Clinical trial NCT05071430
Conditions: Panic Disorder
Keywords: panic mental illness
Sponsor: Honeybrains Biotech LLC
Start date: 2022-02-03; Completion date: 2022-12-12
Enrollment: 86 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the safety and efficacy of potential new treatment called "HB-1" versus placebo in male and female adult patients aged 18 to 60 years, inclusive, with panic disorder.

Detailed description:
This is a multicenter, randomized, double-blind, placebo-controlled trial. All patients with panic disorder, with or without specified co-morbidities, who meet all of the inclusion and none of the exclusion criteria will be eligible. Patients and researchers will be blinded to their treatment group.

The study will enroll approximately 80 adult patients who meet the diagnosis of panic disorder.

The patients will be treated for 12 weeks including a 1 week safety follow up visit following the last dose of study drug.

Arms: arm 1: Approximately 40 patients will receive HB-01 active study drug. arm 2: Approximately 40 patients will receive a matched placebo.
Interventions: intervention 1: HB-01 intervention 2: Placebo
Intervention descriptions: intervention 1: HB-1 will be supplied as a dual active pharmaceutical ingredient tablet. intervention 2: HB-1 matched placebo

Protocol documents:
Prot_000.pdf: 
Protocol HB-001
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Honeybrains Biotech
STUDY PROTOCOL
Protocol HB-001
Safety and Efficacy of HB-1 for Panic Disorder: A Multicenter, Randomized, 
Double-Blind, Placebo-Controlled Trial
Protocol Number:
Protocol HB-001
Phase:
2
Date of Protocol:
02 Dec 2021
Version:
4.0
Sponsor:
Honeybrains Biotech
515 W 20th St, Ste 4e
New York, NY 10011
Not for Distribution Do Not Copy
This study protocol contains confidential information and is the proprietary property of 
Honeybrains Biotech. The protocol is for use by the Principal Investigator and his/her 
designated representatives participating in this clinical trial. This protocol may not be copied or 
made available for review by an unauthorized person or firm without the prior written 
authorization of Honeybrains Biotech.


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INVESTIGATOR PROTOCOL APPROVAL 
 
I agree to the terms of this study protocol. I will conduct the study according to the procedures 
specified herein, and according to principles of the Declaration of Helsinki and the International 
Council for Harmonisation (ICH) Guideline for Good Clinical Practice E6 (R2), and all local 
laws and regulations. 
 
Institution/Clinic:  ___________________________________________ 
 
Principal Investigator 
 
Print Name:  ______________________________________ 
 
Signature:  
______________________________________ 
 
Date (dd/mmm/yyyy): ______________________________ 
 


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SPONSOR PROTOCOL APPROVAL 
 
I have read this protocol and approve the design of this study: 
 
 
 
 
Alon Seifan, MD, MS 
Chief Medical Officer 
Honeybrains Biotech 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date (dd/mmm/yyyy) 


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CONTACT INFORMATION 
 
Sponsor: 
 
Tomer Seifan, Managing Partner 
917-685-1351 
Honeybrains Biotech 
515 W 20th St, Ste 4e 
New York, NY 10011 
 
Dr. Alon Seifan, Chief Medical Officer  
786-620-3204 
Honeybrains Biotech  
515 W 20th St, Ste 4e 
New York, NY 10011 
 


