Clinical trial NCT05193409
Conditions: Social Anxiety Disorder
Sponsor: Bionomics Limited
Start date: 2022-02-02; Completion date: 2022-10-17
Enrollment: 151 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the effects of an acute dose of BNC210 compared to placebo on reducing anxiety provoked by a speaking challenge and measured using the Subjective Units of Distress Scale (SUDS) in patients with Social Anxiety Disorder (SAD).

Detailed description:
This is a randomized, double-blind, placebo-controlled, 3-arm, parallel-group, multi-center study. Participants will attend a Screening Visit to confirm eligibility and then return to the clinic within 14 days to be randomized into the study. Randomized participants will receive a single dose of their allocated study intervention (225 mg BNC210, 675 mg BNC210 or placebo) and approximately 1 hour later participate in a speaking challenge. After 1 week, a safety follow-up assessment will be conducted by phone/video conference.

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: 225 mg BNC210 intervention 2: 675 mg BNC210 intervention 3: Placebo
Intervention descriptions: intervention 1: 225 mg BNC210 intervention 2: 675 mg BNC210 intervention 3: Placebo

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
Protocol BNC210.013 
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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. 
 
 
 
 
 
 


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Sponsor Signatory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bionomics Limited 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 
 
 
 
 
   
 
 


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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 


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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 


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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 


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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). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






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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. 
 
 


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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 
 
 
 
 
 
 
 
 
 
 


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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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 




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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). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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.






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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. 
 
 
 
 
 
 
 
 
 
 




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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. 
 


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5. 
Study Population 
Investigators will be responsible for evaluating potential participants against the study eligibility 
criteria during the Screening Period.  At the initial Screening Visit, each participant will 
participate in the informed consent process and sign and date the ICF before any procedures 
specified in this protocol are performed. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant 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 


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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). 


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• 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. 


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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 
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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 
 


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6. 
Study Intervention(s) and Concomitant Therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
 
 
 
 
 
  
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. 
 
 
 
 
 


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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. 
 


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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. 
 
 


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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. 
 


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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. 
 


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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 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
The process for discontinuation of specific sites or the study as a whole are detailed in Appendix 
1: 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 
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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. 
 
 
 


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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 
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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. 
 
 


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For safety monitoring purposes, the Investigator or designee must review, sign, and date all ECG 
tracings.  Paper copies will be kept at the study center with the 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. 


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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 
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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 
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• 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 
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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 


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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 
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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 
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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. 
 
 
 
 
 
 
 
 
 
 
 


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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable International Conference on Harmonization (ICH) Good Clinical Practice 
(GCP) Guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, 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. 
 
 


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10.1.3. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study, including 
the risks and benefits, to the participant and answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB or study center. 
• The rights and welfare of the participants will be protected by emphasizing to them that 
the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant. 
• Informed consent will be obtained before the participant can participate in the study. 
• The Investigator or his/her representative must also explain to the participant that they are 
completely free to refuse to enter the study or to withdraw from it at any time. 
• Participants who are rescreened are required to sign a new ICF. 
• Participants who are rescreened will not need to repeat routine clinical laboratory 
assessments or ECGs if an eligible result from the prior screening period has been 
obtained within 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 
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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. 
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• 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. 
 
 
 


















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• 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. 
 
 
 


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


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


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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments 
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 
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• 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. 
 


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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 
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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 
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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 
 
 
 


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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. 

SAP_001.pdf: 




 
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Table of Contents 
Approvals ........................................................................................................................................ 1 
Document History ........................................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
List of Abbreviations ...................................................................................................................... 6 
1. 
Overview ............................................................................................................................. 9 
2. 
Study Objectives and Endpoints ......................................................................................... 9 
2.1. 
Study Objectives ........................................................................................................... 9 
2.1.1. Primary Objective ......................................................................................................... 9 
2.1.2. Secondary Objectives.................................................................................................... 9 
 
 
2.2. 
Study Endpoints .......................................................................................................... 10 
2.2.1. Efficacy Endpoints ...................................................................................................... 10 
2.2.2. Safety Endpoints ......................................................................................................... 12 
 
 
3. 
Overall Study Design and Plan ......................................................................................... 13 
3.1. 
Overall Design ............................................................................................................ 13 
 
 


 
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3.3. 
Study Population ......................................................................................................... 13 
3.4. 
Treatments Administered ............................................................................................ 14 
3.5. 
Method of Assigning Participants to Treatment Groups ............................................ 14 
3.6. 
Blinding and Unblinding............................................................................................. 14 
3.7. 
Schedule of Events ...................................................................................................... 15 
Table 2. Schedule of Activities (SoA) - Efficacy Assessments on Treatment Day ................ 17 
4. 
Statistical Analysis and Reporting .................................................................................... 18 
4.1. 
Introduction ................................................................................................................. 18 
4.2. 
Interim Analysis and Data Monitoring ....................................................................... 18 
5. 
Analysis Populations ......................................................................................................... 18 
6. 
General Issues for Statistical Analysis .............................................................................. 19 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 19 
6.1.1. Baseline ....................................................................................................................... 19 
6.1.2. Adjustments for Covariates......................................................................................... 19 
6.1.3. Multiple Comparisons ................................................................................................. 19 
6.1.4. Handling of Dropouts or Missing Data ....................................................................... 19 
6.1.5. Pooling of Sites ........................................................................................................... 23 
6.1.6. Derived Variables ....................................................................................................... 23 
 
