A 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
Phase: PHASE3
Conditions: Social Anxiety Disorder
Sponsor: VistaGen Therapeutics, Inc.

CONFIDENTIAL 
VistaGen Therapeutics, Inc. 
PH94B Nasal Spray 
Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
Page 1 
CONFIDENTIAL 
CLINICAL TRIAL PROTOCOL 
TITLE OF CLINICAL TRIAL: 
A 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-1)  
Clinical Trial Protocol PH94B-CL026 
NCT04754802  
Version number: 2.0 
Date of issue: 03 January 2022 
Previous version: 
Version 1.0  dated: 12 April 2021 
Sponsor: 
VistaGen Therapeutics, Inc.   
343 Allerton Avenue 
South San Francisco, CA   94080 
1

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Y

CONFIDENTIAL 
VistaGen Therapeutics, Inc. 
PH94B Nasal Spray 
Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
 
 
Page 3 
Acknowledgment of Responsibilities (Clinical Trial Protocol Version 2.0) 
This Phase 3 Clinical Trial Protocol (the Protocol) is the property of VistaGen Therapeutics, Inc., 
a Nevada corporation (VistaGen). I understand that the information within it is confidential and is 
provided to me for review by myself, my staff, and applicable institutional review board or 
independent ethics committee. I understand that the Protocol must be kept in a confidential manner 
and must be returned to VistaGen, or destroyed per VistaGen’s instructions, upon request. No part 
of this Protocol may be reproduced in any form without prior written permission from VistaGen. 
By accepting this Protocol, I agree that I will not disclose the information contained herein to any 
third-party without prior written authorization from VistaGen. 
I have read and understood the Protocol and agree that it contains all of the necessary information 
to carry out the Phase 3 clinical trial described therein.  
I agree to conduct this Phase 3 clinical trial in accordance with all stipulations of the current 
Protocol and in accordance with the following: Good Clinical Practice, the ethical principles that 
have their origin in the Declaration of Helsinki; Title 21 of the Code of Federal Regulations, 
Parts 50 (Protection of Human Subjects), and 56 (Institutional Review Boards), and 312 
(Investigational New Drug Application); and International Council for Harmonisation E6 
(Guideline for Good Clinical Practice). 
I agree that I will not modify or deviate from the Protocol without obtaining the prior written 
approval of VistaGen and of the institutional review board or independent ethics committee, except 
when necessary to protect the safety, rights, or welfare of subjects.  
Affiliation 
Name 
Signature 
Date: 
Investigator: 
 
 
 
 
Investigator:  
NAME, DEGREE(S)  
 
TITLE 
 
Phone: ###-###-#### 
 
Fax: ###-###-#### 
 
E-mail:  
 
 
Research facilities:  
NAME  
 
ADDRESS 
Institutional review boards/ 
NAME  
independent ethics committees 
ADDRESS 
 
Phone: ###-###-#### 
 
Fax: ###-###-#### 
 
E-mail:  
 
 
 
3

CONFIDENTIAL 
VistaGen Therapeutics, Inc. 
PH94B Nasal Spray 
Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
STUDY SYNOPSIS (continued) 
 
 
Page 5 
6. Women of child bearing-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 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 either in the presence of COVID-19 symptoms or after direct exposure to 
someone with a positive COVID-19 test. 
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 Rating Scale (C-SSRS) with reference to a 6-month period prior to 
screening; or 
b.  At Screening (Visit 1): the subject has had one 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.  Considered to be an imminent danger to themselves or others. 
4. Clinically significant nasal pathology or history of significant nasal trauma, nasal surgery, 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, 
taken at any time during the lifetime of the patient, whereby an adequate treatment trial is defined 
as that documented 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 allowed 
medication for insomnia, such as eszopiclone, ramelteon, melatonin, zaleplon, zolpidem, or 
antihistamines). 
8. Concomitant use of any anxiolytics, such as benzodiazepines or unapproved treatments such as beta 
blockers, during the Study and within 30 days before Study entry. Subjects who have been taking 
benzodiazepines daily for 1 month or longer at the time of Visit 1 are not eligible to participate. 
9. Concomitant use of any over-the-counter, prescription product, or herbal preparation for treatment 
of the symptoms of anxiety or social anxiety during the Study and within 30 days before Study entry. 
10. Prior participation in a clinical trial involving PH94B. 
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CONFIDENTIAL 
VistaGen Therapeutics, Inc. 
PH94B Nasal Spray 
Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
TABLE OF CONTENTS (continued) 
 
Page 
 
 
 
Page 10 
8.2.3 
Estimand Framework and Sensitivity Analyses ............................................................ 57 
8.2.4 
Safety Analysis ........................................................................................................... 58 
8.2.5 
Subgroups ................................................................................................................... 58 
8.2.6 
Sample Size Determination .......................................................................................... 58 
8.2.7 
Missing Data ............................................................................................................... 59 
9.0 
STUDY ADMINISTRATION........................................................................................................ 61 
9.1 
INFORMED CONSENT AND AUTHORIZATION FOR USE AND DISCLOSURE OF 
PROTECTED HEALTH INFORMATION ...................................................................................... 61 
9.2 
STUDY DOCUMENTATION ......................................................................................................... 61 
9.2.1 
Investigator Information .............................................................................................. 61 
9.2.2 
Investigator Study Files ............................................................................................... 61 
9.2.3 
Case Report Forms and Source Documentation ............................................................ 62 
9.2.4 
Retention of Study Documents..................................................................................... 62 
9.3 
CONFIDENTIALITY ...................................................................................................................... 62 
9.3.1 
Data ............................................................................................................................ 63 
9.3.2 
Subject Anonymity ...................................................................................................... 63 
9.4 
PROTOCOL COMPLIANCE .......................................................................................................... 63 
9.5 
STUDY MONITOR FUNCTIONS AND RESPONSIBILITY .......................................................... 64 
9.5.1 
Clinical Monitoring ..................................................................................................... 64 
9.5.2 
Quality Assurance, Auditing and Inspection ................................................................. 64 
9.6 
GENERAL INFORMATION ........................................................................................................... 65 
9.7 
PUBLICATION PLAN .................................................................................................................... 65 
10.0 
REFERENCES .............................................................................................................................. 66 
APPENDICES ..................................................................................................................................................... 71 
 
