be at least 1 
year post-vasectomy to be considered of non-child bearing potential. Acceptable 
forms of sterilization include bilateral tubal ligation, bilateral oophorectomy, and 
hysterectomy for women or vasectomy for men. 
Females and males of childbearing potential must agree to use two effective methods 
of contraception (double barrier contraception or hormonal contraceptive along with a 
barrier contraceptive) during the study and for 16 weeks following last study 
treatment.  Contraception that is deemed acceptable in this study includes the 
following:  
• Condoms  
• Hormonal (includes oral, injected, intrauterine, transdermal, or implanted).  
Females must be using hormonal contraceptives for at least 3 months prior to 
randomization and not change the contraceptive during the trial. 
Rhythm methods will not be considered as an effective method of birth control, 
however, abstinence may be allowed based on the opinion of the Investigator.  
Requirement for contraception can be waived in certain circumstances (i.e. same sex 
relationships) if approved by the Sponsor. 
Males must agree to not donate sperm for at least 16 weeks following last study 
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7. In the opinion of the Investigator the participant has a high probability for adherence 
with and completion of the study, and willing and able to withdraw and refrain from 
specific therapies. 
8. Fluent in English and able to understand and comply with written and verbal protocol-
related requirements. 
3.3.2 
Exclusion Criteria 
If any of the following exclusion criteria apply, the subject will not be allowed to participate 
in the study: 
1. Current and ongoing exposure to the trauma that caused the PTSD. 
2. 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. 
3. The use of psychiatric medications within 2 weeks of Screening except for SSRIs, 
SNRIs or limited PRN BZD use as per inclusion criterion 4. Restricted Psychiatric 
medications include (but are not limited to) antidepressants not allowed by inclusion 
criterion 4, antianxiety drugs (except limited BZD use per inclusion criterion 4), mood 
stabilizers, stimulants, antipsychotics, hypnotics and acetylcholinesterase inhibitors. 
4. History of significant traumatic brain injury. 
5. Depression as measured by Montgomery-Äsberg depression scale (MADRS) rating 
> 23. 
6. Bipolar and psychotic disorders as identified at Screening using the MINI 
International Neuropsychiatry Interview (V7.0) (M.I.N.I). 
7. A score > 7 on the McLean Screening Instrument for Borderline Personality Disorder 
(MSI-BPD) at Screening. 
8. History of seizure disorders, uncontrolled sleep apnoea or severe neurologic disease 
9. Increased risk of suicide, defined as: 
• Any previous suicide attempt disclosed by the participant at Screening 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 year, as captured at Screening using the C-SSRS. 
• A score > 4 on item 10 of the MADRS at Screening. 
10. The use of cytochrome P450 3A4 inducers within 30 days of Screening. 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, grapefruit or 
grapefruit-containing products. 
11. The use of alprazolam or flunitrazepam within 3 months of Screening. 
12. 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 (glomerular filtration 
rate (GFR) <50 mL/min). 


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13. Liver disease or liver injury as indicated by abnormal liver function tests (LFTs), 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase (ALP), or serum bilirubin (>2x upper limit of normal [ULN]) or history 
of hepatic cirrhosis. 
14. Any clinically significant abnormalities in laboratory test results at Screening 
(biochemistry, hematology or urinalysis) as assessed by an Investigator. 
15. Fridericia-corrected QT interval (QTcF) >460 msec for males and QTcF >480 msec 
for females as measure by ECG at Screening. 
16. Any clinically significant ECG abnormality as determined by the Investigator at 
Screening. 
17. A family history of congenital long QT syndrome, Brugada syndrome or unexplained 
sudden cardiac death.  
18. Positive result for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C (HCV) at Screening. 
19. Any moderate to severe substance use disorder (any type) in the 12 months prior to 
Screening as identified by the DSM-5 using the M.I.N.I (V7.0). 
20. Participation in an investigational study within 30 days of Screening. 
21. Current Australian serving Defense personnel or any member of the US military 
currently serving on active duty. 
22. Participants involved with ongoing insurance or workplace claims that in the opinion 
of the Investigator are likely to have an impact on the mental health, presentation or 
capacity of the patient to engage in the study. 
23. Females who are pregnant, nursing, or intend to become pregnant during the study or 
within 16 weeks of last dose of Investigational Product, or any males who plan to 
father/conceive a child within 16 weeks of last dose of Investigational Product. 
24. Blood or plasma donation or significant blood loss within 60 days of Day 1. 
25. Known to have poor peripheral venous access. 
26. Subjects 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 subject at risk or any other reason, the 
investigator deems applicable. 
27. History of allergies, allergic reactions or hypersensitivity to BNC210 or excipients. 
28. BP systolic >160 mmHg or diastolic >90 mmHg.  Allow two repeat measures at the 
discretion of the Investigator. 
 
 


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4 TREATMENTS 
 
 
 
  
4.2 
Identity of Investigational Product 
BNC210 will be supplied in an amber single-use bottle as an 8 mL suspension in a vehicle.  
Placebo will be supplied in an amber single-use bottle as an 8 mL suspension of a suspension 
agent and yellow coloring agent in the same vehicle.  These treatments will be very similar in 
appearance. 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.3 
Methods of Assigning Subjects to Treatment 
The IP in this study will only be administered to subjects included in the study following the 
procedures set out in the protocol.  Treatment will be randomly assigned using an IWRS. 
 
 
 patients will be randomly 
assigned to the four treatment groups in a 1:1:1:1 ratio until the close of randomization.  
4.4 
Selection of Dose in the Study 
The doses selected span the effective plasma exposure levels in the Phase II GAD patient 
study where significant results were obtained with single doses of 300 mg and 2000 mg 
BNC210. 
 
 
 
 
 


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4.5 
Selection and Timing of Dose for Each Subject 
Subjects will take 150 mg or 300 mg or 600 mg BNC210 or placebo bid, with food, as oral 
suspensions from single-use bottles for 12 weeks. Doses should be administered 
approximately 12 hours apart (+2 hours), with breakfast, and with an evening meal. Subjects 
must document all missed and partially administered doses in their Dosing Diary.  
4.6 
Dose Interruptions and Reductions 
Dose interruptions will be allowed following AEs. 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 treatment. Dose reductions will not be allowed. 
4.7 
Blinding 
This study will be double-blind with the subject, Investigator, and rater being unaware of the 
treatment the subjects will receive. 
4.8 
Emergency Unblinding of Study Subjects 
The Investigator should contact the Medical Monitor to discuss the need to break the blind. In 
the event that an emergency unblinding is required and the Medical Monitor is unavailable, 
the Investigator will be able to unblind via the Interactive Web Response System (IWRS). 
Refer to the IWRS User Guide for further instructions. The Sponsor and Medical Monitor 
must be notified within 24 hours of any emergency unblinding. Blinding codes should only be 
broken in emergency situations for reasons of subject safety and when knowledge of the 
treatment assignment will impact the clinical management of the subject. Every reasonable 
attempt should be made to complete the Early Termination Visit prior to unblinding, as 
knowledge of the treatment arm could influence subject assessment. In all cases, the reasons 
and rationale for unblinding will be documented in writing and maintained in the study file. 
4.9 
Supply, Packaging and Labeling of the Investigational Product 
The IPs will be packaged in treatment kits according to Good Manufacturing Practice (GMP) 
and all local regulations. They will be labeled in accordance with Australian and USA 
requirements. Treatment kits will be supplied to each study site with an acknowledgement of 
receipt form. The manufacturer will provide a certificate of analysis and a batch release 
certificate for IPs used in the study. 
The Investigator, or Designee, will only dispense treatment kits to subjects enrolled in this 
study. Kits will be allocated using the IWRS. All dispensing episodes, including the kit and 
batch number, will be captured in IWRS. Each subject will maintain a Dosing Diary where 
the time and date of each dose is recorded. These diaries will be returned at each visit after 
Baseline and a new diary issued. The data will then be captured in the eCRF. 
 
 
 
 
  
 
 


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4.10 Storage of the Investigational Product 
Prior to dispensing, all IP must be stored in a secure and locked storage area with limited 
access, under monitored, temperature controlled conditions. The Pharmacist or Designee will 
be responsible for the correct storage and handling of the IP, the details of which are provided 
in the BNC210.007 Pharmacy Manual. Deviations from the storage requirements, including 
corrective action, must be documented.   
Once the subjects have received their treatment kits, the clinical site will instruct them on the 
correct storage requirements. 
4.11 Accountability, Reconciliation and Return of the Investigational Product 
The Investigator must maintain complete and current IWRS dispensing and inventory 
records.  The Investigator is accountable for all IP supplied by the Sponsor. The IWRS logs 
must be printed at the conclusion of the study and will contain the following information: 
• Date of receipt. 
• Number of kits received. 
• Batch number(s). 
• The identification of the subject to whom the kit was dispensed. 
• The date(s) and quantity of kits dispensed to the subject. 
• The cumulative total of kits at site. 
• Kits damaged, destroyed, or returned. 
Supplies will be shipped to the investigational site as needed. The Monitor will complete drug 
accountability during routine monitoring visits. 
At the completion or termination of the study, final drug accountability and reconciliation 
will be completed and any discrepancies must be investigated and their resolution 
documented.  All full, partially full, and empty bottles of IP must be returned to the 
Pharmacy, Manufacturer or Sponsor for destruction, and the appropriate form sent to the 
Sponsor. 
Please refer to the Pharmacy Manual for further details and the storage, handling, and 
dispensing of IP. 
4.12 Prior and Concomitant Therapy 
Use of any investigational drug 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 one month 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.   
Moderate – 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. 


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Subjects that are under consideration for the study and are being treated with a psychiatric 
medication that is not permitted under inclusion criterion 4, must have discontinued the 
medication for at least two weeks prior to Screening and be titrated off their treatment in 
accordance with current prescribing guidelines. The withdrawal of psychiatric medication is 
at the discretion of the subject in consultation with their primary physician and falls outside 
the scope of this study protocol. 
Concurrent use of no more than one SSRI (fluvoxamine is excluded) or SNRI within the 
licensed prescribing dose range, is permitted from Screening through Week 15.  Subjects 
must have been on a stable dose for at least 3 months prior and through Screening and no 
dose adjustments are allowed on study,  
The use of any other psychiatric medication is prohibited during all stages of the study. This 
includes, but is not limited to, antidepressants / anxiolytics not otherwise listed under 
inclusion criterion 4, mood stabilizers, stimulants, antipsychotics, hypnotics, and 
acetylcholinesterase inhibitors. 
Limited use of BZD is permitted on a PRN basis as rescue medication. The frequency of use 
must not exceed 2 times per week and the total dose in diazepam equivalents must not exceed 
30 mg/day.  
The use of antihistamines as a sleep medication is permitted. However, subjects must avoid 
the use of antihistamines for 12hrs prior to visits where cognitive function is assessed 
(Baseline, V3, and V7). 
Subjects must not have been treated with alprazolam or flunitrazepam for 3 months prior to 
Screening and the use of these medications in prohibited during the study. 
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.  The use of all concomitant medication 
(including non-prescription medications) must be recorded for each subject over the duration 
of the study. The indication for use, generic name of the drug, dosage, and date of 
administration will be recorded. 
Ongoing long-term supportive counseling or intensive regular psychotherapy is allowed only 
if the subject commenced therapy > 3 months prior to Screening and is willing to continue 
therapy at the same frequency through Week 15 or study withdrawal, whichever occurs last. 
If a medication or treatment is administered that is in breach of these restrictions, the 
Sponsor’s Medical Monitor must be promptly notified in order to assess the subject’s 
suitability for continued study participation. 
4.13 Treatment Compliance 
Treatment compliance will be assessed by the following procedures: 
• Blood sampling for the assessment of BNC210 concentrations at Screening and three 
times during treatment. 
• Doses administered based on the number of IP bottles returned used and unused. 
 
 


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4.14 Measures to Minimize Bias 
4.14.1 Randomization Procedures 
At Screening, subjects will be allocated a sequential five-digit study subject identification 
number (SSID), the first two numbers of which denote the study center. This is followed by 
the sequential three-digit subject number. As an example, the first subject screened at site 10 
will be allocated the SSID 10-001. Subjects will retain the same SSID for the duration of the 
study. An IWRS will allocate a randomization number at the baseline visit but the number 
will not be used for subject identification purposes. 
Data associated with subjects that fail screening will not be entered into the eCRF.  
 
 patients will be randomly 
assigned to the four treatment groups in a 1:1:1:1 ratio until the close of randomization.  
The IWRS vendor will be supplied with a validated randomization list by an Independent 
Statistician. 
4.14.2 Maintenance of Consistent Behaviors 
Over the course of the study, subjects will be counseled on the importance of maintaining 
consistent behaviors. This includes limiting any change to alcohol or tobacco use, dietary 
intake, and sleep patterns when compared to baseline. Subjects will also be encouraged to 
attend study visits at the same time of day to avoid possible diurnal variation in measurement 
responses.  
Cognitive function must be assessed at the same time during each visit (+ 1hr of baseline 
assessment start time). The use of rescue benzodiazepines, recreational drugs (e.g. cannabis, 
amphetamines), antihistamines, and excessive alcohol use within 12hrs prior to the 
assessment of cognitive function should also be avoided. Subjects who have used these 
medications / drugs within 12hrs should be invited to re-attend the following day where the 
visit can be completed. Should a subject refuse an invitation to re-attend, the Investigator 
should proceed with the assessment making a note within the CANTAB system indicating the 
results may be influenced by drug or medication use. 
 
