A Phase 2, Randomized, Double-blind Study to Evaluate the Efficacy and Safety of BNC210 Compared to Placebo for the Acute Treatment of Social Anxiety Disorder
Phase: PHASE2
Conditions: Social Anxiety Disorder
Sponsor: Bionomics Limited

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
1 
Title Page 
Protocol Title:  
A Phase 2, Randomized, Double-blind Study to Evaluate the Efficacy and Safety of BNC210 
Compared to Placebo for the Acute Treatment of Social Anxiety Disorder  
Protocol Number: BNC210.013 
Amendment Number: 1 
Compound: BNC210 
Brief Title: A Phase 2 Study of BNC210 for the Acute Treatment of Social Anxiety Disorder 
Study Phase: 2 
Sponsor Name: Bionomics Limited 
Legal Registered Address: 200 Greenhill Road, Eastwood, SA, 5063, AUSTRALIA 
Regulatory Agency Identifier Number(s): 
Registry 
ID 
IND 
 
NCT 
 
 
Approval Date: 17-NOV-2021 
Confidentiality Statement 
This document contains the confidential information of Bionomics Limited.  It is provided to you 
as an Investigator or consultant for review by you, your personnel, and the applicable Institutional 
Review Board (IRB). Your acceptance of this document constitutes an agreement that you will not 
disclose the information contained herein to others without the prior written consent of Bionomics 
Limited, unless it is necessary to obtain informed consent from potential study participants.  No 
other use or reproduction is authorized by Bionomics Limited, nor does Bionomics Limited 
assume any responsibility for unauthorized use of this protocol. 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
2 
 
 
Sponsor Signatory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bionomics Limited 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
3 
Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Rationale for Amendment 
Original Protocol 
Version 1.0 
30-Sep-2021 
Not applicable 
Protocol Version 1.1 
17-Nov-2021 
 
 
 
 
   
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
4 
Table of Contents 
1. 
Protocol Summary ..........................................................................................................7 
1.1. 
Synopsis ............................................................................................................................7 
 
 
1.3. 
Schedule of Activities (SoA) - Overview .......................................................................11 
1.4. 
Schedule of Activities (SoA) - Efficacy Assessments on 
Treatment Day ................................................................................................................13 
2. 
Introduction ...................................................................................................................14 
2.1. 
Study Rationale ...............................................................................................................14 
2.2. 
Background .....................................................................................................................15 
2.2.1. 
Disease Background........................................................................................................15 
 
 
 
 
 
 
 
 
2.3. 
Benefit/Risk Assessment ................................................................................................17 
3. 
Objectives, Endpoints, and Estimands .......................................................................18 
4. 
Study Design ..................................................................................................................21 
4.1. 
Overall Design ................................................................................................................21 
4.2. 
Scientific Rationale for Study Design ............................................................................21 
 
 
4.4. 
End of Study Definition ..................................................................................................23 
5. 
Study Population ...........................................................................................................24 
5.1. 
Inclusion Criteria ............................................................................................................24 
5.2. 
Exclusion Criteria ...........................................................................................................25 
5.3. 
Lifestyle Considerations .................................................................................................27 
5.4. 
Screen Failures ................................................................................................................27 
5.5. 
Criteria for Temporarily Delaying Randomization or 
Administration of Study Intervention .............................................................................28 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................29 
6.1. 
Study Intervention(s) Administered................................................................................29 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................30 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................31 
6.4. 
Study Intervention Compliance ......................................................................................32 
6.5. 
Dose Modification ..........................................................................................................32 
6.6. 
Continued Access to Study Intervention After the End of the 
Study ...............................................................................................................................32 
6.7. 
Treatment of Overdose ...................................................................................................33 
6.8. 
Concomitant Therapy .....................................................................................................33 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................35 
7.1. 
Discontinuation of Study Intervention ............................................................................35 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................35 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
5 
7.3. 
Lost to Follow-up............................................................................................................35 
8. 
Study Assessments and Procedures.............................................................................36 
8.1. 
Efficacy Assessments .....................................................................................................37 
 
 
8.1.2. 
Subjective Units of Distress Scale (SUDS) ....................................................................37 
8.1.3. 
Spielberger State-Trait Anxiety Inventory (STAI) .........................................................37 
8.1.4. 
Self-Statements During Public Speaking (SSPS) ...........................................................37 
8.2. 
Safety Assessments .........................................................................................................38 
8.2.1. 
Physical Examinations ....................................................................................................38 
8.2.2. 
Vital Signs .......................................................................................................................38 
8.2.3. 
Electrocardiograms .........................................................................................................38 
8.2.4. 
Clinical Safety Laboratory Assessments ........................................................................39 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring ...........................................................39 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and 
Other Safety Reporting ...................................................................................................40 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................40 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................40 
8.3.3. 
Follow-up of AEs and SAEs ...........................................................................................41 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................41 
8.3.5. 
Pregnancy ........................................................................................................................41 
8.4. 
Plasma Bioanalysis .........................................................................................................42 
8.5. 
Genetics ..........................................................................................................................42 
8.6. 
Biomarkers ......................................................................................................................42 
8.7. 
Immunogenicity Assessments.........................................................................................42 
8.8. 
Medical Resource Utilization and Health Economics ....................................................42 
9. 
Statistical Considerations .............................................................................................43 
9.1. 
Statistical Efficacy Hypotheses ......................................................................................43 
9.1.1. 
Multiplicity Adjustment ..................................................................................................44 
9.2. 
Analysis Sets ...................................................................................................................44 
9.3. 
Statistical Analyses .........................................................................................................44 
9.3.1. 
General Considerations ...................................................................................................44 
9.3.2. 
Study Participants and Demographics ............................................................................45 
9.3.3. 
Primary Endpoint(s)/Estimand(s) Analysis ....................................................................45 
9.3.4. 
Secondary and Exploratory Endpoints Analysis.............................................................46 
 
 
9.4. 
Interim Analysis ..............................................................................................................46 
 
 
10. 
Supporting Documentation and Operational Considerations ..................................47 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................47 
10.1.1. Regulatory and Ethical Considerations ...........................................................................47 
10.1.2. Financial Disclosure........................................................................................................47 
10.1.3. Informed Consent Process ..............................................................................................48 
10.1.4. Data Protection................................................................................................................48 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
6 
10.1.5. Data Quality Assurance ..................................................................................................49 
10.1.6. Source Documents ..........................................................................................................49 
10.1.7. Study and Site Closure ....................................................................................................50 
10.1.8. Publication Policy ...........................................................................................................50 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................51 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................53 
10.3.1. Definition of AE .............................................................................................................53 
10.3.2. Definition of SAE ...........................................................................................................54 
10.3.3. Recording and Follow-Up of AE and/or SAE ................................................................55 
10.3.4. Reporting of SAEs ..........................................................................................................58 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................60 
10.4.1. Definitions.......................................................................................................................60 
10.4.2. Contraception Guidance..................................................................................................61 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................62 
10.6. 
Appendix 6: Abbreviations .............................................................................................64 
11. 
References ......................................................................................................................67 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
7 
1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: A Phase 2, Randomized, Double-blind Study to Evaluate the Efficacy and 
Safety of BNC210 Compared to Placebo for the Acute Treatment of Social 
Anxiety Disorder 
Brief Title: 
A Phase 2 Study of BNC210 for the Acute Treatment of Social Anxiety 
Disorder 
Rationale: 
This Phase 2 study will assess the potential efficacy of BNC210 in the acute treatment of social 
anxiety disorder (SAD). Anxiety symptoms in adults with SAD will be evaluated during an 
induced public speaking challenge following single-dose acute administration of BNC210 (or 
placebo). 
Previous human studies with BNC210 have established its safety and tolerability and 
demonstrated statistically significant results in a Phase 1 study using a panic model in healthy 
volunteers and in a Phase 2a study in patients with generalized anxiety disorder (GAD). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
10 
Brief Summary: 
The purpose of this study is to assess the effects of an acute dose of BNC210 compared to p
lacebo on reducing the severity of anxiety levels provoked by a public speaking challenge and 
measured using the SUDS in patients with SAD. 
Number of Participants: 
Approximately 250 participants will be screened to achieve a total enrollment of approximately 
150 randomly assigned participants. 
Intervention Groups and Duration: 
The total duration for each participant enrolled in the study is expected to be approximately 
3 weeks following the sequence below: 
• Screening Period: 14 days (+3) 
• Treatment Period with public speaking challenge: 1 day 
• Follow-up Period: 7 (±3) days after treatment 
Details of study assessments to be conducted at each visit are included in the Schedule of 
Activities (SoA) in Sections 1.3 and 1.4. 
Each participant will be randomized in a 1:1:1 ratio to receive a single dose of 225 mg BNC210, 
675 mg BNC210, or placebo. Treatment assignments will be double-blinded. 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
 
