A US, Phase 3 Multicenter, Randomized, Double-blind, Placebo Controlled Trial of PH94B Nasal Spray for the Acute Treatment of Anxiety Induced by a Public Speaking Challenge in Adult Subjects With Social Anxiety Disorder (PaliSADe-2)
Phase: PHASE3
Conditions: Social Anxiety Disorder
Sponsor: VistaGen Therapeutics, Inc.

 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

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Baseline (Visit 2), prior to investigational product (IP) administration. Effective 
methods of contraception include: condoms with spermicide, diaphragm with 
spermicide, hormonal contraceptive agents (oral, transdermal, or injectable), or 
implantable contraceptive devices. 
7. Negative COVID-19 test for subjects with COVID-19 symptoms or those who 
have had direct exposure to someone with a positive COVID-19 test, and/or 
completion of quarantine period consistent with requirements at the study site 
as determined by the Investigator. 
 
Exclusion criteria:  
 
1. Any history of bipolar disorder (I or II), schizophrenia, schizoaffective disorder, 
psychosis, anorexia or bulimia, premenstrual dysphoric disorder, autism-spectrum 
disorder, or obsessive-compulsive disorder. 
Any other current Axis I disorder, other than SAD, which is the primary focus of 
treatment. Note that subjects with concurrent Generalized Anxiety Disorder are 
eligible for the study provided that Generalized Anxiety Disorder is not the primary 
diagnosis. 
2. Subjects who meet criteria for moderate or severe alcohol or substance use disorder 
within the 1 year prior to Study entry. 
3. In the opinion of the investigator, the subject has a significant risk for suicidal 
behavior during the course of their participation in the study, or 
a.  
At Screening (Visit 1): the subject scores “yes” on items 4 or 5 in the Suicidal 
Ideation section of the Columbia-Suicide Severity Rating Scale (C-SSRS) with 
reference to a 6-month period prior to screening; or 
b.  At Screening (Visit 1): the subject has had 1 or more suicidal attempts with 
reference to a 2-year period prior to screening; or 
c.  
At Baseline (Visit 2): the subject scores “yes” on items 4 or 5 in the Suicidal 
Ideation section of the C-SSRS with reference to screening; or 
d.  The subject is considered to be an imminent danger to themself or others. 
4. Clinically significant nasal pathology or history of significant nasal trauma, nasal 
surgery, total anosmia, or nasal septum perforation that may have damaged the nasal 
chemosensory epithelium. 
5. An acute or chronic condition, including an infectious illness, uncontrolled seasonal 
allergies at the time of the study, or significant nasal congestion that potentially could 
affect drug delivery to the nasal chemosensory epithelium.  
6. Two or more documented failed treatment trials with a registered medication 
approved for SAD, at any time during the lifetime of the subject, whereby an 
adequate treatment trial is defined as that described in the package insert for a 
particular drug during which the subject received an adequate medication dosage 
(defined as the treatment dose indicated in the package insert to obtain efficacy for 
that particular drug).  
7. Use of any psychotropic medication within 30 days before study entry (other than 
medication permitted for insomnia: eszopiclone, ramelteon, melatonin, zaleplon, 
zolpidem, or antihistamines). 
8. Use of any anxiolytics, such as benzodiazepines or unapproved treatments such as 
beta blockers, within 30 days before study entry; concomitant use is prohibited 
during the study. Subjects who have been taking benzodiazepines daily for 1 month 
or longer at the time of Visit 1 are not eligible to participate. 
9. Use of any over-the-counter product, prescription product, or herbal preparation for 
treatment of the symptoms of anxiety or social anxiety within 30 days before study 
entry; concomitant use is prohibited during the study. 
10. Prior participation in a clinical trial involving PH94B. 
11. Women who have a positive urine pregnancy test prior to IP administration. Women 
who are currently breastfeeding are not eligible unless they are willing to stop 
breastfeeding for the duration of time between Visit 2 and Visit 4. 

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3. TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES ...................................................................................................2 
2. 
PROTOCOL SUMMARY ........................................................................................................4 
2.1. Synopsis ..........................................................................................................................4 
2.2. Schedule of Events ........................................................................................................10 
3. 
TABLE OF CONTENTS .......................................................................................................12 
3.1. List of In-Text Tables....................................................................................................16 
3.2. List of In-Text Figures ..................................................................................................16 
REASONS FOR AMENDMENT .................................................................................................17 
SUMMARY OF AMENDED SECTIONS ....................................................................................18 
AMENDED PROTOCOL .............................................................................................................20 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...........................................21 
5. 
INTRODUCTION ..................................................................................................................22 
5.1. Background and Rationale ............................................................................................22 
5.1.1 Social Anxiety Disorder ....................................................................................22 
5.1.2 Nasal Chemosensory Systems ...........................................................................22 
5.1.3 PH94B ...............................................................................................................23 
5.2. Clinical Experience .......................................................................................................24 
5.2.1 Phase 1 Studies ..................................................................................................24 
5.2.2 Phase 2 Studies ..................................................................................................24 
5.3. Summary of Potential Risks and Benefits .....................................................................25 
6. 
OBJECTIVES .........................................................................................................................26 
6.1. Primary Objective .........................................................................................................26 
6.2. Secondary Objectives ....................................................................................................26 
6.3. Exploratory Objectives..................................................................................................26 
6.4. Endpoint Mapping .........................................................................................................26 
7. 
STUDY DESIGN ...................................................................................................................29 
7.1. Overall Study Design and Plan .....................................................................................29 
7.2. Rationale and Discussion of Study Design ...................................................................30 
7.3. Selection of Doses in the Study ....................................................................................30 
7.4. Study Sites .....................................................................................................................30 
7.5. End of Study Definition ................................................................................................31 
8. 
SUBJECT POPULATION .....................................................................................................32 
8.1. Selection of Study Population .......................................................................................32 
8.2. Study Entry Criteria ......................................................................................................32 
8.2.1 Inclusion Criteria ...............................................................................................32 
8.2.2 Exclusion Criteria ..............................................................................................33 
8.3. Premature Subject Withdrawal .....................................................................................34 

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8.4. Subject Replacement Criteria ........................................................................................35 
9. 
TREATMENTS ......................................................................................................................36 
9.1. Identification of Investigational Products .....................................................................36 
9.2. Selection of Timing of Dose for Each Subject..............................................................36 
9.3. Dose Adjustment Criteria ..............................................................................................36 
9.4. Treatment Compliance ..................................................................................................36 
9.5. Method of Assigning Subjects to Treatment Groups ....................................................37 
9.6. Blinding and Unblinding Treatment Assignment .........................................................37 
9.7. Permitted and Prohibited Therapies ..............................................................................38 
9.7.1 Permitted Therapies ...........................................................................................38 
9.7.2 Prohibited Therapies ..........................................................................................38 
9.7.3 Restrictions ........................................................................................................39 
9.8. Treatment After End of Study .......................................................................................39 
9.9. Dispensing and Storage .................................................................................................39 
9.10. Drug Accountability ......................................................................................................39 
9.11. Labeling and Packaging ................................................................................................39 
9.11.1 Labeling .............................................................................................................39 
9.11.2 Packaging ..........................................................................................................39 
10. STUDY PROCEDURES ........................................................................................................40 
10.1. Study Duration ..............................................................................................................40 
10.2. Study Periods and Visits ...............................................................................................40 
10.2.1 Screening and Washout .....................................................................................40 
10.2.1.1 Screening (Visit 1) ................................................................................40 
10.2.1.2 Washout Period .....................................................................................42 
10.2.2 Visit 2 (Baseline): 
Public Speaking Challenge .............................43 
10.2.3 Visit 3 (Treatment):
Public Speaking Challenge ........................46 
10.2.4 Follow-up (or Early Termination) Evaluation ...................................................46 
10.3. Assessments ..................................................................................................................47 
10.3.1 Efficacy Variables .............................................................................................47 
10.3.1.1 Public Speaking Challenge ...................................................................47 
10.3.1.2 Subjective Units of Distress Scale ........................................................47 
10.3.1.3 Liebowitz Social Anxiety Scale ............................................................48 
 
10.3.1.5 Patient Global Impression of Change ...................................................48 
10.3.1.6 Clinical Global Impression of Improvement.........................................48 
 
10.3.2 Safety Variables ................................................................................................49 
10.3.2.1 Clinical Laboratory Safety Assessments ...............................................49 

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10.3.2.2 Clinical Examinations ...........................................................................51 
10.3.2.3 Adverse Events......................................................................................52 
11. ADVERSE EVENTS..............................................................................................................53 
11.1. Definitions .....................................................................................................................53 
11.1.1 Adverse Events ..................................................................................................53 
11.1.2 Unexpected Adverse Event ...............................................................................53 
11.1.3 Serious Adverse Events .....................................................................................53 
11.1.4 Significant Adverse Events ...............................................................................54 
11.1.5 Treatment-emergent Adverse Events ................................................................54 
11.2. Event Assessment and Follow-up of Adverse Events ..................................................54 
11.2.1 Assessment ........................................................................................................55 
11.2.2 Evaluation ..........................................................................................................55 
11.2.2.1 Severity of Adverse Events ...................................................................55 
11.2.2.2 Seriousness ............................................................................................55 
11.2.2.3 Actions Taken .......................................................................................56 
11.2.2.4 Outcome at the Time of Last Observation ............................................56 
11.2.2.5 Adverse Event Relationship to Investigational Product........................56 
11.2.3 Documentation ..................................................................................................56 
11.2.4 Treatment of Adverse Events ............................................................................57 
11.2.5 Follow-up ..........................................................................................................57 
11.2.6 Reporting ...........................................................................................................57 
11.2.6.1 Serious Adverse Events.........................................................................57 
11.2.6.2 Nonserious Adverse Events ..................................................................58 
11.3. Special Considerations ..................................................................................................59 
11.3.1 Pregnancy ..........................................................................................................59 
11.3.2 Overdose ............................................................................................................59 
12. DATA SAFETY MONITORING BOARD ...........................................................................60 
13. STATISTICS ..........................................................................................................................61 
13.1. Statistical Analysis ........................................................................................................61 
13.1.1 Analysis Populations .........................................................................................61 
13.1.2 Study Subjects and Demographics ....................................................................61 
13.1.2.1 Disposition and Withdrawals ................................................................61 
13.1.2.2 Protocol Deviations ...............................................................................61 
13.1.2.3 Demographics and Other Baseline Characteristics ...............................62 
13.1.3 Exposure and Compliance .................................................................................62 
13.1.4 Efficacy Analysis ..............................................................................................62 
13.1.4.1 Efficacy Endpoints ................................................................................62 
13.1.4.2 Primary Analysis ...................................................................................63 