 
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CONFIDENTIAL 
VistaGen Therapeutics, Inc. 
PH94B Nasal Spray 
Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
 
 
Page 12 
LIST OF APPENDICES 
 
 
Appendix A 
Subjective Unit of Distress Scale 
Appendix B 
 
Appendix C 
 
Appendix D 
Liebowitz Social Anxiety Scale 
Appendix E 
 
Appendix F 
 
Appendix G 
Hamilton Depression Rating Scale 
Appendix H 
Clinical Global Impression Improvement Scale 
Appendix I 
 
 
 
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CONFIDENTIAL 
VistaGen Therapeutics, Inc. 
PH94B Nasal Spray 
Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
 
 
Page 13 
LIST OF ABBREVIATIONS 
 
 
AE 
adverse event 
C-SSRS 
Columbia Suicidality Severity Rating Scale  
CGI-I 
Clinical Global Impression Scale of Improvement 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
 
 
HAM-D 
Hamilton Depression Scale 
ICF 
informed consent form 
i.n. 
intranasal 
IP 
investigational product 
IRB 
institutional review board 
LSAS 
Liebowitz Social Anxiety Scale 
MINI 
Mini International Neuropsychiatric Interview 
 
 
PH94B 
PH94B Nasal Spray 
SAD 
social anxiety disorder 
SAE 
serious adverse event 
SUDS 
Subjective Units of Distress Scale 
UDS 
urine drug screen 
VistaGen 
VistaGen Therapeutics, Inc., a Nevada corporation 
 
 
13

CONFIDENTIAL 
VistaGen Therapeutics, Inc. 
PH94B Nasal Spray 
Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
 
 
Page 14 
1.0 
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. 
1.1 
BACKGROUND  
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 
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CONFIDENTIAL 
VistaGen Therapeutics, Inc. 
PH94B Nasal Spray 
Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
 
 
Page 15 
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.  
1.1.1 
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 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. 
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 
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 
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CONFIDENTIAL 
VistaGen Therapeutics, Inc. 
PH94B Nasal Spray 
Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
 
 
Page 16 
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 epithelium[14, 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 awareness[12, 
14] and can modulate brain autonomic and psychophysiologic response.[11, 13, 15, 29, 37-39] 
1.2 
STUDY RATIONALE 
PH94B (3β-androsta-4,16-dien-3-ol) is a synthetic neuroactive steroid discovered and 
initially developed at Pherin Pharmaceuticals that targets human nasal chemosensory 
cells[11, 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 receptor chemosensory receptors 
that are expressed in human nasal chemosensory neurons.[32, 42] 
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VistaGen Therapeutics, Inc. 
PH94B Nasal Spray 
Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
 
 
Page 17 
In vitro screening studies using isolated, living, human nasal chemosensory neurons 
have shown that picomolar quantities of PH94B can selectively induce inward currents 
in a concentration-dependent and reversible fashion.[43] These membrane currents are 
carried by calcium ions.[41] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2.1 
Phase 1 Studies 
 
 
 
 
 
 
 
 
 
 
. 
 
 
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VistaGen Therapeutics, Inc. 
PH94B Nasal Spray 
Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
 
 
Page 18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2.2 
Phase 2 Studies 
Two previously completed Phase 2 clinical studies have had similar population and 
efficacy endpoints of Protocol PH94B-CL026. These double-blind, randomized, 
placebo-controlled Phase 2 clinical studies (PH94B-CL016 and -CL022), included a 
total of 91 female subjects who met criteria for SAD (generalized subtype) as defined 
by the DSM-4. PH94B (1.6 µg) was administered i.n. in spray form 
 prior 
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). SUDS scores range from zero 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 
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CONFIDENTIAL 
VistaGen Therapeutics, Inc. 
PH94B Nasal Spray 
Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
 
 
Page 20 
2.0 
OBJECTIVES 
2.1 
PRIMARY EFFICACY OBJECTIVE 
The primary efficacy objective of the Study is to evaluate whether the efficacy of 
PH94B to relieve acute anxiety induced during a public speaking challenge in adult 
subjects with SAD is greater than that for placebo as measured by the SUDS.    
2.2 
SECONDARY EFFICACY OBJECTIVE 
The secondary efficacy objective of the Study is the comparison of PH94B-treated 
subjects with placebo-treated subjects with regard to clinician observed change in 
subject’s response to the anxiety-provoking situation between Visit 2 and Visit 3 as 
measured by CGI-I. 
2.3 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
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VistaGen Therapeutics, Inc. 
PH94B Nasal Spray 
Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
 
 
Page 21 
2.4 
SAFETY OBJECTIVE 
The safety objective of the Study is the determination of safety and tolerability of 
PH94B compared to placebo in adult subjects with SAD from reported AEs and 
changes in laboratory parameters, suicidality, level of depression, and physical 
examinations. 
 
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VistaGen Therapeutics, Inc. 
PH94B Nasal Spray 
Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
 
 
Page 23 
3.2 
STUDY POPULATION  
Eligibility for participation in the Study will be determined from demographic 
information, medical and psychiatric history, physical and psychiatric examination, 
electrocardiogram (ECG), clinical laboratory findings, and clinical rating scale 
assessments performed at the Screening Visit. Subjects may be recruited from the 
Investigator or sub-Investigator clinical practices, 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 central IRB prior to use and implementation. 
3.2.1 
Inclusion Criteria   
To be considered eligible to participate in the Study, a subject must meet the inclusion 
criteria listed below: 
1. 
Written informed consent provided prior to conducting any study-specific 
assessment. 
2. 
Male or female adult, 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, as confirmed by the Mini International 
Neuropsychiatric Interview (MINI).  
4. 
Clinician-rated LSAS total score ≥70 at Screening (Visit 1). 
5. 
Clinician-rated Hamilton Depression Scale (HAM-D) 17-item total score <18 at 
Screening (Visit 1). 
6. 
Women of child bearing-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. 
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CONFIDENTIAL 
VistaGen Therapeutics, Inc. 
PH94B Nasal Spray 
Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
 