11 
1.3. 
Schedule of Activities (SoA) - Overview 
 
ASSESSMENTS1 
Screening 
≤ 14 days 
(+3 days) 
Treatment Day 
Follow-up 
via phone/video 
conference 
7 days post 
treatment 
(±3 days) 
Baseline / 
Pre-Dose2 
Dosing 
Public 
Speaking 
Challenge 
Post-
Challenge 
Informed consent 
X 
 
 
 
 
 
Inclusion and exclusion criteria3 
X 
X 
 
 
 
 
Demography 
X 
 
 
 
 
 
Medical history including current & prior medications 
X 
 
 
 
 
 
Structured Clinical Interview for DSM-5 Disorders - Clinical 
Trials version (SCID-5-CT)  
X 
 
 
 
 
 
Liebowitz Social Anxiety Scale (LSAS) 
X 
 
 
 
 
 
Hamilton Depression Rating Scale (HAM-D) 
X 
 
 
 
 
 
Columbia-Suicide Severity Rating Scale (C-SSRS)4 
X 
X 
 
 
 
 
Human immunodeficiency virus (HIV), Hepatitis B surface 
antigen (HBsAg) and Hepatitis C virus (HCV) antibody 
screen 
X 
 
 
 
 
 
Serum pregnancy test (if applicable) 
X 
 
 
 
 
 
Urine drug screen5 
X 
X 
 
 
 
 
Physical examination6 
X 
X 
 
 
 
 
Vital signs7 
X 
X 
 
 
X8 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
 
12 
ASSESSMENTS1 
Screening 
≤ 14 days 
(+3 days) 
Treatment Day 
Follow-up 
via phone/video 
conference 
7 days post 
treatment 
(±3 days) 
Baseline / 
Pre-Dose2 
Dosing 
Public 
Speaking 
Challenge 
Post-
Challenge 
12-lead electrocardiogram (ECG)9 
X 
 
 
 
X10 
 
Clinical laboratory tests (hematology, biochemistry, 
urinalysis) 
X 
X 
 
 
X11 
 
Concomitant medications recording 
X 
X 
 
 
 
 
Urine pregnancy test (if applicable)12 
 
X 
 
 
 
 
Randomization13 
 
X 
 
 
 
 
Subjective Units of Distress Scale (SUDS)14 
 
X 
 
X 
X 
 
Spielberger State-Trait Anxiety Inventory-State component 
(STAI-State)15 
 
X 
 
X 
X 
 
Self-Statements During Public Speaking () (SSPS)16 
 
X 
 
X 
X 
 
Dosing with Study Intervention17 
 
 
X 
 
 
 
Blood sample collection for BNC210 concentration18 
 
 
 
 
X 
 
Assessment of participant’s readiness for discharge19 
 
 
 
 
X 
 
Adverse Event (AE) recording 
 
 
X 
X20 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
14 
2. 
Introduction 
Bionomics Limited is developing BNC210 for the treatment of anxiety disorders and trauma- 
and stressor-related disorders.  BNC210 is a negative allosteric modulator of the alpha-7 
nicotinic acetylcholine receptor (alpha-7 nAChR), which represents a novel target for the 
treatment of these disorders.  BNC210 is a new chemical entity that has exhibited potent 
anxiolytic activity in a range of animal models at low doses with a wide therapeutic window.  
There is an absence of adverse effects, particularly those associated with treatments for acute 
anxiety disorders, such as benzodiazepines, and the antidepressants used in first-line 
pharmacotherapy for chronic anxiety disorders. 
2.1. 
Study Rationale 
This Phase 2 study will assess the potential benefits of BNC210 in the acute treatment of social 
anxiety disorder (SAD). Anxiety symptoms in adults with SAD will be evaluated during a public 
speaking challenge, following single-dose acute administration of 1 of 2 dosages of BNC210 or 
placebo. 
Previous human studies with BNC210 have established its safety and tolerability and 
demonstrated statistically significant results in a Phase 1 study using a panic model in healthy 
volunteers and in a Phase 2a study in patients with generalized anxiety disorder (GAD). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
15 
2.2. 
Background 
2.2.1. 
Disease Background 
Social Anxiety Disorder is a serious anxiety disorder characterized by the persistent, intense fear 
of social or performance-related situations in which an individual is exposed to unfamiliar people 
or to possible scrutiny by others. Social Anxiety Disorder can also manifest from specific 
triggers such as a fear of public speaking or be induced by social interactions across any variety 
of situations. Those suffering from SAD often fear that they will act in a way or show anxiety 
symptoms that will be embarrassing and humiliating, thus further inducing anxiety. This fear can 
affect work, school, and other day-to-day activities and can even make it hard to develop and 
maintain friendships.  Most cases of SAD develop in adolescence or early adulthood and without 
treatment can persist and prevent individuals from reaching their full potential. 
Antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin 
noradrenaline reuptake inhibitors (SNRIs), currently serve as first-line pharmacotherapies for 
SAD. However, SSRIs/SNRIs typically require several weeks of chronic administration before 
onset of action, making them inadequate for the treatment of acute anxiety episodes in SAD. 
There are no approved drugs for the acute treatment of SAD, although anti-anxiety medications 
such as benzodiazepines, or beta blockers which help reduce the physical symptoms of anxiety, 
are commonly used off-label. Benzodiazepines are potent, fast-acting anxiolytic drugs, but they 
are sedating and carry significant safety risks, including memory and motor impairment, serious 
risk of abuse, addiction, physical dependence, and withdrawal reactions, as highlighted in the 
FDA Drug Safety Communication, September 2020. Those with SAD are also at increased risk 
of alcohol use disorder, turning to alcohol and other substances in anticipation of social 
situations. 
Thus, there is a need for improved therapeutics for acute treatment of SAD, with fast onset of 
action and fewer side effects, which might be achieved by targeting a different mechanism of 
action. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
17 
 
 
 
 
 
 
 
 
 
 
 
 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of BNC210 can be found in the Investigator’s Brochure (IB) and the participant 
Informed Consent Form (ICF). 
No potential significant risks have been identified in the nonclinical or clinical studies of 
BNC210.  At this stage in development, the benefit-risk profile of BNC210 appears favorable.