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13.1.4.3 Secondary Analyses ..............................................................................63 
 
 
13.1.4.6 Estimand Framework and Sensitivity Analyses ....................................64 
13.1.5 Safety and Tolerability Analyses ......................................................................65 
13.1.5.1 Adverse Events......................................................................................65 
13.1.5.2 Clinical Laboratory Evaluations ...........................................................66 
13.1.5.3 Vital Signs .............................................................................................66 
13.1.5.4 Twelve-lead Electrocardiograms ..........................................................66 
13.1.5.5 Physical Examination Findings .............................................................67 
13.1.5.6 Hamilton Depression Scale ...................................................................67 
13.1.5.7 Columbia-Suicide Severity Rating Scale ..............................................67 
13.1.6 Interim Analysis ................................................................................................67 
13.2. Sample Size Determination ...........................................................................................68 
14. STUDY CONDUCT ...............................................................................................................69 
14.1. Sponsor and Investigator Responsibilities ....................................................................69 
14.1.1 Sponsor Responsibilities ...................................................................................69 
14.1.2 Investigator Responsibilities .............................................................................69 
14.1.3 Confidentiality and Privacy ...............................................................................69 
14.2. Site Initiation .................................................................................................................70 
14.3. Screen Failures ..............................................................................................................70 
14.4. Study Documents ..........................................................................................................70 
14.4.1 Informed Consent ..............................................................................................71 
14.4.2 Investigator’s Regulatory Documents ...............................................................71 
14.4.3 Case Report Forms ............................................................................................71 
14.4.4 Source Documents .............................................................................................72 
14.5. Data Quality Control .....................................................................................................72 
14.5.1 Monitoring Procedures ......................................................................................72 
14.5.2 Data Management ..............................................................................................72 
14.5.3 Quality Assurance/Audit ...................................................................................73 
14.6. Study Termination .........................................................................................................73 
14.6.1 Premature Study Termination ...........................................................................73 
14.7. Study Site Closure .........................................................................................................74 
14.7.1 Record Retention ...............................................................................................74 
14.7.2 Sample Retention ..............................................................................................74 
14.8. Changes to the Protocol ................................................................................................74 
14.9. Use of Information and Publication ..............................................................................75 
15. FINAL CLINICAL STUDY REPORT ..................................................................................76 

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16. ETHICAL AND LEGAL CONSIDERATIONS ....................................................................77 
16.1. Good Clinical Practice ..................................................................................................77 
16.2. Subject Information and Informed Consent ..................................................................77 
16.3. Approval by Institutional Review Board ......................................................................77 
16.4. Finance and Insurance ...................................................................................................77 
17. REFERENCES .......................................................................................................................78 
18. ATTACHMENTS ...................................................................................................................82 
18.1. Investigator’s Agreement ..............................................................................................82 
APPENDICES ...............................................................................................................................83 
A. 
Subjective Units of Distress Scale ................................................................................84 
 
 
 
 
D. 
Liebowitz Social Anxiety Scale ....................................................................................88 
 
 
 
 
G. 
Hamilton Depression Scale ...........................................................................................95 
H. 
Patient Global Impression of Change ...........................................................................99 
I. 
Clinical Global Impression of Improvement...............................................................100 
J. 
Regulations and Good Clinical Practice Guidelines ...................................................101 
 
 
3.1. List of In-Text Tables 
Table 2-1:  
Schedule of Events ............................................................................................10 
 
3.2. List of In-Text Figures 
Figure 7-1: 
Study Design .....................................................................................................29 
Figure 10-1: 
Public Speaking Challenge Schematic ..............................................................45 
Figure 13-1: 
Power Curve for Sample Size Determination ...................................................68 
 
 
 
 

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REASONS FOR AMENDMENT 
 
1. The purpose is to add a futility interim analysis, based on the recent topline results from the 
similar Phase 3 study (PALISADE-1; Study PH94B-CL026), for which the study did not 
meet its primary endpoint.   
 
 
 

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AMENDED PROTOCOL 
The following are the amended protocol and appendices, including all revisions specified above. 
 
 

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4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION 
EXPLANATION 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CGI-I 
Clinical Global Impression – Improvement scale 
COVID-19 
coronavirus 2019 
CRA 
clinical research associate 
CSR 
clinical study report 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eCRF 
electronic case report form 
GCP 
Good Clinical Practice 
 
 
HAM-D 
Hamilton Depression Scale 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
i.n. 
intranasal 
IND 
Investigational New Drug 
IP 
investigational product 
IRB 
institutional review board 
ITT 
Intent-to-Treat 
IWRS 
interactive web response system 
LSAS 
Liebowitz Social Anxiety Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini International Neuropsychiatric Interview 
PGI-C 
Patient Global Impression of Change 
SAD 
social anxiety disorder 
SAE 
serious adverse event 
SD 
standard deviation 
SUDS 
Subjective Units of Distress Scale 
WHO-DD 
World Health Organization Drug Dictionary 

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5. INTRODUCTION 
This document is a protocol for a Phase 3 human research study. This study is to be conducted 
according to United States and international standards of Good Clinical Practice (Food and Drug 
Administration Title 21 part 312 and International Council for Harmonisation guidelines), 
applicable government regulations and Institutional research policies and procedures. 
5.1. Background and Rationale 
5.1.1 Social Anxiety Disorder 
The essential features of social anxiety disorder (SAD) are defined as intense, marked, and 
persistent fear of social or performance situations, in which the subject believes embarrassment, 
humiliation, judgement, or rejection could occur as a consequence of exposure to unfamiliar people 
or possible scrutiny by others in the social or performance (e.g., public speaking) situation. The 
anxiety or fear resulting from the social or performance situation is profound. The avoidance, fear, 
or anxious anticipation of these situations interferes significantly with the person’s daily routine, 
having a marked impact on occupational functioning and social life. The disorder has a lifetime 
prevalence estimated at up to 13%, with onset typically in the mid-teens or earlier, and it is 
diagnosed slightly more frequently in females than in males. Social anxiety tends to be a chronic 
disorder with periods of exacerbation, and a reported mean duration of illness of approximately 
20 years.1,2 
Two subtypes of social anxiety are described in Diagnostic and Statistical Manual of Mental 
Disorders, 5th Edition: (i) social anxiety (formerly called generalized subtype) in which fear and 
avoidance extend to a wide range of social situations, and (ii) performance subtype only, in which 
the subject fears only one or a few circumscribed situations. Public speaking is by far the most 
prevalent of social fears.1 
Social anxiety disorder has a lifetime comorbidity rate of approximately 81% with other 
psychiatric disorders (particularly affective disorders, other anxiety disorders, and substance abuse 
disorders), as well as being associated with increased non-psychiatric medical difficulties. People 
with SAD identify themselves as struggling with social impairment, inadequate social support, 
overall role impairment, specific impairment in education, work, and other activities, as well as 
interference in their efforts at self-improvement. Unfortunately, for these subjects, there is a strong 
consensus that SAD is one of the least commonly recognized and treated mental disorders.1,2  
Current treatments for SAD include both psychosocial and pharmacologic measures. Psychosocial 
treatments include exposure therapy and cognitive behavioral therapy. Pharmacological measures 
vary widely and include antidepressants (monoamine oxidase inhibitors, selective serotonin 
reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors), benzodiazepines, 
beta-blockers, and alpha-2-delta voltage gated calcium channel modulators. 
5.1.2 Nasal Chemosensory Systems 
In humans, as in other mammals, the olfactory system is a rostral projection of the telencephalon 
and it is the only sensory system with direct neural connections to the limbic system without a 
previous relay in the thalamus. Therefore, the limbic amygdala is the only brain structure that 
receives rapid afferent neural inputs from peripheral nasal chemosensory receptors.3,4 Chemical 
cues acting on nasal chemosensory neurons trigger sensory inputs that reach the limbic amygdala 
through a rapid (oligosynaptic) neural path. 

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The relevance of the olfactory system in behavior is revealed by the serious behavioral impairment 
that occurs after bilateral olfactory bulbectomy in laboratory animals,5,6 and the development of 
anxiety and depression in humans with congenital anosmia.7,8  
Stimulation of human olfactory chemosensory cells with primary odors produces olfactory 
awareness via the main olfactory neural circuits,9,10 but in humans, odorless chemosensory cues 
also engage nasal chemosensory receptors and induce behavioral and neuroendocrine responses, 
without olfactory awareness.11-16  
In most mammals, odorless chemosignals induce activation of accessory olfactory neural 
circuits.17-22  
However, some mammals including humans do not have an accessory olfactory system, and there 
are instead neural connections arising in nasal chemosensory neurons that connect with a subset 
of neurons in the main olfactory bulb. These main olfactory bulb neurons in turn project directly 
to the cortical and the medial amygdala and trigger an important contingent of forward inhibitory 
GABAergic neural circuits in the central amygdala involved in the modulation of fear and 
anxiety.21-26 
These olfactory-limbic neural circuits play an important role in social behavior and 
emotions.11-13,19,27,28 The independent sensory contribution of the olfactory system projections to 
the limbic amygdala on social behavior has been also confirmed in molecular biology/behavioral 
studies, in studies using knockout mouse lines with loss of function in different zones of the 
olfactory bulbs,20 in human functional magnetic resonance imaging studies,12,29 in clinical studies 
in human subjects with isolated congenital anosmia,7,30 and in subjects with congenital 
hypogonadotropic hypogonadism.31 
It has been suggested that olfactory receptor repertoires differ significantly across species.32 Since 
these receptors have different roles in different behaviors (e.g., social behavior, fear, reproductive 
behavior) the rapid evolutionary divergences may have contributed to behavior differentiation and 
speciation. Therefore, the action of chemosignals on nasal chemosensory neurons differs 
significantly across species.33-35 
Pherines are a family of synthetic neuroactive steroid molecules that engage specifically with 
human nasal chemosensory receptors. Pherines stimulate receptor neurons in the human nasal 
chemosensory epithelium14,36 that activate olfactory bulb neurons and in turn trigger neural circuits 
in the limbic amygdala. This leads to activation of the anterior gyrus, hypothalamus, hippocampus 
and prefrontal cortex, and it is different from the brain areas activated by primary olfactory 
stimuli.12,29 Pherines are odorless, and brain activation by pherines does not produce olfactory 
awareness12,14 and can modulate brain autonomic and psychophysiologic response.11,13,15,29,37-39 
5.1.3 PH94B 
PH94B (3ȕ-androsta-4,16-dien-3-ol) is a synthetic neuroactive steroid discovered and initially 
developed at Pherin Pharmaceuticals that targets human nasal chemosensory cells11,36 and has been 
demonstrated in Phase 2 clinical trials to have benefits for the acute treatment of SAD.40 
Pherines induce calcium ion entry in human nasal chemosensory neurons.37,41 Pherines such as 
PH94B target G-protein-coupled receptors that are expressed in human nasal chemosensory 
neurons.32,42 

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91 female subjects who met criteria for SAD (generalized subtype) as defined by the Diagnostic 
and Statistical Manual of Mental Disorders, 4th Edition. PH94B (1.6 μg) was administered i.n. in 
spray form 
 to both a performance (public speaking) challenge and a social 
interaction challenge simulation which took place at the clinical sites. 
 