 
Page 24 
7. 
Negative COVID-19 test either in the presence of COVID-19 symptoms or after 
direct exposure to someone with a positive COVID-19 test. 
3.2.2 
Exclusion Criteria   
To be considered eligible for entry into the Study, the subject must not meet any of the 
exclusion criteria listed below: 
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 (including cannabinoids) 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 Suicidality 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 one or more suicidal attempts 
with reference to a 2-year period prior to screening; or 
c. 
At the 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. 
Considered to be an imminent danger to themselves or others. 
4. 
Clinically significant nasal pathology or history of significant nasal trauma, nasal 
surgery, anosmia, or nasal septum perforation that may have damaged the nasal 
chemosensory epithelium. 
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CONFIDENTIAL 
VistaGen Therapeutics, Inc. 
PH94B Nasal Spray 
Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
 
 
Page 27 
 
 
 
 
 
3.3.3 
Safety 
Safety and tolerability of PH94B will be assessed and summarized through changes 
from Screening in laboratory values, ECGs, physical examinations, and vital sign 
assessments following exposure to PH94B, as well as by comparison of AEs, suicidal 
ideation (C-SSRS), and level of depression (HAM-D) reported during treatment with 
PH94B and placebo. 
3.4 
RANDOMIZATION AND BLINDING 
Overall, the randomization will be stratified by study site with a ratio of 1:1. 
Each study site will be provided with a supply of blinded IP, each vial individually 
numbered with a unique alpha-numeric identification code. For Visit 2 and Visit 3, the 
interactive system 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 electronic case report form (eCRF). 
The vial number can be used to break the blind if necessary. Contact information will 
be provided to the study site.   
3.5 
WITHDRAWAL OF SUBJECTS 
3.5.1 
When and How to Withdraw Subjects 
A subject may voluntarily discontinue from participating in the Study at any time. The 
Investigator, at his or her discretion, may also withdraw a subject from participating in 
the Study at any time. Criteria for premature withdrawal from the Study include: 
• 
Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
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Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
 
 
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4.2.2 
Treatment Regimen 
IP will be administered once in each nostril before each public speaking challenge. Men 
and women will be treated with the same dose of PH94B: 3.2 µg. 
 
 
 Therefore, the spray volume administered to each nostril 
(100 µL) will be below the nasal retention volume and will be retained in the nasal 
passages. 
 
 
 
  
4.3 
HANDLING OF INVESTIGATIONAL PRODUCT 
4.3.1 
Receipt of Drug Supplies 
Upon receipt of each IP shipment, an inventory must be performed, and a drug receipt 
log filled out and signed by the person accepting the shipment. It is important that the 
designated Study staff counts and verifies that the shipment contains all the items noted 
in the shipment inventory. Any damaged or unusable IP in a given shipment (active 
drug or comparator) will be documented in the Study files.  
4.3.2 
Storage 
 
 
 Access should be 
restricted to the designated responsible member/s of the Investigator’s staff and to the 
clinical monitor. The Investigator agrees that neither he/she nor any of the Study staff 
will supply IP to any person other than subjects enrolled in the Study.  
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Protocol PH94B-CL026, Version 2.0 
Clinical Trial Protocol 
 
 
 
 
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4.3.3 
Drug Dispensing and Return Procedures 
At Visit 2 and Visit 3, subjects will be dispensed the appropriate vial of IP as supplied 
by the interactive system. The vial number of the dispensed vial will be recorded in the 
eCRF for each subject. 
 
   
Current and accurate inventory and dispensing records will be kept for all IP, and upon 
Study completion a final inventory of all clinical supplies will be compiled. All IP 
containers, whether empty or containing unused IP, will be returned per the Sponsor’s 
instructions from the clinical monitor. A copy of the Drug Receipt Form and the Drug 
Accountability Form will be retained in the Investigator’s files. 
4.4 
COMPLIANCE WITH INVESTIGATIONAL PRODUCT 
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. 
4.5 
PRIOR AND CONCOMITANT MEDICATIONS 
All medications taken by or administered to the subject during the month prior to 
Screening (Visit 1) should be recorded in the eCRF. With the exception of those noted 
in the protocol (refer to Section 3.2.2, Exclusion Criteria) all medications (prescription 
or over-the-counter) that were started prior to Screening may be continued during the 
course of the trial. During the course of the Study, subjects should stay on stable doses 
of their usual allowable medication regimens. Medications for treatment of minor 
concurrent illnesses that arise after Screening may be allowed at the discretion of the 
Investigator, with the exception of the prohibited therapies specified in the protocol. 
In order to ensure that appropriate concomitant therapy is administered, it is essential 
that subjects be instructed not to take any medication (either self-administered 
non-prescription drugs or prescription therapy prescribed by another physician) without 
prior consultation with the Investigator. The Investigator should examine the 
acceptability of all concomitant medications not explicitly prohibited. Sites should 
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contact the Medical Monitor when uncertain about the acceptability of concomitant 
medications. All concomitant medication taken during the Study will be recorded on 
appropriate pages of the eCRF. 
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 PK of the medication being 
discontinued. The subject must be consented before any tapering is started. 
With the exception of eszopiclone, ramelteon, melatonin, zaleplon, zolpidem, or 
anti-histamines as allowable concomitant medications for the treatment of insomnia, 
no other psychotropic medication besides IP is permitted to be used by any subject 
between Screening (Visit 1) and Follow-up (Visit 4). At Visit 1, the investigator should 
consider checking the local Prescription Drug Monitoring Database to verify the lack 
of use of scheduled central nervous system active drugs, such as benzodiazepines. 
 