 
6.1.8. Data Adjustments/Handling/Conventions .................................................................. 24 
6.2. 
Special Handling for COVID-19 Disruptions............................................................. 26 
7. 
Study Patients/Participants and Demographics ................................................................ 26 
7.1. 
Disposition of Patients/Participants and Withdrawals ................................................ 26 
7.2. 
Protocol Violations and Deviations ............................................................................ 26 
7.3. 
Demographics and Other Baseline Characteristics ..................................................... 27 
8. 
Efficacy Analysis .............................................................................................................. 27 
8.1. 
Primary Efficacy Analysis .......................................................................................... 27 
8.2. 
Secondary Efficacy Analysis ...................................................................................... 29 
 
 
9. 
Safety and Tolerability Analysis ....................................................................................... 31 
9.1. 
Adverse Events ........................................................................................................... 31 
9.1.1. Adverse Events Leading to Withdrawal ..................................................................... 32 
9.1.2. Deaths and Serious Adverse Events ........................................................................... 32 
9.2. 
Clinical Laboratory Evaluations ................................................................................. 32 
9.3. 
Vital Signs ................................................................................................................... 32 


 
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9.4. 
Electrocardiograms ..................................................................................................... 33 
9.5. 
Physical Examinations ................................................................................................ 33 
9.6. 
Further Safety Evaluations .......................................................................................... 33 
9.6.1 Columbia Suicide Severity Rating Scale (C-SSRS) ................................................... 33 
9.7. 
Concomitant Medication ............................................................................................. 34 
 
 
11. 
Changes from Planned Analysis ....................................................................................... 34 
12. 
References ......................................................................................................................... 35 
 
 
 








 
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1. 
Overview 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Bionomics 
Limited protocol number BNC210.013 (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) dated 17-Nov-2021 Version 1.1. Reference materials for this statistical plan 
include the protocol and the accompanying sample data collection documents. Operational 
aspects related to collection and timing of planned clinical assessments are not repeated in this 
SAP unless relevant to the planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials (ICH, 1998) All work planned and reported for this SAP will follow internationally 
accepted guidelines, published by the American Statistical Association (ASA, 2018) and the 
Royal Statistical Society (RSS, 2014), for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post-hoc 
or unplanned, exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be approved before any 
unblinded inferential or descriptive analysis of data pertaining to Bionomics Limited’s study 
BNC210.013. 
2. 
Study Objectives and Endpoints 
2.1. 
Study Objectives 
2.1.1. Primary Objective 
The primary objective is to assess the effects of BNC210 compared to placebo in reducing self-
reported anxiety severity as measured by the Subjective Units of Distress Scale (SUDS) in the 
performance phase of a public speaking challenge. 
2.1.2. Secondary Objectives 
The secondary objectives 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;  


 
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• Assess the effects of BNC210 compared to placebo in reducing self-reported symptoms 
of anxiety as measured by the Spielberger State-Trait Anxiety Inventory – State 
component (STAI-State) in a public speaking challenge; 
• Assess the effects of BNC210 compared to placebo in reducing self-reported negative 
cognitions during speaking as measured by the Self-Statements During Public Speaking 
Scale (Negative Self-Statements subscale; SSPS-N) in a public speaking challenge; 
• To assess the safety and tolerability of BNC210; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2. 
Study Endpoints 
2.2.1. Efficacy Endpoints 
2.2.1.1. 
Primary Efficacy Endpoint  
The primary efficacy endpoint of this study is the mean change between Baseline to the average 
of the performance phase of a public speaking challenge in the SUDS for participants receiving a 
single dose of BNC210 (225 mg or 675 mg) compared to participants receiving placebo, where 
the average of the performance phase is defined as the mean of up to six timepoints (0, 1, 2, 3, 4, 
5 minutes) measured during a public speaking challenge. 
2.2.1.1.1 
Primary Estimand 
The primary question of interest for this Phase 2 study is: What is the intervention difference in 
self-reported anxiety severity, measured by the mean of the SUDS in up to six timepoints (0, 1, 
2, 3, 4, 5 minutes) measured during a public speaking challenge after approximately 1 hour post 
dose in participants with social anxiety disorder (SAD), regardless of task discontinuation or 
staff intervention for any reason? 
Although all efficacy variables will be measured during 1 day reducing the likelihood that 
intercurrent events may impact the research question, participants may have experienced possible 
known or unknown intercurrent events prior to arriving at the study site. Participants may 
discontinue the study for any reason and may differentially experience initiation of task 




 
Statistical Analysis Plan,  
 
Sponsor Bionomics Limited  
 
Protocol Number BNC210.013  
 
PCN Number BION.5537 
 
 
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2.2.2. Safety Endpoints 
The safety endpoints of this study include the following from Baseline to the 7-day Follow-Up 
Visit. In the event that a measurement is not recorded at Baseline (i.e., ECG), the Screening visit 
will be used instead: 
• Continuous adverse events (AEs) and serious adverse events (SAEs); 


 
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• Electrocardiograms (ECGs); 
• Vital signs (body temperature, pulse rate, respiratory rate, systolic and diastolic blood 
pressure); 
• Clinical laboratory results (hematology, blood chemistry, and urinalysis). 
 
 
 
 
 
3. 
 Overall Study Design and Plan 
3.1. 
Overall Design 
This is a randomized, double-blind, placebo-controlled, three arm, parallel group, multi-center 
Phase 2 study in participants with SAD, who are between the ages of 18 to 65, with a single day 
treatment period and seven day follow up period. 
Approximately 150 participants will be enrolled and randomized using a 1:1:1 ratio to receive 
either BNC210 (225 or 675 mg) or matched placebo. Participants will complete a single dose of 
treatment with their allocated study intervention and will then engage in a public speaking task. 
Participants will also receive a follow up phone/video call 7 days after their study day for AE 
recording. 
 