 


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5 STUDY ASSESSMENTS AND PROCEDURES 
On days where study visits occur, subjects must take their scheduled morning dose of IP with 
food prior to attending clinic for the scheduled visit. Dispensing of IP should occur last, after 
all study tests and assessments have been completed. All visits should be scheduled to occur 
at approximately the same time of day. 
5.1 
Screening Evaluation 
The Screening evaluation will take place up to 21 days prior to randomization. Subjects will 
sign and date the informed consent form before any study-related procedures are completed. 
The following assessments will be performed during Screening: 
• Register subject via IWRS. 
• Medical and surgical history. 
• Prior and concomitant medications. 
• Record of nicotine use. 
• Full physical examination including height and weight. 
• HIV, HBsAg and HCV antibody testing. 
• Vital signs. 
• Triplicate 12-lead ECG. 
• Serum pregnancy test (if applicable). 
• Laboratory testing (hematology, clinical chemistry, C-reactive protein, urinalysis). 
• FSH testing for postmenopausal female subjects only. 
• Blood sample collection for BNC210 concentration. 
 
 
 
• Assessment of eligibility using the following instruments: 
• M.I.N.I. (V7.0). 
• ‘Standard’ Life Events Checklist for DSM-5 (LEC-5). 
• CAPS-5 (Past Month). 
• MSI-BPD. 
• C-SSRS. 
• MADRS. 
• Check inclusion and exclusion criteria. 
• A practice run on the CANTAB Cognitive Assessment occurring no later than 7 days 
prior to the Baseline visit. 
5.2 
Baseline Visit (Day 1 +2 days) 
Subjects must report to the clinic on Day 1 where the following assessments will be 
completed: 
• Vital signs. 
• Urine pregnancy test (if applicable). 
• Check eligibility. 


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• Baseline measures using the following instruments: 
• CAPS-5 (Past Week). 
• Assessment of Quality of Life (AQoL-8D). 
• C-SSRS (Since Last Visit). 
• MADRS. 
• Hamilton Anxiety Rating Scale (HAM-A). 
• CANTAB Cognitive Assessment. 
• Clinical Global Impression – Severity Scale (CGI-S). 
• Patient Global Impression – Severity Scale (PGI-S). 
• Standard PTSD checklist (PCL-5). 
• Sheehan Disability Scale (SDS). 
• Pittsburgh Sleep Quality Index (PSQI). 
• Record concomitant medication use. 
• Record of nicotine use. 
• Randomization in IWRS. 
• Dispensation of IP. 
• Dispensation of Dosing Diary. 
• Subjects will be provided with information on the storage and administration of the IP 
and instructed to administer their first dose in the evening with food. 
5.3 
Visit 1 (Week 1, Day 8 ±2 days)  
Subjects must report to the clinic at the start of Week 1 where the following assessments 
will be completed:  
• Vital signs. 
• Assessment of efficacy using the following instruments: 
• CAPS-5 (Past Week). 
• Clinical Global Impression –Improvement Scale (CGI-I). 
• CGI-S 
• Patient Global Impression – Improvement Scale (PGI-I). 
• PGI-S 
• PSQI 
• C-SSRS (Since Last Visit). 
• AE monitoring. 
• Record concomitant medication use. 
• Record of nicotine use.  
• Review of IP for compliance purposes. 
 
 


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5.4 
Visit 2 (Week 2, Day 15 ±2 days) 
Subjects must report to the clinic at the start of Week 2 where the following assessments 
will be completed: 
• Abbreviated physical examination.  
• Vital signs. 
• Triplicate 12-lead ECG. 
• Laboratory testing (hematology, clinical chemistry, urinalysis, C-reactive protein 
(CRP)). 
• Blood sample collection for BNC210 concentration. 
 
 
 
• Assessment of efficacy using the following instruments: 
• CGI-I/CGI-S. 
• PGI-I/PGI-S. 
• C-SSRS (Since Last Visit). 
• AE monitoring. 
• Record concomitant medication use. 
• Record of nicotine use. 
• Return and dispensation of IP. 
• Return and dispensation of Dosing Diary. 
5.5 
Visit 3 (Week 4, Day 29 ±2 days) 
Subjects must report to the clinic at the beginning of Week 4 where the following 
assessments will be completed: 
• Vital signs. 
• Assessment of efficacy using the following instruments: 
• CAPS-5 (Past Week). 
• MADRS. 
• HAM-A. 
• CANTAB Cognitive Assessment. 
• CGI-I/CGI-S. 
• PGI-I/PGI-S 
• AQoL-8D 
• PCL-5. 
• SDS. 
• PSQI. 
• C-SSRS (Since Last Visit). 
• AE monitoring. 
• Record concomitant medication use. 
• Record of nicotine use. 
• Return and dispensation of IP 
• Return and dispensation of Dosing Diary. 


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5.6 
Visit 4 (Week 6, Day 43 ±2 days) 
Subjects must report to the clinic at the beginning of Week 6 where the following 
assessments will be completed:  
• Abbreviated physical examination. 
• Vital signs. 
• Triplicate 12-lead ECG. 
• Laboratory testing (hematology, clinical chemistry, urinalysis, CRP). 
• Blood sample collection for BNC210 concentration. 
• Assessment of efficacy using the following instruments: 
• CGI-I/CGI-S. 
• PGI-I/PGI-S. 
• C-SSRS (Since Last Visit). 
• AE monitoring. 
• Record concomitant medication use. 
• Record of nicotine use. 
• Return and dispensation of IP. 
• Return and dispensation of Dosing Diary. 
5.7 
Visit 5 (Week 8, Day 57 ±2 days) 
Subjects must report to the clinic at the beginning of Week 8 where the following 
assessments will be completed: 
• Vital signs. 
• Assessment of efficacy using the following instruments: 
• CAPS-5 (Past Week). 
• MADRS. 
• HAM-A. 
• CGI-I/CGI-S. 
• PGI-I/PGI-S. 
• AQoL-8D. 
• PCL-5. 
• SDS. 
• PSQI. 
• C-SSRS (Since Last Visit). 
• AE monitoring. 
• Record concomitant medication use. 
• Record of nicotine use. 
• Return and dispensation of IP. 
• Return and dispensation of Dosing Diary. 
 
 


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5.8 
Visit 6 (Week 10, Day 71 ±2 days) 
Subjects must report to the clinic at the beginning of Week 10 where the following 
assessments will be completed: 
• Vital signs. 
• Assessment of efficacy using the following instruments: 
• CGI-I/CGI-S. 
• PGI-I/PGI-S. 
• C-SSRS (Since Last Visit). 
• AE monitoring. 
• Record concomitant medication use. 
• Record of nicotine use. 
• Return and dispensation of IP. 
• Return and dispensation of Dosing Diary. 
5.9 
Visit 7 (Week 12, Day 85 ±2 days / Early Termination) 
Subjects report to the clinic at the beginning of Week 12, or at Early Termination, where 
the following assessments will be completed: 
• Full physical examination. 
• Vital signs. 
• Triplicate 12-lead ECG. 
• Laboratory testing (hematology, clinical chemistry, urinalysis, CRP). 
• Urine pregnancy test (if applicable). 
• Blood sample collection for BNC210 concentration. 
 
 
 
• Assessment of efficacy using the following instruments: 
• CAPS-5 (Past Week). 
• MADRS. 
• HAM-A. 
• CANTAB Cognitive Assessment. 
• CGI-I/CGI-S. 
• PGI-I/PGI-S. 
• AQoL-8D. 
• PCL-5 
• SDS. 
• PSQI. 
• C-SSRS (Since Last Visit). 
• AE monitoring. 
• Record concomitant medication use. 
• Record of nicotine use. 
• Return of IP,
  


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• Return of Dosing Diary. 
5.10 Post-study (Week 15, Day 106 ± 5 days) 
Subjects must report to the clinic at the beginning of Week 15 where the following 
assessments will be completed: 
• Abbreviated physical examination. 
• Vital signs.  
• Assessment efficacy using the following instruments: 
• CAPS-5 (Past Week). 
• MADRS. 
• HAM-A. 
• CGI-I/CGI-S. 
• PGI/PGI-S. 
• AQoL-8D. 
• PSQI. 
• PCL-5 
• SDS. 
• PSQI. 
• C-SSRS (Since Last Visit). 
• AE monitoring. 
• Record of nicotine use. 
• 
Record concomitant medication use. 
5.11 Unscheduled Visits 
Subjects may attend an unscheduled visit at any time. All assessments completed during an 
unscheduled visit must be captured in the electronic case report form (eCRF). This 
includes the results of all pathology tests scheduled by the Investigator. 
Visits scheduled due to an increase in ALT or AST >3 x ULN (see Section 6) must be 
captured as an unscheduled visit.  
A visit with a Subject’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.  
5.12 Re-screening of Study Subjects. 
In the event that a subject fails a clinical laboratory or ECG screening assessment, that 
assessment can be repeated once only. The repeat assessment must be completed within 
the allowed screening period (21 days + 2 days of Baseline) for eligibility purposes. If the 
repeat assessment cannot be completed within the screening period, the subject must be re-
screened in entirety. Subjects who fail any other screening assessment must be screen-
failed.  Subjects can be re-screened once only. 
 
 


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6 WITHDRAWAL OF SUBJECTS OR TERMINATION OF THE 
STUDY 
Subjects should be encouraged to complete all study assessments. However, subjects may 
withdraw consent to participate in this study at any time and for any reason without penalty or 
loss of benefits to which they were otherwise entitled.  The Sponsor or the Investigator may 
withdraw subjects at any time for safety or administrative reasons.  If a subject is withdrawn 
from the study or treatment, the reason will be recorded on the eCRF and the Sponsor notified 
promptly. 
Subjects who are withdrawn from treatment early due to SAEs must be followed-up and 
provided appropriate medical care until their signs and symptoms have remitted or stabilized, 
until the subject is lost to follow-up, or until the post study visit, whichever comes last. 
Subjects who experience an SAE that is deemed to be related to the IP will have treatment 
withdrawn. 
A subject may be withdrawn from the study if any of the following occur during the study: 
1. Subject withdraws consent; 
2. AE makes the continuation of the subject impossible or inadvisable; 
3. Pregnancy; 
4. Subject is lost to follow-up; 
5. Subject discovered after enrollment not to have met the protocol inclusion criteria; 
6. Subject refuses to comply with required study procedures; 
7. Use of any restricted medication (including experimental) or therapy; 
8. The study Sponsor terminates the Investigator Site or the study. 
Subjects are to have treatment withdrawn by the Investigator for any of the following: 
• Any new suicidal behavior since Screening, as disclosed by the subject during 
administration of the C-SSRS. 
• Any suicidal ideation with intent (yes to item 4 and / or 5) since Screening, as 
disclosed by the subject during administration of the C-SSRS. 
• A score > 4 on item 10 of the MADRS. 
• Prolonged QTcF interval: Subjects with prolonged QTcF interval of ≥500 msec 
(confirmed after triplicate repeated measurement at least 2 minutes apart) should be 
discontinued from treatment either temporarily or permanently and monitored for 
safety by the Investigator. 
• Elevated serum transaminases (LFT abnormalities) confirmed to be: 
o ALT or AST >5 x ULN; 
o ALT or AST >3 x ULN for more than 2 weeks; 
o ALT or AST >3 x ULN and total bilirubin >2 x ULN (Hy’s Law); or 
o ALT or AST >3 x ULN with the appearance of worsening of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia. 
Should a subject experience an elevation of ALT or AST >3 x ULN, the subject should return 
to the clinic for repeat LFT testing every 3 to 5 days while on study drug until the ALT or 
AST returns to baseline, becomes stable, or reaches any of the stopping rules for LFT 
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All subjects that have treatment withdrawn prior to Visit 7 (week 12) for any reason should 
return to the study site within 10 calendar days of last dose and an Early Termination (ET) 
Visit completed. Should treatment be withdrawn during a visit, that visit becomes the ET 
Visit. After withdrawal from treatment, subjects will be asked to return to the study site at the 
regular protocol-defined visit schedule (calculated from Day 1) where only the following 
assessments will be completed as per the regular schedule of assessments: 
• 
CAPS-5. 
• HAM-A. 
• 
MADRS. 
• PCL-5. 
• 
CANTAB Cognitive Assessment. 
• SDS. 
• AQoL-8D. 
• PSQI. 
• CGI-I/CGI-S. 
• C-SSRS 
• PGI-I/PGI-S. 
• AE recording. 
• Record concomitant medication use. 
• Record of nicotine use. 
The measurement of vital signs, the collection of pathology samples (including the BNC210 
compliance, 
 samples), and the completion of ECGs during 
visits that occur after the treatment withdrawal are not required unless clinically indicated. 
The timing of the post treatment withdrawal visits are calculated from Day 1 and should 
follow the study schedule of assessments through Visit 7 (week 12) as captured in Table 1. 
During this period, subjects must adhere to all concomitant medication and therapy 
restrictions as captured in protocol section 4.11. Those subjects unable to adhere to the 
medication and therapy restrictions post treatment withdrawal must be withdrawn from the 
study completely and attend an Early Termination Visit within 10 calendar days of their last 
dose.  No further study visits are required. Subjects are also free to withdraw from the study 
at any time and without prejudice to further care according to standard clinical practice. 
 