 
 
 
 
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5.2 
VISIT PROCEDURES 
5.2.1 
Visit 1 (Screening) 
Screening begins after the written informed consent has been obtained. The purpose of 
the screening phase is to: 
• 
Ensure that appropriate subjects are entered into the trial; 
• 
Determine that the subject meets all eligibility criteria; 
• 
Collect demographic and medical data permitting characterization of the subject; 
• 
Ensure that prohibited medications are discontinued; and 
• 
Determine that subjects are willing to undertake up to two 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. 
Generally, healthy subjects who are thought to meet inclusion and exclusion criteria 
and express an interest in participating will be informed about the Study, investigational 
product (PH94B and placebo), required visits and scheduling, and asked whether they 
wish to participate. All subjects agreeing to participate must give written informed 
consent using the IRB-approved informed consent form (ICF) before any study-related 
procedures are performed (including tapering of prohibited medications). The ICF will 
be signed and dated by the subject and Investigator or other appropriate site staff, and 
a copy of the signed ICF will be given to the subject. The informed consent process 
will be documented in the source records for each subject. 
After the ICF process is complete, a subject number will be allocated by the site, by 
assigning the next sequential subject number available. Subject numbers will be 
four-digit numbers beginning with the site number. Subject numbers will not be 
sex-specific and will be assigned sequentially in the order in which the ICF is signed, 
and the Screening (Visit 1) occurs. 
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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 5.1 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). 
5.2.2 
Visit 2 (Baseline) 
For subjects continuing to meet all eligibility criteria, the following Visit 2 assessments 
will be completed: 
• 
Measure vital signs after the subject has rested for 5 minutes: seated systolic and 
diastolic blood pressure, heart rate, respiratory rate, and body temperature. 
• 
Obtain urine sample for Urine Drug Screen: Instant Exam to be performed on 
site, with results thoroughly documented in the source; urine sample to be sent to 
central laboratory for confirmation if on-site UDS is positive 
 
. 
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• 
For females of child-bearing potential, obtain urine sample and complete on-site 
urine pregnancy test. 
• 
Record concomitant medication use including the completion of any washout. 
• 
Review all inclusion and exclusion criteria. 
For subjects meeting all study inclusion criteria and no study exclusion criteria, the 
following Visit 2 procedures will be performed: 
• 
Introduce the self-rated anxiety scale, the Subjective Units of Distress Scale 
(SUDS), to the subject and review the descriptions of the various SUDS scores 
(Appendix A). 
• 
 
• 
Dispense and instruct subject to self-administer IP 
 
 
• 
The subject will be returned to a waiting area after IP dosing. 
• 
 the subject will be informed that they must give a 5-minute 
speech to a live audience of 
 
 
• 
 
 
 
• 
The subject will be given 3 minutes to organize their thoughts on their upcoming 
speech. 
• 
The subject will be escorted into a room to give a 5-minute speech in front of 
three neutral observers after the last SUDS anticipatory anxiety score is collected 
 
 
 
 
 
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• 
 
, the subject will be given information on attending the next visit 
(Visit 3), else the subject will complete the remaining assessments for Visit 2, 
will not be randomized, and will be discharged from the study 
 
 
• 
If the subject cannot complete the speech 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.  
• 
Record any AEs reported. 
• 
 
For the subject attending the next visit (Visit 3), it will be scheduled 1 week (± 2 days) 
after the date of Visit 2. 
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5.2.3 
Visit 3 (Treatment) 
At Visit 3, subjects should return to the study site and the following assessments will 
be completed: 
• 
Measure vital signs after the subject has rested for 5 minutes: seated systolic and 
diastolic blood pressure, heart rate, respiratory rate, and body temperature. 
• 
Urine Drug Screen (Instant Exam, to be performed on site, with results 
documented in the source). 
• 
Record Concomitant Medication use. 
• 
Review and record AEs. 
• 
Randomize the subject. 
• 
follow the instructions for the Visit 3 
public speaking challenge (as described in Section 5.2.2 and Figure 5-1) with the 
same trained observer as in Visit 2. 
After the completion of the Visit 3 public speaking challenge: 
• 
 
• 
Complete the CGI-I (by the trained observer of the public speaking challenge). 
• 
Review and record AEs. 
• 
Administer C-SSRS (Since Last Visit) 
 
The Follow-Up visit (Visit 4) will be scheduled for 1 week ±2 days after the date of 
Visit 3.  
5.2.4 
Visit 4 (Follow-Up) 
At Visit 4, the following assessments will be completed: 
• 
Obtain 12-lead ECG in supine position after subject has rested for 5 minutes. 
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• 
Obtain blood and urine samples for evaluation by the central clinical laboratory, 
including hematology, chemistry, thyroid functioning, and urinalysis (refer to 
Section 5.4 for complete list). 
• 
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. Also 
includes an examination of the nasal passages. 
• 
Obtain urine sample for Urine Drug Screen: Instant Exam to be performed on 
site, with results thoroughly documented in the source; urine sample to be sent to 
central laboratory for confirmation if on-site UDS is positive (with the exception 
of on-site UDS positive for cannabinoids only). 
• 
For females of child-bearing potential, obtain urine sample and complete on-site 
urine pregnancy test. 
• 
Administer LSAS. 
• 
Administer HAM-D. 
• 
 
• 
 
• 
Record Concomitant Medication use. 
• 
Review and record AEs. 
• 
 
• 
Complete the Subject Summary Record. 
 
 
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5.3 
EFFICACY ASSESSMENTS 
5.3.1 
Public Speaking Challenge 
The public speaking challenge has been used in previous studies as an 
anxiety-provoking situation and has been designed to be consistently applied across all 
clinical sites. 
 
 
 
 
5.3.2 
Subjective Units of Distress Scale 
The Subjective Units of Distress Scale (SUDS), used at Visit 2 and Visit 3 as part of 
each public speaking challenge, is scored in the range of 0 to 100 (operationalized for 
the participants in this study as 0 = totally relaxed or no anxiety and 100 = most distress 
of anxiety imaginable). It is a standard instrument for rating social and performance 
anxiety in patients with SAD during role playing situations. 
 