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
20 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
21 
4. 
Study Design 
4.1. 
Overall Design 
This is a randomized, double-blind, placebo-controlled, 3-arm, parallel-group, multi-center study c
omparing the effects of single acute doses of BNC210 and placebo when participants with SAD 
perform an induced public speaking challenge.  Participants will attend a Screening Visit to 
confirm eligibility. Approximately 150 participants who fulfill the inclusion criteria and none of 
the exclusion criteria will return to the clinic within 14 days after the Screening Visit and be 
randomized to receive either 225 mg BNC210, 675 mg BNC210, or matched placebo (in a ratio 
of 1:1:1). Randomized participants will then receive a single dose of their allocated study 
intervention and approximately 1 hour later, each will participate in a public speaking challenge. 
Approximately 1 week later, a follow-up assessment will be conducted by phone/video 
conference for any reports of AEs. 
Details are included in the Schedule of Activities (SoA), Section 1.3 and 1.4). 
4.2. 
Scientific Rationale for Study Design 
The primary objective of this study is to assess the effects of BNC210 compared to placebo on 
public speaking anxiety symptom severity using the SUDS, a commonly used scale for 
measuring performance anxiety in behavioral avoidance tasks such as a public speaking 
challenge. A public speaking challenge is a very consistent experimental model for the induction 
of anxiety in both healthy volunteers and in individuals diagnosed with SAD or social phobia, 
and has been used in studies investigating the effects of pharmacological and 
nonpharmacological interventions on subjective measures of anxiety in patients with SAD 
 
 
 
 
 
 
A double-blind, placebo-controlled study design has been chosen as a well-established and 
appropriate study design to minimize the potential for bias in study assessments or in reporting 
of AEs. Clinic staff and participants are blinded to treatment assignments to ensure objective 
reporting. In addition, participants will be randomized 1:1:1 to receive 1 of 2 doses of BNC210 
or placebo to ensure there are no order effects and to further minimize bias. 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
23 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the follow-up assessment for the last participant in 
the study. 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
24 
5. 
Study Population 
Investigators will be responsible for evaluating potential participants against the study eligibility 
criteria during the Screening Period.  At the initial Screening Visit, each participant will 
participate in the informed consent process and sign and date the ICF before any procedures 
specified in this protocol are performed. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant is 18 to 65 years of age (inclusive) at the time of signing informed consent. 
Type of Participant and Disease Characteristics 
2. Participant has a current diagnosis of SAD as defined in the Diagnostic and Statistical M
anual of Mental Disorders, fifth edition (DSM-5) and confirmed by the Structured 
Clinical Interview for DSM-5 Disorders - Clinical Trials version (SCID-5-CT). 
3. Participant has a Liebowitz Social Anxiety Scale (LSAS) total score of ≥70 and a sub-
score of 3 on Question 6 (Fear or Anxiety subscale) at Screening. 
4. In the opinion of the Investigator, the participant has a high probability for adherence 
with and completion of the study. 
5. Participant is fluent in English and able to understand and comply with written and 
verbal protocol-related requirements. 
6. Participant is able to swallow tablets. 
Sex and Contraceptive/Barrier Requirements 
 
7. Participants’ contraceptive use should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
a. Male participants are eligible to participate if they agree to the following during the 
study intervention period and for at least 60 days after the dose of study 
intervention: 
• Refrain from donating sperm PLUS, either: 
o Be abstinent from heterosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long-term and persistent basis) and agree to remain 
abstinent 
OR 
o Must agree to use a male condom with female partner using an additional 
highly effective contraceptive method with a failure rate of < 1% per year as 
described in Appendix 4: Contraceptive and Barrier Guidance, when having 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
25 
sexual intercourse with a woman of childbearing potential (WOCBP) who is 
not currently pregnant 
b. Female participants are eligible to participate if they are not pregnant or 
breastfeeding and the following conditions apply: 
o Is of nonchildbearing potential (WONCBP) as defined in Appendix 4: 
Contraceptive and Barrier Guidance. 
OR 
o Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of < 1% per year), preferably with low user dependency, as 
described in Appendix 4: Contraceptive and Barrier Guidance during the study 
intervention period and for at least 60 days after the dose of study intervention 
and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction 
during this period. The Investigator should evaluate the potential for 
contraceptive method failure (e.g., noncompliance, recently initiated) in 
relationship to the first dose of study intervention. 
• A WOCBP must have a negative serum pregnancy test at Screening and a 
negative urine test at baseline (within 24 hours before the first dose of study 
intervention). 
The Investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy. 
Informed Consent 
8. Capable of giving signed informed consent as described in Appendix 1: Regulatory, 
Ethical, and Study Oversight Considerations which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Participant has a history of schizophrenia, bipolar disorder, or psychotic disorders as 
identified at Screening, or has a current clinically predominant diagnosis of any other 
Axis I disorder, other than SAD, at the time of the Screening Visit.  
2. Participant has a score of ≥18 on the Hamilton Rating Scale for Depression (HAM-D) 
at Screening. 
3. Participant has moderate or severe alcohol-use disorder, or any other substance-use 
disorder (any severity), according to DSM-5, in the 12 months prior to Screening. 
4. Participant has increased risk of suicide, defined as: 
• Any suicide attempt in the 12 months prior to Screening disclosed by the 
participant using the Columbia-Suicide Severity Rating Scale (C-SSRS). 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
26 
• Any suicidal ideation with intent (yes to item 4 and/or 5) or suicidal behavior in the 
past 12 months, as captured at Screening using the C-SSRS. 
5. Participant has 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). 
6. Participant has alanine transaminase (ALT), aspartate transaminase (AST) or alkaline 
phosphatase (ALP) >2.0 × upper limit of normal (ULN). 
7. Participant has total bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable 
if total bilirubin is fractionated and direct bilirubin <35%). 
8. Participant has current or chronic history of liver disease. This includes, but is not 
limited to, hepatitis virus infections, drug- or alcohol-related liver disease, nonalcoholic 
steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson’s disease, α-1 
antitrypsin deficiency, primary biliary cholangitis, primary sclerosing cholangitis, or 
any other liver disease considered clinically significant by the Investigator. 
9. Participant has any clinically significant abnormalities in laboratory test results 
(biochemistry, hematology, or urinalysis) as assessed by the Investigator. 
10. Participant has blood pressure systolic >160 mmHg or diastolic >90 mmHg. Two 
repeat measures are allowed at the discretion of the Investigator. 
11. Fridericia-corrected QT interval (QTcF) >450 msec for males and QTcF >470 msec for 
females, or QTc >480 msec in participants with bundle branch block, as measured by 
ECG at Screening. 
12. Participant has any clinically significant ECG abnormality as determined by the 
Investigator at Screening. 
13. Participant has a family history of congenital long QT syndrome, Brugada syndrome, 
or unexplained sudden cardiac death. 
Prior/Concomitant Therapy 
14. Participant has used psychotropic medications, including antidepressants, mood 
stabilizers, stimulants, antipsychotics, anticonvulsant drugs (including gabapentinoids), 
hypnotics (zolpidem, zopiclone, eszopiclone, zaleplon), acetylcholinesterase inhibitors, 
or anxiolytics such as benzodiazepines within 30 days of Screening. Participants who 
have been taking benzodiazepines daily within 90 days of Screening are also not 
eligible to participate. No concurrent use of these medications is allowed on study. 
15. Participant has used beta blockers, doxazosin, prazosin, clonidine, first-generation 
sedating H1 antihistamines, any recreational drugs, over-the-counter medication, or 
herbal preparations to treat symptoms of anxiety or SAD within 30 days of Screening. 
No concurrent use of these medications is allowed on study. 
16. Participant has used cytochrome P450 3A4 inducers within 30 days of Screening. 
17. Participant has used moderate-strong cytochrome P450 3A4 inhibitors within 2 weeks 
of Screening.  This includes, but is not limited to, grapefruit or grapefruit-containing 
products. 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
27 
Prior/Concurrent Clinical Study Experience 
18. Participant is currently enrolled OR has previously participated in another 
investigational study in which an investigational intervention (e.g., drug, vaccine, 
invasive device) was administered within 30 days before signing of consent in this 
clinical study. 
19. Participant has previously participated in a study that involved a public speaking 
challenge. 
Diagnostic Assessments 
20. Participant has a positive result for human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HBsAg), or hepatitis C (HCV) at Screening. 
21. Participant has a positive urine test for an illicit substance, including cannabis. No 
concurrent use of these substances is allowed on study. 
Other Exclusions 
22. Participant has a history of allergies, allergic reactions, or hypersensitivity to BNC210 
or its excipients. 
23. Participants who, in the opinion of the Investigator, are not suitable to participate in the 
study due to clinically significant findings from medical history that could interfere 
with the objectives of the study or put the participant at risk or any other reason the 
Investigator deems applicable. 
 