 


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7 EFFICACY VARIABLES 
7.1 
Definitions of Variables 
All the assessments/questionnaires below will be assessed at time-points as captured in the 
Schedule of Assessments (Table 1). 
7.1.1 
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 week. Information about the frequency and intensity of each item is 
combined into a severity rating, and the CAPS-5 total severity is calculated by adding the 
severity scores for the 20 PTSD symptoms in the DSM-5 (National Centre for PTSD). The 
severity of PTSD is rated from 0 (absent) to 4 (extreme/incapacitating).  
7.1.2 
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).  
7.1.3 Clinical Global Impression scales – Improvement and Severity (CGI-I/CGI-S) 
The CGI-S is a rating scale designed to assess the severity of the subject’s symptoms, and the 
CGI-I is designed to assess the change in the subject’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 subjects). The changes in the subject’s condition are rated on the CGI-I from 1 (very 
much improved) to 7 (very much worse). 
7.1.4 
Patient Global Impression Scales – Improvement and Severity (PGI-I/PGI-S) 
The PGI-S is a self-rating scale designed to assess the severity of the subject’s symptoms, and 
the PGI-I is designed to assess the change in the subject’s condition since the initial 
assessment. Severity is rated on the CGI-S from 1 (normal) to 4 (severe). The changes in the 
subject’s condition are rated on the CGI-I from 1 (very much better) to 7 (very much worse). 
7.1.5 
Assessment of Quality of Life (AQoL-8D) 
The AQoL-8D is a 35 question self-rating scale designed to assess a subject’s quality of life 
on the following eight dimensions; Independent Living, Happiness, Mental Health, Coping, 
Relationships, Self-Worth, Pain and the Senses. The scale takes approximately 5 minutes to 
complete.  
7.1.6 
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). It takes approximately 15-20 minutes to 
complete and each parameter is rated on a scale of 0 (not present) to 4 (very severe). 
 


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7.1.7 
Montgomery-Asberg 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). 
7.1.8 
CANTAB Cognitive Assessment 
The CANTAB cognitive assessment is a battery of tests designed to detect both cognitive 
impairment and enhancement. The battery will measure cognitive function through assessing 
sustained attention, episodic memory, working memory and executive function. All tests will 
be completed electronically using iPads. The test battery will take approximately 20-25 
minutes to complete. The CANTAB cognitive assessment must be completed at the same 
time during each visit (+ 1hr of baseline assessment start time). 
 
A Paired Associates Learning (PAL) task will be used to assess episodic memory. During the 
test, boxes are displayed on the screen and open in turn to reveal a number of patterns. 
Participants are instructed to try to remember the location in which each pattern was shown. 
After all the boxes have been opened, each pattern is then shown in the center of the screen in 
a randomized order, and the participant touches the box in which the pattern was located. If 
an error is made, all the patterns are re-presented to remind the participant of their locations. 
As the test progresses so the stages become more difficult as the number of patterns to be 
remembered increases, up to a maximum of 8 patterns. For participants who fail to complete 
all levels, an adjusted total is calculated that allows for errors predicted in the stages that were 
not attempted. The key outcome measures for this task are total errors and first trial memory 
score. 
 
A Spatial Working Memory (SWM) task will be used to assess the ability of the subject to 
retain spatial information and manipulate it in working memory. It is a self-ordered task that 
also gives a measure of strategy. A number of colored boxes are presented on the screen, and 
the computer hides a token in these boxes one at a time. The participant is instructed to touch 
the boxes in turn to search for the token that has been hidden. When a token is found it should 
be placed in a home area on the right side of the screen. The participant then searches for 
more tokens until the same number of tokens as the number of colored boxes has been found. 
The key task instruction is that the computer will never hide a token in the same colored box 
twice in the same problem. As the test progresses, so it becomes more difficult. The key 
outcome measures for this task are between errors and strategy. 
 
A Rapid Visual Information Processing (RVP) task will be used to assess sustained attention, 
outputting measures of response accuracy, target sensitivity and reaction times. For the RVP 
task, single digits appear in a pseudo-random order at a rate of 100 digits per minute in box in 
the center of the screen. Subjects must detect a series of 3-digit target sequences (e.g. 3-5-7; 
2-4-6; 4-6-8) and respond by touching the button at the bottom of the screen when they see 
the final number of the sequence. Nine target sequences appear every minute. Key outcome 
measures include target sensitivity and reaction times. 
 


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Factors that could influence the cognitive function assessments must be captured within the 
CANTAB system. This includes, but is not limited to, drug and medication use within 12hrs 
of assessment, lack of sleep, and failure to understand the test requirements. Please refer to 
the CANTAB User Manual for details on how to capture this information. 
7.1.9 
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.  
7.1.10 Pittsburgh Sleep Quality Index (PSQI) 
The PSQI is a questionnaire consisting of 19 questions designed to assess the following 
7 components of sleep quality: subjective sleep quality, sleep latency (i.e., how long it takes 
to fall asleep), sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping 
medication, and daytime dysfunction over the previous month. Each question is weighted on 
a scale from 0 to 3 and a global score is obtained, with lower scores correlating with better 
sleep quality.  
 
 


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8 COMPLIANCE, 
 
 
8.1 
Blood Sampling for Plasma BNC210 Concentrations 
Blood samples for the assessment of plasma BNC210 concentrations will be collected at 
Screening, Visit 2, Visit 4 and Visit 7/ET (Table 1). Samples will be collected to assess a 
subject’s treatment compliance. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9 SAFETY VARIABLES 
9.1 
Safety Endpoint(s) 
Safety will be assessed during the study through physical examination, urinalysis, vital signs, 
ECG, laboratory tests, C-SSRS and continuous AE reporting, as outlined in the Schedules of 
Assessment (Table 1). 
9.2 
Physical Examination 
A complete physical examination will be performed at Screening, Visit 7 (Week 12), and 
Early Termination. A complete physical examination will include assessments of 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. 
An abbreviated physical examination will be performed at Visit 2 (Week 2), Visit 4 (Week 6), 
and Post Study (Week 15). An abbreviated physical examination will include assessments of 
eyes, 
ears, 
nose, 
throat, 
cardiovascular 
system, 
respiratory 
system, 
and 
abdomen/gastrointestinal system. Other body systems may also be examined as required. 
Clinically significant changes from first dose of Investigational Product will be recorded as 
AEs. 
Height and weight will be recorded in centimeters (cm) and kilograms (kg), respectively and 
only at Screening. Weight is measured with subjects wearing light clothing without shoes. 
9.3 
Vital signs 
Vital signs will be measured at every visit from Screening to Week 15 (Post Study Visit). 
Vital signs include systolic and diastolic blood pressure, pulse rate, respiration rate and body 
temperature.  Blood pressure and heart rate will be measured in a sitting position after resting 
for 5 minutes.  Systolic blood pressure (SBP) and diastolic blood pressure (DBP) should be 
measured in millimeters of mercury (mmHg), heart rate in beats per minute, respiration rate 
in breaths per minute and temperature (oral) in degrees Celsius (°C). 
9.4 
12-lead ECGs 
ECGs will be taken at time-points as indicated in the Schedule of Assessments (Screening, 
Visit 2, Visit 4, Visit 7 / ET). 
ECG recordings will be taken in triplicate, with at least a 2-minute break between each test.  
The QTcF value will be calculated as the mean of the 3 ECG readings. One repeat is allowed 
for screening purposes if abnormal findings are observed. The repeat must also be completed 
in triplicate. 
The subject 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 subject, where possible.  ECGs will be read by the Investigator or designated 
physician at the unit.  Machine-read automated ECG intervals (PR, QRS, QT and HR), and 
calculated RR intervals will be captured in the eCRF and any other abnormalities noted.  
QTcF values will be derived from the data available and the average QTcF will be used when 
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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 subject's clinical file as 
part of the permanent record.  The ECG intervals and interpretation will be recorded on the 
appropriate eCRF form. 
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. 
9.5 
Clinical Laboratory Tests 
Blood samples for laboratory assessments will be taken at Screening, Visit 2, Visit 4, Visit 7 / 
ET. 
Laboratory data obtained at Screening will be used as baseline in the safety analyses.  Safety 
Laboratory Data include: 
• Complete blood count (CBC):  hemoglobin, hematocrit, red blood cell (RBC) count, 
MCV, white blood cell (WBC) with differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils), and platelet count.  
• Chemistry panel: Albumin, ALP, ALT (SGPT), aspartate aminotransferase (AST, 
SGOT), gamma glutamyltransferase (GGT) bicarbonate, total and direct bilirubin, 
BUN or plasma urea, corrected calcium, chloride, sodium, creatinine, eGFR 
(Cockcroft Gault), glucose, potassium, uric acid and total protein. 
• CRP. 
• FSH on postmenopausal females. 
• Urinalysis: specific gravity, pH, protein, glucose, ketones, bilirubin, blood, nitrite, and 
leukocyte esterase. 
o Specimens with abnormal Protein, WBC or RBC will be submitted for 
microscopy testing and reporting on WBCs, RBCs, epithelial cells, casts, 
crystals, yeast, and bacteria.  Specimens with elevated WBC may be submitted 
for microbiological testing for infection. 
Screening blood tests include: 
Serology: hepatitis (HepB surface antigen, anti-HCV), HIV.  
Pregnancy Tests 
A serum pregnancy test will be performed on all females of childbearing potential at 
Screening and a urine pregnancy test on Day 1 before randomization and at Visit 7 / ET. 
 
 
 
 
 
 
 
 
 


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9.6 
Columbia Suicide Severity Rating Scale (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. 
9.7 
Adverse Events (AEs) 
The Principal Investigator and clinical facility staff are responsible for detection, recording, 
and reporting of events that meet the criteria and definition of various AEs as listed below. 
AEs will be recorded from first administration of IP through Week 15 (Post Study Visit). The 
Principal Investigator and clinical facility staff are responsible for detection, recording and 
reporting of pregnancy and appropriate follow up. 
9.7.1 
Definitions 
An AE is any untoward medical occurrence in a patient or clinical investigational subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not related to the medicinal product. 
AEs will not include: 
• A medical or surgical procedure such as surgery, endoscopy, tooth extraction, or 
transfusion (although the condition that leads to the procedure may be an AE).  
• A pre-existing disease or condition present at the start of the study that does not 
worsen during the study  
• Any situation where an untoward medical occurrence has not occurred (for example, 
hospitalizations for cosmetic elective surgery or social admissions)  
• An overdose of either the IP or a concurrent medication without any resulting signs or 
symptoms. 
9.7.2 
Grading of Adverse Events 
The maximum intensity of an AE during a day should be graded according to the definitions 
below and recorded as indicated in the eCRF.  If the intensity of an AE changes over a 
number of days, then separate entries should be made with distinct onset dates. 
The severity of each AE will be categorized using the following criteria: 
• Grade 1 (Mild):  usually transient; requires no special treatment and does not interfere 
with the subject’s daily activities.  No limitation in daily activity. 
• Grade 2 (Moderate):  produces a low level of inconvenience to the subject and may 
interfere with daily activities.  These events are usually ameliorated by simple 
therapeutic measures.  Some limitation in daily activity. 


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• Grade 3 (Severe):  interrupts daily activity and requires systemic drug therapy or other 
medical treatment.  Unable to perform daily activity. 
An AE that is assessed as severe should not be confused with a SAE. Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An AE is defined as ‘serious’ when it meets one of the pre-defined serious outcomes as 
described in Section 9.8. 
9.7.3 
Causal Relationship to Investigational Product  
The relationship of an AE to the IP is a clinical decision by the Investigator based on all 
available information at the time of reporting. The causal relationship must be graded as 
follows: 
• Not related: a reaction for which sufficient information exists to indicate that the 
etiology is unrelated to the study drug; the subject did not receive the study 
medication or the temporal sequence of the AE onset relative to administration of the 
study medication is not reasonable or the event is clearly related to other factors such 
as the ’s clinical state, therapeutic intervention or concomitant therapy. 
• Possible: a clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug but which could also be explained by 
concurrent disease or other drugs or chemicals, information on drug withdrawals may 
be lacking or unclear. 
• Probable: a clinical event including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to concurrent 
disease or other drugs or chemicals and which follows a clinically reasonable response 
on withdrawal (de-challenge): re-challenge information is not required to fulfill this 
definition. 
• Definite: a reaction that follows a reasonable temporal sequence from administration 
of the drug or in which the drug level has been established in body fluids or tissues, 
that follows a known or expected response pattern to the suspected drug, and that is 
confirmed by improvement on stopping or reducing the dosage of the drug, and 
reappearance of the reaction on repeated exposure (re-challenge). 
9.7.4 
Documentation of Adverse Events by the Investigator 
When an AE occurs, it is the responsibility of the Principal Investigator to review all 
documentation (e.g. progress notes, laboratory, and diagnostics reports) relative to the event. 
The Principal Investigator will then record the AE on the AE eCRF. Additional reporting 
requirements for an AE meeting serious criteria are discussed in Section 9.8 below. The 
Principal Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In all cases, when available, the diagnosis 
should be reported as the event and not the individual signs/symptoms.  
9.7.5 
Laboratory Test and other Test Abnormalities as Adverse Events 
Abnormal assessments (e.g., ECGs and vital signs) that are judged by the Principal 
Investigator as clinically significant or if the abnormal assessment results in clinical sequelae 
will be recorded as AEs.  
 


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Laboratory abnormalities will be reported by the Investigator as AEs if the abnormality is 
considered clinically significant or if the abnormality results in clinical sequelae.  
Clinically significant abnormal laboratory findings or other abnormal assessments that are 
detected during the study or are present at baseline and significantly worsen following the 
first administration of IP will be reported as AEs.  
The Principal Investigator and Co-Investigators will exercise their medical and scientific 
judgment in deciding whether an abnormal laboratory finding or other abnormal assessment 
is clinically significant. 
9.8 
Serious Adverse Events (SAE) 
An SAE is any AE that: 
• Results in death, or 
• Is life-threatening, or 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event/reaction in which 
the subject was at immediate risk of death at the time of the event/reaction; it does not refer to 
an event/reaction, which hypothetically might have caused death, if it were more severe.  
Any planned procedures that require admission to hospital for compliance with this protocol 
as well as any planned elective procedures are not considered SAEs (unless the underlying 
condition has worsened or the procedure results in a worsening of the subject’s condition).  In 
addition pregnancy that occurs during the course of the study or absence of a treatment effect 
will also not be considered to be an SAE. 
9.8.1 
Reporting for Serious Adverse Events (24 Hours) 
SAEs must be followed until their signs and symptoms have remitted or stabilized, until the 
subject is lost to follow-up, or until Week 15 (Post Study Visit), whichever comes last. 
Investigators are not obligated to actively seek SAEs after Week 15 (Post Study Visit). 
However, if an Investigator learns of any SAEs that occur after study participation for a 
subject has concluded and the event is deemed relevant to the use of study drug, it should be 
promptly reported. 
AEs meeting serious criteria MUST be reported promptly to the designated Clinical Research 
Organization (CRO) Safety Desk within 24 hours, and to the HREC/IRB in accordance with 
their safety reporting policy. The SAE report form will always be completed as thoroughly as 
possible with all available details of the event and signed by the Principal Investigator (or 
Designee). If the Principal Investigator does not have all information regarding an SAE, 
he/she will not wait to receive additional information before reporting the event. The SAE 
report form will be updated when additional information is received. 