 
 
 
 
 
 
5.3.3 
Liebowitz Social Anxiety Scale 
The Liebowitz Social Anxiety Scale (LSAS) is a clinician-rated scale that has been 
shown to be sensitive to treatment-related change in social anxiety symptoms. The time 
frame for rating symptomatology is the past week. The scale consists of 24 items. Each 
item is given two ratings: fear or anxiety on scale of 0 to 3 and avoidance on a scale of 
0 to 3 with the total maximum overall score of 144. The items in the scale can be 
divided into performance and social interaction items, and corresponding subscores can 
be derived. 
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5.3.4 
 
 
  
5.4 
LABORATORY ASSESSMENTS 
The following laboratory tests will be performed by the central laboratory during the 
Study: 
• 
Chemistry Panel:  alanine aminotransferase, aspartate aminotransferase, albumin, 
calcium, chloride, alkaline phosphatase, bicarbonate, cholesterol, creatine kinase, 
creatinine, direct bilirubin, lactate dehydrogenase, magnesium, globulin, glucose, 
gamma-glutamyl transferase, indirect bilirubin, phosphorous, potassium, sodium, 
total bilirubin, total protein, triglycerides, urea nitrogen, uric acid 
• 
Hematology/ Hemogram Panel:  hematocrit, hemoglobin, mean corpuscular 
hemoglobin, mean corpuscular concentration, mean corpuscular volume, 
platelets, red blood cell count, white blood cell count, red blood cell morphology 
• 
Hematology Differential Panel:  basophils, eosinophils, lymphocytes, monocytes, 
neutrophils 
• 
Thyroid stimulating hormone 
• 
Free thyroxine (T4) (if thyroid stimulating hormone is above the upper or below 
the lower normal limits, then Free thyroxine will automatically be performed) 
• 
Urinalysis macroscopic panel:  bilirubin, blood, clarity, color, glucose, ketones, 
leucocyte esterase, nitrite, pH, protein, specific gravity, urobilinogen 
• 
Urine Drug Screen (if on-site UDS is positive, urine sample will be submitted to 
central laboratory for confirmatory UDS, 
 
: antidepressants, opiates, 
cocaine, 
benzodiazepines, 
amphetamines, 
barbiturates, 
cannabinoids, 
methadone, phencyclidine, propoxyphene, methamphetamine, buprenorphine, 
ecstasy, oxycodone 
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The following laboratory tests will be performed on site during the Study: 
• 
Urine pregnancy test (for all female subjects of child-bearing potential) 
• 
Urine Drug Screen 
The central laboratory should be used for any unscheduled and follow-up labs, if 
needed. Additional urine and blood samples may be collected for further evaluation of 
safety as warranted by the Investigator’s judgment. 
Results and reports from the central laboratory should be filed with the source 
documents for each subject. The central laboratory will provide laboratory results to 
the Study site as soon as they are available and will be provided to Sponsor or 
designated data manager with agreed timelines. 
Any laboratory value outside the normal range will be flagged for the attention of the 
Investigator, who must indicate whether or not the value is of clinical significance. If 
the result of any laboratory test performed during Screening is clinically significant, 
the subject should not be advanced to Visit 2. However, any abnormal result may be 
repeated to confirm the finding before excluding the subject from potential inclusion in 
the Study. In addition, subjects should be excluded if they have any other abnormal 
laboratory test at Screening that, in the Investigator’s judgment, is medically significant 
in that it would impact the safety of the subject, the conduct of the Study, or the 
interpretation of the Study results. 
Follow-up/unscheduled laboratory tests may be performed on clinically significant 
abnormalities as indicated by the Investigator. Unscheduled laboratory tests may be 
repeated at any time at the discretion of the Investigator for appropriate medical care. 
 
 
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6.0 
PROCEDURES FOR HANDLING ADVERSE EVENTS AND SERIOUS 
ADVERSE EVENTS 
6.1 
MEDICAL MONITORING 
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 below. Medical monitoring will include a regular 
assessment of the number and type of SAEs. 
6.2 
DEFINITIONS OF ADVERSE EVENT AND SERIOUS ADVERSE EVENT 
6.2.1 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in intensity during the course of the study. Any newly developed illnesses or 
injuries should be regarded as adverse events. 
Abnormal results of diagnostic procedures are considered to be AEs if the abnormality: 
• 
results in study withdrawal and is associated with a serious adverse event 
• 
is associated with clinical signs or symptoms 
• 
leads to additional treatment or to further diagnostic tests 
• 
is considered by the Investigator to be of clinical significance 
In addition, a clinical laboratory abnormality must be documented as an AE if any one 
of the following conditions is met: 
• 
The laboratory abnormality is not otherwise refuted by a repeat test to confirm 
the abnormality 
• 
The abnormality suggests a disease and/or organ toxicity 
• 
The abnormality is of a degree that requires active management, e.g., change of 
dose, discontinuation of the drug, more frequent follow-up assessments, further 
diagnostic investigation, etc. 
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A preexisting condition is one that is present at the start of the study. A preexisting 
condition should be recorded as an AE if the frequency, intensity, or the character of 
the condition worsens during the study period (between after IP administration at 
Visit 2 and Visit 4/Follow-Up). 
At Screening through IP administration at Visit 2, any clinically significant abnormality 
should be recorded as a preexisting condition in the medical history, not as an AE. At 
the end of the Study, any new clinically significant findings/abnormalities that meet the 
definition of an AE must also be recorded and documented as an AE. 
Pregnancy is not considered an AE, but it is an important medical event, which must be 
followed up as described in Section 6.5.3. 
6.2.2 
Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event (SAE) 
is any AE that is: 
• 
fatal, 
• 
life-threatening, 
• 
requires or prolongs hospital stay, 
• 
results in persistent or significant disability or incapacity, a congenital anomaly 
or birth defect, or an important medical event. 
Important medical events are those that may not be immediately life-threatening but 
are clearly of major clinical significance. They may jeopardize the subject and may 
require intervention to prevent one of the other serious outcomes noted above. For 
example, drug overdose or abuse, a seizure that did not result in in-patient 
hospitalization, or intensive treatment of bronchospasm in an emergency department 
would typically be considered serious. 
AEs that do not meet any of the criteria for SAEs should be regarded as non-serious AEs. 
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6.2.3 
Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE unless specifically instructed otherwise in this 
protocol. Any condition responsible for surgery should be documented as an AE if the 
condition meets the criteria for an AE. 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an AE in the following circumstances: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition. Surgery should not be reported as an 
outcome of an AE if the purpose of the surgery was elective or diagnostic and the 
outcome was uneventful. 
• 
Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the Study. 
• 
Hospitalization or prolonged hospitalization for therapy of the target disease of 
the Study, unless it is a worsening or increase in frequency of hospital admissions 
as judged by the clinical Investigator. 
6.3 
RECORDING ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
6.3.1 
Recording of Adverse Events 
At each contact with the subject, the Investigator must seek information on AEs by 
questioning and, as appropriate, by examination. Information on all AEs should be 
recorded immediately in the source document, and also in the appropriate AE module 
of the eCRF. All clearly related signs, symptoms, and abnormal diagnostic procedures 
results should be recorded in the source document, though should be grouped under 
one diagnosis. 
All AEs occurring during the Study period must be recorded. The clinical course of 
each event should be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause. Serious adverse 
events that are still ongoing at the end of the Study period must be followed up to 
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determine the final outcome. Any SAE that occurs after the Study period and is 
considered to be possibly related to either or both IP administered and/or study 
participation should be recorded and reported immediately. 
6.4 
ASSESSMENT OF INTENSITY 
A clinical determination will be made of the intensity of an AE. The intensity 
assessment for a clinical AE must be completed using the following definitions as 
guidelines. 
Table 6-1. 
Classification of AEs by Intensity 
Intensity 
Definition 
Mild AE 
 