 The primary outcome measures were the Clinical Global 
Impression Scale of Improvement (CGI-I) and the Subjective Units of Distress Scale (SUDS). The 
SUDS scores range from 0 to 100, with higher scores indicating greater levels of anxiety. Subjects 
receiving PH94B were more likely than those who received placebo to show improvement on the 
CGI-I following treatment. In the PH94B group, 34 of 45 subjects (75.6%) were rated very much 
less anxious or much less anxious compared to only 17 of 46 subjects (37%) in the placebo group. 
A test for the difference between proportions indicated a Z value of 4.03, p = 0.0001 (Fisher’s 
exact test). 
During the public speaking challenge, subjects randomized to PH94B (n=45) showed an 
improvement of 26.7 points in the mean score on the SUDS at Visit 3 (initial treatment visit) as 
compared to Visit 2 (baseline visit, at which all subjects received placebo). In comparison, subjects 
randomized to placebo (n=46) showed an improvement of only 14.0 in the mean SUDS score 
across visits. The PH94B group’s improvement from Visit 2 to Visit 3 significantly exceeded the 
placebo group’s improvement from Visit 2 to Visit 3 (t = 3.16, p = 0.002) on this challenge. No 
SAEs were reported, and no subjects were terminated prematurely from the study due to AEs. 
5.3. Summary of Potential Risks and Benefits 
There are no direct benefits to participation for subjects in this study. Subjects will receive a single 
i.n. dose of PH94B or placebo at the study site. PH94B is intended for acute treatment of SAD, 
and the activity is not expected to last long beyond the subjects’ study visit. 
Based on previous clinical studies conducted with PH94B, it is believed to be safe and well 
tolerated, and risks to subjects are considered minimal. Intranasal administration of PH94B may 
increase the risk of local site reactions including itching, burning, runny nose, sneezing and 
soreness inside the nose. In completed clinical studies, the most commonly reported AE was 
headache. None of these effects was reported in more subjects receiving PH94B than in subjects 
receiving placebo. 
A summary of the pharmaceutical properties and known potential risks of PH94B is provided in 
the current version of the investigator brochure (IB). The investigator must become familiar with 
all sections of the PH94B IB before the start of the study. 

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7.5. End of Study Definition 
A clinical trial is considered completed when the last subject’s last study visit has occurred. 

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8. SUBJECT POPULATION 
8.1. Selection of Study Population 
Eligibility for participation in the study will be determined from demographic information, medical 
and psychiatric history, physical and psychiatric examination, ECG, clinical laboratory findings, 
and clinical rating scale assessments performed at Screening (Visit 1). Subjects may be recruited 
from the Investigator or sub-Investigator clinical practices, the center’s existing database, referring 
physicians, or direct advertisement or other lead generation source. Any information to be 
disseminated to potential subjects (handouts, brochures, etc.), as well as direct advertisements, 
including direct electronic or digital advertising, must be approved by VistaGen and by the IRB 
prior to use and implementation. 
8.2. Study Entry Criteria 
Subjects who do not meet all of the eligibility criteria will not be enrolled. 
8.2.1 Inclusion Criteria 
To be considered eligible to participate in the study, a subject must meet the following inclusion 
criteria: 
1. Written informed consent provided prior to conducting any study-specific assessment. 
2. Male and female adults, 18 through 65 years of age, inclusive. 
3. Current diagnosis of SAD as defined in the Diagnostic and Statistical Manual of Mental 
Disorders, 5th Edition, and confirmed by the MINI.  
4. Clinician-rated LSAS total score 70 at Screening (Visit 1). 
5. Clinician-rated Hamilton Depression Score 17-items total score <18 at Screening (Visit 1). 
6. Women of childbearing-potential must be able to commit to the consistent and correct use 
of an effective method of birth control throughout the study and must also have a negative 
urine pregnancy test result at both Screening (Visit 1) and Baseline (Visit 2), prior to IP 
administration. Effective methods of contraception include: condoms with spermicide, 
diaphragm with spermicide, hormonal contraceptive agents (oral, transdermal, or 
injectable), or implantable contraceptive devices. 
7. Negative COVID-19 test for subjects with COVID-19 symptoms or those who have had 
direct exposure to someone with a positive COVID-19 test, and/or completion of 
quarantine period consistent with requirements at the study site as determined by the 
Investigator. 

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8.2.2 Exclusion Criteria 
To be considered eligible for entry into the study, a subject must not meet any of the following 
exclusion criteria: 
1. Any history of bipolar disorder (I or II), schizophrenia, schizoaffective disorder, psychosis, 
anorexia or bulimia, premenstrual dysphoric disorder, autism-spectrum disorder, or 
obsessive-compulsive disorder. 
Any other current Axis I disorder, other than SAD, which is the primary focus of treatment. 
Note that subjects with concurrent Generalized Anxiety Disorder are eligible for the study 
provided that Generalized Anxiety Disorder is not the primary diagnosis. 
2. Subjects who meet criteria for moderate or severe alcohol or substance use disorder within 
the 1 year prior to Study entry. 
3. In the opinion of the investigator, the subject has a significant risk for suicidal behavior 
during the course of their participation in the study, or 
a. At Screening (Visit 1): the subject scores “yes” on items 4 or 5 in the Suicidal 
Ideation section of the Columbia-Suicide Severity Rating Scale (C-SSRS) with 
reference to a 6-month period prior to screening; or 
b. At Screening (Visit 1): the subject has had 1 or more suicidal attempts with 
reference to a 2-year period prior to screening; or 
c. At Baseline (Visit 2): the subject scores “yes” on items 4 or 5 in the Suicidal 
Ideation section of the C-SSRS with reference to screening; or 
d. The subject is considered to be an imminent danger to themself or others. 
4. Clinically significant nasal pathology or history of significant nasal trauma, nasal surgery, 
total anosmia, or nasal septum perforation that may have damaged the nasal chemosensory 
epithelium. 
5. An acute or chronic condition, including an infectious illness, uncontrolled seasonal 
allergies at the time of the study, or significant nasal congestion that potentially could affect 
drug delivery to the nasal chemosensory epithelium.  
6. Two or more documented failed treatment trials with a registered medication approved for 
SAD, at any time during the lifetime of the subject, whereby an adequate treatment trial is 
defined as that described in the package insert for a particular drug during which the subject 
received an adequate medication dosage (defined as the treatment dose indicated in the 
package insert to obtain efficacy for that particular drug).  
7. Use of any psychotropic medication within 30 days before study entry (other than 
medication permitted for insomnia: eszopiclone, ramelteon, melatonin, zaleplon, zolpidem, 
or antihistamines). 
8. Use of any anxiolytics, such as benzodiazepines or unapproved treatments such as beta 
blockers, within 30 days before study entry; concomitant use is prohibited during the study. 
Subjects who have been taking benzodiazepines daily for 1 month or longer at the time of 
Visit 1 are not eligible to participate. 

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9. Use of any over-the-counter product, prescription product, or herbal preparation for 
treatment of the symptoms of anxiety or social anxiety within 30 days before study entry; 
concomitant use is prohibited during the study. 
10. Prior participation in a clinical trial involving PH94B. 
11. Women who have a positive urine pregnancy test prior to IP administration. Women who 
are currently breastfeeding are not eligible unless they are willing to stop breastfeeding for 
the duration of time between Visit 2 and Visit 4. 
12. Subjects with clinically significant abnormalities in hematology, blood chemistry, 
urinalysis, electrocardiogram, or physical examination identified at the Screening visit or 
Baseline visit that in the clinical judgment of the Investigator, could place the subject at 
undue risk, interfere with study participation, or confound the results of the study. 
13. Subjects with a positive urine drug screen at either Screening (Visit 1) or Baseline (Visit 2) 
(
). 
14. Any current clinically significant and/or uncontrolled medical condition, based on medical 
history or as evidenced in screening assessments, such as COVID-19, HIV, cancer, stroke, 
congestive heart failure, uncontrolled diabetes mellitus, or any other medical condition or 
disease that, in the clinical judgment of the Investigator, could place the subject at undue 
risk, interfere with study participation, or confound the results of the study.  
15. History of cancer or malignant tumor not in remission for at least 2 years. Basal cell skin 
cancers are not exclusionary. 
8.3. Premature Subject Withdrawal 
A subject will be considered to have completed the Study when he or she completes Visit 4. 
All subjects will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. The investigator should make every reasonable 
attempt to keep subjects in the study; however, subjects must be withdrawn from the study if they 
withdraw consent to participate. Investigators must attempt to contact subjects who fail to attend 
scheduled visits by telephone or other means to exclude the possibility of an AE being the cause 
of withdrawal. Should this be the cause, the AE must be documented, reported, and followed as 
described in Section 11.2. 
The sponsor reserves the right to request the withdrawal of a subject due to protocol deviations or 
other reasons. 
The investigator also has the right to withdraw subjects from the study at any time for the following 
reasons: 
x Any AE, laboratory abnormality, or concomitant illness which, in the opinion of the 
Investigator, indicates that continued treatment with IP or any other aspect of the study is 
not in the best interest of the subject 
x Disease progression that, in the Investigator’s opinion, precludes the subject’s continued 
participation in the study 
x Significant non-compliance with the requirements of the protocol or treatment 

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x The subject requires a medication prohibited by the protocol 
x Termination of the Study by VistaGen 
x At the discretion of the Investigator or VistaGen 
x Pregnancy 
If a subject is withdrawn before completing the study, the reason for withdrawal and the date of 
discontinuation will be recorded on the appropriate page of the electronic case report form (eCRF). 
Whenever possible and reasonable, the evaluations that were to be conducted at the completion of 
the study should be performed at the time of premature discontinuation. 
All attempts will be made to have subjects return to the study center to complete Visit 4 in the 
event of early withdrawal from Visit 3 after IP administration. All attempts, including phone or 
email, to contact the subject must be recorded in the source documents. If the subject fails to 
respond to those methods, a certified, return receipt letter must be sent to the subject’s address 
indicating that they should contact the study center, with a copy retained in the source documents. 
Only if all of these attempts fail will it be deemed that the subject is in fact Lost to Follow-up and 
no final safety data can be collected. 
Subjects who sign the ICF and are subsequently withdrawn will not be replaced. 
8.4. Subject Replacement Criteria 
Withdrawn subjects will not be replaced. If a substantial number of subjects are withdrawn from 
the study, the sponsor will evaluate the need for developing replacement criteria. 
Enrolled subjects who are withdrawn from the study may not re-enter. The subject number for a 
withdrawn subject will not be reassigned to another subject. 
 