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The Principal Investigator will always provide an assessment of causality at the time of the 
initial report as described in Section 9.7.3.  
Facsimile or email transmission of the SAE report form is the preferred methods to transmit 
this information to the designated CRO Safety Desk. In rare circumstances notification by 
telephone is acceptable, with a copy of the SAE report form sent by overnight mail.  
Initial notification via the telephone does not replace the need for the Principal Investigator to 
complete and sign the SAE report form within the outlined time frames. The Sponsor will 
provide a list of project contacts for SAE receipt, fax numbers, telephone numbers, and 
mailing addresses 
The Principal Investigator, or responsible person according to local requirements, will comply 
with the applicable local regulatory requirements related to the reporting of SAEs to 
regulatory authorities and the HREC/IRB. 
9.9 
Safety Review Committee 
An independent Safety Review Committee will be established to monitor subject safety 
throughout the study. The meetings will occur approximately every 6 months and will review 
all safety data including vitals signs, ECG, pathology results, physical examinations, C-
SSRS and continuous AE reporting. 
 
 


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10 DATA MANAGEMENT AND STATISTICS 
10.1 Data Collection 
Designated investigator staff must enter all information required by the Protocol into the 
eCRF. Monitors will review the eCRFs for completeness and accuracy and instruct site 
personnel to make any required corrections or additions.  All data will be collected in an 
eCRF with controlled access and audit trail. 
10.2 Data Management and Quality Control 
eCRF data will be validated by a series of programmed checks and listing reviews as defined 
in the Data Validation Plan and in accordance with the Data Management group’s own 
internal standard operating systems (SOPs) that have been reviewed and approved by the 
study Sponsor. Queries will be either automatically generated or manually added to the eCRF 
for resolution by the site. Responses to queries will be entered directly into the eCRF by site 
staff. Quality control audits of all key safety and efficacy data in the database are made prior 
to locking the database.  
Concomitant medications entered into the database will be coded using the World Health 
Organization Drug Dictionary (WHODRUG) terminology. 
Medical history/current medical conditions and AEs will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology. 
The eCRFs will be reviewed and approved by the study Sponsor. The eCRFs and associated 
programmed validation checks and listings will undergo User Acceptance Testing prior to 
being released for use in the study. All access to the eCRF is controlled by user permissions 
and reviewed via audit trail. 
Data Retention procedures will be conducted in accordance with the Data Management 
group’s own internal SOPs that have been reviewed and approved by the study Sponsor. All 
eCRF and biometrics study related data to be archived will be maintained in the Biometrics 
Trial Master File. 
Data will be retained in the electronic Biometrics Trial Master file for a period of 15 years 
after release of any related batch of finished product in accordance with the Data 
Management group’s own internal SOPs. Bionomics Ltd, the study Sponsor will retain 
CDISC files and in addition the following documents will be provided by the Data 
Management group for inclusion in the Trial Master File, and other documents would most 
likely be provided from other sources: 
• Blank copy of approved eCRF (including AE forms) 
• Training records – eCRF system 
• Relevant correspondence 
• pdf of completed CRFs (including audit trail, discrepancies and AEs) 
10.3 Statistical Considerations 
The Biostatistical Department of 
  will be responsible for the 
analysis of demographic, safety, efficacy and compliance data. 
 
 using SAS® software version 9.3 (or higher) (SAS Institute Inc., 


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Cary, NC, USA).  A detailed statistical analysis plan (SAP) will be compiled before data base 
lock describing the methods used for the statistical analyses. 
10.4 Sample Size 
Sample size estimation is based on the following: 
 
 
 
 
 
 
 
 
 
  
 
 
.  With the 
level of significance set to 0.05 and a 2-sided test, a sample size of 36 subjects per arm is 
required to achieve a power of 80%.  For PTSD patients a relatively high withdrawal rate is 
anticipated, therefore the sample size was increased by 33% to 48 per arm (=1.33x36) 
(Hoskins et al. 2015, Marshall et al. 2001; Marshall et al. 2007; Tucker et al. 2001). Because 
this is a Phase II study the level of significance will be 0.05 with no adjustment for multiple 
comparisons. 
10.4.1 Review of Sample Size calculation 
 
 
 
 
 
 
 
 
10.5 Statistical Methods 
Descriptive statistics will be supplied according to the nature of the criteria where 
Quantitative variables will be presented as follows: sample size, arithmetic mean, SD, 
median, minimum and maximum.  Qualitative variables will be presented as follows: sample 
size, frequencies and percentages per category 
10.6 Analysis Populations and/or Subsets 
The Intent-to-treat (ITT) population will comprise all randomised subjects; analysed as per 
randomised treatment.  The Modified ITT (mITT) population will be those subjects from the 
ITT population who received at least one dose of study medication.  The mITT population 
will be used for all efficacy analyses, tabulations, and listings. 


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The safety population will comprise all randomised subjects who receive at least one dose of 
study medication and will be analyzed as per treatment received.  The safety population will 
be used for all safety analyses and listings.  
The analysis sets will be validated during a blind review meeting. 
10.6.1 Description of the Populations 
A summary table with the description of the number of subjects in each analysis set, the 
number of subjects who completed the study, and the number of subjects who discontinued 
classified by reason of withdrawal, will be prepared.  Corresponding individual listings will 
be prepared. 
Listings with end of study status and visit dates will also be prepared. 
10.7 Demographics and Baseline Characteristics 
The following analysis will be performed on the Randomized (mITT) set. 
The subject’s demographic characteristics and baseline characteristics (including the 
applicable questionnaires) will be summarized by treatment and overall. Details of drug 
dosing will be listed by subject. 
10.8 Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or 
noncompliance with, the approved protocol procedures or requirements. Deviations may 
result from the action or inaction of the subject, Investigator, or site staff. All deviations will 
be tracked and should be reported to IRBs in accordance with their reporting policy. 
Examples of deviations include, but are not limited to:  
• Failure to adhere to study exclusion and inclusion criteria.  
• Failure to comply with dispensing or dosing requirements.  
• Use of medications, herbal remedies, supplements, or therapies that are specifically 
prohibited in the protocol.  
• Missed or out-of-window visits.  
• Drug dosing not administered within the time frame specified in the protocol  
• Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, medical history, etc. – either tests not done, incorrect tests done, or not 
done within the time frame specified in the protocol.  
• Procedural deviations such as incorrect storage of study drug, failure to update the 
PICF when new risks become known, failure to obtain HREC/IRB approvals for the 
protocol and PICF revisions.  
10.9 Efficacy Analysis 
10.9.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is CAPS-5 total symptom severity score at Week 12 and will 
be analyzed with a MMRM with sequential Multiple Imputation (MI) used to estimate the 


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missing observations. The repeated measurements will range from Baseline to Week 12 for 
the primary endpoint.  
The primary efficacy model will include the CAPS-5 total symptom severity scores from 
Baseline to Week 12 as the dependent variable, the Baseline CAPS-5 value as a Baseline 
covariate, Week, and treatment group as factors, and treatment group by Week as an 
interaction term. Additional covariates in the model will include gender, age, country 
(Australia/USA), nicotine use at Baseline (Current/Former/Never), and concomitant 
antidepressant use at Baseline (Yes/No).  
Further details of the MMRM and MI for missing values will be included in the SAP prior to 
database lock and subsequent unblinding. 
Each dose group will be compared to placebo. Because this is a Phase II study, the level of 
significance will be 0.05 with no adjustment for multiple comparisons. Additional sensitivity 
analyses will include: 
• MMRM with the ‘as observed’ (i.e. no imputation for missing values) dataset. 
• MMRM with the last observation carried forward (LOCF) dataset. 
• MMRM with the baseline observation carried forward (BOCF) dataset. 
10.9.2 Secondary Efficacy Endpoints 
The effect of each dose of BNC210 on Investigator-rated and self-reported PTSD symptom 
severity, depression, anxiety, cognitive function, global function, quality of life, social 
functioning, and sleep quality after 12 weeks of treatment, will be compared to placebo using 
the following instruments: 
• Cluster score for CAPS-5 Criterion B: Intrusion. 
• Cluster score for CAPS-5 Criterion C: Avoidance. 
• Cluster score for CAPS-5 Criterion D: Negative Alterations in Cognition and Mood. 
• Cluster score for CAPS-5 Criterion E: Arousal and Reactivity. 
• PCL-5. 
• MADRS. 
• HAM-A. 
• CANTAB Cognitive Assessment  
• CGI-S/CGI-I. 
• PGI-S/PGI-I. 
• AQoL-8D. 
• Social functioning: SDS. 
• Sleep monitoring: PSQI. 
The CAPS-5 symptom cluster severity scores, PCL-5, MADRS HAM-A, CANTAB 
Cognitive Assessment, SDS and PSQI, will be analysed as continuous variables using 
MMRM (and MI) as described for the CAPS-5 total symptom severity score. The covariate 
will be the respective baseline continuous variable.  The MMRM analyses for the secondary 
efficacy variables will be repeated using the ‘as observed’ (i.e. no imputation) dataset. For all 
secondary efficacy variables the level of significance will be 0.05 with no adjustment for 
multiple comparisons.  
 


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For all variables the data will be graphed over time as adjusted means with 95% confidence 
intervals (CIs). As appropriate the means and 95% CI at Week 12 will be summarized as 
forest plots.  
The CGI-I/CGI-S & PGI-I /PGI-S will be reported as tables of frequencies and percentages.  
Treatment adherence will be summarized as frequencies and percentages. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
10.11 Compliance Analysis 
Plasma levels of BNC210 taken at Screening, Week 2, Week 6 and Week 12 will be used as a 
dichotomic compliance marker.  
 
 
 
 


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10.12 Safety Analysis 
10.12.1 Safety Analysis Criteria 
The safety criteria include the following: 
• AEs 
• Vital signs  
• Standard 12-lead ECG 
• Haematology, blood chemistry, urinalysis 
• Physical examination, weight. 
• C-SSRS 
10.12.2 Statistical Methodology 
Analysis of safety parameters will be performed on the Safety Population. 
10.12.3 Columbia Suicide Severity Rating Scale Safety Analysis 
The C-SSRS comprises several categorical questions, which are not summarized into a total 
score. The categorical responses will be summarized by tables of frequencies and percentages 
at Week 15, and over time.  
10.12.4 Adverse Event Analysis  
All AEs will be listed by and summarized by treatment group. 
AEs will be considered as treatment-emergent according to the rule set out in Section 9.7.1. 
Repetitions will only be counted once in summary tables. Repetitions are defined as follows: 
If a given subject presents several AEs with the same verbatim text during the treatment 
period, only one event is defined; the others are considered repetitions or recurring episodes. 
The start time of the event will be the start time of the first occurrence, the end time will be 
the end time of the last episode. The intensity will be the highest recorded intensity for all 
episodes. The causality will be the highest likelihood recorded for all episodes. 
AEs will be summarized by system organ class and preferred term in tables with: 
• The number of subjects with at least one AE and number of AEs for each treatment 
group and overall, 
• Analyses taking into account intensity and drug relationship to treatment could also be 
carried out. 
Other Safety parameters (vital sign measurements, ECG readings, physical examination, and 
laboratory tests) will also be described using descriptive statistics by treatment group when 
applicable, by visit otherwise.  
Description of potentially clinically significant values will be performed for vital signs, ECG 
parameters, blood chemistry and hematology parameters. All these parameters will be listed 
by subject and measurement time. The data outside of normal ranges will be flagged. 
 
 


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11 STUDY ADMINISTRATION 
11.1 Ethical Considerations 
11.1.1 Ethical Principles 
This study will be conducted in accordance with the ICH Guideline for Good Clinical 
Practice E6(R1) as adopted within Australia and the United States of America and all relevant 
statements, guidelines, regulations and legislation. The Protocol will be submitted for 
approval to the appropriate HREC/IRB and written approval obtained before subjects are 
enrolled. If approval is suspended or terminated by the HREC/IRB, the Principal Investigator 
will notify the Sponsor immediately.  
Bionomics Ltd and all clinical sites will abide by the agreed upon compensation guidelines 
within each country for injury resulting from participating in a company-sponsored study. A 
copy of these guidelines must be made available to all study subjects upon request. 
11.1.2 Informed Consent 
Informed consent will be obtained before the subject can participate in the study. The 
contents and process of obtaining informed consent will be in accordance with all applicable 
regulatory requirements. Study participation includes any and all screening procedures, as 
well as any washout of excluded medications. 
It is the responsibility of the Principal Investigator (or medically qualified designee) to obtain 
a written informed consent from each individual participating in this study after adequate 
explanation of the aims, methods, objectives, and potential hazards of the study. The Principal 
Investigator (or medically qualified designee) must also explain to the subjects that they are 
completely free to refuse to enter the study or to withdraw from it at any time.  
11.1.3 Human Research Ethics Committee / Institutional Review Board Approval 
Prior to initiation of the study, written HREC/IRB approval of the Protocol and Consent 
Forms, based on the principles of ICH GCP procedures, will be provided to Bionomics Ltd. 
Any written information and/or advertisements to be used for subject recruitment will be 
approved by the HREC/IRB prior to use. A list of the HREC/IRB voting members, their titles 
or occupations, and their institutional affiliations will be requested before study initiation. 
Protocol modifications that may impact subject safety or the validity of the study will also be 
approved by the HREC/IRB.  
11.2 Data Handling and Record Keeping 
11.2.1 Data Collection and Reporting 
The Investigator must maintain required documents for all study subjects.  Data for this study 
will be recorded in the subject’s source documents and on the eCRFs.  The source documents 
are to be separate and distinct from the CRFs, except for cases in which the Sponsor has 
predetermined that direct data entry into specified pages of the subject’s eCRF is appropriate. 
All data collected in the eCRFs should be recorded completely and promptly.  