 
5.3. 
Lifestyle Considerations 
There are no specific lifestyle considerations or restrictions applicable to this study outside of the 
criteria detailed in Sections 5.1, 5.2, and 6.8.  
 
 
 
 
 
 
5.4. 
Screen Failures 
Participants who sign and date the ICF but who fail to meet the inclusion and exclusion criteria 
are considered screen failures. Reason(s) for screen failure must be documented by the 
Investigator and provided to the Sponsor in a timely fashion. 
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAEs. 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
28 
In the event that a participant fails a clinical laboratory or ECG screening assessment, that 
assessment can be repeated once only during the Screening Period. The repeat assessment must 
be completed within the allowed Screening Period (14 days) for eligibility purposes. If the repeat 
assessment cannot be completed within the Screening Period, the participant must be re-screened 
in entirety. Participants who fail any other screening assessment must be screen-failed. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened, if deemed appropriate by the Investigator and with prior approval from the 
sponsor/medical monitor.  Rescreened participants should be reconsented and be assigned a new 
participant number (Subject ID) for every screening/rescreening event. 
5.5. 
Criteria for Temporarily Delaying Randomization or Administration 
of Study Intervention 
Section not applicable 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
29 
6. 
Study Intervention(s) and Concomitant Therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
 
 
 
 
 
  
6.1. 
Study Intervention(s) Administered 
In this parallel-group, randomized study, participants who meet study entry criteria will be 
randomly assigned in a 1:1:1 ratio to receive either 225 mg BNC210, 675 mg BNC210, or 
placebo. 
 
 
 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
30 
 
Table 3.  Study Arm(s) 
Arm Title 
225 mg BNC210  
675 mg BNC210 
Placebo 
Arm Type 
Experimental 
Experimental 
Placebo 
Comparator 
Associated Intervention 
Labels 
225 mg BNC210 
675 mg BNC210 
Placebo 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and ensure any discrepancies 
are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention, and only 
authorized site staff may administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information on the handling, storage, accountability, dispensing and 
for the final disposition of unused study interventions are provided in the Investigational 
Product Manual. 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
31 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
 