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Subjects will self-administer the IP in the presence of study personnel at each visit. The study 
personnel will be responsible for documenting the administration in the eCRF. 
9.5. Method of Assigning Subjects to Treatment Groups 
In this parallel-group randomized study, subjects who meet study entry criteria, and who complete 
the Visit 2 public speaking challenge, will be randomly assigned in a 1:1 ratio to 
 
The randomization schedule will be computer generated using a permuted block 
algorithm and will randomly allocate IP to randomization numbers. The randomization numbers 
will be assigned sequentially through a central interactive web response system (IWRS) as subjects 
are entered into the study. Randomization will be stratified by study site; blocks will be allocated 
to sites by IWRS in real-time. 
The randomization schedule will be prepared by Premier Research 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 subject will be randomized into this study more 
than once. 
9.6. Blinding and Unblinding Treatment Assignment 
Each study site will be provided with a supply of blinded IP, each vial individually numbered with 
a unique identification code. For Visit 2 and Visit 3, the IWRS will provide a unique vial 
identification code indicating the medication vial to be dispensed to the subject. The vial 
identification codes will be recorded in the drug dispensing record and the eCRF. 
The vial number can be used to break the blind if necessary. Contact information will be provided 
to the study site. 
All subjects, investigators, 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 a member of the Interactive Response Technology team from Premier 
Research 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. If an interim analysis is to be conducted, then unblinded personnel who 
are not otherwise involved in the study will prepare the data for review. 
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 
subject’s treatment assignment. 
Unblinding should be discussed in advance with the medical monitor, if possible. For emergency 
unblinding, study personnel will use the IWRS. If the investigator is not able to discuss treatment 
unblinding in advance, then he/she must notify the medical monitor as soon as possible about the 
unblinding incident without revealing the subject’s treatment assignment.  
The investigator or designee must record the date and reason for treatment unblinding on the 
appropriate eCRF for that subject. In all cases that are not emergencies, the investigator must 
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10. STUDY PROCEDURES 
Subjects must provide written informed consent and/or assent before any study-related procedures 
are initiated, including the cessation of prohibited concomitant therapy. 
For the timing of assessments and procedures throughout the study, refer to the schedule of events 
(Table 2-1). Throughout the study, every reasonable effort should be made by study personnel to 
follow the timing of assessments and procedures in the schedule of events for each subject. If a 
subject misses a study visit for any reason, the visit should be rescheduled as soon as possible. 
10.1. Study Duration 
The study comprises a 
phase on Day 0, followed by a double-blind exposure for 1 day 
approximately 1 week later. 
Following participation in the PALISADE-2 study, subjects will have the option to participate in 
the PALISADE LTS study (PH94B-CL030), pending their provision of consent and confirmation 
of eligibility. The PALISADE LTS study is an open-label study in which subjects participate for 
up to 12 months. Participating subjects will self-administer PH94B nasal spray prior to or during 
anxiety-provoking social situations or events, as needed. 
10.2. Study Periods and Visits 
A comprehensive schedule of study assessments is presented in Table 2-1 and described in the 
following sections. Every effort should be made to complete all required procedures and 
evaluations at the designated visits. For each study visit, a window of ±2 days is permitted. 
10.2.1 Screening and Washout 
10.2.1.1 Screening (Visit 1) 
Screening begins after the written informed consent has been obtained. The purpose of the 
screening phase is to: 
x 
Ensure that appropriate subjects are entered into the trial 
x 
Determine that the subject meets all eligibility criteria 
x 
Collect demographic and medical data permitting characterization of the subject 
x 
Ensure that prohibited medications are discontinued and 
x 
Determine that subjects are willing to undertake up to 2 anxiety-provoking 
situations at the site 
To meet these objectives, the duration of screening must be tailored to the individual subject and 
may last from a minimum of 3 to a maximum of 35 days. Subjects continuing to meet all eligibility 
requirements at Baseline (Visit 2) will undergo a Visit 2 public speaking challenge 
(APPENDIX B). 

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b. Administer HAM-D 
c. 
 
d. Administer C-SSRS (Long Term/Recent) 
5. Physical assessments (recommend blood draw last to avoid any potential impact 
on vitals and ECG assessment) to include: 
a. Perform physical examination, including height (inches), body weight 
(pounds), body temperature (°F), and vital signs after the subject has 
rested for 5 minutes: seated systolic and diastolic blood pressure, heart 
rate, and respiratory rate. The physical examination includes a review 
of the nasal passages 
b. Obtain 12-lead ECG in supine position after the subject has rested for 
5 minutes 
c. Obtain blood and urine samples for evaluation by the central clinical 
laboratory, including hematology, chemistry, thyroid functioning, and 
urinalysis (refer to Section 10.3.2.1.1 for complete list) 
6. After these assessments are complete, review all inclusion and exclusion 
criteria 
7. Train subjects on the use of IP and dosing. The subject will be given instructions 
on: 
a. how to position the nozzle in the nasal passages and self-administer IP, 
using a demonstration vial 
b. number of sprays per nostril per dose (one per nostril) 
Procedures for rescreening subjects who initially fail to meet study entry criteria are described in 
Section 14.3. 
 
10.2.1.2 Washout Period 
In accordance with the study entry criteria (Section 8.2), the use of any psychotropic medications, 
anxiolytics, or other preparation for the treatment of anxiety or social anxiety is prohibited within 
30 days before study entry (considered as Visit 2). 
Where washout of prohibited medications is required before Baseline (Visit 2), tapering rates are 
at the discretion of the Investigator and are to be determined on an individual basis, with 
consideration to subject state, dose, and known pharmacokinetics of the medication being 
discontinued. The subject must be consented before any tapering is started. 

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x 
The subject will be escorted 
 into a room to 
give a 5-minute speech in front of 
 after the last SUDS 
anticipatory anxiety score is collected. 
 
 
 
 
 
 At these timepoints, 
 
 
 
x 
 
 the subject will be given information on attending the next visit 
(Visit 3) - otherwise, the subject will complete the remaining assessments for 
Visit 2, will not be randomized, and will be discharged from the study 
 
 
x 
If the subject cannot complete the speech during the performance phase due to 
anxiety levels, the SUDS level will be requested from them before they leave the 
room and all remaining time points will be marked as not done 
x 
Record any AEs reported 
x 
Administer C-SSRS (Since Last Visit) as the last part of Visit 2 
For the subjects attending the next visit (Visit 3), it will be scheduled 1 week (±2 days) after the 
date of Visit 2. 
 

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10.2.3 Visit 3 (Treatment): 
Public Speaking Challenge 
At Visit 3, subjects should return to the study site and the following assessments will be completed: 
x 
Measure vital signs after the subject has rested for 5 minutes: seated systolic and 
diastolic blood pressure, heart rate, respiratory rate, and body temperature 
x 
Perform urine drug screen (Instant Exam, to be performed on site, with results 
documented in the source)  
x 
For females of child-bearing potential, obtain urine sample and complete on-site 
urine pregnancy test 
x 
Record concomitant medication use 
x 
Review and record AEs 
x 
Randomize the subject 
x 
 follow the instructions for the Visit 3 
public speaking challenge (as described in Section 10.2.2 and Figure 10-1) with 
the same trained observer as in Visit 2; the subject will record SUDS accordingly 
After the completion of the Visit 3 public speaking challenge: 
x 
Complete the PGI-C (by the subject) 
x 
Complete the CGI-I (by the trained observer of the public speaking challenge) 
x 
Review and record AEs 
x 
Administer C-SSRS (Since Last Visit) as the last part of the visit 
The Follow-up visit (Visit 4) will be scheduled for 1 week ±2 days after the date of Visit 3. 
10.2.4 Follow-up (or Early Termination) Evaluation 
At Visit 4, 1 week (±2 days) after Visit 3, the following procedures will be performed: 
x 
Obtain 12-lead ECG in supine position after the subject has rested for 5 minutes 
x 
Obtain blood and urine samples for evaluation by the central clinical laboratory, 
including hematology, chemistry, thyroid functioning, and urinalysis (refer to 
Section 10.3.2.1.1 for complete list) 

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The Investigator is responsible for ensuring that all study samples that are to be transported to 
another location are packed and shipped appropriately according to the applicable regulations.  
10.3.2.1.3 Evaluation of Clinical Laboratory Values 
The normal ranges of values for the clinical laboratory assessments in this study will be provided 
by the responsible laboratory and submitted to VistaGen Therapeutics, Inc. prior to the beginning 
of the study. They will be regarded as the reference ranges on which decisions will be made. 
If a laboratory value is out of the reference range, it is not necessarily clinically relevant. The 
investigator must evaluate the out-of-range values and record his or her assessment of the clinical 
relevance in the appropriate eCRF. 
All clinical laboratory values that in the investigator’s opinion show clinically relevant or 
pathological changes during or after termination of treatment must be reported as AEs and 
followed, as described in Section 11.2.5. 
All measurements described in this section are recognized standard methods. 
10.3.2.2 Clinical Examinations 
10.3.2.2.1 Vital Signs 
Vital signs, including heart rate, respiratory rate, and seated systolic and diastolic blood pressure 
will be measured after the subject has been in a seated position for 5 minutes. Temperature will 
also be measured. 
10.3.2.2.2 Twelve-lead Electrocardiogram 
A standard 12-lead ECG will be performed after the subject has been seated for at least 5 minutes. 
All ECG recordings will be identified with the subject number, initials, date, and time of the 
recording and will be attached to the subject’s eCRF. 
10.3.2.2.3 Physical Examination 
A complete physical examination (excluding the genitourinary examination) will be performed as 
indicated in the schedule of events (Table 2-1). The physical examination will include 
measurement of weight and height, and an examination of the nasal passages. 
10.3.2.2.4 Hamilton Depression Scale 
The Hamilton Depression scale is a 17-item instrument that evaluates symptoms of expression 
experienced over the past week (see APPENDIX G). Items are scored on a variety of scales, 
including 3-, 4-, and 5-point questions. An overall score of 0 to 7 is generally accepted to be within 
the normal range, while a score of 20 or higher indicates at least moderate severity. 
10.3.2.2.5 Columbia-Suicide Severity Rating Scale 
The C-SSRS is a semi structured interview that captures the occurrence, severity, and frequency 
of suicide-related thoughts and behaviors during the assessment period. The interview includes 

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definitions and suggested questions to solicit the type of information needed to determine if a 
suicide-related thought or behavior has occurred. The C-SSRS has a “baseline” version which will 
be completed at Screening and a “since last visit” version that will be completed at all subsequent 
visits. There are a maximum of 19 items to be completed: 7 that are required, 10 potential 
additional items if there is a positive response to a required item, and 2 items for suicide/suicide 
behavior present during the interview. The C-SSRS uses dichotomous scales (i.e., yes or no), 
Likert scales, and text or narrative to further describe the thoughts or behaviors. 
10.3.2.3 Adverse Events 
The definitions and management of AEs, and any special considerations for AEs, are provided in 
Section 11. 