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PROTOCOL SYNOPSIS 
Study Title: Safety and Efficacy of HB-1 for Panic Disorder: A Mulitcenter, Randomized, 
Double-Blind, Placebo-Controlled Trial 
Protocol Number: 
HB-001 
Phase: 2 
HB-1 and Study Rationale: 
New treatments that safely improve whole brain functional connectivity could radically 
transform outcomes for people suffering from Psychiatric Disorders (Tumati S. 2021).  
Anxiety Disorders (ie, Panic Disorder, Social Anxiety Disorder, Generalized Anxiety 
Disorder, Obsessive Compulsive Disorder, and Specific Phobia) are a clinically diverse group 
of disorders that have significant pathophysiological overlap.  Anxiety disorders commonly 
feature disequilibrium in functional connectivity.  Specifically, simultaneous alterations within 
more than one functional brain network, such as default mode, salience and somatomotor 
networks, are common to these disorders (Kim Y., Yoon H. 2018).  Anxiety disorders also 
commonly feature dysregulations in both adrenergic and angiotensin systems (Winter A. 2019, 
Killgore W. 2014, Milani A. 2017).  For example, patients with Panic Disorder and also 
patients with Post-Traumatic Stress Disorder display atypical brain connectivity in regions that 
govern autonomic nervous system regulation (Faravelli C. 1997, Rotella F. 2014, Reiman E. 
1984, Owega A. 2001).  In fact, successful treatment of symptoms for anxiety disorders is 
associated with resolution of multiple atypical patterns of regional cerebral connectivity 
(Zandvakili A. 2020, Lai C. 2013). 
Currently, no FDA-approved treatments for anxiety disorders are designed to improve whole 
brain functional connectivity by targeting the angiotensin and adrenalin systems 
simultaneously.  This is a critical research gap because anxiety disorders are 1) common, 
2) debilitating, 3) co-morbid and 4) difficult to treat (Cerda M. 2010).  Panic Disorder, for 
example, is prevalent in 6% of primary care patients (Katon W. 1986).  Current FDA-approved 
treatments, which target symptomatology using neurotransmitter-specific approaches, are 
limited due to adverse reactions, including abuse potential.  For example, current treatments 
for Panic Disorder include selective serotonin reuptake inhibitors (SSRIs), which have small to 
medium effects, and benzodiazepines, which are not beneficial for long-term use due to 
tolerance, dependence, cognitive disturbance, and exacerbation of co-morbid mood disorders 
(Otto M. 1989, Edwards R. 1980).  Regarding future treatments, the drugs currently being 
tested for Panic Disorder target mechanisms of action similar to currently approved treatments. 
This study introduces HB-1, a fixed dose combination of 96 mg telmisartan and 288 mg 
verapamil, two previously FDA-approved antihypertensives, as a novel therapeutic agent 
targeting symptoms and quality of life (QoL) for patients with Panic Disorder. HB-1 works by 
re-equilibrating functional networks within the telencephalon and the mesencephalon brain 
regions. HB-1 is a promising treatment for Panic Disorder because Panic Disorder is 
characterized by abnormal physiological stress responses associated with disequilibrium in 


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more than one functional brain network. 
This study hypothesizes that, in patients with Panic Disorder, HB-1 demonstrates a 
comparable safety profile compared to the safety profiles of the individual agents; and a 
statistically significant reduction in disease severity, compared to placebo. This study will also 
examine the effects of HB-1 in treating the most commonly experienced co-morbidities in 
patients diagnosed with Panic Disorder. 
These hypotheses are based on literature that describes relationships between psychosocial 
stress, emotional intelligence, theories of human motivation, the adrenergic system, functional 
connectivity, angiotensin receptors, and calcium channels (Lea R. 2019, Zheng Z. 2016, Sagar-
Ouriaghli I. 2018, Keller S. 2003).  This work builds upon a prior observational pilot study 
that demonstrated improvement in anxiety and cognitive symptomatology in a diverse group 
of Neurology & Psychiatry patients who received these co-administered medications in a 
community-based Neuropsychiatry specialty practice.  Regarding safety, adverse events were 
minimal, and systolic and diastolic blood pressure did not change significantly before and after 
an average of nine months of treatment observations.  Regarding effectiveness, drastic 
reductions in symptomatology were noted across a broad array of disabling symptoms in 
patients not only with Panic Disorder but also with common co-morbidities.   
Objectives and Endpoints: 
Primary Objective 
To determine the safety and efficacy of HB-1 versus placebo in male and female adult 
patients aged 18 to 60 years, inclusive, with Panic Disorder. 
Safety Endpoints 
Incidence of Treatment Emergent Adverse Events (TEAEs), clinically significant 
changes in clinical laboratory values, electrocardiogram (ECG), Columbia Suicide 
Severity Rating Scale (C-SSRS) (Oquendo MA 2003), and orthostatic vital signs. 
Efficacy Endpoints 
 Change in Panic Disorder Symptom Severity Scale (PDSS) (Furukawa TA. 
2009)-primary efficacy endpoint 
 Number of panic attacks 
 Change in Clinical Global Impression-Severity Scale (CGI-S) (Guy W. 1976) 
 Change in Quality of Life Enjoyment and Satisfaction Questionnaire Short Form 
(Q-LES-Q-SF) (Endicott J. 1993) 
 Change in Leibowitz Social Anxiety Scale (LSAS) (Heimberg R. 1999, 
Baker S. 2002) 
 Change in Assessment of Overall Sleep Quality -- Question #6 from the 
Pittsburgh Sleep Quality Index (Buysse DJ. 1989) 
 
 