 
 
 
 
 
 
 
 
 
 
  
3.3. 
Study Population 
The study population is comprised of male and female participants who are 18 to 65 years of age, 
with a current diagnosis of SAD as defined in the Diagnostic and Statistical Manual of Mental 
Disorders, fifth edition (DSM-5) and confirmed by the Structured Clinical Interview for DSM-5 
Disorders – Clinical Trials version (SCID-5-CT). Furthermore, the participants must receive a 
total score of ≥70 on the Leibowitz Social Anxiety Scale (LSAS) and a sub-score of 3 on 
Question 6 of the LSAS (Fear and Anxiety subscale) at screening. 


 
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3.4. 
Treatments Administered 
Participants will be randomized to one of three treatment groups: 
• BNC210 225 mg 
• BNC210 675 mg 
• Placebo 
 
 
 
 
3.5. 
Method of Assigning Participants to Treatment Groups 
Participants who meet inclusion criteria and none of the exclusion criteria will be randomly 
assigned in a 1:1:1 ratio to receive BNC210 225 mg, BNC210 675 mg, or placebo. 
3.6. 
Blinding and Unblinding 
This is a double-blind study in which participants, investigators, raters, and study personnel 
involved in the conduct of the study are blinded to study intervention. 
For emergency unblinding, study personnel will use the interactive web response system 
(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 for the unblinding must be recorded. Overall unblinding will 
take place at the end of the study only after database lock. 
 


 
 
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3.7. 
Schedule of Events 
Detailed schedules of events for the study are provided in Tables 1 and 2. 
Table 1 Schedule of Activities - Overview 
ASSESSMENTS1  
Screening  
Treatment Day 
Follow-up 
 
≤ 14 days 
(+3 days) 
Baseli
ne / 
Pre-
Dose2 
Dosin
g 
Public 
Speaking 
Challenge 
Post-
Challenge 
7 days post 
treatment 
(±3 days) 
Informed consent 
X 
 
 
 
 
 
Inclusion and exclusion criteria3 
X 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
Medical history including current & prior 
medications 
X 
 
 
 
 
 
Structured Clinical Interview for DSM-5 Disorders 
– Clinical Trials version (SCID-5-CT) 
X 
 
 
 
 
 
Leibowitz 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 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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ASSESSMENTS1  
Screening  
Treatment Day 
Follow-up 
 
≤ 14 days 
(+3 days) 
Baseli
ne / 
Pre-
Dose2 
Dosin
g 
Public 
Speaking 
Challenge 
Post-
Challenge 
7 days post 
treatment 
(±3 days) 
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 
(STAI)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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
18 
4. 
Statistical Analysis and Reporting 
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will primarily use SAS (release 9.4 or higher). If the use of other 
software is warranted, the final statistical methodology report will detail what software was used 
for what purposes. 
Continuous (quantitative) variable summaries will include the number of participants (n) with 
non-missing values, mean, standard deviation (SD) median, minimum, and maximum.  
Categorical (qualitative) variable summaries will include the frequency and percentage of 
participants who are in the particular category or each possible value. In general, the 
denominator for the percentage calculation will be based upon the total number of participants in 
the study population for the treatment groups, unless otherwise specified. The denominator for 
by-visit displays will be the number of participants in the relevant study population with non-
missing data at each visit. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and measures of spread (SD) will 
be reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
Unless otherwise indicated, all statistical tests will be conducted at the ≤0.05 significance level 
using 2-tailed tests. p values and corresponding 95% confidence intervals (CIs) will be presented 
for statistical tests.  
Statistical testing will be performed at the 0.05 level using two-tailed tests. A p value of  0.10 
but > 0.05 will be considered evidence of a trend.  
4.2. 
Interim Analysis and Data Monitoring 
No interim analyses are planned. 
5. 
Analysis Populations 
The following analysis populations are planned for this study:  
• Safety Population (SAF): The 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. 


 
 
19 
• Full Analysis Set (FAS): The FAS population includes all randomized participants who 
receive any amount of the study intervention. Participants will be analyzed by 
randomized treatment. 
• Per Protocol (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. 
 
 
 
6. 
 General Issues for Statistical Analysis 
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
The last non-missing observation recorded before receiving the first dose of study drug will be 
used as the baseline observation for all calculations of change from baseline.  
6.1.2. Adjustments for Covariates 
The primary endpoint analyzing the change in SUDS Scores from Baseline to the average of the 
public speaking challenge will be assessed with a Mixed Model for Repeated Measures 
(MMRM). The model will include fixed effects for treatment, interaction between treatment and 
timepoint, sex, use of a mask, and a covariate for baseline score. See Section 8 for more details. 
6.1.3. Multiple Comparisons 
Because this is a Phase 2 study, the level of significance will be set at 0.05 for primary and 
secondary endpoints with no adjustment for multiple comparisons. 
6.1.4. Handling of Dropouts or Missing Data 
All possible efforts will be made to ensure that participants stay in the study and all data are 
collected as scheduled however, the occurrence of missing data cannot be completely eliminated. 
The primary endpoint will be analyzed using MMRM. 
 