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The Investigator or the appointed persons agree to complete the subject's eCRF forms after 
each study visit. Only the Investigator or the Investigator designee may enter and correct 
eCRF data.  
Prior to database lock and when authorized by Data Management, the Investigator must sign 
and date the eCRF in order to attest respectively to: 
• authenticity of the data collected in the eCRF, 
• coherence between the data in the eCRF and those in the source documents. 
At the end of the study, the Investigator will keep a .pdf copy of the correctly completed 
eCRFs for his/her own records. The Investigator will keep a log of study volunteers screened 
for study participation and as appropriate, will indicate the reason individual study volunteers 
did not enter the study. The Investigator must submit to the Sponsor or its representatives a 
completed eCRF for each subject who receives any IP. 
The Investigator must guarantee the safety of the study data in the medical files by 
implementing security measures to prevent unauthorized access to the data and to the 
computer system. 
11.2.2 Monitoring 
All aspects of the study will be monitored carefully by the Sponsor’s Designee with respect to 
current GCP and SOPs for compliance with applicable government regulations, the study 
protocol and Investigator’s obligations.  It is the responsibility of the Investigator to provide 
all study records, including eCRFs, source documents, among other records, for review and 
inspection by the Monitor. 
All CRFs will be 100% verified against corresponding source documentation for each subject.  
Monitors will periodically evaluate the progress of the study, including the verification of the 
accuracy and completeness of the eCRFs.  Prior to database lock, the completed eCRFs must 
be reviewed, signed and dated by a qualified physician who is delegated this responsibility by 
the Principal Investigator. 
11.2.3 Audit 
The study may be selected for an audit to inspect the facilities and review the study-related 
records in order to evaluate the trial conduct and compliance with the protocol, ICH, GCP and 
applicable regulatory requirements. 
The Investigator will be informed that an audit will be carried out, at the request of the 
Sponsor, before, during or after the study. 
The Investigator will be informed that the Regulatory Authorities may also carry out an 
inspection. In this case, the Investigator must inform the Sponsor as soon as he/she receives 
the notification of inspection. 
The Investigator must allow the representatives of the Regulatory Authorities and persons 
responsible for the audit to inspect the site, facilities and material used for the study, meet all 
members of his team involved in the study, have direct access to study data and source 
documents and consult all the documents relevant to the study. 
 
 


Bionomics Limited 
Version 4.0 
Protocol No.: BNC210.007 
Date: 30-May-2018 
CONFIDENTIAL  
     Page 60 of 62 
 
11.2.4 Study Records Retention 
A file for each subject is maintained, and it includes the signed ICF and the copies of all 
source documents for that subject.  Investigators are required to maintain all documentation, 
including documents in electronic format, for a minimum of 15 years following the end of the 
study.  The Investigator must inform the Sponsor immediately if any documents are to be 
destroyed, transferred to a different facility or transferred to a different owner.  The Sponsor 
will notify the site if the trial records are no longer needed. 
11.3 Data Disclosure and Subject Confidentiality 
All information provided by Bionomics Ltd and all data and information generated by the site 
as part of the study, (other than a subject’s medical records), will be kept confidential by the 
Principal Investigator and other site staff. The Principal Investigator or other site personnel 
will not use this information and data for any purpose other than conducting the study. These 
restrictions do not apply to: (1) information which becomes publicly available through no 
fault of the Principal Investigator or site staff; (2) information which it is necessary to 
disclose in confidence to an HREC/IRB solely for the evaluation of the study; (3) information 
which it is necessary to disclose in order to provide appropriate medical care to a study 
subject; or (4) study results which may be published as described in the next paragraph. If a 
written contract for the conduct of the study which includes confidentiality provisions 
inconsistent with this statement is executed, that contract’s confidentiality provisions shall 
apply rather than this statement.  
11.4 Publication Policy 
No publication of the results shall take place without the express consent of the study 
Sponsor, Bionomics Ltd. Prior to submitting for any publication, presentation, use for 
instructional purposes or otherwise disclosing the study results generated by the site 
(collectively, a “Publication”), the Principal Investigator shall provide Bionomics Ltd. with a 
copy of the proposed Publication and allow Bionomics Ltd. a period of at least forty (40) days 
[or for abstracts, at least five (5) working days] to review the proposed Publication. Proposed 
publications shall not include either Bionomics Ltd. or confidential information.  
 
At the request of Bionomics Ltd, the submission or other disclosure of a proposed Publication 
will be delayed for a sufficient length of time to allow Bionomics Ltd. to seek patent or 
similar protection of any inventions, know-how or other intellectual or industrial property 
rights disclosed in the proposed Publication. 
If a written contract for the conduct of the study, which includes publication provisions 
inconsistent with the statement is executed, that contract’s publication provisions shall apply 
rather than this statement.  


Bionomics Limited 
Version 4.0 
Protocol No.: BNC210.007 
Date: 30-May-2018 
CONFIDENTIAL  
     Page 61 of 62 
 
12 REFERENCES 
Berger W, Coutinho ES, Figueira I, Marques-Portella C, Luz MP, Neylan TC,Marmar CR, 
Mendlowicz MV. Rescuers at risk: a systematic review and meta-regression analysis of the 
worldwide current prevalence and correlates of PTSD in rescue workers. Soc Psychiatry 
Psychiatr Epidemiol. 2012 Jun;47(6):1001-11. 
 
 
 
 
 
Bandelow B, Zohar J, Hollander E, et al; WFSBP Task Force on Treatment Guidelines for 
Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders. World Federation of 
Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of 
anxiety, obsessive-compulsive and post-traumatic stress disorders—first revision. World J 
Biol Psychiatry. 2008;9(4):248–312.  
Breslau N, Davis GC, Andreski P, Peterson E. Traumatic events and posttraumatic stress 
disorder in an urban population of young adults. Arch Gen Psychiatry. 1991 Mar;48(3):216-
22. 
Burri A, Maercker A. Differences in prevalence rates of PTSD in various European countries 
explained by war exposure, other trauma and cultural value orientation. BMC Res Notes. 
2014 Jun 28;7:407. 
Clinician Administered PTSD Scale for DSM-5. Accessed on 26 January 2016 at 
http://www.ptsd.va.gov/professional/assessment/adult-int/caps.asp 
George KC, Kebejian L, Ruth LJ, Miller CW, Himelhoch S. Meta-Analysis of the Efficacy 
and Safety of Prazosin versus Placebo for the Treatment of Nightmares and Sleep 
Disturbances in Adults with Post-Traumatic Stress Disorder. J Trauma Dissociation. 2016 
Feb 2. 
Hamilton M. "The assessment of anxiety states by rating." Br. J. Med. Psychol. 1959. 32:50–
55. 
Hawkins EJ, Malte CA, Grossbard J, Saxon AJ, Imel ZE, Kivlahan DR. Comparative safety 
of benzodiazepines and opioids among veterans affairs patients with posttraumatic stress 
disorder. J Addict Med. 2013 Sep-Oct;7(5):354-62. 
Hoskins M, Pearce J, Bethell A, Dankova L, Barbui C, Tol WA, van Ommeren M, de Jong J, 
Seedat S, Chen H, Bisson JI. Pharmacotherapy for post-traumatic stress disorder: systematic 
review and meta-analysis. Br J Psychiatry. 2015Feb;206(2):93-100.  
Jordan BK, Schlenger WE, Hough R, Kulka RA, Weiss D, Fairbank JA, Marmar CR. 
Lifetime and current prevalence of specific psychiatric disorders among Vietnam veterans 
and controls. Arch Gen Psychiatry. 1991 Mar;48(3):207-15. 
Kobayashi TM, Patel M, Lotito M. Pharmacotherapy for posttraumatic stress disorder at a 
Veterans Affairs facility. Am J Health Syst Pharm. 2015 Jun 1;72(11 Suppl 1):S11-5.  
Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in 
the National Comorbidity Survey. Arch Gen Psychiatry. 1995 Dec;52(12):1048-60. 


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CONFIDENTIAL  
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Lund BC, Bernardy NC, Alexander B, Friedman MJ. Declining benzodiazepine use in 
veterans with posttraumatic stress disorder. J Clin Psychiatry. 2012 Mar;73(3):292-6. 
Marshall RD, Beebe KL, Oldham M, Zaninelli R. Efficacy and safety of paroxetine treatment 
for chronic PTSD: a fixed-dose, placebo-controlled study. AmJ Psychiatry. 2001 
Dec;158(12):1982-8. 
Marshall RD, Lewis-Fernandez R, Blanco C, Simpson HB, Lin SH, Vermes D, Garcia W, 
Schneier F, Neria Y, Sanchez-Lacay A, Liebowitz MR. A controlled trial of paroxetine for 
chronic PTSD, dissociation, and interpersonal problems in mostly minority adults. Depress 
Anxiety. 2007;24(2):77-84. 
Otis JD, Keane TM, Kerns RD, Monson C, Scioli E. The development of an integrated 
treatment for veterans with comorbid chronic pain and posttraumatic stress disorder. Pain 
Med. 2009 Oct;10(7):1300-11. 
 
 
 
 
Rosen CS, Greenbaum MA, Schnurr PP, Holmes TH, Brennan PL, Friedman MJ. Do 
benzodiazepines reduce the effectiveness of exposure therapy for posttraumatic stress 
disorder? J Clin Psychiatry. 2013 Dec;74(12):1241-8. 
Rothbaum BO, Price M, Jovanovic T, Norrholm SD, Gerardi M, Dunlop B, Davis M,Bradley 
B, Duncan EJ, Rizzo A, Ressler KJ. A randomized, double-blind evaluation of D-cycloserine 
or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder 
in Iraq and Afghanistan War veterans. Am J Psychiatry. 2014 Jun;171(6):640-8. 
Shore JH, Vollmer WM, Tatum EL. Community patterns of posttraumatic stress disorders. J 
Nerv Ment Dis. 1989 Nov;177(11):681-5. 
Thomas JL, Wilk JE, Riviere LA, McGurk D, Castro CA, Hoge CW. Prevalence of mental 
health problems and functional impairment among active component and National Guard 
soldiers 3 and 12 months following combat in Iraq. Arch Gen Psychiatry. 2010 
Jun;67(6):614-23.  
Tucker P, Zaninelli R, Yehuda R, Ruggiero L, Dillingham K, Pitts CD. Paroxetine in the 
treatment of chronic posttraumatic stress disorder: results of a placebo-controlled, flexible-
dosage trial. J Clin Psychiatry. 2001 Nov;62(11):860-8. 
Williams, J. B. and K. A. Kobak. "Development and reliability of a structured interview guide 
for the Montgomery Asberg Depression Rating Scale (SIGMA)." Br.J.Psychiatry. 2008. 
192.1:52-58. 
Winfield I, George LK, Swartz M, Blazer DG. Sexual assault and psychiatric disorders 
among a community sample of women. Am J Psychiatry. 1990 Mar;147(3):335-41. 
 
 
 

SAP_001.pdf: 
 
Page 1 of 35 
 
STATISTICAL ANALYSIS PLAN 
 
PROTOCOL NUMBER: 
BNC210.007 
TITLE: 
A Randomized, Double-blind, Placebo-
controlled Phase II Study of BNC210 in 
Adults with Post-Traumatic Stress Disorder 
(PTSD) 
STUDY DRUG: 
BNC210 
AUTHOR: 
 
 
 
 
 
 
SPONSOR: 
Bionomics Limited 
31 Dalgleish Street 
Thebarton SA 5031 
AUSTRALIA 
 
DATE FINAL: 
27th  September 2018 
DOCUMENT VERSION: 
FINAL V1.6 


Page 2 of 35 
 
TITLE: 
A Randomized, Double-blind, Placebo-controlled Phase II Study of 
BNC210 in Adults with Post-Traumatic Stress Disorder (PTSD) 
 
 
AUTHORS: 
 
NAME (TITLE): 
DATE 
SIGNATURE 
  
 
 
 
 
___________ 
___________________ 
 
 
REVIEWERS: 
 
NAME (TITLE): 
DATE 
SIGNATURE 
   
 
 
 
 
___________ 
___________________ 
 
NAME (TITLE): 
DATE 
SIGNATURE 
  
 
 
 
 
 
___________ 
___________________ 
 
 
 
 
 
 


 
Page 3 of 35 
 
VERSION HISTORY 
Document 
Summary of Change 
Date of Issue 
Draft Version 1.0  
 
31 May 2018 
Final Version 1.1 
Revised following comments from 
Bionomics Ltd 
 
 
15th July 2018 
Final Version 1.2 
Revised following comments from 
Bionomics Ltd 
 
10th August 2018 
Final Version 1.3 
Included repeating Demographic 
outputs for mITT Population 
21st August 2018 
Final Version 1.4 
Included 
additional 
subgroup 
analysis (Section 6.4), and clarified 
how non-numeric laboratory results 
will be reported (Section 11.4) 
23rd August 2018 
Final Version 1.5 
Include analysis of PGI-I and CGI-I 
results (Sections 9.1.3, 9.1.4 and 
10.2) 
25th September 2018 
Final Version 1.6 
Include Subgroup analyses for 
MADRS and HAM-A (Section 6.4), 
and the analysis of the CAPS-5 
Criterion B – Question B5 score 
(Sections 9.1.1, 10.1.2 and 10.2) 
27th September 2018 
 