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Exploratory Objective 
To explore the effectiveness of HB-1 on Common Neuropsychiatric Co-Morbidities. 
Exploratory Endpoints 
 Change in Toronto Alexithymia Scale (TAS-20) (Bagby R. 2020) 
 Change in Hamilton Anxiety Rating Scale (HAM-A) (Bech P. 1990)  
 Change in CogScreen Symbol Digit Coding test (SDC) (Kay G. 1995) 
 Change in Montgomery-Asberg Depression Rating Scale (MADRS) (Fantino B., 
Moore N. 2009) only for patients with a medical history of depression 
 
 (Walls B. 2017) only 
for patients with a medical history of ADHD 
 Change in The PTSD Checklist for DSM-5 (Blake D. 1995, Blevins C. 2015) 
only for patients with a medical history of PTSD 
 Change in Short Form McGill Pain Questionnaire (SF-MPQ) (Melzack R. 1987) 
only for patients with a medical history of chronic pain 
 
Change in Migraine Disability Assessment Questionnaire (MIDAS) 
(Lipton R. 2001) only for patients with a medical history of migraine 
Abbreviations: ADHD=Attention deficit hyperactivity disorder; AE=adverse event, DSM-5=Diagnostic and Statistical 
Manual of Mental Disorders 5th edition; ECG=electrocardiogram, PTSD=post traumatic stress disorder 
 
HB-1 Administration: 
All patients will receive an oral dose of HB-1 or matching placebo once a day (QD) nightly at 
bedtime (QHS) with or without food. HB-1 is a proprietary combination of telmisartan and 
verapamil in a once-daily, extended release formulation. 
Study Population: 
This study will enroll approximately 80 adult patients who meet DSM-5 criteria for the 
diagnosis of Panic Disorder. 
Study Duration: 
The study will consist of a 12-week treatment period and a one-week post-treatment period for 
safety follow-up. 
Study Centers: 
Enrollment is anticipated at approximately 8-10 clinical research sites in the United States. 
Study Design: 
This is a multicenter, randomized, double-blind, placebo-controlled trial.  All patients with 
Panic Disorder, with or without specified co-morbidities, who meet all of the inclusion and 


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none of the exclusion criteria will be eligible.  Patients and researchers will be blinded to their 
treatment group. 
Approximately 80 patients with Panic Disorder will be enrolled and randomized in a 1:1 ratio 
to HB-1 or placebo. 
Assessment of Safety: 
Safety will be assessed through the monitoring of TEAEs, clinical laboratory assessments, 
ECG, Columbia Suicide Severity Rating Scale (C-SSRS) (Oquendo MA 2003), and orthostatic 
vital signs.  Patients will be monitored for safety, from the first dose of study treatment at Visit 
2/Week 0 through the Safety Follow-up/End-of-Study (EOS) Visit. 
Inclusion Criteria 
All patients must meet the following criteria for inclusion: 
1. Male or female aged 18 to 60 years old, inclusive, at the time of informed consent. 
2. Meets DSM-5 Criteria for Panic Disorder. 
3. Documented moderate to severe levels of symptoms at baseline (Panic Disorder 
Severity Scale of 13 or above) (Furukawa TA. 2009). 
4. Medically stable on current medication regimen for at least 3 months (including PRN 
medications), as determined by Investigator. 
5. Willing to remain on current doses of other psychiatric medications throughout the 
length of the trial. 
6. Willing and able to safely stop any of the following medications at least 5 days prior to 
Visit 2: Inhibitors or inducers of CYP3A4 (erythromycin, ritonavir, telithromycin, 
rifampin), HMG-CoA Reductase Inhibitors (Simvastatin, Lovastatin, Atorvastatin), 
Beta Blockers (Timolol eyedrops, Metoprolol), Neuromuscular Blocking Agents 
(curare-like and depolarizing), Antihypertensive Agents (Prazosin and vasodilators, 
angiotensin-converting enzyme inhibitors, diuretics, beta blockers, alpha agonists), 
Inhalation Anesthetics, Disopyramide, Flecainide, Quinidine, Cimetidine, Lithium, 
Carbamazepine, Phenobarbital, Cyclosporine, Aliskiren, Ramipril and Ramiprilat, 
aspirin, Theophylline, mTOR inhibitors. 
7. Willing and able to avoid consumption of grapefruit, grapefruit juice and Seville 
oranges within two weeks of screening through the last dose of study treatment. 
8. Willing and able to limit consumption of alcohol to three servings per day defined as: 1 
serving of beer=12 ounces (5% alcohol content); 1 serving of malt liquor=8 ounces 
(7% alcohol content); 1 serving of wine=5 ounces (12% alcohol content); 1 serving of 
distilled spirits=1.5 ounces (40% alcohol content). 
9. Willing and able to avoid concomitant administration of sensitive P-glycoprotein 
substrates (digoxin, fexofenadine, dabigatran etexilate, talinolol, loperamide, 
vinblastine). 
10. Fluent in English. 
11. Willing to take HB-1 or placebo. 