An event that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities 
Moderate AE 
 
An event that is sufficiently discomforting to the extent of interfering 
with normal everyday activities 
Severe AE 
 
An event that prevents the subject from performing normal everyday 
activities 
AE = adverse event. 
 
 
6.5 
ASSESSMENT OF CAUSALITY 
6.5.1 
Relationship to Investigational Product or Study Procedure 
The Investigator is to determine whether or not there is a reasonable causal relationship 
between the IP and the AE. 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. 
The relationship assessment for an AE is to be completed by indicating if an AE is 
related or not related to IP administered. 
 
 
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6.5.2 
Reporting of Serious Adverse Events and Unanticipated Problems 
For any SAE occurring during the Study period starting at Visit 1 after signing the 
informed consent, whether or not related to the treatment, expected or not, the 
Investigator is to take the following steps: 
• 
Take prompt and appropriate medical action, if necessary. The safety of Study 
subjects is the first priority. 
• 
Immediately inform VistaGen of the event and if necessary, contact the Medical 
Monitor by telephone to discuss any immediate and/or further steps to be taken. 
• 
Complete as fully as possible the AE page in the eCRF. 
• 
Complete the SAE form provided in the Study Procedures Manual at the Study 
start. Fax or scan and email the completed SAE form along with copies of the 
eCRF pages documenting demography, medical history, Concomitant 
Medications, and AEs, and any other relevant information (e.g., test results) 
within 24 hours to VistaGen. 
• 
Report the SAE to the IRB, following the IRB’s reporting guidelines and 
requirements. 
• 
Monitor and record the progress of the event until it resolves or reaches a clinically 
stable outcome, with or without sequelae. For all additional follow-up 
evaluations, fax or scan and email all additional follow-up information to 
VistaGen within 24 hours. 
• 
SAEs will be followed until the Investigator at the Study site and Sponsor agree 
that the event is satisfactorily resolved. 
• 
Obtain and maintain in the source documents all pertinent medical records, 
information, and medical judgments from colleagues who assisted in the 
treatment and follow-up of the subject. If necessary, contact the subject’s personal 
physician or hospital staff to obtain further details. 
• 
Inform the Sponsor of the final outcome of the event. Send a revised or updated 
SAE Form and AE form, if appropriate. 
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• 
Comply with the applicable regulatory requirement/s related to the reporting of 
SAEs to the IRB. 
Table 6-2. 
Timeline for Reporting SAEs 
Initial SAE Report 
Follow-up SAE Report 
Time Frame 
Documents 
Time Frame 
Documents 
24 hours 
SAE report 
7 days 
Updated SAE report 
SAE = serious adverse event. 
 
 
6.5.3 
Pregnancy 
Any pregnancy occurring during the Study where the fetus may have been exposed to 
the IP must be reported to VistaGen. Follow-up information will be obtained regarding 
the course and outcome of the pregnancy, including any post-natal sequelae in the 
infant. All information will be documented on appropriate forms. (see the Study 
Procedures Manual). 
 
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• 
A decision on the part of the sponsor to suspend or discontinue testing, evaluation, 
or development of the product 
A study conducted at a single site in a study may also warrant termination under the 
following conditions: 
• 
Failure of the Investigator to enroll subjects into the study at an acceptable rate 
• 
Failure of the Investigator to comply with pertinent regulations of appropriate 
regulatory authorities 
• 
Submission of knowingly false information from the site to the sponsor, study 
monitor, or appropriate regulatory authority 
• 
Insufficient adherence to protocol requirements 
Study termination and follow-up will comply with the conditions set forth in 
International Council for Harmonisation E6, Guideline for Good Clinical Practice, 
Sections 4.12, 4.13, 5.20, and 5.21. 
 
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8.0 
DATA COLLECTION AND PROCESSING AND STATISTICAL ANALYSIS 
8.1 
DATA COLLECTION AND PROCESSING 
Electronic case report forms (eCRFs) will be used to capture Study assessments and 
data. The Investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. All eCRFs will be reviewed and source verified by the study 
monitor during periodic site visits, and the study monitor will ensure that all data in the 
eCRF are correct and complete. Before or between visits, the Medical Monitor or study 
monitor may conduct a preliminary medical review of the eCRFs. Once the eCRFs are 
completed and source-verified, the investigator must electronically sign all required 
eCRF pages, verifying the accuracy of all data contained in the eCRFs. 
Training will be provided for the electronic data capture (EDC) system. All Study staff 
using the EDC system must have the necessary education, training, and experience or 
any combination of these. The Investigator will be responsible for documenting 
employee education, training, and previous experience that pertain to the EDC system 
for all Study site staff using the EDC system.  
The Investigator must maintain adequate security of the EDC system, including 
documentation that all users have been trained on the appropriate standard operating 
procedure and a list of authorized users. To ensure all data entries can be tracked, all 
personnel responsible for data entry must obtain a unique user identification (user ID) 
and password before any data can be entered in the eCRFs. Authorized Study staff will 
be assigned a unique user ID only after receiving standard operating procedure training.  
If electronic data systems other than those provided and maintained by the Sponsor are 
used for documentation and data capture, the Investigator must ensure that the systems 
are validated, and that data are backed up. 
8.2 
STATISTICAL ANALYSIS 
The data will be summarized in tables, as appropriate, showing the number of subjects 
with non-missing data (n), mean, standard deviation, 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. 
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The statistical analysis plan will be finalized and approved before final database lock 
and unblinding of the randomization code. 
8.2.1 
Populations for Analyses 
8.2.1.1 
Intent to Treat Population 
The Intent-to-Treat Population in the Study includes all subjects who are randomized. 
8.2.1.2 
Safety Populations 
The safety population will include all subjects who receive IP.  
8.2.2 
Efficacy Analysis 
8.2.2.1 
Primary Endpoint 
The primary endpoint for the Study is the difference in average SUDS scores during 
the
Visit 3 public speaking challenge versus the average SUDS scores during 
 Visit 2 public speaking challenge 
 