 
 


 
Page 4 of 35 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
AIC 
Akaike’s Information Criterion 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase (SGPT) 
AQoL 
Assessment of Quality of Life 
AST 
Aspartate Aminotransferase (SGOT) 
ASL 
Arterial Spin Labeling 
AUC 
Area Under Curve 
BIC 
Bayesian Information Criterion 
b.i.d. 
Twice Daily 
BMI 
Body Mass Index 
BOCF 
Baseline Observation Carried Forward 
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 
CHRNA7 
Nicotinic Acetylcholine Receptor Subunit Alpha-7 
CI 
Confidence Interval 
Cmax 
Maximal Observed Plasma Concentration 
CRP 
C-reactive Protein 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
HAM-A 
Hamilton Anxiety Rating Scale 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
LEC-5 
Life Events Checklist for DSM-5 including interview with abuse ratings. 
LOCF 
Last Observation Carried Forward 
LSMeans 
Least Squares Means 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MAR 
Missing At Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
mITT 
Modified Intent-to-Treat 


 
Page 5 of 35 
 
MMRM 
Mixed Model for Repeated Measurements 
MSI-BPD 
McLean Screening Instrument for Borderline Personality Disorder 
PAL 
Paired Associates Learning 
PCL-5 
Standard PTSD Checklist for DSM-5 
PD 
Pharmacodynamic 
PGI-I 
Patient Global Impressions – Improvement 
PGI-S 
Patient Global Impressions – Severity 
PK 
Pharmacokinetics 
PRN 
As Needed 
PSQI 
Pittsburgh Sleep Quality Index 
PT 
Preferred Term 
PTSD 
Post-traumatic Stress Disorder 
QTcF 
Fridericia-corrected QT Interval 
RVP 
Rapid Visual Information Processing 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDS 
Sheehan Disability Scale 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SSID 
Study Subject Identification Number 
SSRI 
Selective Serotonin Reuptake Inhibitor 
SWM 
Spatial Working Memory 
TEAE 
Treatment-emergent Adverse Event 
ULN 
Upper Limit of Normal 


 
Page 6 of 35 
 
CONTENTS 
Version History ....................................................................................................................3 
List of Abbreviations ...........................................................................................................4 
Contents ...............................................................................................................................6 
1. 
INTRODUCTION .......................................................................................................9 
2. 
Study Objectives ..........................................................................................................9 
2.1 
Primary Objective ................................................................................9 
2.2 
Secondary Objectives ..........................................................................9 
 
 
3. 
Study Design .............................................................................................................10 
3.1 
General Description ...........................................................................10 
3.2 
Length of Study .................................................................................10 
3.3 
Schedule of Events ............................................................................11 
3.4 
Treatment Assignment .......................................................................11 
3.5 
Determination of Sample Size ...........................................................11 
3.6 
Internal safety review ........................................................................12 
3.7 
Independent Safety Review Committee ............................................12 
3.8 
Interim Analysis ................................................................................12 
3.9 
Final Analysis ....................................................................................12 
4. 
Analysis Populations .................................................................................................13 
4.1 
All Enrolled Population .....................................................................13 
4.2 
ITT/mITT Populations .......................................................................13 
4.3 
Safety Population ...............................................................................13 
4.4 
Description of the Populations ..........................................................13 
5. 
Data Handling Conventions ......................................................................................14 
5.1 
Treatment Groups ..............................................................................14 
5.2 
Data Presentation ...............................................................................14 
5.3 
Premature Withdrawal and Missing Data ..........................................15 


 
Page 7 of 35 
 
5.4 
Common Derivations .........................................................................16 
5.4.1 
Baseline .............................................................................................16 
5.5 
Visit Window Conventions ...............................................................16 
5.6 
Software .............................................................................................16 
6. 
StatistIcal Considerations ..........................................................................................16 
6.1 
Multiplicity Adjustments ...................................................................16 
6.2 
Multi-center Studies ..........................................................................16 
6.3 
Other Strata and Covariates ...............................................................16 
6.4 
Sub-Group Analyses ..........................................................................17 
7. 
Output Shells .............................................................................................................17 
8. 
Study Population .......................................................................................................17 
8.1 
Subject Disposition ............................................................................17 
8.2 
Protocol Deviations ...........................................................................18 
8.3 
Demographics and Baseline Characteristics .....................................18 
9. 
Efficacy Variables .....................................................................................................19 
9.1 
Definitions of Variables ....................................................................19 
9.1.1 
Clinician-Administered PTSD Scale for the DSM-5 
(CAPS-5)   .............................................................................................19 
9.1.2 
PTSD Checklist for DSM-5 (PCL-5) ................................................20 
9.1.3 
 Clinical Global Impression scale–Improvement and 
Severity (CGI-I/CGI-S) .........................................................................20 
9.1.4 
 Patient Global Impression Scales – Improvement and 
Severity (PGI-I/PGI-S)..........................................................................20 
9.1.5 
Assessment of Quality of Life (AQoL-8D) .......................................21 
9.1.6 
Hamilton Anxiety Rating Scale (HAM-A) ........................................21 
9.1.7 
 Montgomery-Asberg Depression Rating Scale 
(MADRS)  .............................................................................................21 
9.1.8 
CANTAB Cognitive Assessment ......................................................22 
9.1.9 
Sheehan Disability Scale (SDS) ........................................................24 
9.1.10 
Pittsburgh Sleep Quality Index (PSQI) .............................................24 


 
Page 8 of 35 
 
10. Efficacy analysis ........................................................................................................24 
10.1 
Primary Efficacy Endpoint ................................................................24 
10.1.1 
Multiple Imputation of Missing Data in Primary 
Analysis .................................................................................................26 
10.1.2 
Sensitivity Analyses ..........................................................................28 
10.2 
Secondary Efficacy Measures ...........................................................28 
 
 
10.4 
Compliance Analysis .........................................................................30 
11. Safety .........................................................................................................................30 
11.1 
Exposure ............................................................................................30 
11.2 
Columbia Suicide Severity Rating Scale (C-SSRS) ..........................31 
11.3 
Adverse Events (AEs) .......................................................................31 
11.4 
Laboratory Test and other Test Abnormalities as 
Adverse Events ..................................................................................32 
11.5 
Pregnancy Test ..................................................................................33 
11.6 
Vital Signs .........................................................................................34 
11.7 
12-lead ECG ......................................................................................34 
11.8 
Physical Examination ........................................................................34 
11.9 
Concomitant Medications/Treatments ...............................................34 
12. References .................................................................................................................35 
 
 
 


 
Page 9 of 35 
 
1. 
INTRODUCTION 
This document describes the planned statistical analyses for Protocol BNC210.007, a 
randomized, double-blind, placebo-controlled Phase II study of BNC210 in adults with 
Post-Traumatic Stress Disorder (PTSD). 
The planned statistical analyses of Protocol BNC210.007 shall be described in this 
statistical analysis plan (SAP). 
This SAP supplements the study protocol BNC210.007 Final Version 4.0 dated 30th May 
2018. If the protocol is amended, this SAP will be revised as required. The plan will be 
finalized before the study database is locked. 
2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
 To assess the effects of BNC210 on Investigator-rated symptoms of PTSD 
measured by Clinician-Administered PTSD Scale for the Diagnostic and Statistical 
Manual of Mental Disorders, 5th Edition (DSM-5) (CAPS-5) scores. 
2.2 
Secondary Objectives 
 To assess the effects of BNC210 on Investigator-rated symptoms of PTSD 
measured by each of the four symptom clusters (Intrusion; Avoidance, Negative 
Alterations in Cognition and Mood; Arousal and Reactivity) of the CAPS-5.  
 To assess the effects of BNC210 on other psychiatric outcomes in subjects with 
PTSD including anxiety and depression. 
 To assess the effects of BNC210 on global functioning and Quality of Life in 
subjects with PTSD. 
 To assess the effects of BNC210 on patient-reported outcomes in subjects with 
PTSD. 
 
To assess the safety and tolerability of BNC210 in subjects with PTSD. 


 
Page 10 of 35 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
3. 
STUDY DESIGN 
3.1 
General Description 
This is a randomized, double-blind, parallel, placebo-controlled, multi-centre study with a 
12-week, 4-arm treatment phase (placebo and BNC210). Subjects will attend a Screening 
visit within 3 weeks before randomization to confirm eligibility. Approximately 192 
subjects who fulfil the inclusion criteria and none of the exclusion criteria will be 
randomized on Day 1 using a 1:1:1:1 ratio. Subjects will then complete 12 weeks of their 
allocated treatment. The Investigational Product (IP) (total daily dose 300 mg, 600 mg or 
1200 mg) or Placebo will be taken twice daily (b.i.d.) with food. Subjects will return to the 
clinical site at weekly or 2-weekly intervals to receive study medication, complete safety 
assessments and questionnaires. Subjects are then requested to attend a post-study visit at 
15 weeks (that is 3 weeks after the last treatment).  
 
3.2 
Length of Study 
Screening evaluation within 3 weeks of randomization. Treatment phase: 12 weeks of 
treatment, b.i.d. (weekly or fortnightly visits to the clinic). Post-study visit: 3 weeks after 


 
Page 11 of 35 
 
the last treatment (i.e. 15 weeks after the first treatment).  Recruitment timeframe estimate 
is 2 years. 
3.3 
Schedule of Events 
The schedule of assessments can be found on pages 9-10 of the final protocol. 
3.4 
Treatment Assignment 
An Interactive Web Response System (IWRS) will allocate a randomization number at the 
baseline visit but the number will not be used for subject identification purposes. Data 
associated with subjects who fail screening will not be entered into the eCRF. 
 
 
 subjects will be randomly 
assigned to the four treatment groups in a 1:1:1:1 ratio until the close of randomization. 
The IWRS vendor will be supplied with a validated randomization list by an Independent 
Statistician. 
 
3.5 
Determination of Sample Size 
Sample size estimation is based on the following. 
 
 
 
 
 
 
 
 
 
 
 


 
Page 12 of 35 
 
 
 
 
 
 With the level of significance set to 0.05 and a 2-sided 
test, a sample size of 36 subjects per arm is required to achieve a power of 80%. For PTSD 
patients a relatively high withdrawal rate is anticipated, therefore the sample size was 
increased by 33% to 48 per arm (=1.33x36) (Hoskins et al. 2015; Marshall et al. 2001; 
Marshall et al. 2007; Tucker et al. 2001). Because this is a Phase II study the level of 
significance will be 0.05 with no adjustment for multiple comparisons. 
3.6 
Internal safety review 
The safety data shall be monitored throughout by a subject matter expert. 
3.7 
Independent Safety Review Committee 
An independent Safety Review Committee will be established to monitor subject safety 
throughout the study. The meetings will occur approximately every 6 months and will 
review all safety data including vital signs, electrocardiogram (ECG), pathology results, 
physical examinations, Columbia Suicide Severity Rating Scale (CSSRS) and continuous 
adverse event (AE) reporting. 
3.8 
Interim Analysis 
There are no planned interim analyses.  
3.9 
Final Analysis 
The final analysis will be conducted once all enrolled subjects have completed the study 
and the database lock has occurred. 


 
Page 13 of 35 
 
4. 
ANALYSIS POPULATIONS 
4.1 
All Enrolled Population 
The All Enrolled population will include all subjects who provided informed consent.  
4.2 
ITT/mITT Populations 
The Intent-to-treat (ITT) population will comprise all randomised subjects; analysed as per 
randomised treatment. This population will be used for subject disposition summaries and 
all listings unless otherwise specified. The Modified ITT (mITT) population will be those 
subjects from the ITT population who received at least one dose of study medication. The 
mITT population will use treatment groups as randomised and will be used for all efficacy 
analyses, tabulations, and listings.       
4.3 
Safety Population 
The safety population will comprise all randomised subjects who receive at least one dose 
of study medication and will be analyzed as per actual treatment received. The safety 
population will be used for all safety analyses and listings. 
The analysis sets will be validated during a blind review meeting. 
4.4 
Description of the Populations 
A summary table with the description of the number of subjects in each analysis set, the 
number of subjects who completed the study, and the number of subjects who discontinued 
classified by reason of withdrawal, will be prepared. Corresponding individual listings will 
be prepared. 
Listings with end of study status and visit dates will also be prepared. 