 
 
 
  


 
 
20 
 
 
 
 
 
 
 
 
 
6.1.4.1. 
Multiple Imputation Methods 
Data are considered MAR (missing at random) if, conditional upon the independent variables in 
the analytic model, the missingness depends on the observed outcomes of the variable being 
analyzed but does not depend on the unobserved outcomes of the variable being analyzed. This 
assumption implies that the behavior of the post dropout observations can be predicted from the 
observed variables, and therefore that treatment effect can be estimated without bias using the 
observed data (European Medicines Agency, 2010). For studies of missing data in a controlled 
clinical trial setting, MAR is usually considered as a plausible underlying missing mechanism 
(Molenberghs and Kenward, 2007; Siddiqui et al., 2009; Mallinckrodt et al., 2008; Mallinckrodt 
et al., 2013). The assumption of MAR is often reasonable because, particularly in longitudinal 
studies wherein the evolution of treatment effects is assessed by design over time, the observed 
data and the models used to analyze them can explain much of the missingness (Little and Rubin, 
1987; Verbeke and Molenberghs, 2000). This point may be especially relevant in well-controlled 
studies, in which extensive efforts are made to observe all outcomes and factors that influence 
them while participants are following protocol-defined procedures. Thus, longitudinal clinical 
trials by their very design aim to reduce the amount of MNAR (missing not at random) data 
(missingness explained by unobserved responses), thereby increasing the plausibility of MAR 
(Mallinckrodt et al., 2008).  
Although the assumption of MAR is often reasonable in clinical trials, the possibility of MNAR 
data cannot be ruled out. Therefore, analysis valid under MNAR will be performed as the 
primary/main analysis.  
Any participants who do not begin or who discontinue the public speaking challenge early will 
have these efficacy assessments analyzed as imputed using MI techniques. This analysis will be 
presented as the main analysis. 
Multiple imputation (MI) is a simulation-based approach where missing values are replaced 
using an appropriate stochastic model given the observed data and covariates, creating multiple 
completed data sets. These completed datasets are then analyzed using standard analysis methods 
(MMRM for this study), and the different parameter estimates across the datasets are then 
combined to produce unique point estimates, standard errors, and confidence intervals taking into 
account the uncertainty of the imputation process. 
In most randomized clinical trials that collect data over time, the great majority of missing data 
follow a monotone pattern. That is, once a participant has a missing data for some timepoint, 


 
 
21 
data will be missing for all subsequent timepoints. In this study, if a subject does not begin the 
public speaking challenge or discontinues the public speaking challenge early, then all 
subsequent measures for the public speaking challenge will be missing. Typically, there is also a 
small amount of non-monotone missing data (i.e., some participants have missing values for 
intermediate timepoints, but have non-missing data at subsequent timepoints). 
MI with Placebo-Based Imputation 
A placebo-based (jump to control) multiple imputation for missing primary and some secondary 
endpoints will be carried out for participants who discontinue the public speaking challenge 
early, as indicated previously. The imputation has three broad components; i) the multiple 
imputation process for the placebo data; ii) the multiple imputation process for the BNC210 data; 
and iii) the analysis model that will be used to draw inference regarding the primary causal 
estimands along with the method for combining the results across the multiply-imputed datasets.  
Multiple imputation based on a standard MAR imputation approach will be performed in SAS 
using a general three-step approach. Each step will be conducted separately for the primary and a 
subset of secondary endpoints: 
Step 1:  If the data has a non-monotone pattern of missingness, then a monotone data 
augmentation method using Markov-Chain Monte-Carlo (MCMC) will be used to impute data 
that is missing and required to make the missing data pattern monotone. Fifty datasets with a 
monotonic missing pattern will be generated. This method will use a non-informative Jeffreys 
prior to derive the posterior mode from the expectation-maximization (EM) algorithm as the 
starting values for the MCMC method. Intermittent missing values will be imputed using the 
MCMC method assuming a multivariate normal distribution over all variables included in the 
imputation model (i.e., treatment group, baseline, and each post-baseline timepoint). The MCMC 
statement of the MI procedure in SAS (PROC MI) will specify the CHAIN=MULTIPLE option, 
so that the procedure uses multiple chains and completes the default 200 burn-in iterations before 
each imputation, and the IMPUTE=MONOTONE option to create the 50 partially imputed 
datasets with a monotone missing pattern. The seed of the pseudorandom number generator used 
to randomly generate imputations for the missing values in Step 1 is 6411776. 
Assumptions underlying the partial imputation step are such that participants with missing data 
follow the same model as other participants in their respective treatment arm that have complete 
data. 
If the raw data has a monotone pattern of missingness, then the same procedures described above 
can be followed to create 50 identical datasets that will be used as an input dataset for the next 
step including both treatments. This step will re-impute the BNC210 group with placebo-based 
data. 
Step 2:  The second stage will impute missing post-informative participant withdrawal monotone 
data in a sequential manner, using a method proposed by Ratitch and O’Kelly. The post-
informative participant withdrawal values in each of the imputed datasets for the BNC210 arm 
will be set to missing, thus leaving a dataset with multiply-imputed values and monotone missing 


 
 