 
 
Change from Visit 2 to Visit 3 in average SUDS scores 
will be used. 
An ANCOVA model with baseline SUDS as covariate will be used to test the null 
hypothesis that there is no difference in change from baseline average SUDS scores 
between PH94B- and placebo-treated subjects. 
8.2.2.2 
Secondary Endpoints 
The secondary efficacy endpoint in the Study is the difference between proportions of 
PH94B- and placebo-treated groups in Clinical Global Impression Scale of 
Improvement (CGI-I) scores of 1 
) or 2 
 
recorded at the end of Visit 3. 
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This secondary endpoint will be analyzed using a normal approximation test for the 
difference between two binomial proportions. The null hypothesis to be tested is that 
the population proportions are equal. 
8.2.2.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
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8.2.3 
Estimand Framework and Sensitivity Analyses 
8.2.3.1 
Primary Estimand 
The treatment of interest is PH94B, 3.2 μg administered as an i.n. solution 
 
 The population of interest is adult patients with SAD as 
defined by the protocol inclusion and exclusion criteria (Section 3.2). 
 
 
 Intercurrent events are 
expected to be rare. Any intercurrent event that does occur will be handled using the 
treatment policy strategy, i.e., included in the treatment regimen under evaluation. The 
difference of means from Visit 2 to Visit 3 in SUDS will be estimated for each 
treatment group. PH94B will be compared to placebo using differences in group means. 
8.2.3.2 
Secondary Estimand 
The treatment of interest is PH94B, 3.2 μg administered as an i.n. solution 
 
. The population of interest is adult patients with SAD as 
defined by the protocol inclusion and exclusion criteria (Section 3.2). The endpoint to 
be measured is the CGI-I score at Visit 3. Intercurrent events are expected to be rare. 
Any intercurrent event that does occur will be 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 
 or 2 
 for 
PH94B will be compared to placebo using a comparison of binomial proportions. 
8.2.3.3 
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.  
 
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8.2.4 
Safety Analysis 
8.2.4.1 
Safety and Tolerability 
Descriptive statistics will be used to portray safety and tolerability of PH94B (3.2 µg) as 
measured by reports of AEs and SAEs, changes in laboratory values, ECGs, and 
physical examination. 
8.2.4.2 
Safety Procedures 
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 Time and Events (Table 5-1). The schedule of 
clinical laboratory tests is listed in Section 5.4. 
8.2.5 
Subgroups 
The primary and secondary endpoints may also be summarized by subgroups of interest 
including age, sex, and by site. 
8.2.6 
 
 
 
 
 
 
 
 
 
 
 
 
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8.2.7 
Missing Data 
8.2.7.1 
Prevention of Missing Data 
Prevention of missing data is central to this Study design.  All participants 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.   
8.2.7.2 
Unavoidable Loss of Data 
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 
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reasons (intercurrent events) that arise during Visit 3, appropriate imputation will be 
performed. 
Details around missing data treatments will be finalized in the Statistical Analysis Plan.  
 
 
 
 
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9.0 
STUDY ADMINISTRATION 
9.1 
INFORMED 
CONSENT 
AND 
AUTHORIZATION 
FOR 
USE 
AND 
DISCLOSURE OF PROTECTED HEALTH INFORMATION 
Written informed consent and authorization of use and disclosure of protected health 
information must be obtained from each subject (or the subject’s legally acceptable 
representative) before performing any Study-specific screening or baseline period 
evaluations. One copy of the signed informed consent form (ICF) and authorization for 
use and disclosure of protected health information form will be given to the subject, 
and the Investigator will retain the original. The ICF and authorization for use and 
disclosure of protected health information, which is prepared by the Investigator or the 
Study site, must have been reviewed and approved by the Sponsor, the Study monitor, 
and the Investigator’s IRB or IEC and privacy board (if separate from the IRB) before 
the initiation of the Study. The ICF must contain the 20 elements of informed consent 
described in International Council for Harmonisation E6, Section 4.8. The 
authorization for use and disclosure of protected health information must contain the 
elements required by Title 45 of the Code of Federal Regulations, Section 164.508(b), 
and any local regulations for valid authorizations.  
9.2 
STUDY DOCUMENTATION 
9.2.1 
Investigator Information 
Investigator information is included in the Study Procedures Manual, which is updated 
as needed. 
9.2.2 
Investigator Study Files 
Documentation about the Investigator and Study staff, the IRB, and the institution is 
required before site initiation. Copies of these documents will be kept on-site in 
site-specific binders or electronic folders, along with the following supplemental 
information: a list of Investigator’s obligations, the Investigator’s Brochure, the 
Protocol and amendments, safety information, information about the IP, biological 
samples, and the laboratory, the Study Procedures Manual and study logs, electronic 
case report forms (eCRFs), records of monitoring activities, and correspondence 
between Sponsor or Study monitor and the Investigator.  
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Audit trails are generated automatically for eCRFs.  
9.2.3 
Case Report Forms and Source Documentation 
The Investigator must make Study data accessible to the site monitor, other authorized 
representatives of the Sponsor, and the appropriate regulatory authority inspectors. The 
eCRF for each subject will be checked by the site monitor, and a final copy of the eCRF 
will be signed by the Investigator with an electronic signature. A copy of the final 
eCRFs will be provided to the Investigator after Study closure to be kept in the 
Investigator’s Study files.  
9.2.4 
Retention of Study Documents 
It is the Investigator’s responsibility to retain Study essential documents for at least 
2 years after the last approval of a marketing application in their country and until there 
are no pending or contemplated marketing applications in their country or 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 if required by an agreement 
with the Sponsor. In such an instance, it is the responsibility of the Sponsor to inform 
the Investigator/institution as to when these documents no longer need to be retained. 
9.3 
CONFIDENTIALITY 
Information about Study subjects will be kept confidential and managed according to 
the requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA). Those regulations require a signed subject authorization informing the 
subject of the following: 
• 
What protected health information (PHI) will be collected from subjects in the 
Study. 
• 
Who will have access to that information and why. 
• 
Who will use or disclose that information. 
• 
The rights of a research subject to revoke their authorization for use of their PHI. 
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In the event that a subject revokes authorization to collect or use PHI, the Investigator, 
by regulation, retains the ability to use all information collected prior to the revocation 
of subject authorization. For subjects that have revoked authorization to collect or use 
PHI, attempts should be made to obtain permission to collect at least vital status (i.e., 
that the subject is alive) at the end of their scheduled Study period. 
9.3.1 
Data 
The Investigator must keep all information confidential about the nature of the 
proposed investigation provided by the Sponsor or Study monitor to the Investigator 
(with the exception of information required by law or regulations to be disclosed to the 
IRB, the subject, or the appropriate regulatory authority). 
9.3.2 
Subject Anonymity 
The anonymity of participating subjects must be maintained. Subjects will be identified 
by an assigned subject number on eCRFs and other documents retrieved from the site 
or sent to the Study monitor, Sponsor, regulatory agencies, central laboratories, or 
blinded reviewers. Documents that identify the subject (e.g., the signed informed 
consent form) must be maintained in strict confidence by the Investigator, except to the 
extent necessary to allow auditing by the appropriate regulatory authority, the Study 
monitor, or Sponsor representatives. 
9.4 
PROTOCOL COMPLIANCE 
A protocol deviation is any noncompliance with the Protocol or Good Clinical Practice 
(GCP). Noncompliance may be on the part of the subject, the Investigator, or the Study 
site staff. As a result of major deviations as determined by the Study monitor, corrective 
actions are to be developed by the site and implemented promptly. Documentation of 
the deviation and corrective actions will be included in the data quality assessment 
during blinded review. 
 