 
Page 14 of 35 
 
5. 
DATA HANDLING CONVENTIONS 
5.1 
Treatment Groups 
Data will be grouped by treatment group, using the following treatment names. 
 Placebo 
 BNC210 150 mg b.i.d. 
 BNC210 300 mg b.i.d. 
 BNC210 600 mg b.i.d. 
Subjects will take 150 mg or 300 mg or 600 mg BNC210 or placebo b.i.d., with food, as 
oral suspensions from single-use 
 bottles for 12 weeks. Doses should be 
administered approximately 12 hours apart (+2 hours), with breakfast, and with an evening 
meal.  
5.2 
Data Presentation 
In the Schedule of Assessments in the Protocol the visit representing 12 weeks after the 
start of treatment is labelled Week 13. The outputs presenting the results from this study 
will label this visit as Week 12. Similarly, other visits will be labelled as in the table below: 
Protocol - Schedule of 
Assessments 
Outputs for 
Reporting 
Day 
Week 
Week 
1 
1 
Baseline 
8 
2 
1 
15 
3 
2 
29 
5 
4 
43 
7 
6 
57 
9 
8 
71 
11 
10 
85 
13 
12 
106 
16 
15 
: 


 
Page 15 of 35 
 
Descriptive analyses will be completed for this study. For continuous parameters, these 
will include the number of observations, mean, median, standard deviation, minimum and 
maximum. The minimum and maximum values will be presented to the same number of 
decimal places as recorded in the database. Mean, median and standard deviation will be 
presented to 1 more decimal place than the raw data. Categorical parameters will be 
summarised as frequency counts and percentages. Percentages will be rounded to 1 decimal 
place, with the denominator being the number of subjects in the relevant population, unless 
otherwise stated. All confidence intervals reported will be two-sided 95% confidence 
levels, unless specified otherwise. 
Summary tables, and listings for baseline data, drug exposure, efficacy and safety will be 
presented as four treatment groups as described in Section 5.1.  
The baseline assessment at Day 1 will be used as a reference point for all four treatment 
groups when summarising the change from baseline. 
The expected number of subjects in each treatment group will be as follows: 
 Placebo (N=48) 
 BNC210 150 mg b.i.d. (N=48) 
 BNC210 300 mg b.i.d. (N=48) 
 BNC210 600 mg b.i.d. (N=48) 
5.3 
Premature Withdrawal and Missing Data 
The primary analysis of the CAPS-5 measure will be conducted based on observed and 
imputed data. All observed data for subjects who withdraw early will be used for the 


 
Page 16 of 35 
 
analysis up to the point of their discontinuation. The Multiple Imputation (MI) approach 
used to impute values for missing data is described in Section 10.1.1.  
5.4 
Common Derivations 
5.4.1 
Baseline 
For all parameters presented by visit in the summary tables, baseline will be defined as the 
last, valid, non-missing assessment prior to the first study drug administration. 
5.5 
Visit Window Conventions 
Visit windows will not be applied to the data except for deriving baseline assessments 
(Section 5.4.1). Visit numbers (Weeks post Baseline) recorded on the eCRF will be used 
for the analysis and reporting of the data (except for BNC210 plasma concentration data 
where the recorded dates will be used to determine time (days) since Baseline).  
5.6 
Software 
All analyses will be performed using SAS version 9.4 or later. Some figures will be created 
using R 3.2.2. The data processing, analysis, and validation for the figures created in R will 
be conducted using SAS version 9.4 or later. 
6. 
STATISTICAL CONSIDERATIONS 
6.1 
Multiplicity Adjustments 
There will be no adjustment for multiplicity. 
6.2 
Multi-center Studies 
Given the small sample sizes at some centers there will be no adjustment for center. 
6.3 
Other Strata and Covariates 
Gender, Age, Country (Australia/USA), Nicotine Use at Baseline (Current/Former/Never) 
and Concomitant Antidepressant Use at Baseline (Yes/No) will be included as covariates 
in the primary efficacy analysis model (two subjects reported to be transgender will be 


 
Page 17 of 35 
 
excluded from this analysis). Concomitant Antidepressant Use will be based on data 
recorded on the Concomitant Medication page on the eCRF and where the Start to Stop 
date period includes the Date of First Dose of Study Medication. The list of medications, 
and associated indication, will be reviewed by a Clinician (this will be completed prior to 
database lock).   
6.4 
Sub-Group Analyses 
The primary endpoint (CAPS-5 Total Score) and key secondary endpoints (MADRS and 
HAM-A) will be repeated for the following sub-group:  
 Country: Australia, USA     
 Baseline Nicotine use (Current/Former/Never) 
 Age (≤median, > median) 
 Concomitant Antidepressant Use at Baseline (Yes/No) 
 Gender (Male, Female) (subjects reported to be transgender will not be included). 
 Time (Years) since initiating PTSD event (≤10 years, > 10 years). 
7. 
OUTPUT SHELLS 
Template shells for the tables, listings, and figures are presented in 
 
8. 
STUDY POPULATION 
8.1 
Subject Disposition 
The number and percentage of subject who were included in each analysis population, 
completed the study, and completed each visit will be presented by treatment group. The 
reason for early withdrawal will be summarized and listed by treatment group. In addition, 
the number of days from Randomisation to Withdrawal/Last Visit will be determined for 
each subject and the treatment group results summarized and presented using Kaplan-
Meier methodology.    


 
Page 18 of 35 
 
8.2 
Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or 
noncompliance with, the approved protocol, procedures, or requirements. Deviations may 
result from the action or inaction of the subject, investigator, or site staff. All deviations 
will be tracked and should be reported to Institutional Review Boards (IRBs) in accordance 
with their reporting policy.  
Possible protocol deviations will be documented in the source documents and tracked by 
the Sponsor. 
A final list of protocol deviations will be approved by the Sponsor, the Medical Monitor, 
and others as appropriate, and after database lock provided to McCloud Consulting Group. 
The final list of Important protocol deviations will include date of deviation, deviation, 
reason for deviation, action taken, and comments, and will be included in the final study 
report. 
8.3 
Demographics and Baseline Characteristics 
Baseline data will be used to describe the safety population (and repeated for the mITT 
population). This information will include the following: 
 Demographics including gender (and female reproductive status), age, race and 
country (Australia or USA)  
 Medical History 
 Screening weight, height, and Body Mass Index (BMI)  
 Time (Years) since initiating PTSD event 
 Screening Nicotine Use Status 
 Baseline Antidepressant Use 
Baseline measurements will be summarised, by treatment group, as number of 
observations, mean, standard deviation, minimum, median, and maximum for continuous 
variables, and number of observations, frequencies and percentages for categorical 


 
Page 19 of 35 
 
variables. Age will be derived as (date of initial informed consent–date of birth+1)/365.25. 
All baseline data will be summarized descriptively in tables and listed by treatment group.  
9. 
EFFICACY VARIABLES 
9.1 
Definitions of Variables 
All the assessments/questionnaires below will be assessed at time-points as captured in the 
Schedule of Assessments found in the protocol. Imputation of missing Domain or Total 
Scores will be performed using MI as described in Section 10.1.1. The imputation will be 
at the level of the Domain or Total Scores. In other words the imputation of the Domain 
or Total Scores will not be done for the individual questions comprising each Domain or 
Total Score. 
 
9.1.1 
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 week. Information about the frequency and intensity of each item 
is combined into a severity rating, and the CAPS-5 total severity is calculated by adding 
the severity scores for the 20 PTSD symptoms in the DSM-5 (National Centre for PTSD). 
The severity of PTSD is rated from 0 (absent) to 4 (extreme/incapacitating). 
In addition to the total CAPS-5 score, the cluster scores for: 
 Criterion B: Intrusion (the sum of the individual severity scores for Intrusion 
symptoms items 1-5);  
 Criterion B: Intrusion – Question B5 
 Criterion C: Avoidance (the sum of Avoidance symptoms items 6 and 7);  
 Criterion D: Negative Alterations in Cognition and Mood (the sum of Cognitions 
and mood symptoms items 8-14); and  


 
Page 20 of 35 
 
 Criterion E: Arousal and Reactivity (the sum of Arousal and reactivity symptoms 
items 15-20) 
will be analysed and reported separately as secondary measures of efficacy. 
 
9.1.2 
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). The Total Score is the sum of the responses to the 20 items. If some responses 
are missing then the following approach will be adopted - if no more than 5 responses are 
missing then calculate a Total score (and assume missing responses have a value of zero); 
if more than 5 responses are missing then Total score is missing. 
 
9.1.3 
Clinical Global Impression scale–Improvement and Severity (CGI-I/CGI-
S) 
The CGI-S is a rating scale designed to assess the severity of the subject’s symptoms, and 
the CGI-I is designed to assess the change in the subject’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 subjects). The changes in the subject’s condition are rated on the 
CGI-I from 1 (very much improved) to 7 (very much worse). Improvement will also 
summarised as binary responses (1) (very much improved/much improved OR other) and 
(2) (very much improved OR other). 
 
9.1.4 
Patient Global Impression Scales – Improvement and Severity (PGI-
I/PGI-S) 
The PGI-S is a self-rating scale designed to assess the severity of the subject’s symptoms, 
and the PGI-I is designed to assess the change in the subject’s condition since the initial 
assessment. Severity is rated on the PGI-S from 1 (normal) to 4 (severe). The changes in 
the subject’s condition are rated on the PGI-I from 1 (very much improved ) to 7 (very 


 
Page 21 of 35 
 
much worse). Improvement will also summarised as binary responses (1) (very much 
improved/much improved OR other) and (2) (very much improved OR other). 
 
9.1.5 
Assessment of Quality of Life (AQoL-8D) 
The AQoL-8D is a 35 question self-rating scale designed to assess a subject’s quality of 
life on the following eight dimensions; Independent Living, Happiness, Mental Health, 
Coping, Relationships, Self-Worth, Pain and the Senses. The scale takes approximately 5 
minutes to complete. The Total Score is the sum of the responses to the 35 items. If some 
responses are missing then the following approach will be adopted - if no more than 5 
responses are missing then calculate a Total score (and assume missing responses have a 
value of zero); if more than 5 responses are missing then Total score is missing. 
 
9.1.6 
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 behaviour during the interview (Hamilton, 1959). It takes approximately 
15-20 minutes to complete and each parameter is rated on a scale of 0 (not present) to 4 
(very severe). 
 
9.1.7 
Montgomery-Asberg 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). 
 


 
Page 22 of 35 
 
9.1.8 
CANTAB Cognitive Assessment 
The CANTAB cognitive assessment is a battery of tests designed to detect both cognitive 
impairment and enhancement. The battery will measure cognitive function through 
assessing sustained attention, episodic memory, working memory and executive function. 
All tests will be completed electronically using iPads. The test battery will take 
approximately 20-25 minutes to complete. The CANTAB cognitive assessment must be 
completed at the same time during each visit (+ 1hr of baseline assessment start time). 
A Paired Associates Learning (PAL) task will be used to assess episodic memory. During 
the test, boxes are displayed on the screen and open in turn to reveal a number of patterns. 
Participants are instructed to try to remember the location in which each pattern was 
shown. After all the boxes have been opened, each pattern is then shown in the centre of 
the screen in a randomized order, and the participant touches the box in which the pattern 
was located. If an error is made, all the patterns are re-presented to remind the participant 
of their locations. As the test progresses so the stages become more difficult as the number 
of patterns to be remembered increases, up to a maximum of 8 patterns. For participants 
who fail to complete all levels, an adjusted total is calculated that allows for errors 
predicted in the stages that were not attempted. The key outcome measures for this task 
are total errors and first trial memory score. 
A Spatial Working Memory (SWM) task will be used to assess the ability of the subject to 
retain spatial information and manipulate it in working memory. It is a self-ordered task 
that also gives a measure of strategy. A number of coloured boxes are presented on the 
screen, and the computer hides a token in these boxes one at a time. The participant is 
instructed to touch the boxes in turn to search for the token that has been hidden. When a 
token is found it should be placed in a home area on the right side of the screen. The 
participant then searches for more tokens until the same number of tokens as the number 
of coloured boxes has been found. The key task instruction is that the computer will never 
hide a token in the same coloured box twice in the same problem. As the test progresses, 


 
Page 23 of 35 
 
so it becomes more difficult. The key outcome measures for this task are between errors 
and strategy. 
A Rapid Visual Information Processing (RVP) task will be used to assess sustained 
attention, outputting measures of response accuracy, target sensitivity and reaction times. 
For the RVP task, single digits appear in a pseudo-random order at a rate of 100 digits per 
minute in box in the centre of the screen. Subjects must detect a series of 3-digit target 
sequences (e.g. 3-5-7; 2-4-6; 4-6-8) and respond by touching the button at the bottom of 
the screen when they see the final number of the sequence. Nine target sequences appear 
every minute. Key outcome measures include target sensitivity and reaction times. 
 
Factors that could influence the cognitive function assessments must be captured within 
the CANTAB system. This includes, but is not limited to, drug and medication use within 
12 hours of assessment, lack of sleep, and failure to understand the test requirements.  
 
In addition to the total composite score, the six z-scores: 
 Z-Score (ZPALFAMS) for PAL first attempt memory score (PALFAMS)  
 Z-Score (ZPALTEA) for PAL total errors adjusted (PALTEA) 
 Z-Score (ZSWMBE) for SWM between errors (SWMBE) 
 Z-Score (ZSWMS) for SWM strategy (SWMS) 
 Z-Score (ZRVPA) for RVP A’ prime (RVPA) 
 Z-Score (ZRVPMDL) for RVP median latency (RVPMDL)  
 
will be analysed and reported separately as secondary measures of efficacy. 
 
 
 
 


 
Page 24 of 35 
 
9.1.9 
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. 
 
In addition to the total SDS score, the three domain scores: 
 
Work/School 
 
Social Life 
 
Family Life/Home Responsibilities 
will be analysed and reported separately as secondary measures of efficacy. 
 
9.1.10 
Pittsburgh Sleep Quality Index (PSQI) 
The PSQI is a questionnaire consisting of 19 questions designed to assess the following 7 
components of sleep quality: subjective sleep quality, sleep latency (i.e., how long it takes 
to fall asleep), sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping 
medication, and daytime dysfunction over the previous month. Each question is weighted 
on a scale from 0 to 3 and a global score is obtained, with lower scores correlating with 
better sleep quality. 
 
 
10. 
EFFICACY ANALYSIS 
10.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is CAPS-5 total symptom severity score and will be 
analysed with a Mixed Model for Repeated Measurements (MMRM) with sequential 
multiple imputation used to estimate the missing observations (as described below in 
Section 10.1.1). The repeated measurements will range from baseline to Week 12 (Day 85) 
for the primary endpoint.  