 
22 
data patterns due to early termination as a result of AEs, lack of efficacy, i.e. these data will 
contain the complete data for all placebo participants (observed and imputed under MAR) and 
the BNC210 participants (intermittent missing data imputed under MAR and monotone missing 
data for non-informative withdrawal imputed under MAR), with monotone missing data due to 
informative withdrawal left as missing (to be imputed under MNAR). The second stage of the 
imputation procedure will handle the MNAR imputation for the monotone missing post-
informative participant withdrawal data in the BNC210 participants. A new dataset will then be 
created with all placebo data. Once the MNAR data are imputed, these data (containing all 
placebo data and imputed MNAR data for BNC210) will then be combined with non-missing 
and imputed MAR data from BNC210 participants to create the datasets to be used for analysis. 
The second state imputation will be done sequentially by timepoint for each first stage 
imputation. The seed number of 1592065 will be used for the imputation procedure described in 
Step 2. 
For both Steps 1 and 2, minimum and maximum values for the SUDS (0 and 100) will be 
specified (separately) in the MI procedure to avoid imputed values outside the possible range of 
values. When an intended imputed value is less than the minimum or greater than the maximum 
value specified, the MI procedure in SAS will redraw another value for imputation. 
Step 3:  MMRM analyses will be performed separately for each of the 50 complete analysis 
datasets and the results will be combined into one multiple imputation inference (estimated 
treatment effect, standard error, p-value and associated 95% CI) using the SAS MIANALYZE 
procedure. The treatment difference will be tested at the 2-sided 0.05 level and corresponding 
95% CIs will be calculated. In the case that there are no missing data for a particular timepoint, 
p-values and 95% CIs will come from the MMRM analysis on the observed data. 
6.1.4.2. 
Supportive Analysis for Primary and Secondary Efficacy Endpoints 
Supportive analyses will be performed on the primary and a subset of secondary efficacy 
endpoints to demonstrate the robustness of the conclusions. As a supportive analysis, the primary 
and select secondary efficacy endpoints will be analyzed in the FAS population using MMRM 
with no MI, described below. The primary efficacy endpoint and select secondary endpoints will 
also be analyzed in the PP population using MMRM with no MI.  
6.1.4.3. 
MMRM Analysis Method 
Primary and select secondary efficacy variables will be assessed with a MMRM with MI, and 
with a MMRM with no imputation as supportive analyses. The other secondary endpoints will be 
assessed with a MMRM with no MI. The model will include fixed effects for treatment, 
interaction between treatment time, sex, use of a mask, and covariate for Baseline score. The 
MMRM method has been demonstrated extensively as an appropriate choice for the primary 
analysis in longitudinal confirmatory clinical trials with continuous endpoints (Mallinckrodt et 
al., 2008). This analysis method, which is from a broader class of direct-likelihood analyses 
methods, makes use of fully and partially observed data sequences from individual participants 
by estimating the covariance between data from different time points (Molenberghs and 
Kenward, 2007). Further, it is often useful to implement MMRM using an unstructured approach 


 
 
23 
to modeling both the treatment-by-time means and the (co)variances, leading to what is 
essentially a multivariate normal model wherein treatment group means at the primary time point 
are adjusted to reflect both the actual observed data and the projected outcomes from the 
participants with missing data (Cnaan et al., 1997; Molenbergs et al., 2004; Molenbergs and 
Kenward, 2007). 
Despite careful planning and study conduct, the occurrence of missing data cannot be completely 
eliminated. As a direct likelihood method, the MMRM is a preferred approach for handling 
missing data in such designs. MMRM is a full multivariate model in nature, which avoids 
potential bias as a predetermined model and operates in a more general MAR framework 
(Mallinckrodt et al., 2001).  
6.1.5. Pooling of Sites 
This is a multicenter study and there will be no pooling of a site factor. 
6.1.6. Derived Variables 
• Change from baseline = value at current time point – value at Baseline. 
• Body Mass Index (BMI) kg/m2 =  
(
𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
ℎ𝑒𝑖𝑔ℎ𝑡(𝑐𝑚)
100
∗ℎ𝑒𝑖𝑔ℎ𝑡(𝑐𝑚)
100
) 
 
• Treatment Emergent Adverse Event (TEAE) = any AE that starts or deteriorates on or 
after the first dose of study medication and through Follow-up Day 7 visit. 
 
 
 
𝑏
𝑎
 
 
 


 
 
24 
 
 
6.1.8. Data Adjustments/Handling/Conventions 
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included only in the data listings. 
All p values will be displayed in four decimals and rounded using standard scientific notation 
(e.g., 0.XXXX). If a p value less than 0.0001 occurs it will be shown in tables as < 0.0001. 
Adverse Events and Concomitant Medication Coding 
An AE is any untoward medical occurrence in a clinical study participant, temporally associated 
with the use of study intervention, whether or not considered related to study intervention. All 
SAEs will be collected from the signing of the ICF until the Follow-up Visit at the timepoints 
specified in Table 2. All AEs will be collected from the start of intervention until the Follow-up 
Visit timepoints specified in Table 2. Any medical occurrence that begins before the start of 
study intervention, but after obtaining informed consent will be recorded as medical 
history/current medical conditions and not as an AE.  
Adverse events will be coded using the MedDRA version 23.0 or higher thesaurus. Concomitant 
medications will be coded using the World Health Organization Drug Dictionary (WHO-DD 
Global B3 version March 2020). 
Concomitant Treatment Definition and Handling of Data 


 
 