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12. Willing and able to provide informed consent indicating an understanding of the 
requirements of the study and a willingness to comply with scheduled visits and all 
study procedures. 
13. Female patients must be surgically sterile (or have a monogamous partner who is 
surgically sterile) or be least 2 years postmenopausal or commits to use 2 acceptable 
forms of birth control (defined as the use of an intrauterine device, a barrier method 
with spermicide, condoms, or any form of hormonal contraceptives) for the duration of 
the study and for 4 months following the last dose of study treatment.  Male patients 
must be sterile (biologically or surgically) or commit to the use of a reliable method of 
birth control (condoms with spermicide) for the duration of the study and for 4 months 
following the last dose of study treatment.  Individuals who are involved exclusively in 
same-sex relationships are exempt from the birth control requirements but must agree 
to abide by the recommendations if they do engage in a heterosexual relationship. 
14. Female patients who are women of childbearing potential (WOCBP) must have a 
negative pregnancy test at Screening, within 7 days of dosing with study treatment. 


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Exclusion Criteria 
Patients are to be excluded from the study if they meet any of the following criteria: 
1. Severe uncontrolled cardiac disease within 6 months of Screening, including but not 
limited to uncontrolled hypertension, hypotension (defined as below 90/60); unstable 
angina; myocardial infarction (MI) or cerebrovascular accident (CVA). 
2. Any clinically significant electrocardiogram (ECG) abnormalities at screening. 
3. History of atrial flutter, atrial fibrillation or hypertrophic cardiomyopathy. 
4. Inadequate hepatic function defined as total bilirubin >1.5 × the upper limit of normal 
(ULN) ranges of each institution, aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) >3 × the ULN range of each institution. 
5. Inadequate renal function defined as serum creatinine >1.5 × the ULN range of each 
institution and/or eGFR <60. 
6. Any clinically significant abnormalities in clinical laboratory assessments as assessed 
by the Investigator. 
7. Any other systemic conditions or organ abnormalities that in the opinion of the 
Investigator may interfere with the conduct and/or interpretation of the current study. 
8. Unable to complete neuropsychological testing. 
9. Diagnosis of Bipolar I, Bipolar II disorder or Schizophrenia. 
10. History of suicidal behaviors including ideation. 
11. Current treatment with doses of benzodiazepines that are outside the FDA-approved 
. 
12. Use of tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) is 
prohibited. 
13. Already on treatment with either telmisartan or verapamil or both. 
14. Documented prior drug allergy to either telmisartan or verapamil. 
15. Documented contraindication to taking telmisartan or verapamil: (eg, Duchenne's 
muscular dystrophy, myasthenia gravis). 
16. Documented moderate to severe substance abuse within the last 6 months (recreational 
cannabis use is allowed). 
17. Pregnant or breastfeeding. 
Sample Size Justification 
A sample size of 80 patients is planned for the study to be randomized in a 1:1 ratio of active 
to control.   
Assuming a standard deviation of 4.5 in the PDSS, 80 patients will provide for in excess of 
95% power to detect a difference in the mean change (from baseline) in the PDSS score of 
3.75 at an alpha-level of 0.05. This corresponds to a 50% reduction in mean PDSS scores on 
HB-1 and a 25% reduction in mean PDSS scores on placebo, assuming baseline mean PDSS 
scores of 15 for both groups.. 
In addition, with respect to adverse events, the study has approximately 95% power to detect at 


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least one patient with an event that occurs in 7.2% of patients in either treatment group. 
Statistical Methodology 
The study data will be reported using tabular and graphical displays.  Baseline information and 
safety results will be presented for the safety population consisting of patients who received at 
least one dose of study treatment (active or placebo) during the trial.  Effectiveness 
assessments will be compared on an intent-to-treat basis using the randomized treatment 
assignment.  Demographics and baseline information will be summarized descriptively.  Study 
treatment accountability and exposure will be summarized descriptively.  Study drug exposure 
information will include information of compliance such as the percentage of planned 
treatment used. 
Safety Analyses: 
Descriptive summaries of treatment adverse events, laboratory results, and orthostatic vital 
signs will be provided. C-SSRS (Oquendo MA 2003) results will be provided in a listing. 
Efficacy Analyses: Efficacy will be evaluated by comparing change from baseline of HB-1 
patients versus placebo patients in gold standard outcome measures for panic disorder and its 
common co-morbidities.  For efficacy, the primary endpoint will be change from baseline in 
the PDSS. 
Descriptive summaries and inferential tests are identified in the analysis section.  Significance 
testing will be at the two-sided 0.05 alpha-level and confidence intervals will be at 95% 
confidence. 
 