 
Page 25 of 35 
 
The primary model will include the endpoint from days 8 to 85 as the dependent variable, 
the baseline (day 1) value as a baseline covariate, day, and treatment group as factors, and 
treatment group by day as an interaction term. Additional covariates in the model will 
include Gender (two subjects reported to be transgender will be excluded from this 
analysis), 
Age, 
Country 
(Australia/USA), 
Nicotine 
Use 
at 
Baseline 
(Current/Former/Never) and Concomitant Antidepressant Use at Baseline (Yes/No). 
The following variance-covariance structures will be investigated (in the model using the 
observed CAPS-5 data): Compound Symmetry, Ante-Dependence Order 1, Unstructured, 
Autoregressive Order1, Toeplitz, and Variance Component. The most appropriate structure 
will be chosen for the final model by comparing the Akaike Information Criterion (AIC), 
and the Bayesian Information Criterion (BIC) statistics, as well as using statistical 
judgement. If appropriate, the same variance-covariance structure will be used for all 
variables. 
The primary comparisons of interest will be the difference in Least Squares means 
(LSMeans, means adjusted for the covariates in the model) at Week 12 between each of 
the three active study medication groups (separately) and placebo. The results will be 
presented as LSMeans for each of the four treatment groups at Week 12, and the LSMeans 
of treatment differences (between each of the three active medication dose groups and 
placebo at Week 12) and their associated 95% confidence intervals. The treatment group 
LSMeans overall, and the difference between the groups will also be presented 
 
.    
Because this is a Phase II study, the level of significance will be 0.05 with no adjustment 
for multiple comparisons. 
In addition to the analysis results, the summary statistics for the actual values at each of 
the visits (up to Week 15), and the change from Baseline, will be presented for each of the 
treatment groups. Plots of the observed treatment group means (and 95% confidence 


 
Page 26 of 35 
 
intervals) over time, as well as the LSMeans (and 95%CI) over time from the MMRM for 
Imputed and Observed data will be produced 
.    
10.1.1 
Multiple Imputation of Missing Data in Primary Analysis 
For the primary analysis, missing CAPS-5 values will be assumed to be missing at random 
(MAR). Under the MAR assumption, it is assumed that missing values are conditional on 
the independent variables in the missing data model and the observed dependent variable. 
In other words, subject dropout can be modelled by the observed covariates and outcomes. 
It is assumed that the statistical behaviour of the unobserved data, conditional on the 
observed covariates and outcomes, is what it would have been, had it been observed. The 
MAR mechanism assumes that missing data is not related to unobserved covariates. 
This clinical trial was designed to observe all relevant information, therefore, it is 
reasonable to assume that the missing data follows the MAR mechanism. As such, missing 
values in the primary analysis will be imputed using multiple imputation with 100 samples 
drawn, which is an appropriate method for handling data which is MAR.  
The analysis will be conducted using all subjects in the mITT population. For subjects with 
a missing baseline CAPS-5 score the screening assessment score will be used as the 
baseline score. The analysis will include subjects who were randomised but did not go on 
to complete any post baseline efficacy assessments.        
There are 3 stages to the multiple imputation process, as described below (Mallinckrodt 
C, and Lipkovich I, 2017). 
1. Imputation Phase 
During this phase, 100 datasets will be created where missing CAPS-5 values will be 
imputed by randomly selecting data from an appropriate distribution.  


 
Page 27 of 35 
 
First, only intermittent missing data will be imputed, so that the remaining missing data 
has a monotone missing data pattern. For the imputation of the intermittent missing data, 
all variables in the imputation model will be assumed to have a multivariate joint normal 
distribution and will be modelled as continuous variables. The variables in the imputation 
model will include the variables in the primary analysis MMRM model. 
A Markov Chain Monte Carlo (MCMC) procedure will be used, where missing data will 
be selected from a multivariate joint normal distribution conditional on the observed data.  
Following the imputation of the intermittent missing data, the remaining monotone missing 
data will be imputed using stepwise sequential Bayesian regression.  
The multiple imputation procedures will be implemented using PROC MI in SAS with a 
random seed of 9023476. Imputed data that falls outside the plausible range for the CAPS-
5 (i.e. 0 to 80) will not be truncated and will be used in the analysis as imputed. This is 
because post-imputation truncation of data can lead to biased estimates (Rodwell, Lee, 
Romaniuk, & Carlin, 2014).   
2. Analysis Phase 
The 100 imputed datasets will each be analysed using the planned statistical model 
described in Section 10.1.  
3. Pooling Phase 
The parameter estimates from the 100 analyses conducted in step 2 will be combined into 
a single set of statistics that reflect the uncertainty associated with the imputed values using 
PROC MIANALYZE in SAS. Using the parameter estimates and standard errors from the 
100 imputed datasets, this procedure applies Rubin’s (1987) rules to make valid univariate 
statistical inferences.  


 
Page 28 of 35 
 
10.1.2 
Sensitivity Analyses 
 
As a sensitivity analysis of the CAPS-5 Total Score and four cluster scores, and the CAPS-
5 Criterion B – Question B5, the MMRM will be implemented on: 
 The observed data (no imputation will be applied for the missing data). Mixed 
models with repeated measures are an alternative method that can be used in the 
presence of missing data, when the data is assumed to be MAR. 
 
Additional sensitivity analysis of the CAPS-5 Total Score the MMRM will be implemented 
on: 
 The data where the missing values are substituted using the Last Observation 
Carried Forward (LOCF) approach 
 The data where the missing values are substituted using the Baseline Observation 
Carried Forward (BOCF) approach. 
10.2 
Secondary Efficacy Measures 
For each continuous secondary efficacy variables listed in Section 9, including the four 
CAPS-5 Cluster scores, the analysis methodology described, and outputs proposed, in 
Section 10.1 will be followed. These continuous secondary efficacy measures include: 
 CAPS-5 Criterion B: Intrusion (the sum of the individual severity scores for 
Intrusion symptoms items 1-5);  
 Criterion B: Intrusion – Question B5 
 CAPS-5 Criterion C: Avoidance (the sum of Avoidance symptoms items 6 and 7);  
 CAPS-5 Criterion D: Negative Alterations in Cognition and Mood (the sum of 
Cognitions and mood symptoms items 8-14); and  
 CAPS-5 Criterion E: Arousal and Reactivity (the sum of Arousal and reactivity 
symptoms items 15-20). 


 
Page 29 of 35 
 
 MADRS 
 HAM-A 
 PCL-5 
 PSQI 
 AQoL-8D 
 Social functioning: SDS Total (and three domain scores separately) 
 CANTAB Cognitive Assessment Composite Score (and separately the six z-scores 
used in the composite score formula) 
 Sleep monitoring: PSQI 
 
The categorical endpoints listed below will be summarised at each time point by treatment 
group for the observed data (i.e. no imputation for missing data). The number and 
percentage of subjects with each response will be presented 
 
.    
 CGI-S/CGI-I 
 
PGI-S/PGI-I 
Overall treatment group differences in the binary response rates for Improvement, using 
the response classifications described in Sections 9.1.3 and 9.1.4 respectively, will be 
performed at each post-baseline timepoint with a Chi-Square test. 
 
 
 
 
 
 


 
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Individual estimates of area under the plasma concentration-time curve (AUC) will be 
made using appropriate pharmacokinetic modelling techniques (by third party supplier). 
Relationship between exposure (as measured by AUC) and efficacy will be explored 
initially by correlation analysis.  
10.4 
Compliance Analysis 
Plasma levels of BNC210 taken at Screening, Week 2, Week 6 and Week 12 will be used 
as a dichotomic compliance marker.   A participant with 3 detectable levels will be 
determined to be a good complier; with one or 2 detectable levels an intermittent complier 
and with 3 non-detectable levels will be determined to be a non-complier.  Individual 
estimates of area under the plasma concentration-time curve will be made (by a third party 
supplier).       
11. 
SAFETY 
11.1 
Exposure 
Study medication compliance will be calculated as the planned versus actual dose received 
(based on the number of 
 bottles dispensed and the number of used 
 
 bottles returned) over the duration of the treatment period (first to last treatment 


 
Page 31 of 35 
 
dates). Treatment compliance and treatment duration will be summarized with descriptive 
statistics (n, mean, SD, median, minimum and maximum). A listing will display the date 
study medication was consumed, medication interruptions, duration of study drug and 
percentage treatment compliance. 
11.2 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a suicidal ideation rating scale designed to identify behaviours 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 
behaviour is also assessed.  
The approach described in document Columbia–Suicide Rating Scale Scoring and Data 
Analysis Guide (Version 2.0, Finalized February 2013, Contributors: Mary E. Nilsson, 
et.al.) 
 will be followed (descriptive 
summary statistics, excluding the optional formal hypothesis testing but producing outputs 
consistent with the Tables 1,2 and 4 and the Listing, 
). 
11.3 
Adverse Events (AEs) 
The Principal Investigator and clinical facility staff are responsible for detection, recording, 
and reporting of events that meet the criteria and definition of AEs as listed below. AEs 
will be recorded from first administration of IP through Week 15 (Post Study Visit). The 
Principal Investigator and clinical facility staff are responsible for detection, recording and 
reporting of pregnancy and appropriate follow up. 
 
An AE is any untoward medical occurrence in a patient or clinical investigational subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 


 
Page 32 of 35 
 
disease temporally associated with the use of a medicinal product, whether or not related 
to the medicinal product. 
 
AEs with an onset date on or after the date of administration of study drug will be recorded. 
If the onset date is missing, the AE will still be recorded. Each subject will have their 
adverse event assigned to their treatment group.  
AEs will be summarized using the latest version of the Medical Dictionary for Regulatory 
Activities by System Organ Class (SOC) and Preferred Term (PT). The incidence and 
percentage of subjects with at least 1 occurrence of a PT will be included, according to the 
most severe grade using a 3-point scale (mild, moderate, severe). The number of events per 
PT will also be summarized. Causality (relationship to study treatment) will be summarized 
separately. 
The incidence and frequency of AEs, serious AEs (SAEs), related AEs, and AEs leading 
to treatment discontinuation will be summarized by treatment group according to SOC and 
PT. Adverse events will be listed. The duration of AEs will be determined and included in 
listings, along with the action taken and outcome.  
Duration of Adverse Events in days will be calculated as the AE stop date minus the AE 
onset date + 1. Duration will not be calculated for subjects who do not have both a full AE 
onset date and a full AE stop date. 
11.4 
Laboratory Test and other Test Abnormalities as Adverse 
Events 
Abnormal assessments (e.g., ECGs and vital signs) that are judged by the Principal 
Investigator as clinically significant or if the abnormal assessment results in clinical 
sequelae will be recorded as AEs. 
Laboratory abnormalities will be reported by the Investigator as AEs if the abnormality is 
considered clinically significant or if the abnormality results in clinical sequelae. Clinically 
significant abnormal laboratory findings or other abnormal assessments that are detected 


 
Page 33 of 35 
 
during the study or are present at baseline and significantly worsen following the first 
administration of IP will be reported as AEs. 
The Principal Investigator and Co-Investigators will exercise their medical and scientific 
judgment in deciding whether an abnormal laboratory finding or other abnormal 
assessment is clinically significant. 
The following clinical laboratory tests will be performed: 
 Haematology 
 Biochemistry 
 C-reactive protein 
 Urinalysis 
Complete blood count and clinical chemistry will be summarized by descriptive statistics 
and the associated changes from baseline will be calculated and presented by treatment 
group and scheduled visit. Where results were recorded as ‘<value’ or ‘>value’ then the 
value used for the descriptive statistics will be (value-0.1) or (value+0.1) respectively. For 
example, the numeric value 3.9 will used were a result was recorded as ‘<4.00’.   The last 
available assessment prior to the first drug administration will be defined as baseline value.  
Data listings will include actual laboratory values, the relevant normal ranges for that 
subject’s site, and whether or not the measurement was normal or abnormal according to 
the relevant laboratory normal ranges.  
11.5 
Pregnancy Test 
Female subjects will have a serum pregnancy test performed at screening. The results will 
be only listed. 


 
Page 34 of 35 
 
11.6 
Vital Signs  
Vital Signs (systolic blood pressure, diastolic blood pressure, pulse rate, temperature, and 
respiration rate) will be assessed throughout the study and weight and height at the 
Screening assessment only. 
Vital sign results and change from baseline will be summarized over time by treatment 
group, and listed by treatment and subject 
).    
11.7 
12-lead ECG 
12-lead ECG measurements include QT and QTc intervals. 
Where three ECG measurements are recorded at an assessment, then the average of those 
three measurements will be used as the measure at that visit in the summary table. The 
observed ECG results, and change from Screening, will be summarized at each scheduled 
visit and listed by treatment group 
.    
11.8 
Physical Examination 
A complete physical examination will be completed at screening, Weeks 2, 6, and 12/Early 
Termination, and the Post Study Visit. The results will be classified as “Normal”, 
“Abnormal” or “Not done” and subjects with any abnormalities will have the reason listed. 
Physical Examination results will be listed by Treatment 
.    
11.9 
Concomitant Medications/Treatments 
Concomitant medications will by coded using the WHO drug dictionary (latest release). 
The start and stop dates will be used to identify when a concomitant medication was taken 
during the study. 
Concomitant medications, Benzodiazepine Use, Psychotherapy and Nicotine Use will 
summarized separately by treatment group and the details included in listings. 
 
Concomitant medications prescribed due to an AE will also be listed separately.  


 
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12. 
REFERENCES 
1. SAS/STAT Software. 9.4 ed. Cary, NC: SAS Institute 
2. Rodwell, L., Lee, K., Romaniuk, H., & Carlin, J. (2014). Comparison of methods 
for imputing limited-range variables: a simulation study. BMC Medical Research, 
14-57. 
3. Mallinckrodt, C. Lipkovich I, (2017). Analysing Longitudinal Clinical Trial Data, 
A Practical Guide, Chapman and Hall 
4. Liang, K.-Y., and Zeger, S. L. (1986). “Longitudinal Data Analysis Using 
Generalized Linear Models.” Biometrika 73:13–22.  
5. Stokes, M. E., Davis, C. S., and Koch, G. G. (2012). Categorical Data Analysis 
Using SAS. 3rd ed. Cary, NC: SAS Institute Inc.