 
25 
A concomitant treatment refers to all treatment, including concomitant therapies, vaccines, 
herbal treatments, vitamins, recreational drugs, and non-pharmacological or behavioral 
treatments such as psychotherapy, taken from time of Screening or during the study.  
Partial Date Imputation 
If partial dates occur, the convention for replacing missing dates for the purpose of statistical 
analysis is as follows: if just day is missing then the day assigned is the first day of the month or 
the date of first dose (if in the same month), whichever is later; if just month is missing then the 
month assigned is the month of the first dose, unless that results in a date prior to the first dose in 
which case the date of first dose is assigned; and if both month and day are missing then the 
month assigned is the month of the first dose and the day assigned is either the first day of the 
month or the first dose date, whichever is later. 
If partial times occur, the convention is as follows: if the missing time occurs on the day of the 
first dose and both the hour and minute are missing then the time assigned is the time of the first 
dose, otherwise if both the hour and minute are missing and the date is not the date of first dose 
the time assigned is 12:00; if the date is the same as the date of the first dose and only hour is 
missing the hour assigned is 12 or the hour of first dose, whichever is later, and if the date is the 
same as the date of first dose and only the minute is missing the minute assigned is 30 or the 
minute of first dose, whichever is later. Otherwise the hour assigned is 12 if the hour is missing 
and the date is not the same as the date of first dose and the minute assigned is 30 is the the date 
is not the same as the date of first dose. 
These conventions will be applied only to adverse event onset and concomitant medication dates 
and times with the following precaution:  if the missing date and time reflect the date and time of 
onset of an adverse event, the modified date and time will be constructed to match the first 
documented date/time post drug administration while preserving the order in which the AE was 
reported in the CRF. 
Lower and Upper Limit of Quantitation 
In general, for quantitative laboratory values reported as “<” or “≤” the lower limit of 
quantitation (LLOQ), one-half of the reported value (i.e., LLOQ/2) will be used for analysis. The 
exception to this data treatment is for plasma concentrations of BNC210 that are reported as 
<LLOQ, where a value of zero will be used in calculating summary statistics. 
For quantitative laboratory values reported as “>” or “≥” the upper limit of quantitation (ULOQ), 
the reported value (i.e., ULOQ) will be used for analysis. 
Laboratory Test Results 
For analysis purposes, repeat laboratory test results will not be used unless the original 
laboratory value is missing or indicated as invalid, in which case the first non-missing repeat 
laboratory value will be used for data analysis. 


 
 
26 
The International System of Units (SI) will be used in reporting all efficacy and safety laboratory 
values. 
Treatment Duration and Exposure 
Treatment Duration and Exposure will not be calculated given this is a single dose study with 
study drug given at the site. Participants who are not dosed will not be included in the safety or 
efficacy analyses.   
6.2. 
Special Handling for COVID-19 Disruptions 
Study visits may be delayed/not performed as a result of COVID-19 disruptions (e.g., sites were 
closed or participants were under stay-at-home orders). Participants who must delay their study 
visit past the screening period will be re-screened. 
7. 
Study Patients/Participants and Demographics 
7.1. 
Disposition of Patients/Participants and Withdrawals 
The number of participants randomized, completing the treatment day visit, completing all visits 
through follow-up, 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. 
7.2. 
Protocol Violations and Deviations 
Protocol deviations will be listed. Protocol deviations will be classified as “Important” or “Non-
Important”. An important deviation poses a possible safety issue to the participant or it has a 
potential impact on the statistical analysis of the clinical data. A non-important deviation is 
identified as any protocol deviation that does not meet the criteria for an important deviation. 
 
Protocol deviations which are deemed to be “Important” and “Non-Evaluable” 
(i.e., a deviation that has a potential impact on the efficacy analysis), will be classified as major 
protocol deviations. Participants with at least 1 major deviation will be excluded from the PP 
analysis population. 
Important protocol deviations may include: 
• Significant and/or persistent dosing error 
• Participant did not meet eligibility criteria and did not have a waiver or dispensation by 
medical monitor 
• Error in randomization (i.e., received wrong drug) 
• Use of prohibited concomitant treatment during participation in the trial 
The final decision regarding inclusion and exclusion of participants from the analysis 
populations will be based on a final listing of protocol deviations. This will be determined during 


 
 
27 
a (blinded) review meeting before any unblinding occurs or database freeze/lock, with input from 
the Clinical and Biostatistics team members and approval from the Sponsor. 
Protocol deviations will be summarized by type and by treatment group for the SAF population.   
7.3. 
Demographics and Other Baseline Characteristics 
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. These analyses will be presented for the SAF, FAS, and PP 
populations.  
8. 
Efficacy Analysis 
Efficacy analyses on the primary efficacy endpoint using MI will also evaluate select secondary 
endpoints, including evaluations of the change from baseline and 
, the average 
of the anticipation phase, and the average of the performance phase and will be performed on the 
FAS population. The primary efficacy analysis using observed data will also evaluate select 
secondary endpoints, including evaluations of the change from baseline and 
, 
the average of the anticipation phase, and the average of the performance phase and will be 
performed on the FAS and PP populations. Efficacy analyses on the other secondary endpoints 
will be performed on the FAS population, 
 
. The FAS will be considered the primary population for efficacy analyses. 
For all efficacy analyses, participants will be analyzed by the randomized treatment group 
assignment (BNC210 225 mg, BNC210 675 mg or placebo). All efficacy data will be presented 
in participant listings. 
8.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint for this study is the mean change between Baseline and the 
average of the performance phase of a public speaking challenge in the SUDS for participants 
receiving a single dose of BNC210 (225 mg or 675 mg) compared to participants receiving 
placebo, where the performance phase is defined as up to six timepoints (0, 1, 2, 3, 4, 5 minutes) 
measured during a public speaking challenge and the average is defined as the mean of all 
measured timepoints during that phase. 
A restricted maximum likelihood (REML)-based MMRM model with MI will be used as the 
primary analysis method. The repeated measures include post-baseline timepoints (i.e., the 
resting period and the average of up to 0, 1, 2 minutes in the anticipation phase) with change 
from baseline SUDS scores during a public speaking challenge as the dependent variable. Each 
change from baseline score will be derived as the difference from that timepoint (i.e., the resting 