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11. ADVERSE EVENTS 
It is the responsibility of the Investigator at the site to oversee the safety of the study at his/her site. 
This safety monitoring will include careful assessment and appropriate reporting of SAEs as noted 
in this section. Medical monitoring will include a regular assessment of the number and type of 
SAEs. 
11.1. Definitions 
11.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not related to the medicinal product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. (Worsening of a 
pre-existing condition is considered an AE.) 
In this study, AEs will be classified by time of occurrence and Visit 3 group assignment to more 
clearly identify those arising after exposure to placebo only and those arising after exposure to 
PH94B.  
Pregnancy is not considered an AE, but it is an important medical event, which must be followed 
up as described in Section 11.3.1. 
11.1.2 Unexpected Adverse Event 
An expected AE is one for which the nature or severity is consistent with the known AE profile of 
the product. For a pre-approval test product, the known information is contained in the IB. For a 
marketed product, the known information is contained in the current package insert for the product. 
An unexpected adverse event (UAE) is one for which the nature or severity of which is not 
consistent with the applicable product information (e.g., IB for an unapproved investigational 
product or package insert/summary of product characteristics for an approved product). For 
example, hepatic necrosis would be unexpected (greater severity) if the IB only listed elevated 
hepatic enzymes or hepatitis. Likewise, cerebral thromboembolism and cerebral vasculitis would 
be unexpected (greater specificity) if the IB only listed cerebral vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, already 
documented adverse reaction constitute unexpected events. Examples would be (a) acute renal 
failure as an expected adverse reaction with a subsequent new occurrence of interstitial nephritis 
(interstitial nephritis would be unexpected) and (b) hepatitis with a first occurrence of fulminant 
hepatitis (fulminant hepatitis would be unexpected.) 
11.1.3 Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
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x is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
x requires inpatient hospitalization or prolongation of existing hospitalization 
An elective hospital admission to treat a condition present before exposure to the IP, or a 
hospital admission for a diagnostic evaluation of an AE, does not qualify the condition or 
event as an SAE. 
x results in persistent or significant disability/incapacity 
x is a congenital anomaly 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the IP 
during pregnancy is an SAE. However, a newly diagnosed pregnancy in a subject that has 
received an IP is not considered an SAE unless it is suspected that the IP(s) interacted with 
a contraceptive method and led to the pregnancy.  
x is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result 
in hospitalization, development of drug dependency, or drug abuse. 
11.1.4 Significant Adverse Events 
Other significant AEs are defined as marked hematological and other laboratory abnormalities 
(other than those meeting the definition of serious) and any events that led to an intervention, 
including withdrawal of test drug, dose reduction, or significant additional concomitant therapy. 
11.1.5 Treatment-emergent Adverse Events 
Treatment-emergent AEs are defined as: 
x AEs with onset at the time of or following the start of treatment with IP through the 
Follow-up Visit or 
x AEs starting prior to the start of treatment but increasing in severity or relationship at the 
time of, or following, the start of treatment with IP through the Follow-up Visit. 
11.2. Event Assessment and Follow-up of Adverse Events 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study subject presenting for medical care, or upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate eCRF. Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All 

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AEs occurring while on study must be documented appropriately regardless of relationship. All 
AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the subject is screened will be considered as 
baseline and not reported as an AE. However, if the study subject’s condition deteriorates at any 
time during the study, it will be recorded as an AE. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
The Investigator will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 days after the last day of study participation. At each study visit, the 
investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be 
followed for outcome information until resolution or stabilization. 
11.2.1 Assessment 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. At each visit, the subject will be allowed 
time to spontaneously report any issues since the last visit or evaluation. The investigator will then 
monitor and/or ask about or evaluate AEs using nonleading questions, such as 
x “How are you feeling?” 
x “Have you experienced any issues since your last visit?” 
x “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. 
11.2.2 Evaluation 
11.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as: 
Mild 
An event that is easily tolerated by the subject, causing minimal discomfort and 
not interfering with everyday activities 
Moderate 
An event that is sufficiently discomforting to the extent of interfering with 
normal everyday activities 
Severe 
An event that prevents the subject from performing normal everyday activities 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.3. 
11.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.3. 

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11.2.2.3 Actions Taken 
Actions taken may consist of: 
Dose not changed 
An indication that a medication schedule was maintained. 
Drug withdrawn 
An indication that a medication schedule was modified through 
termination of a prescribed regimen of medication. 
Not applicable 
Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
11.2.2.4 Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as: 
x Recovered/resolved 
x Recovered/resolved with sequelae 
x Recovering/resolving 
x Not recovered/not resolved 
x Fatal* 
x Unknown 
*Investigators should only select fatal as an outcome when the AE results in death. If more than 1 
AE is judged to be possibly related to the subject’s death, the outcome of death should be indicated 
for each such AE. Although “fatal” is usually an event outcome, events such as sudden death or 
unexplained death should be reported as SAEs. 
11.2.2.5 Adverse Event Relationship to Investigational Product 
The investigator must make an assessment of each AEs relationship to the IP. The categories for 
classifying the investigator’s opinion of the relationship are as follows: 
Related 
A reasonable possibility exists of a relationship between the AE and IP. 
Not related 
No reasonable possibility exists of a relationship between the AE and IP. 
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, relevant medical history, and confounding 
factors such as co-medication or concurrent diseases. 
11.2.3 Documentation 
All AEs that occur within the period of observation for the study must be documented in the eCRF 
with the following information, where appropriate. (The period of observation for the study is 
described in Section 11.2). 
x AE name or term 
x When the AE first occurred (start date and time) 

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x When the AE stopped (stop date and time or an indication of “ongoing”) 
x Severity of the AE 
x Seriousness (hospitalization, death, etc.) 
x Actions taken 
x Outcome 
x Investigator opinion regarding the AE relationship to the IP 
11.2.4 Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care. If such treatment constitutes a deviation from the protocol, the subject should be withdrawn 
from the study and the reason must be documented in the eCRF. The decision about whether the 
subject may continue in the study will be made by the sponsor after consultation with the 
investigator and/or medical monitor. 
If AEs occur in a subject that are not tolerable, the investigator must decide whether to stop the 
subject’s involvement in the study and/or treat the subject. Special procedures may be 
recommended for the specific IP, such as the collection of a serum sample for determining blood 
concentrations of IP, specific tapering procedures, or treatment regimens, as appropriate. 
For double-blinded studies, it is not necessary to unblind a subject’s treatment assignment in most 
circumstances, even if an SAE has occurred. If unblinding is necessary, see Section 9.6 for a 
description of the unblinding procedures. 
11.2.5 Follow-up 
Any AE will be followed to a satisfactory resolution, until it becomes stable, or until it can be 
explained by another known cause(s) (i.e., concurrent condition or medication) and clinical 
judgment indicates that further evaluation is not warranted. All findings relevant to the final 
outcome of an AE must be reported in the subject’s medical record and recorded on the eCRF 
page.  
11.2.6 Reporting 
11.2.6.1 Serious Adverse Events 
The investigator or designee must report all SAEs promptly to Premier Research within 24 hours 
of first becoming aware of the event by completing, signing, and dating the Serious Adverse Event 
Report Form, verifying the accuracy of the information recorded in the form with the source 
documents and eCRF, and sending the SAE Report Form to Premier Research by one of the 
following methods:  
Email: PVDS-NA@premier-research.com 
Fax number (back-up): +1 215 972 8765 
This written report should be submitted on the SAE form provided for this purpose. At the time of 
first notification, the investigator or designee should provide the following information, if 
available: 

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x Protocol number 
x Reporter (study site and investigator) 
x Subject’s study number 
x Subject’s date of birth 
x Subject’s gender 
x Date of first dose of IP 
x Date of last dose of IP, if applicable 
x Adverse event term 
x Date of occurrence of the event 
x A brief description of the event, outcome to date, and any actions taken 
x The seriousness criteria(on) that were met 
x Concomitant medication at onset of the event 
x Relevant medical history information 
x Relevant laboratory test findings 
x Investigator’s opinion of the relationship to IP (“Is there a reasonable possibility that the IP 
caused the SAE? Yes or No?”) 
x Whether and when the investigator was unblinded as to the subject’s treatment assignment  
Any missing or additional relevant follow-up information concerning the SAE should be sent to 
the sponsor/sponsor representative via the same contact details above as soon as possible, and 
within 7 days, on a follow-up SAE Report Form, together with the following minimal information 
(initial report, AE, date of occurrence, subject identification (ID), study ID, IP, and site number); 
this will allow the follow-up information to be linked to the initial SAE report.  
Specific information may be requested by the Premier Research Pharmacovigilance Department 
using a follow-up request form sent 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. 
11.2.6.2 Nonserious Adverse Events 
Nonserious AEs will be recorded in the eCRF and reported by Premier Research to the sponsor in 
accordance with the study-specific safety management plan. 