IWRS 
After a participant signs the ICF at Screening, site personnel will register 
the participant in the interactive web response system (IWRS). 
Upon successful completion of the Screening Module, the system will 
assign the participant a unique participant number (Subject ID). 
Randomization will be performed as double-blind, central randomization. 
The randomization schedule will be computer generated using a permuted 
block algorithm and will randomly allocate study intervention to 
randomization numbers. The randomization numbers will be assigned 
sequentially through the IWRS as participants enter the study. Study 
center will not be a blocking factor in the randomization schedule. 
The randomization schedule will be prepared before the start of the study. 
No one involved in the study performance will have access to the 
randomization schedule before official unblinding of treatment 
assignment. No participant will be randomized into this study more than 
once. 
Upon successful completion of randomization in the IWRS, the system 
will determine the correct study intervention to dispense. Once a 
participant is randomized to a treatment arm, the randomization will 
remain documented as such. The system will never reuse the same 
randomization number. 
The system will then determine which specific wallet (with assigned 
number) of the assigned study intervention type is available for 
dispensing and inform the study site to dispense that specific wallet. The 
assigned wallet will correspond to the correct treatment for the 
participant. 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
32 
Blinding and 
breaking of the 
blind via IWRS 
This is a double-blind study in which all participants, investigators, raters, 
and study personnel involved in the conduct of the study, including data 
management, will be blinded to treatment assignment, with the exception 
of a specified unblinded statistician and programmer who will have access 
to the randomization code. The unblinded study personnel will not 
participate in study procedures or data analysis prior to unblinding of the 
study data to all study-related personnel. 
Study personnel will make every effort to safeguard the integrity of the 
study blind to minimize bias in the conduct of the study. Treatment 
unblinding is discouraged if knowledge of the treatment assignment will 
not materially change the planned management of a medical emergency. 
Unblinding will be permitted in a medical emergency that requires 
immediate knowledge of the participant’s treatment assignment. 
Participant safety must always be the first consideration in making such a 
determination. 
Unblinding should be discussed in advance with the Medical Monitor, if 
possible. If the investigator is not able to discuss treatment unblinding in 
advance, then they must notify the Medical Monitor as soon as possible 
about the unblinding incident without revealing the participant’s treatment 
assignment. 
For emergency unblinding, study personnel will use the IWRS. The IWRS 
will be programmed with blind-breaking instructions. If a participant’s 
intervention assignment is unblinded, the sponsor must be notified within 
24 hours of this occurrence. The date and reason that for the unblinding 
must be recorded. 
Overall unblinding will take place at the end of the study only after 
database lock. 
6.4. 
Study Intervention Compliance 
Study intervention will be administered at the study site under direct supervision of authorized 
site staff. A mouth check will be performed to ensure that the dose was swallowed. 
6.5. 
Dose Modification 
Dose reductions or increases will not be allowed in this study. 
6.6. 
Continued Access to Study Intervention After the End of the Study 
Participants will not have access to study interventions after completion of their participation in 
the study.  Participants should be directed to receive standard of care treatments as directed by 
the Investigator or their primary care physician. 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
33 
6.7. 
Treatment of Overdose 
For this study, any dose of BNC210/placebo greater than 675 mg will be considered an overdose. 
In the event of a suspected overdose, the investigator should: 
• Contact the Medical Monitor immediately. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until they 
have resolved or stabilized. 
• Document the quantity of the excess dose. 
6.8. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) or other specific categories of interest that the 
participant is receiving at the time of Screening or receives during the study must be recorded 
along with: 
• Reason for use 
• Dates of administration, including start and end dates 
• Dosage information, including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Use of any investigational drug, vaccine, or invasive device within 30 days prior to Screening 
and at any point during the study is prohibited. 
Inducers of cytochrome P450 3A4 should not be used within 30 days of Screening and their use 
is prohibited during the study. This includes, but is not limited to: carbamazepine, phenytoin, 
oxcarbazepine, barbiturates, phenobarbital, butalbital, St. John's wort, rifampicin, rifabutin, 
efavirenz, nevirapine, pioglitazone, troglitazone, corticosteroids by the systemic route (refer to 
the following website for a more extensive list https://drug-
interactions.medicine.iu.edu/MainTable.aspx).  
Moderate to strong inhibitors of cytochrome P450 3A4 should not be used within 14 days of 
Screening and their use is prohibited during the study.  These include grapefruit juice, verapamil, 
diltiazem, fluvoxamine, fluconazole and itraconazole, and HIV antivirals (refer to the following 
website for a more extensive list https://drug-interactions.medicine.iu.edu/MainTable.aspx). 
Participants who are being treated with an antidepressant medication must have discontinued the 
medication for at least 30 days prior to Screening (as per exclusion criterion #14) and be titrated 
off their medication in accordance with current prescribing guidelines. Participants must also 
have discontinued chronic daily use of benzodiazepines for at least 90 days prior to Screening. 
The withdrawal of these medications is at the discretion of the participant in consultation with 
their primary physician and falls outside the scope of this study protocol. Concurrent use of these 
medications is also prohibited during all stages of the study. 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
34 
The use of any other central nervous system (CNS)-acting medications, including intermittent 
use of benzodiazepines, beta blockers, recreational drugs, over-the-counter medications, or 
herbal preparations for the treatment of symptoms of anxiety or SAD, is also not allowed within 
30 days of Screening and at no time during the study. 
The CNS-acting medications prohibited during the study include, but are not limited to, 
antidepressants, mood stabilizers, methylphenidate and other stimulants, quetiapine and other 
antipsychotics, anticonvulsant drugs (including gabapentinoids), zaleplon and other hypnotics, 
benzodiazepines, doxazosin, prazosin, clonidine, first generation sedating H1 antihistamines, 
zopiclone, eszopiclone, zolpidem extended-release and acetylcholinesterase inhibitors.  
The use of other nonprescription medications (including herbal medications not for the treatment 
of symptoms of anxiety or SAD) 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.  
If a medication or treatment is administered that is in breach of these restrictions, the medical 
monitor must be notified promptly in order to assess the participant’s suitability for continued 
study participation. 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
35 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
The process for discontinuation of specific sites or the study as a whole are detailed in Appendix 
1: Regulatory, Ethical, and Study Oversight Considerations. 
7.1. 
Discontinuation of Study Intervention 
Section not applicable. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
• If the participant had received study intervention prior to discontinuing from the study, a 
Follow-up Visit should be conducted if possible, as shown in the SoA (Section 1.3). 
• If the participant withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she repeatedly is unable to be contacted 
by the study site for the Follow-up Visit. 
The following actions must be taken if a participant initially is unable to be contacted for the 
Follow-up Visit: 
• The site must attempt to contact the participant and reschedule the missed 
visit/appointment as soon as possible and counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the participant 
wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
36 
8. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA (Sections 1.3 and 1.4). 
Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Medical Monitor immediately 
upon occurrence or awareness to determine if the participant should continue on study. 
• Adherence to the study design requirements, including those specified in the SoA 
(Sections 1.3 and 1.4), is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
• At the conclusion of the post-challenge assessment period on the Treatment Day, the 
Investigator should assess the participant’s suitability to be discharged from the study site 
based on their medical judgment. 
• Visits scheduled due to increased safety monitoring, if applicable, must be captured as an 
unscheduled visit. 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. 
• A visit with a participant’s primary physician (i.e., not a study Investigator) is not 
considered an unscheduled visit. Similarly, hospital admissions due to SAEs are also not 
considered unscheduled visits. Assessments completed by external institutions should not 
be entered into the eCRF. 
 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
37 
8.1. 
Efficacy Assessments 
Planned timepoints for all efficacy assessments are provided in the SoA (Section 1.3 and 1.4). 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
8.1.2. 
Subjective Units of Distress Scale (SUDS) 
The SUDS measures the subjective intensity of disturbance or distress currently experienced by 
an individual and is a standard instrument for rating social and performance anxiety in patients 
with SAD during role-playing situations. The individual self-assesses where they are on the 
scale, between 0-100, with higher numbers indicating more anxiety/greater discomfort (Wolpe, 
1969, Heimberg 1998, 2002). 
8.1.3. 
Spielberger State-Trait Anxiety Inventory (STAI) 
The STAI (Spielberger 1983) is a widely used self-report measure of subjective anxiety in 
clinical practice. It comprises 2 scales of 20 items asking participants to report their feelings of 
anxiousness: the STAI-State scale requires reporting of feelings at the time of questionnaire 
completion and the STAI-Trait scale requires reporting of how the subject generally feels. 
Responses are marked on a 4-point scale from “not at all” to “very much so.” The STAI-State 
component only will be used in this study. 
8.1.4. 
Self-Statements During Public Speaking (SSPS) 
The SSPS is a self-report instrument that assesses cognitions related to public speaking 
(Hofmann 2000). The original version of the SSPS assesses how a participant typically 
thinks/feels during any public speaking situation (SSPS-Trait). The SSPS has also been modified 
and validated to assess how a participant feels at the time of questionnaire completion in relation 
to a current public speaking situation (SSPS-State) (Osorio 2013). Both the SSPS-Trait and 
SSPS-State versions will be used in this study at the time points specified in Section 1.4. The 
SSPS is a 10-item questionnaire consisting of two 5-item subscales, the Positive Self-Statements 
(SSPS-P) and the Negative Self-Statements (SSPS-N). Only the SSPS-N subscale will be 
included in the secondary endpoint analyses in this study. 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
38 
8.2. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the general 
appearance, skin and lymphatics, eyes, ears, nose, throat, cardiovascular system, 
respiratory system, abdomen/gastrointestinal system, musculoskeletal, and neurological 
systems.  Other body systems may also be examined as required. Height and weight will 
also be measured at Screening only. 
• An abbreviated physical examination will include, at a minimum, assessments of the 
eyes, ears, nose, throat, cardiovascular system, respiratory system, and 
abdomen/gastrointestinal system. Other body systems may also be examined as required. 
8.2.2. 
Vital Signs 
• Body temperature, pulse rate, respiratory rate, and systolic and diastolic blood pressure 
will be assessed. 
• Blood pressure and pulse measurements will be assessed in a seated position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
in a seated position for the participant in a quiet setting without distractions (e.g., 
television, cell phones). 
8.2.3. 
Electrocardiograms 
• Triplicate 12-lead ECGs will be obtained as outlined in the SoA (Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. 
• At each time point, 3 individual ECG tracings should be obtained in succession, 
approximately 2 minutes apart. 
• One repeat is allowed for screening purposes if abnormal findings are observed. The 
repeat must also be completed in triplicate. 
• Participants must be resting in a semi-supine or supine position for at least 5 minutes 
prior to obtaining ECG.  
• The same ECG machine should be used for all recordings from an individual participant, 
where possible.  
• ECGs will be read by the Investigator or designated physician.  
• QTcF values will be derived from the data available and the average QTcF will be used 
when assessing eligibility. 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
39 
For safety monitoring purposes, the Investigator or designee must review, sign, and date all ECG 
tracings.  Paper copies will be kept at the study center with the participant's clinical file as part of 
the permanent record.  The ECG intervals and interpretation will be recorded on the appropriate 
eCRF. 
Paper ECG recordings should be photocopied and maintained as a permanent source document.  
The Sponsor reserves the right to request copies of paper ECG recordings for independent 
cardiology review. 
8.2.4. 
Clinical Safety Laboratory Assessments 
• See Appendix 2: Clinical Laboratory Tests for the list of clinical laboratory tests to be 
performed and to the SoA (Section 1.3) for the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline 
or are no longer considered clinically significant by the Investigator or Medical Monitor. 
o If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the Investigator, the etiology should be identified, and the 
medical monitor/sponsor notified. 
o All protocol-required laboratory tests, as defined in Appendix 2: Clinical Laboratory 
Tests, must be conducted in accordance with the Laboratory Manual and the SoA 
(Section 1.3). 
o If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE), then the results 
must be recorded. 
o All events of ALT or AST ≥3 × ULN and total bilirubin ≥2 × ULN (>35% direct 
bilirubin) which may indicate severe liver injury (possible Hy’s Law), as well as all 
events of ALT or AST  5 x ULN, must be reported to the medical monitor in an 
expedited manner. Details of required actions and follow-up are given in Appendix 5: 
Liver Safety: Suggested Actions and Follow-up Assessments. 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring 
BNC210 is considered to be a CNS-active intervention. 
Baseline assessment of suicidal ideation and behavior will be assessed using the C-SSRS. 
The C-SSRS is a suicidal ideation rating scale designed to identify behaviors that may be 
indicative of a participant’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. 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
40 
Prior to the participant being discharged from the study site on the Treatment Day, the 
Investigator will assess any intervention-emergent suicidal behavior as part of their overall 
assessment of the participant’s suitability to be discharged. 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting 
The definitions of AEs and SAEs can be found in Appendix 3: AEs and SAEs: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs/SAEs. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3: AEs and 
SAEs: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the signing of the ICF until the Follow-up Visit at the timepoints 
specified in the SoA (Section 1.3). 
All AEs will be collected from the start of intervention until the Follow-up Visit at the timepoints 
specified in the SoA (Section 1.3). Medical occurrences that begin before the start of study 
intervention, but after obtaining informed consent will be recorded as medical history/current 
medical conditions, not as AEs. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3: AEs and SAEs: 
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting. The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
41 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the participant is lost to follow-up (as defined in Section 
7.3). Further information on follow-up procedures is provided in Appendix 3: AEs and SAEs: 
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities to the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Board (IRB) 
and Investigators. 
• An Investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file it along with the IB and will notify the IRB, if appropriate according 
to local requirements. 
8.3.5. 
Pregnancy 
• Details of all pregnancies in female participants and female partners of male participants w
ill be collected after the start of study intervention and until 1 week after the last dose of 
study intervention is administered. 
• If a pregnancy is reported in a female participant or female partner of male participant 
(after obtaining the necessary signed informed consent from the female partner), the 
Investigator will record pregnancy information on the appropriate form and submit it 
promptly, within 24 hours of learning of the pregnancy, signing and dating the Pregnancy 
Data Collection Form, verifying the accuracy of the information recorded in the form 
with the source documents and eCRF.  Pregnancy reporting contact information can be 
found in Appendix 3, Section 10.3.4. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the 
participant/pregnant female partner and the neonate and the information will be 
forwarded to the Sponsor. 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
42 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4.  While the Investigator is not obligated to actively seek this information in 
former study participants/pregnant female partner, he or she may learn of an SAE through 
spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and be withdrawn from the study. 
8.4. 
Plasma Bioanalysis 
• Whole blood samples of approximately 4 mL will be collected for measurement of 
plasma concentrations of BNC210 as specified in the SoA (Section 1.3). 
• As the study is double-blind, samples will be collected from all participants, but only 
those allocated to BNC210 treatment arms will have their samples analyzed. 
• Instructions for the collection and handling of biological samples will be provided by the 
Sponsor in the study-specific Laboratory Manual. 
8.5. 
Genetics 
Genetics are not evaluated in this study. 
8.6. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.7. 
Immunogenicity Assessments 
Not applicable. 
8.8. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics parameters are not evaluated in this study. 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
43 
9. 
Statistical Considerations 
The statistical analysis plan (SAP) will be finalized prior to database lock and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints, 
including primary and secondary endpoints. 
9.1. 
Statistical Efficacy Hypotheses 
The primary objective of this study is to assess the effects of a single dose of BNC210 compared 
to placebo on change in self-reported anxiety severity as measured by the SUDS from baseline to 
the performance phase in a public speaking challenge. 
• The null hypothesis for the primary efficacy endpoint of equality of a single dose of 
BNC210 and placebo is: 
H01: Mean changes in SUDS scores between baseline and the average of the performance 
phase in a public speaking challenge between either single dose (225 mg or 675 mg) of 
BNC210 and placebo are equal 
The secondary objectives of this study and their respective null hypotheses of the equality of a 
single dose (225 mg or 675 mg) of BNC210 and placebo are: 
• To assess the effects of BNC210 compared to placebo in reducing self-reported anxiety 
severity as measured by the SUDS in a public speaking challenge 
H02: Mean changes in SUDS scores between baseline and the average of the anticipation 
phase in a public speaking challenge between either single dose (225 mg or 675 mg) of 
BNC210 and placebo are equal 
 