 
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9.5 
STUDY MONITOR FUNCTIONS AND RESPONSIBILITY 
The Study monitor, in accordance with the Sponsor’s requirements, will ensure that the 
Study is conducted and documented properly by carrying out the activities outlined in 
International Council for Harmonisation E6, Section 5.18.4. 
9.5.1 
Clinical Monitoring 
The conduct of the Study will be closely monitored by representatives (Clinical 
Research Associates “CRAs” or study monitors) of the Sponsor, to verify adherence to 
the Protocol, ICH GCP guidelines, and applicable regulations. The CRA will verify 
eCRF entries by comparing them with hospital, clinical, office and/or Study records 
which will be made available for this purpose. CRAs will monitor the Study as outlined 
in the Monitoring Plan prepared for the Study. 
During the Study, CRAs will contact the clinical site on a regular basis to assess and 
assure satisfactory enrollment rate, data recording, maintenance of required regulatory 
documentation, IP accountability, and compliance with the Protocol. The Investigator 
will ensure that all requested materials, including subject charts, eCRFs, source 
documents, laboratory records, and drug inventory records, will be available to the CRA 
if needed. At the end of the Study, a close-out visit will be performed. 
Reports of all monitoring visits will be archived in the Trial Master File. The 
Investigator will allow the Sponsor’s representatives, designee and/or any regulatory 
agency to have direct access to all Study records, eCRFs, corresponding subject 
medical records, IP dispensing records, and IP storage area, and any other documents 
considered source documentation. The Investigator also agrees to assist the 
representative, if required. 
9.5.2 
Quality Assurance, Auditing and Inspection 
The Study is conducted under the sponsorship of VistaGen in compliance with the 
applicable international and local regulatory requirements as well as applicable ICH 
guidelines, Helsinki (1964, 1975, 1983, 1989 and 1996) and in respect of the VistaGen 
or its designee’s SOPs for Study conduct and monitoring. 
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The Investigator will permit Study-related monitoring, audits, and inspections by the 
IRB, the Sponsor, and government regulatory bodies of all Study related documents 
(e.g., source documents, regulatory documents, data collection instruments, study data, 
etc.). 
Participation as an Investigator in this Study implies acceptance of potential inspection 
by government regulatory authorities.  
9.6 
GENERAL INFORMATION 
The Investigator should refer to the Investigator’s Brochure, Study Procedures Manual, 
and any other information provided about this IP and details of the procedures to be 
followed during the Study. 
9.7 
PUBLICATION PLAN 
Neither the partial, complete or any part of the results of the Study carried out under 
this protocol, nor any of the information provided by the Sponsor for the purposes of 
performing the Study, may be published or passed on by Investigator or any member 
of the Study site’s staff to any third party without the prior written consent of VistaGen. 
Any Investigator involved with this Study is obligated to provide VistaGen with 
complete test results and all data derived from the Study in an efficient and timely 
manner. For multi-center studies, the first publication or disclosure shall be a complete, 
joint multi-center publication or disclosure. 
 
 
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10.0 
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system. A review. Ann N Y Acad Sci. 1998;855:373-389. 
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Liebowitz MR, Hanover R, Draine A, Lemming R, Careri J, Monti L. Effect of 
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Winegar B, Monti L. Pherines increase cytosolic Ca in isolated living human 
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Herman R, Monti-Bloch L. Human VNO cDNA libraries: Pertusis toxin 
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APPENDICES 
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APPENDIX A 
 
SUBJECTIVE UNIT OF DISTRESS SCALE 
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APPENDIX D 
 
LIEBOWITZ SOCIAL ANXIETY SCALE 
79

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
  

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APPENDIX G 
 
HAMILTON DEPRESSION RATING SCALE 
89

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
   
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  

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APPENDIX H 
 
CLINICAL GLOBAL IMPRESSION IMPROVEMENT SCALE 
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