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11.3. Special Considerations 
11.3.1 Pregnancy 
All women of childbearing potential who participate in the study should be counseled on the need 
to practice adequate birth control and on the importance of avoiding pregnancy during study 
participation. Women should be instructed to contact the investigator or study staff immediately if 
pregnancy occurs or is suspected. 
Pregnancy testing will be conducted prior to administration of the IP on every woman of 
childbearing potential. A woman who is found to be pregnant at the Screening Visit will be 
excluded from the study and considered to be a screening failure. 
A woman who becomes pregnant during IP treatment or within 7 days of discontinuing the IP will 
be immediately discontinued from study participation. The investigator must report the pregnancy 
within 48 hours of learning of the pregnancy, to Premier Research Pharmacovigilance using the 
Pregnancy Data Collection Form via the same fax number and/or email address as for SAE 
reporting. The investigator should contact the designated individual(s) who receive SAE 
notification and record information related to the pregnancy on an Exposure in Utero form 
provided by the sponsor or its designee. 
Early Termination Visit assessments are required as soon as possible after learning of the 
pregnancy. The investigator is also responsible for following the pregnancy until delivery or 
termination. These findings must be reported on the Exposure in Utero form and forwarded to the 
designated individual(s). The event meets the SAE criterion only if it results in a spontaneous 
abortion or a congenital anomaly. 
11.3.2 Overdose 
The maximal dose of PH94B should not be exceeded during the study. Overdose that occurs during 
the study will be treated and documented as an AE/UAE/SAE if it fulfills the criteria. The 
information contained therein should include study site identification, reporter identification, 
subject identification, IP, dose, action taken (e.g., supportive measures or therapy), and any 
comments.  If the overdose does not result in an AE, it should be reported in the eCRF.  

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12. DATA SAFETY MONITORING BOARD 
A data safety monitoring board will not be used in this study. 

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13. STATISTICS 
13.1. Statistical Analysis 
This section presents a summary of the planned statistical analyses.  
The statistical analysis plan will be finalized and approved before final database lock and 
unblinding of the randomization code. 
Unless otherwise indicated, all testing of statistical significance will be 2-sided, and a difference 
resulting in a p value of < 0.05 will be considered statistically significant.  
For analyses involving study site, if the number of subjects per site is small, sites may be pooled 
for analysis (see Section 13.1.4.2). The final determination will be made prior to database lock. 
The data will be summarized in tables, as appropriate, showing the number of subjects with 
non-missing data (n), mean, standard deviation (SD), median, minimum, and maximum for 
continuous data and showing counts and percentage for categorical data. Data will also be listed 
as deemed appropriate. All statistical analyses will be performed, and data appendices will be 
created by using SAS. 
13.1.1 Analysis Populations 
The following 2 analysis populations are planned for this study: 
x Intent-to-treat (ITT): The Intent-to-Treat Population in the Study includes all subjects who 
are randomized 
x Safety: All subjects who receive IP  
Inclusion in the analysis populations will be determined prior to database lock. 
If a subject is randomized incorrectly or is administered the incorrect IP, analyses of the ITT 
population will be based on the assigned treatment whereas all other analyses will be based on the 
actual treatment. 
13.1.2 Study Subjects and Demographics 
13.1.2.1 Disposition and Withdrawals 
The numbers of subjects randomized, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of subjects in each 
analysis population will be reported. 
13.1.2.2 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) requirements. The noncompliance may be either on the part of the subject, 
the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
Documentation of the deviations and corrective actions will be included in the data quality 
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handled using the treatment policy strategy, i.e., included in the treatment regimen under 
evaluation. The proportion of subjects with CGI-I scores of 1 (Very much less anxious) or 2 (Much 
less anxious) for PH94B will be compared to placebo using a comparison of binomial proportions. 
13.1.4.6.3 Sensitivity Analyses 
Sensitivity analysis focusing on the assumptions about missing data can be performed by varying 
assumptions about the change in the SUDS scores. Details around sensitivity analyses will be 
finalized in the Statistical Analysis Plan. 
13.1.4.6.4 Missing Data and Imputation 
Prevention of missing data is central to this study design. All subjects will be counseled at 
enrollment on the importance of completing the study and communicating all issues and concerns 
to the study coordinator. 
Case report forms will be designed to capture all relevant background information as well as 
objective reasons for early discontinuation when it cannot be prevented. 
It is expected that all study subjects who are randomized at Visit 3 will complete the Visit 3 public 
speaking challenge immediately after randomization and be included in the primary efficacy 
analysis. If Visit 3 SUDS scores are missing for unanticipated reasons (intercurrent events) that 
arise during Visit 3, appropriate imputation methods and sensitivity analyses will be applied. 
Details on the treatment of missing data will be described in the final Statistical Analysis Plan. 
13.1.5 Safety and Tolerability Analyses 
Safety in this study will be determined from evaluation of AEs, clinical laboratory assessments, 
vital signs assessments, changes in suicidality (C-SSRS) and level of depression (HAM-D), 
physical examinations including examination of the nasal passages, and ECGs. Specific visits for 
obtaining clinical laboratory assessment samples are listed in the Schedule of Events (Table 2-1). 
Details of clinical laboratory tests are provided in Section 10.3.2.1.1. 
Descriptive statistics will be used to present safety and tolerability of PH94B (3.2 μg) as measured 
by reports of AEs and SAEs, changes in laboratory values, vital signs, ECGs, and physical 
examination. 
Safety analyses will be conducted using data from the safety population (as defined in 
Section 13.1.1).  
13.1.5.1 Adverse Events 
All AEs will be coded using the most recent version of MedDRA.  
Treatment-emergent AEs are defined as: 
x AEs with onset at the time of or following the start of treatment with IP through the 
Follow-up Visit or 
x AEs starting prior to the start of treatment but increasing in severity or relationship at the 
time of, or following, the start of treatment with IP through the Follow-up Visit. 

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Adverse events will be classified by time of occurrence and Visit 3 group assignment to more 
clearly identify those arising after exposure to placebo only and those arising after exposure to 
PH94B. 
The number and percentage of subjects with AEs will be displayed for each treatment group by 
system organ class and preferred term. Summaries of AEs by severity and relationship to IP will 
also be provided. Serious adverse events and AEs resulting in discontinuation of IP will be 
summarized separately in a similar manner. Subject listings of AEs, SAEs, and AEs causing 
discontinuation of IP will be produced. 
13.1.5.2 Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values 
and changes from baseline values will be presented for clinical laboratory values for each treatment 
group at each time point. 
The number of subjects with clinical laboratory values categorized as below, within, or above 
normal ranges will be tabulated showing change from baseline (shift tables) for each clinical 
laboratory analyte by treatment group and by study visit. 
Laboratory values that are outside the normal range will also be flagged in the data listings and 
presented with the corresponding normal ranges. Any out-of-range values that are identified by 
the investigator as being clinically significant will also be shown in a data listing. 
13.1.5.3 Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline will be calculated for systolic blood pressure, diastolic blood pressure, heart 
rate, and respiratory rate. 
The number of subjects with vital signs values categorized as below, within, or above normal 
ranges will be tabulated showing change from baseline (shift tables) for each parameter by 
treatment group and by study visit. Pre- and post-treatment values may also be presented with an 
analysis of mean changes from baseline. 
13.1.5.4 Twelve-lead Electrocardiograms 
The number and percentage of subjects with normal and abnormal ECG findings will be 
summarized for each treatment group at each time point. Abnormal results will be grouped as 
clinically significant and not clinically significant. 
A comparison of QT results will be presented. Summary statistics for baseline values at Screening, 
and at Visit 4 (Follow-up) will be displayed by treatment group for QT and the QT interval 
corrected for heart rate (QTc). In addition, the number and percent of subjects in each treatment 
group who experienced a change >30 ms or a change >60 ms will be presented. 
Descriptive summaries (mean, SD, median, minimum, and maximum) will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QTc interval, and heart rate for each treatment 
group at each time point. 

 
 
 
 
 
 
 
 
  
 
 
 
 
 
 

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14. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
14.1. Sponsor and Investigator Responsibilities 
14.1.1 Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 16). The sponsor reserves the right to withdraw a subject from the study (Section 8.3), to 
terminate participation of a study site at any time (Section 14.7), and/or to discontinue the study 
(Section 14.6). 
VistaGen Therapeutics, Inc. agrees to provide the investigator with sufficient material and support 
to permit the investigator to conduct the study according to the study protocol. 
14.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 18.1), the investigator indicates that he or she 
has read the protocol carefully, fully understands the requirements, and agrees to conduct the study 
in accordance with the procedures and requirements described in this protocol.  
The trial will be conducted in accordance with ICH GCP and applicable United States Code of 
Federal Regulations (CFR). The principal investigator will assure that no deviation from, or 
changes to, the protocol will take place without prior agreement from the Investigational New 
Drug (IND) sponsor, funding agency and documented approval from the IRB, except where 
necessary to eliminate an immediate hazard(s) to the trial subjects. All personnel involved in the 
conduct of this study have completed Human Subjects Protection and ICH GCP training. 
Investigators should ensure that all persons who are delegated study-related responsibilities are 
adequately qualified and informed about the protocol, the IPs, and their specific duties within the 
context of the study. Investigators are responsible for providing VistaGen Therapeutics, Inc. with 
documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
14.1.3 Confidentiality and Privacy 
Subject confidentiality and privacy are strictly held in trust by the participating investigators, their 
staff, and the sponsor and their staff. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to subjects. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying study product may inspect all 

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documents and records required to be maintained by the investigator, including, but not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the subjects in this study. 
The clinical study site will permit access to such records. 
The study subject’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, institutional policies, or sponsor 
requirements. 
Study subject research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at Premier Research. This will not include the subject’s contact 
or identifying information. Rather, individual subjects and their research data will be identified by 
a unique study identification number. The study data entry and study management systems used 
by clinical sites and by Premier Research staff will be secured and password protected. At the end 
of the study, all study databases will be de-identified and archived at Premier Research. 
14.2. Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification 
from the sponsor or its designee that the study can be initiated at the study site. The study site will 
not be authorized for study initiation until: 
1. The study site has received the appropriate IRB approval for the protocol and the 
appropriate ICF. 
2. All regulatory documents have been submitted to and approved by the sponsor or its 
designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
14.3. Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may be rescreened for the study. Subjects may 
only be rescreened once 30 days or more after the original Screening Visit. If a subject is eligible 
to enter the study after having previously failed screening, the subject will be assigned a new 
subject identification number. 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
subsequently entered in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure subjects to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any SAE. 
14.4. Study Documents 
All documentation and material provided by VistaGen Therapeutics, Inc. for this study is to be 
retained in a secure location and treated as confidential material. 