 
 
 
 
 
 
 
 
• To assess the effects of BNC210 compared to placebo in reducing self-reported 
symptoms of anxiety as measured by the STAI-State in a public speaking challenge 
H06: Mean changes in STAI-State scores between baseline and the performance phase in 
a public speaking challenge between either single dose (225 mg or 675 mg) of BNC210 
and placebo are equal 
H07: Mean changes in STAI-State scores between baseline and the anticipation phase in a 
public speaking challenge between either single dose (225 mg or 675 mg) of BNC210 
and placebo are equal 
• To assess the effects of BNC210 compared to placebo in reducing self-reported negative 
cognitions during speaking as measured by the SSPS-N in a public speaking challenge 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
44 
H08: Mean changes in SSPS-N scores between baseline and the performance phase in a 
public speaking challenge between either single dose (225 mg or 675 mg) of BNC210 
and placebo are equal 
H09: Mean changes in SSPS-N scores between baseline and the anticipation phase in a 
public speaking challenge between either single dose (225 mg or 675 mg) of BNC210 
and placebo are equal 
9.1.1. 
Multiplicity Adjustment 
Because this is a Phase 2 study, the level of significance will be set at 0.05 for primary and 
secondary endpoints with no adjustment for multiple comparisons. 
9.2. 
Analysis Sets 
The following analysis populations are planned for this study: 
• Safety Population (SAF): The safety population includes all participants who receive any 
amount of the study intervention. The safety population will be used for the analysis of 
the safety endpoints. Participants will be analyzed by actual treatment received. 
• Intent-to-Treat Population (ITT): The ITT population includes all randomized 
participants. Participants will be analyzed by randomized treatments. 
• Full Analysis Set (FAS): The FAS population includes all participants in the ITT 
population who receive any amount of the study intervention. Participants will be 
analyzed by randomized treatment. 
• Per-Protocol Population (PP): The per-protocol population will include participants from 
the FAS population who have no major protocol deviations. 
 
 
 
 
 
 Participants will be analyzed by 
randomized treatments. 
 