 
 
 
28 
period, the anticipation phase, and the performance phase) with averages utilized in the 
anticipation and performance phases. The average for the anticipation and performance phases 
will thereby be used as each respective timepoint. The MMRM model will include fixed effects 
for treatment, timepoint, interaction between treatment and timepoint average, sex, use of a 
mask, and a covariate for baseline score, using an unstructured covariance structure. If the 
unstructured covariance model will not converge using the Newton-Raphson algorithm, the 
following alternatives will be tried in the order presented, stopping if convergence occurs:  
1) Fisher Scoring Algorithm 
2) Factor Analytic Structure 
3) Successive univariate analytic regression method as proposed in Lu and Mehrotra (2010) 
If still the mentioned methods fail, a more specific covariance structure, first the Toeplitz 
covariance structure (alternative 4) then the auto-regressive order 1 (AR[1]) (alternative 5) 
structures will be tested. A sandwich estimator will be used with structured covariance models to 
control Type I error. If still the model does not converge, additional covariance structures will be 
explored and the final decision will be documented in the CSR.  
Two comparisons (BNC210 225 mg versus placebo and BNC210 675 mg versus placebo) will be 
made and the least squares (LS) mean difference of averages 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. 
The null hypothesis for the primary efficacy endpoint of the equality of BNC210 and placebo is: 
H01: Mean change 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 null hypothesis of equal treatment effect will be rejected if the statistical analysis results in a 
2-sided p value for treatment through the average of the SUDS scores during the performance 
phase in a public speaking challenge of the study of less than or equal to 0.05. Least squares (LS) 
means will be calculated for each treatment group for each post-baseline timepoint in the model. 
The difference between both levels of BNC210 (225 mg and 675 mg) and placebo change from 
baseline in the average of the SUDS score in the performance phase will be estimated, with the 
corresponding 2-sided 95% CI constructed for each time point. The change from baseline LS 
means with standard error, 95% CI for the LS means, p value for testing if the LS mean is zero, 
LS mean difference between treatment groups (BNC210 225 mg minus placebo, BNC210 675 
mg minus placebo) with standard error, 95% CI for the LS mean difference, and p value for 
testing if the treatment LS means are equal will be presented. 
The trial will be claimed successful if the hypothesis of no treatment effect on the primary 
efficacy endpoint of the FAS population is rejected at the 0.05 (2-sided) significance level. 
As a sensitivity analysis, the primary analysis MMRM without MI will be performed in the FAS 
and PP populations.  


 
 
29 
Descriptive summaries will also be provided for the primary endpoint. Data from all 
performance phase timepoints will be included in the MMRM analysis. 
Graphical displays of the means and LS mean change from baseline in the SUDS Scores over 
time will be presented for each treatment group for all timepoints, with error bars denoting the 
standard error. 
8.2. 
Secondary Efficacy Analysis 
Analyses similar to that described for the primary efficacy endpoint will be performed for each 
of the following secondary endpoints: 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, 
 
 
 will be analyzed using MMRM with MI in the FAS population 
and MMRM without MI in the FAS and PP populations as part of the primary efficacy models.  
 
 
 
 
 
  
The null hypotheses for the secondary efficacy endpoints of the equality of a single dose of 
BNC210 and placebo are: 
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. 
 
 
 
 
 
  
 
 
. 
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 


 
 
30 
and placebo are equal. 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For evaluations of SSPS-N, the SSPS-Trait version is used at Baseline/Pre-Dose and 
Resting/Minute 55 Post-Dose, and the SSPS-State version is used for the anticipation phase, 
performance phase and post-challenge phase.   
Graphical displays of the means and LS mean change from baseline in the STAI-State Scores 
and SSPS-N Scores over time will be presented for each treatment group for all timepoints, with 
error bars denoting the standard error. 
 
 
 
 
 
 
 
 
 
 
  


 
 
31 
9. 
Safety and Tolerability Analysis 
All safety analyses will be performed on the SAF population, defined as all participants who 
were randomized and received 1 dose of study medication. 
For all safety and tolerability analyses, participants will be analyzed by the treatment received 
(BNC210 225 mg, BNC210 675 mg, or placebo) and, if applicable, overall for all participants 
receiving the study medication. 
Safety data collected at the Baseline visit (treatment day) or the last preceding visit if not 
collected at Baseline will be used as the baseline value for safety analyses. 
Safety measures including AEs, C-SSRS, physical examination findings, ECGs, vital signs, and 
clinical laboratory test results (hematology, biochemistry, urinalysis) will be summarized 
descriptively. For quantitative variables, descriptive statistics including number of observations, 
mean, median, standard deviation, minimum, and maximum will be presented for observed and 
change from baseline values at each study visit. Qualitative variables will be summarized using 
counts and percentages. No formal inferential analyses will be conducted for safety variables 
unless otherwise noted. 
All safety and tolerability data will be presented in participant listings. 
9.1. 
Adverse Events 
In general, treatment emergent adverse events (TEAEs) are defined as AEs that are newly 
occurring or worsening after the first dose of study drug. In this study they are defined as AEs 
that start or deteriorate on or after the administration of study medication and no later than 7 days 
following the dose of study medication or reported through the Follow-up Day 7. For any 
participants who die during the study and the date of death is between the date of study 
medication administration and the date of study discontinuation (as entered by the site), 
inclusive, all AEs (including those resulting in death) that occur during the study will be 
considered as TEAEs and will be included in the TEAE summaries. All summaries of AEs will 
be based on TEAEs unless specified otherwise. 
All AEs, TEAEs, and SAEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), Version 23.0 or higher. 
The incidence of TEAEs will be summarized by treatment group, by system organ class (SOC) 
and preferred term (PT), by severity, and by relationship to study intervention. 
The number and percent of participants reporting TEAEs, grouped by MedDRA SOC and PT 
(coded using MedDRA v. 23.0 or higher), will be tabulated by severity and treatment group. In 
the case of multiple occurrences of the same TEAE within the same participant, each participant 
will only be counted once for each preferred term. 
In the summaries showing severity and relationship to study medication the event with the 
maximum severity (severe) or strongest relationship (definitely related) will be reported. If a 
particular event is missing the severity and/or relationship, then the strongest possible severity or 
relationship will be assumed for analysis (severity = severe, relationship = definitely related). 