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14.4.1 Informed Consent 
Informed consent forms describing in detail the study intervention, study procedures, and risks are 
given to the subject and written documentation of informed consent is required prior to starting 
intervention/administering study intervention. 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be 
IRB-approved and the subject will be asked to read and review the document. The investigator 
will explain the research study to the subject and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the subject’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants. Subjects 
will have the opportunity to carefully review the written ICF and ask questions prior to signing. 
The subject should have the opportunity to discuss the study with their family or surrogates or 
think about it prior to agreeing to participate. The subject will sign the informed consent document 
prior to any procedures being done specifically for the study. Subjects must be informed that 
participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the ICF will be given to the subjects for their records. The informed consent 
process will be conducted and documented in the source document (including the date) and the 
ICF signed before the subject undergoes any study-specific procedures. The rights and welfare of 
the subjects 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. 
14.4.2 Investigator’s Regulatory Documents 
The regulatory documents are listed in the Premier Research study plans. 
The regulatory documents must be received from the investigator and reviewed and approved by 
VistaGen Therapeutics, Inc. or its designee before the study site can initiate the study and before 
VistaGen Therapeutics, Inc. will authorize shipment of IP to the study site. Copies of the 
investigator’s regulatory documents must be retained at the study site in a secure location. 
Additional documents, including a copy of the protocol and applicable amendment(s), the PH94B 
IB, eCRF completion guidelines, copies of regulatory references, copies of IRB correspondence, 
and IP accountability records should also be retained as part of the investigator’s regulatory 
documents. It is the investigator’s responsibility to ensure that copies of all required regulatory 
documents are organized, current, and available for inspection. 
14.4.3 Case Report Forms 
By signing the Investigator’s Agreement (Section 18.1), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all subjects who sign an 
ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRF system used during the study to ensure that the study information is captured 
accurately and appropriately. 
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as 
possible after the visit. All requested information must be entered in the electronic data capture 
(EDC) system according to the completion guidelines provided by the sponsor or its designee. 

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The eCRFs must be signed by the investigator. These signatures serve to attest that the information 
contained in the eCRF is accurate and true. 
14.4.4 Source Documents 
Information recorded in the EDC system should be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. 
14.5. Data Quality Control 
VistaGen Therapeutics, Inc. and its designees will perform quality control checks on this clinical 
study. 
14.5.1 Monitoring Procedures 
VistaGen Therapeutics, Inc. and/or its designee will conduct site visits to monitor the study and 
ensure compliance with the protocol, GCP, and applicable regulations and guidelines. The 
assigned clinical research associate(s) (CRA[s]) will visit the investigator and study site at periodic 
intervals and maintain periodic communication. The investigator agrees to allow the CRA(s) and 
other authorized VistaGen Therapeutics, Inc. personnel access. The CRA(s) will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the investigator and staff. While 
on site, the CRA(s) will review 
x regulatory documents, directly comparing entries in the EDC system with the source 
documents 
x consenting procedures 
x AE procedures 
x storage and accountability of IP and study materials 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRFs are described in the Premier Research study plans. As representatives of the 
sponsor, CRAs are responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 18.1), the investigator agrees to meet with the 
CRA(s) during study site visits; to ensure that study staff is available to the CRA(s) as needed; to 
provide the CRA(s) access to all study documentation, to the clinical supplies dispensing and 
storage area; and to assist the monitors in their activities, if requested. Further, the investigator 
agrees to allow VistaGen Therapeutics, Inc. or designee auditors or inspectors from regulatory 
agencies to review records and to assist the inspectors in their duties, if requested.  
Additional details on monitoring will be described in the clinical monitoring plan. 
14.5.2 Data Management 
VistaGen Therapeutics, Inc. or designee will be responsible for activities associated with the data 
management of this study. The standard procedures for handling and processing records will be 
followed per GCP and Premier Research’s standard operating procedures. A comprehensive data 

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management plan will be developed, including a data management overview, description of 
database contents, annotated eCRF, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries are described in the Premier Research study plans. 
14.5.3 Quality Assurance/Audit 
This study will be subject to audit by VistaGen Therapeutics, Inc., or its designee. Audits may be 
performed to check compliance with GCP guidelines and can include: 
x site audits 
x Trial Master File audits 
x database audits 
x document audits (e.g., protocol and/or clinical study report [CSR]) 
VistaGen Therapeutics, Inc. or its designee may conduct additional audits on a selection of study 
sites, requiring access to subject notes, study documentation, and facilities or laboratories used for 
the study. 
The study site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for IRB or regulatory authorities according to GCP 
guidelines. The investigator agrees to cooperate with the auditor during the visit and will be 
available to supply the auditor with eCRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify VistaGen Therapeutics, Inc. immediately. 
14.6. Study Termination 
The study may be terminated at VistaGen Therapeutics, Inc.’s discretion at any time and for any 
reason. 
14.6.1 Premature Study Termination 
The study may be temporarily suspended or terminated prematurely is there is sufficient reasonable 
cause at any time by VistaGen Therapeutics, Inc., IRBs, regulatory authorities, respective steering 
committees, or the coordinating investigator.  
Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study subjects, investigator, funding agency, the IND 
sponsor, and regulatory authorities. If the study is prematurely terminated or suspended, the 
principal investigator will promptly inform study subjects, the IRB, and sponsor and will provide 
the reasons for the termination or suspension. Study subjects will be contacted, as applicable, and 
be informed of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
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x Demonstration of efficacy that would warrant stopping 
x Insufficient compliance to protocol requirements 
x Data that are not sufficiently complete and/or evaluable 
x Determination that the primary endpoint has been met 
x Determination of futility 
Study sites may be asked to have all subjects currently participating in the study complete all of 
the assessments for the Follow-up Visit (Visit 4). 
The Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
14.7. Study Site Closure 
At the end of the study, all study sites will be closed. VistaGen Therapeutics, Inc. may terminate 
participation of a study site at any time. Examples of conditions that may require premature 
termination of a study site include, but are not limited to, the following: 
x Noncompliance with the protocol and/or applicable regulations and guidelines 
x Inadequate subject enrollment 
14.7.1 Record Retention 
The investigator shall retain and preserve 1 copy of all data generated in the course of the study, 
specifically including, but not limited to, those defined by GCP as essential until: 
x At least 2 years after the last marketing authorization for the IP has been approved or the 
sponsor has discontinued its research with the IP, or 
x At least 2 years have elapsed since the formal discontinuation of clinical development of the 
IP. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor has 30 days to respond to the investigator’s notice, and the 
sponsor has further opportunity to retain such materials at the sponsor’s expense. 
14.7.2 Sample Retention 
Samples may be used for purposes related to this research. The samples will be stored until the 
sponsor has determined that specimens are no longer needed, and the decision has been made that 
none of the samples needs to be reanalyzed. In addition, identifiable samples can be destroyed at 
any time at the request of the subject. 
14.8. Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of VistaGen Therapeutics, Inc. The protocol amendment must be 
signed by the investigator and approved by the IRB before it may be implemented. Protocol 

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amendments will be filed with the appropriate regulatory agency(s) having jurisdiction over the 
conduct of the study. 
14.9. Use of Information and Publication 
All information concerning PH94B, PH94B’s operations, patent applications, formula, 
manufacturing processes, basic scientific data, and formulation information supplied by VistaGen 
Therapeutics, Inc. or its designee to the investigator, and not previously published, is considered 
confidential and remains the sole property of VistaGen Therapeutics, Inc. Case report forms also 
remain the property of VistaGen Therapeutics, Inc. The investigator agrees to use this information 
for purposes of study execution through finalization. 
The information developed in this study will be used by VistaGen Therapeutics, Inc. in connection 
with the continued development of PH94B and thus may be disclosed as required to other clinical 
investigators or government regulatory agencies. 
The information generated by this study is the property of VistaGen Therapeutics, Inc. Publication 
or other public presentation of PH94B data resulting from this study requires prior review and 
written approval of VistaGen Therapeutics, Inc. Abstracts, manuscripts, and presentation materials 
should be provided to VistaGen Therapeutics, Inc. for review at least 30 days prior to the relevant 
submission deadline. 
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition, or publication by the investigator until VistaGen Therapeutics, Inc. has reviewed and 
commented on such a presentation or manuscript for publication. If applicable, this study will be 
registered at ClinicalTrials.gov, and results information from this study will be submitted to 
ClinicalTrials.gov. 

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15. FINAL CLINICAL STUDY REPORT 
VistaGen Therapeutics, Inc. will retain ownership of the data. 
The final CSR will be written within 1 year of completion of the clinical part of the study. This 
report will include a summary of the study results based on a statistical evaluation and clinical 
assessment of the protocol-defined endpoints. 
The final CSR may be submitted to the regulatory authorities.  

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16. ETHICAL AND LEGAL CONSIDERATIONS 
16.1. Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry GCP 
E6 (including archiving of essential study documents), the Integrated Addendum to ICH E6 (R2) 
of November 2016, and the applicable regulations of the country(ies) in which the study is 
conducted. 
16.2. Subject Information and Informed Consent 
A properly constituted, valid IRB must review and approve the protocol, the investigator’s ICF, 
and related subject information and recruitment materials before the start of the study. 
It is the responsibility of the investigator to ensure that written informed consent is obtained from 
the subject before any activity or procedure is undertaken that is not part of routine care. 
16.3. Approval by Institutional Review Board 
For IND studies, the minimum standards of conduct and requirements for informed consent are 
defined in the FDA regulations. 
A valid IRB must review and approve this protocol before study initiation. Written notification of 
approval is to be provided by the investigator to the study’s project manager or designee before 
shipment of investigational drug supplies, and will include the date of the committee’s approval 
and the chairperson’s signature. This written approval must consist of a completed Premier 
Research form, IRB Approval Form, or written documentation from the IRB containing the same 
information. 
Until written approval by the IRB has been received by the investigator, no subject may undergo 
any procedure not part of routine care for the subject’s condition. 
Protocol amendments must also be reviewed and approved by the IRB. Written approval from the 
IRB, or a designee, must be received by VistaGen Therapeutics, Inc. before implementation. This 
written approval will consist of a completed Approval form or written documentation from the 
IRB containing the same information. 
16.4. Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the investigator 
and the sponsor. 