 
 
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
This section presents a summary of the planned statistical analyses. A SAP that describes the 
details of the analyses to be conducted will be written prior to the study database being locked. 
Unless otherwise indicated, all testing of statistical significance will be two-sided and a 
difference resulting in a p value of ≤0.05 will be considered statistically significant. 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
45 
Summary statistics will be provided for the variables described below. For continuous variables, 
these statistics will typically include the number of participants, mean, standard deviation (SD), 
median, minimum, and maximum. For categorical variables, these statistics will typically include 
the number and percentage of participants in each category. 
9.3.2. 
Study Participants and Demographics 
9.3.2.1. 
  Disposition and Withdrawals 
The number of participants randomized, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of participants in each 
analysis population will be reported. 
9.3.2.2. 
 Protocol Deviations 
Protocol deviations will be identified and classified as important or non-important for statistical 
analysis purposes before unblinding and will be summarized or listed as appropriate. Important 
protocol deviations that might affect efficacy data will be used to exclude participants from the 
per-protocol analysis. 
9.3.2.3. 
 Demographics and Other Baseline Characteristics 
The following analyses will be conducted for all analysis populations: 
• Demographic variables will include age, sex, height, and weight. Information on race and 
ethnicity will be collected for any eventual analysis of differences in response to the 
study intervention in accordance with local regulatory requirements. Baseline participant 
characteristics will include whether the participant wore a mask during the performance 
phase of the public speaking challenge, medical history, including confirmation of SAD 
diagnosis, and LSAS total score at Screening. Baseline evaluation of the SUDS score, 
STAI-State score, and SPSS-N score will also be reported. 
• Prior and concomitant medications will be summarized by treatment group, by the 
number and percentage of participants taking each medication, classified using World 
Health Organization Drug Dictionary (WHO-DD) Anatomical Therapeutic Chemical 
(ATC) classes and preferred terms. 
9.3.3. 
Primary Endpoint(s)/Estimand(s) Analysis 
The primary efficacy endpoint for the current study will be the difference in change in SUDS sc
ores after oral administration of a single dose of BNC210 and placebo. The analysis of the 
primary efficacy endpoint will be evaluated for the FAS and PP populations according to the 
planned treatment. 
The primary endpoint will be assessed with a longitudinal linear mixed-effects model for each 
SUDS timepoint, with the average of each timepoint in the performance phase used as the final 
timepoint. The model will include fixed effects for treatment, interaction between treatment and 
timepoint, sex, mask usage and a covariate for baseline score. Baseline will be defined in detail 
in the SAP. 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
46 
Two comparisons (BNC210 225 mg versus placebo and BNC210 675 mg versus placebo) will be 
made and the least squares (LS) mean difference along with the corresponding 95% confidence 
interval (CI) will be reported. For each treatment arm, the LS mean difference along with the 
corresponding p value will be weighted equally across the 2 BNC210 arms. 
9.3.4. 
Secondary 
 Endpoints Analysis 
Unless otherwise specified, continuous secondary 
 endpoints will be analyzed on on
ly the FAS population using a longitudinal linear mixed-effects model for each timepoint, as 
described for the primary analysis. 
 
 Additionally, the average 
score of the SUDS will be analyzed for the anticipation 
 
phases as secondary 
 endpoints. STAI-State scores and SSPS-N scores will also 
be analyzed as measured for the performance, anticipation, 
 
phases. 
 
 
 
 
 
 
 
 
  
 
 
9.4. 
Interim Analysis 
No interim analysis is planned for this study. 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
47 
10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable International Conference on Harmonization (ICH) Good Clinical Practice 
(GCP) Guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB by the Investigator and reviewed and 
approved by the IRB before the study is initiated. 
• The protocol cannot be altered or changed except through a formal protocol amendment, 
which requires written approval from the Sponsor.  Any amendments to the protocol will 
require IRB approval and health authority approval, where applicable, and must be signed 
by the Investigator before implementation of changes, except for changes necessary to 
eliminate an immediate hazard to study participants. 
• The Investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB 
o Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, European regulation 536/2014 for 
clinical studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
48 
10.1.3. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study, including 
the risks and benefits, to the participant and answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB or study center. 
• The rights and welfare of the participants will be protected by emphasizing to them that 
the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant. 
• Informed consent will be obtained before the participant can participate in the study. 
• The Investigator or his/her representative must also explain to the participant that they are 
completely free to refuse to enter the study or to withdraw from it at any time. 
• Participants who are rescreened are required to sign a new ICF. 
• Participants who are rescreened will not need to repeat routine clinical laboratory 
assessments or ECGs if an eligible result from the prior screening period has been 
obtained within 14 days of randomization into the study. 
• The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. 
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier as part of their study participation. Any 
participant records or datasets that are transferred to the Sponsor will contain the 
identifier and information collected as part of the study only; participant names or any 
information that would make the participant identifiable will not be transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant, who will be required to give consent for their data to 
be used as described in the ICF. 
• The study data entry and study management systems used by clinical sites and by the 
Sponsor/designee will be secured and password protected. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB members, and by inspectors from regulatory authorities. 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
49 
10.1.5. 
Data Quality Assurance 
• All participant data relating to the study will be recorded in the eCRF unless transmitted 
to the Sponsor or designee electronically (e.g., laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
• Guidance on completion of eCRFs will be provided in the study-specific eCRF 
completion guidelines. 
• The Investigator must permit study-related monitoring, audits, IRB review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Quality tolerance limits (QTLs) will be predefined in the study-specific Risk Log to 
identify systematic issues that can impact participant safety and/or reliability of study 
results. These predefined parameters will be monitored during the study, and important 
deviations from the QTLs and remedial actions taken will be summarized in the Clinical 
Study Report. 
• Monitoring details describing strategy, including definition of study critical data items 
and processes (e.g., risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring), methods, 
responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the 
Clinical Monitoring Plan. 
• The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor. 
10.1.6. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents, or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
50 
• Examples of acceptable source documentation include, but are not limited to, hospital 
records, clinic and office charts, laboratory notes, recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. The Investigator must 
maintain accurate documentation (source data) that supports the information entered in 
the eCRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.7. 
Study and Site Closure 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include, but are 
not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants 
by the Investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IRBs, the regulatory authorities, and any contract research organization(s) used 
in the study of the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.8. 
Publication Policy 
The publication policy is outlined in the study site-specific Clinical Trial Agreement. 
 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
59 
• Severity of the SAE term 
• A brief description of the event, treatment, outcome to date, and any actions taken with 
study intervention 
• The seriousness criteria(on) that were met 
• Investigator causality assessment 
• Concomitant medications taken within 30 days of onset of the event 
• Relevant medical history information 
• Relevant laboratory test findings 
• Whether and when the Investigator was unblinded as to the participant’s treatment 
assignment 
Any missing or additional relevant follow-up information concerning the SAE should be sent 
 via the same contact details above as 
soon as possible on a follow-up SAE Report Form, together with the following minimal 
information: initial report, AE, date of occurrence, study participant identifier, and site 
number. This will allow the follow-up information to be linked to the initial SAE report. 
Specific information may be requested by 
 