 
 
 
32 
In the AE data listings, all AEs will be displayed.  
9.1.1. Adverse Events Leading to Withdrawal 
A data listing of AEs leading to withdrawal from study will also be provided, displaying details 
of the event(s) captured on the CRF. 
9.1.2. Deaths and Serious Adverse Events 
Any deaths that occur during the study will be listed. 
Serious adverse events (SAEs) will be listed. 
An SAE is an AE defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
1) Results in death. 
2) Is life-threatening. 
3) It requires inpatient hospitalization or prolongation of existing hospitalization. 
4) Results in a congenital abnormality or birth defect. 
5) It is an important medical event that may jeopardize the participant or may require 
medical intervention to prevent one of the outcomes listed above. 
6) Results in persistent or significant disability/incapacity 
9.2. 
Clinical Laboratory Evaluations 
Central laboratory tests (hematology, biochemistry, urinalysis) will be performed at Screening, 
Baseline/Pre-Dose, and Post-Challenge. 
A serum pregnancy test (if applicable), HIV, HBsAg, and HCV tests will be performed at 
Screening. A urine pregnancy test (if applicable) will be conducted at Baseline/Pre-Dose. Urine 
drug screening tests will be conducted at Screening and Baseline/Pre-Dose. These results will not 
be reported unless applicable for enrollment/discontinuation reasons. 
Laboratory test results will be summarized descriptively by treatment and time point as both 
observed values and change from baseline values.  
The number of participants with clinical laboratory values below, within, or above the normal 
range by time point and in relation to Baseline will be tabulated for each clinical laboratory 
analyte by treatment group. 
A listing of all laboratory analytes by category (hematology, biochemistry, urinalysis) will be 
provided. 
9.3. 
Vital Signs 
Vital signs will be collected at Screening, Baseline/Pre-Dose, and Post-Challenge. Descriptive 
summaries of actual values and changes from baseline will be calculated for body temperature, 


 
 
33 
pulse rate, respiratory rate, and seated systolic and diastolic blood pressure (at 5 minutes rest). 
Vital sign measurements, including body temperature, will also be listed. 
9.4. 
Electrocardiograms 
Triplicate 12-Lead ECGs will be collected at Screening and Post-Challenge. Descriptive 
summaries and change from screening will be presented for ECG measures of PR interval, QRS 
interval, QT interval, QTCF interval, and HR. These summaries will be presented by study visit 
and treatment group. 
The number and percentage of patients/participants with normal and abnormal ECG results will 
be summarized for the SAF population by treatment group at each visit. Summary statistics for 
all collected visits will be displayed for QT and both QTC correction methods by treatment 
group. Fridericia’s correction for QTC will be applied as follows: 
Fridericia’s correction (QTCf) will be derived as follows: 
 
 
Fridericia’s Correction (QTCf) 
3
sec
RR
QT
QTc
m
f =
 
where: Relative Rate: RR = 60 / HR. HR = Heart Rate obtained from the ECG. 
9.5. 
Physical Examinations 
A full physical examination will be done at Screening and an abbreviated physical exam will be 
completed at Baseline/Pre-Dose. A listing of physical examination findings will be provided for 
complete and brief examinations. 
Complete physical examinations will include assessments of the general appearance, skin and 
lymphatics, eyes, ears, nose, throat, cardiovascular system, respiratory system, 
abdomen/gastrointestinal system, musculoskeletal and neurological systems.  Other body 
systems may also be examined as required. Height and weight will also be measured at 
Screening only. 
Abbreviated physical examinations 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. 
9.6. 
Further Safety Evaluations 
9.6.1 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is an instrument to assess both suicidal behavior and ideation. The Screening 
version will be administered at Screening and the Since Last Visit version of the scale will be 
administered at Baseline/Pre-Dose. C-SSRS data will be listed. 


 
 
34 
9.7. 
Concomitant Medication 
Prior and concomitant treatments are coded using WHO-DD Global B3 version March 2020 and 
will be listed.  
Prior treatments will be flagged separately from concomitant treatments. Treatments that started 
before administration of the study medication will be considered prior treatments, whether or not 
they were stopped before study medication. Any treatments continuing or starting after study 
medication will be considered to be concomitant. If a treatment starts before the study 
medication and continues after the study medication, it will be considered both prior and 
concomitant.  
 
 
 
  
11. Changes from Planned Analysis 
Due to the nature of the repeated measures models for the primary analysis, secondary endpoints 
that evaluate CFB at the 
 anticipation phases are included in all primary efficacy 
analyses and are denoted as select secondary endpoints. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


 
 
35 
 
 
 
  
 
 
  
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