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17. REFERENCES 
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2001;62(Suppl 1):5-10. 
2. Katzelnick DJ, Greist JH. Social anxiety disorder: an unrecognized problem in primary 
care. J Clin Psychiatry. 2001;62 (Suppl 1):11-15. 
3. Papez JW. A proposed mechanism of emotion. Arch Neurol Psychiatry. 1937;38(4):725-
743. 
4. Maclean PD. The limbic system (“visceral brain”) and emotional behavior. AMA Arch 
Neurol Psychiatry. 1955;73(2):130-134. 
5. Cairncross. Olfactory bulbectomy as a model for depression. N.W. Bond ed. In: Animal 
models in psychophysiology. New York. Academic Press, 1976:99-128. 
6. Song C, Leonard B. Effects of olfactory bulbectomy in the rat, alone or in combination 
with antidepressants and endogenous factor, an immune function. Hum Psychopharmacol 
Clin Exp. 1995;10(1):7-18. 
7. Croy I, Nordin S, Hummel T. Olfactory disorders and quality of life--an updated review. 
Chem Senses. 2014;39(3):185-194. 
8. Croy I, Negoias S, Novakova L, Landis BN, Hummel T. Learning about the Functions of 
the Olfactory System from People without a Sense of Smell. 2012. Plos One. 
9. Kevetter GA, Winans SS. Connections of the corticomedial amygdala in the golden 
hamster. II. Efferents of the “olfactory amygdala”. J Comp Neurol. 1981;197(1):99-111. 
10. Sosulski DL, Bloom ML, Cutforth T, Axel R, Datta SR. Distinct representations of 
olfactory information in different cortical centres. Nature. 2011;472(7342):213-216. 
11. Monti-Bloch L, Jennings-White C, Dolberg DS, Berliner DL. The human vomeronasal 
system. Psychoneuroendocrinology. 1994;19(5-7):673-686. 
12. Sobel N, Prabhakaran V, Hartley CA, Desmond JE, Glover GH, Sullivan EV, et al. Blind 
smell: brain activation induced by an undetected air-borne chemical. Brain. 1999;122 
(Pt 2):209-217. 
13. Grosser BI, Monti-Bloch L, Jennings-White C, Berliner DL. Behavioral and 
electrophysiological 
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14. Monti-Bloch L, Grosser BI. Effect of putative pheromones on the electrical activity of the 
human vomeronasal organ and olfactory epithelium. J Steroid Biochem Mol Biol. 
1991;39(4B):573-582. 
15. Monti-Bloch L, Diaz-Sanchez V, Jennings-White C, Berliner DL. Modulation of serum 
testosterone and autonomic function through stimulation of the male human vomeronasal 
organ (VNO) with pregna-4,20-diene-3,6-dione. J Steroid Biochem Mol Biol. 
1998;65(1-6):237-242. 
16. Monti L, Liebowitz M. Neural Circuits of Anxiolytic and Antidepressant Pherine 
Molecules. Epub ahead of print. CNS Spectrums. 2020;23:1-7. 

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17. Kevetter GA, Winans SS. Connections of the corticomedial amygdala in the golden 
hamster. I. Efferents of the "vomeronasal amygdala". J Comp Neurol. 1981;197(1):81-98. 
18. Swanson LW, Petrovich GD. What is the amygdala? Trends Neurosci. 1998;21(8):323-
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19. Dorries KM, Adkins-Regan E, Halpern BP. Sensitivity and behavioral responses to the 
pheromone androstenone are not mediated by the vomeronasal organ in domestic pigs. 
Brain Behav Evol. 1997;49(1):53-62. 
20. Hagino-Yamagishi K. Diverse systems for pheromone perception: multiple receptor 
families in two olfactory systems. Zoolog Sci. 2008;25(12):1179-1189. 
21. Kang N, Baum MJ, Cherry JA. A direct main olfactory bulb projection to the 
'vomeronasal' amygdala in female mice selectively responds to volatile pheromones from 
males. Eur J Neurosci. 2009;29(3):624-634. 
22. Pape HC, Jungling K, Seidenbecher T, Lesting J, Reinscheid RK. Neuropeptide S: a 
transmitter system in the brain regulating fear and anxiety. Neuropharmacology. 
2010;58(1):29-34. 
23. Pro-Sistiaga P, Mohedano-Moriano A, Ubeda-Banon I, Del Mar Arroyo-Jimenez M, 
Marcos P, Artacho-Perula E, et al. Convergence of olfactory and vomeronasal projections 
in the rat basal telencephalon. J Comp Neurol. 2007;504(4):346-362. 
24. Mohedano-Moriano A, de la Rosa-Prieto C, Saiz-Sanchez D, Ubeda-Banon I, Pro-Sistiaga 
P, de Moya-Pinilla M, et al. Centrifugal telencephalic afferent connections to the main 
and accessory olfactory bulbs. Front Neuroanat. 2012;6:19. 
25. Sokolowski K, Corbin JG. Wired for behaviors: from development to function of innate 
limbic system circuitry. Front Mol Neurosci. 2012;5:55. 
26. Tovote P, Fadok JP, Luthi A. Neuronal circuits for fear and anxiety. Nat Rev Neurosci. 
2015;16(6):317-331. 
27. Schaal B, Coureaud G, Langlois D, Ginies C, Semon E, Perrier G. Chemical and 
behavioural 
characterization 
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Nature. 
2003;424(6944):68-72. 
28. Nuss P. Anxiety disorders and GABA neurotransmission: a disturbance of modulation. 
Neuropsychiatr Dis Treat. 2015;11:165-175. 
29. Savic I, Berglund H, Gulyas B, Roland P. Smelling of odorous sex hormone-like 
compounds causes sex-differentiated hypothalamic activations in humans. Neuron. 
2001;31(4):661-668. 
30. Smeets MAM, Veldhuizen MG, Galle S, Gouweloos J, de Haan AJA, Vernooij J, et al. 
Sense of smell disorder and health-related quality of life. Rehabil Psychol. 
2009;54(4):404-412. 
31. Aydogan U, Aydogdu A, Akbulut H, Sonmez A, Yuksel S, Basaran Y, et al. Increased 
frequency of anxiety, depression, quality of life and sexual life in young 
hypogonadotropic hypogonadal males and impacts of testosterone replacement therapy on 
these conditions. Endocr J. 2012;59(12):1099-1105. 

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32. Rodriguez I, Greer CA, Mok MY, Mombaerts P. A putative pheromone receptor gene 
expressed in human olfactory mucosa. Nat Genet. 2000;26(1):18-19. 
33. Grus WE, Shi P, Zhang YP, Zhang J. Dramatic variation of the vomeronasal pheromone 
receptor gene repertoire among five orders of placental and marsupial mammals. Proc 
Natl Acad Sci U S A. 2005;102(16):5767-5772. 
34. Yoder AD, Larsen PA. The molecular evolutionary dynamics of the vomeronasal receptor 
(class 1) genes in primates: a gene family on the verge of a functional breakdown. Front 
Neuroanat. 2014;8:153. 
35. Francia S, Pifferi S, Menini A, Tirindelli R. Vomeronasal Receptors and Signal 
Transduction in the Vomeronasal Organ of Mammals. C. Mucignat-Caretta ed. In: 
Neurobiology of Chemical Communication. Chapter Chapter 10, Boca Raton, FL. CRC 
Press/Taylor & Francis, 2014. 
36. Monti-Bloch L. Patch recorded isolated adult human vomeronasal organ cells are 
electrically excitable and respond to skin steroidal substances androsta-4,16-dien-3-one 
and estra-1,3,5(10),16-tetraen-3-ol. Chemical Senses. 1995;20(6):745. 
37. Monti-Bloch L, Jennings-White C, Berliner DL. The human vomeronasal system. A 
review. Ann N Y Acad Sci. 1998;855:373-389. 
38. Liebowitz MR, Salmán E, Rosenthal N, Nicolini H, Monti L. Evaluation of a Unique 
Nanogram-Dose Intranasal Aerosol for the Acute Management of the Symptoms of Social 
Anxiety Disorder. in New Clinical Drug Evaluation Unit Conference. 2011. Boca Raton, 
FL. 
39. Liebowitz MR, Hanover R, Draine A, Lemming R, Careri J, Monti L. Effect of as-needed 
use of intranasal PH94B on social and performance anxiety in individuals with social 
anxiety disorder. Depress Anxiety. 2016;33(12):1081-1089. 
40. Liebowitz MR, Salman E, Nicolini H, Rosenthal N, Hanover R, Monti L. Effect of an 
acute intranasal aerosol dose of PH94B on social and performance anxiety in women with 
social anxiety disorder. Am J Psychiatry. 2014;171(6):675-682. 
41. Winegar B, Monti L. Pherines increase cytosolic Ca in isolated living human vomeronasal 
chemosensory neurons. ACHEMS abstract. 2003. 
42. Herman R, Monti Bloch L. Human VNO cDNA libraries: Pertussis toxin blockade of 
human VNO receptors (R1). Pherin Pharmaceuticals, Inc.; Los Altos, CA: Pherin Report 
MB 007; 1997. 
43. Monti L. Dose dependent effect of pherine PH94B in isolated female human vomeronasal 
organ cells. Pherin Study Report # CL009; Report date: May 18, 1999.  
44. Monti L, Liebowitz M, Smith M. PH94B: A new intranasal neuroactive steroid with rapid 
onset of anxiolytic activity but a mechanism of action different from benzodiazepines. 
ADAA, 2021. 

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45. Hsiao ST, Liu L, Mehta, CR. Optimal promising zone designs. Biometrical Journal. 
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46. Hung HJ, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics. 1999, 55(3), 853-857.  
 

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18. ATTACHMENTS 
18.1. Investigator’s Agreement 
PROTOCOL 
NUMBER: 
PH94B-CL032 
PROTOCOL TITLE: 
A US, Phase 3 Multicenter, Randomized, Double-blind, Placebo-
controlled Clinical Trial of PH94B Nasal Spray for the Acute 
Treatment of Anxiety Induced by a Public Speaking Challenge in 
Adult Subjects with Social Anxiety Disorder (PALISADE-2) 
FINAL PROTOCOL: 
02-Aug-2021 
AMENDMENT 1: 
25-Aug-2021 
AMENDMENT 2: 
25-Jan-2022 
AMENDMENT 3: 
12-Aug-2022 
I have read this protocol amendment and agree to conduct this clinical study as outlined herein. I 
will ensure that all subinvestigators and other study staff members have read and understand all 
aspects of this protocol. I agree to cooperate fully with VistaGen Therapeutics, Inc. and Premier 
Research during the study. I will adhere to all FDA, ICH, and other applicable regulations and 
guidelines regarding clinical studies on an IP during and after study completion. 
Principal Investigator: 
 
Printed Name: 
 
 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
 

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C. 
 

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D. Liebowitz Social Anxiety Scale 

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E. 
 
Type text here

 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 

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F. 

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G. Hamilton Depression Scale

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J. Regulations and Good Clinical Practice Guidelines 
1. Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
x FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
x FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
x FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
2. Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URLs: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.pdf 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4.pdf