using a follow-up request form or via email communication. 
The Investigator is required to comply with applicable regulations (including local laws and 
guidances) regarding the notification of his or her health authorities, IRB, principal and 
coordinating investigators, study investigators, and institutions. Each Investigator is obligated 
to learn about the reporting requirements for investigators in his/her country. The study 
monitor may be able to assist with this. 
 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
60 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming postmenopausal unless permanently sterile 
(see below) 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement and FSH levels 
within the institutional postmenopausal range is required. 
o Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
• Permanent sterilization methods (for the purpose of this study) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
o For individuals with permanent infertility due to an alternate medical cause other than 
the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
• If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
61 
10.4.2. 
Contraception Guidance 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency  
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of 
the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview. 
Highly Effective Methodsb That Are User Dependent  
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
o 
oral 
o 
intravaginal 
o 
transdermal 
o 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
o 
oral 
o 
injectable 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b) Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c) Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception for this 
study.  Male condom and female condom should not be used together (due to risk of failure from friction). 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
62 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments 
The table below describes suggested actions and follow-up assessments should a participant’s 
post-challenge clinical safety laboratory results meet the following criteria. 
Liver Chemistry Criteria Requiring Increased Follow-up 
ALT or AST-absolute ALT or AST  5 × ULN 
ALT or AST Increase ALT or AST  3 × ULN persists for  4 weeks 
Bilirubin1,2 
ALT or AST  3 × ULN and total bilirubin  2 × ULN (> 35% 
direct bilirubin) 
Cannot Monitor 
ALT or AST  3 × ULN and cannot be monitored weekly for 
4 weeks 
Symptomatic3 
ALT or AST  3 × ULN associated with symptoms (new or 
worsening) believed to be related to liver injury or hypersensitivity 
Suggested Actions, Monitoring, and Follow-up Assessments  
Actions 
Follow-up Assessments 
• Report the event to the Medical Monitor 
within 24 hours. 
• Complete a Serious Adverse Event Report 
Form if the event also met the criteria for 
an SAE.2 
• Perform follow-up assessments as 
described in the Follow-up Assessment 
column. 
• Monitor the participant until liver 
chemistry test abnormalities resolve, 
stabilize, or return to baseline. 
MONITORING: 
If ALT or AST  3 × ULN AND total 
bilirubin  2 × ULN: 
• Repeat liver chemistry tests (include ALT, 
AST, ALP, and total bilirubin) and 
perform liver event follow-up assessments 
within 24 hours. 
• Viral hepatitis serology4 
• Obtain serum creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), 
gamma-glutamyltransferase [GGT], 
glutamate dehydrogenase [GLDH], and 
serum albumin. 
• Fractionate bilirubin, if total bilirubin 
 2 × ULN. 
• Obtain complete blood count with 
differential to assess eosinophilia. 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity. 
• Record use of concomitant medications 
(including acetaminophen, herbal 
remedies, and other over-the-counter 
medications) on the concomitant 
medications eCRF. 
• Record alcohol use 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
63 
• Monitor participant twice weekly until 
liver chemistry test abnormalities resolve, 
stabilize, or return to baseline. 
• A hepatology consultation is 
recommended. 
If ALT or AST  3 x ULN AND total 
bilirubin < 2 x ULN: 
• Repeat liver chemistry tests (include ALT, 
AST, alkaline phosphatase, and total 
bilirubin) and perform liver chemistry 
follow-up assessments within 24 to 72 
hours. 
• Monitor participants weekly until liver 
chemistry abnormalities resolve, stabilize, 
or return to baseline. 
 
If ALT or AST  3 x ULN AND total 
bilirubin  2 x ULN obtain the following in 
addition to the assessments listed above: 
• Antinuclear antibody, antismooth muscle 
antibody, Type 1 antiliver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG), or gamma 
globulins 
• Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
to evaluate liver disease 
• Liver biopsy may be considered and 
discussed with local specialist if available, 
for instance: 
o In participants when serology raises 
the possibility of autoimmune hepatitis 
(AIH) 
o In participants when suspected drug-
induced liver injury (DILI) progresses 
or fails to resolve on withdrawal of 
study intervention 
o In participants with acute or chronic 
atypical presentation 
• Report all assessments conducted to the 
Medical Monitor as they become available  
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation testing is unavailable, 
record the absence/presence of detectable urinary bilirubin on dipstick which is indicative of direct bilirubin elevations 
suggesting liver injury. 
2. All events of ALT or AST >3 × ULN and total bilirubin > 2 × ULN (>35% direct bilirubin) may indicate severe liver injury 
(possible ‘Hy’s Law’) and must be reported to sponsor in an expedited manner and as an SAE if SAE criteria met 
(excluding studies of hepatic impairment or cirrhosis). 
3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, or jaundice) or hypersensitivity (such as fever, rash, or eosinophilia). 
4. Includes: Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot testing); and 
hepatitis E IgM antibody. 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
64 
10.6. 
Appendix 6: Abbreviations 
Abbreviation 
Definition 
AE 
Adverse Event 
 
 
ADL 
Activities of Daily Living 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
 
 
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical 
 
 
 
 
b.i.d. 
Twice Daily 
BUN 
Blood Urea Nitrogen 
 
 
CFR 
Code of Federal Regulations 
 
 
CNS 
Central Nervous System 
CONSORT 
Consolidated Standards of Reporting Trials 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
 
 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
 
 
FSH 
Follicle-Stimulating Hormone 
GAD 
Generalized Anxiety Disorder 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
65 
 
HAM-D 
Hamilton Depression Rating Scale 
HBsAg 
Hepatitis B Surface Antigen 
hCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HRT 
Hormone Replacement Therapy 
ICH 
International Conference on Harmonization 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-To-treat 
IWRS 
Interactive Web Response System 
LSAS 
Liebowitz Social Anxiety Scale 
MCH 
Mean Corpuscular Hemoglobin 
MCV 
Mean Corpuscular Volume 
NCT 
National Clinical Trial 
 
 
 
 
PP 
Per-Protocol 
PTSD 
Post-Traumatic Stress Disorder 
QTcF 
Fridericia-corrected QT Interval 
QTL 
Quality Tolerance Limit 
RBC 
Red Blood Cell 
SAD 
Social Anxiety Disorder 
SAE 
Serious Adverse Event 
SAF 
Safety (Population) 
SAP 
Statistical Analysis Plan 
SCID-5-CT 
Structured Clinical Interview for DSM-5 Disorders - Clinical Trials 
version 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
66 
SD 
Standard Deviation 
SNRI 
Serotonin Noradrenaline Reuptake Inhibitor 
SoA 
Schedule of Activities 
SSPS-N 
Self-Statements During Public Speaking (Negative Self-Statements 
subscale) 
SSPS-State 
Self-Statements During Public Speaking – State Version 
SSPS-Trait 
Self-Statements During Public Speaking – Trait Version 
SSRI 
Selective Serotonin Reuptake Inhibitor 
STAI-State 
Spielberger State-Trait Anxiety Inventory – State component 
SUDS 
Subjective Units of Distress Scale 
TEAE 
Treatment-Emergent Adverse Event 
 
 
ULN 
Upper Limit of Normal 
US 
United States 
 
 
WBC 
White Blood Cell 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
Woman of Childbearing Potential 
WONCBP 
Woman of Non-childbearing Potential 
 
 
 

CONFIDENTIAL 
Protocol BNC210.013 
Version 1.1, 17-NOV-2021 
 
67 
11. 
References 
 
 
 
 
 
 
 
 
 
FDA Drug Safety Communication 23rd Sep 2020: https://www.fda.gov/media/142368/download 
Graeff FG, Parente A, Del-Ben CM, Guimarães FS. Pharmacology of human experimental 
anxiety. Braz J Med Biol Res. 2003 Apr;36(4):421-32. 
Heimberg RG. Cognitive-behavioral therapy for social anxiety disorder: current status and future 
directions. Biol Psychiatry. 2002 Jan 1;51(1):101-8. 
Heimberg RG, Liebowitz MR, Hope DA, Schneier FR, Holt CS, Welkowitz LA, et al. Cognitive 
behavioral group therapy vs phenelzine therapy for social phobia: 12-week outcome. Arch Gen 
Psychiatry. 1998 Dec;55(12):1133-41. 
Hofmann SG, Dibartolo PM. An instrument to assess self-statements during public speaking: 
scale development and preliminary psychometric properties. Behav Ther. 2000;31(3):499-515. 
 
 
 
 
 
 
Osório FL, Crippa JA, Loureiro SR. Validation of the state version of the Self-Statement during 
Public Speaking Scale. Braz J Psychiatry. 2013 Mar;35(1):63-6. doi: 10.1016/j.rbp.2012.02.009. 
PMID: 23567602 
 
 
 
Spielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacobs GA. Manual for the State-Trait 
Anxiety Inventory: STAI (form Y). Palo Alto (CA): Consulting Psychological Press; 1983. 
Wolpe J. The practice of behavior therapy. New York: Pergamon Press; 1969.