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Table 1: 
Schedule of Assessments 
 
Screening  Baseline 
Treatment Period 
Safety 
Follow-up 
Procedure or Assessment 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6/ EOS 
Visitk  
Safety 
Follow-upl 
Study Week 
Week - 1 
Week 0  
Week 2 
Week 4 
Week 8 
Week 12 
Week 13 
Visit Windows 
V2 within 7 days of V1 
+/- 3 days 
Informed Consent  
X 
 
 
 
 
 
 
Medical History and 
Demographicsa 
X 
 
 
 
 
 
 
Eligibility Assessment  
X 
 
 
 
 
 
 
Number of Panic Attacksb 
X 
X 
X 
X 
X 
X 
 
Columbia Suicide Severity 
Rating Scalec 
X 
X 
X 
X 
X 
X 
 
Clinical Laboratory 
Assessmentsd 
X 
X 
X 
 
 
X 
 
Physical Exam 
X 
 
 
X 
X 
X 
 
Height/Weight/BMI 
X 
 
 
 
 
 
 
Urine Pregnancy Teste 
X 
X 
X 
X 
X 
X 
 
Screening Questionnaires (3)f 
X 
 
 
 
 
 
 
Orthostatic Vitalsg 
X 
X 
X 
X 
X 
X 
 
12-Lead ECG  
X 
 
 
X 
X 
X 
 
CogScreen Symbol Digit Coding 
Test o 
X 
 
 
 
 
 
 
Weber Test 
 
X 
 
 
 
X 
 
Placebo-Control Reminder 
Script (PCRS)n 
 
 
X 
X 
X 
X 
 
Efficacy Endpoint 
Questionnaires (5)h 
 
X 
Xm 
X 
X 
X 
 
Exploratory Endpoint 
Questionnaires (8)i 
 
X 
 
 
 
X 
 
Study Treatment 
Dispensation/Return/ 
Accountability j 
 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
Adverse Event Monitoring 
 
X 
X 
X 
X 
X 
X 
Safety Follow-up Phone Call 
 
 
 
 
 
 
Xl 


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a  Demographics will include : Age, Sex, Race, Ethnicity, Education, Gender Identity, Lateral Preference Questions, and Parental Education 
b  Number of Panic Attacks. The clinician 
the reported panic attack(s) meet DSM-5 criteria 
(APA 2013). 
c Columbia Suicide Severity Rating Scale (C-SSRS) (Oquendo MA 2003). At screening, use the Screening/Baseline C-SSRS; at subsequent visits, use the Since Last Visit C-SSRS. 
d  Clinical laboratory assessments will include a comprehensive metabolic panel, CBC including Vitamin B12, urinalysis. 
e  Urine pregnancy test to be administered for women of child-bearing potential (WOCBP) within 7 days prior to Week 0, at Baseline/Week 0, and  at each subsequent study visit 
f  Screening Questionnaires will include: Mini International Neuropsychiatric Interview for DSM-5 (MINI) (Sheehan, DV. 1998; Sheehan, DV. 1992-2016), the Clinical Global Impression-
Severity Scale (CGI-S) (Guy W. 1976), and the Panic Disorder Symptom Severity Scale (PDSS) (Furukawa TA. 2009). 
g  Orthostatic vital signs should be obtained per Section 6.1.7. 
h  Efficacy Endpoint Questionnaires will include: 
 
Panic Disorder Symptom Severity Scale (PDSS) (not repeated at Week 0) (Furukawa TA. 2009) 
 
Clinical Global Impression-Severity Scale (CGI-S) (not repeated at Week 0) (Guy W. 1976) 
 
Quality of Life Enjoyment and Satisfaction Questionaire Short Form (Q-LES-Q-SF) (Endicott J. 1993) 
 
Self-Report Leibowitz Anxiety Scale (LSAS) (Heimberg RG. 1999, Baker SL. 2002) 
 
Assessment of Overall Sleep Quality -- Question #6 from the Pittsburgh Sleep Quality Index (Buysse DJ. 1989) 
i  Exploratory Endpoint Questionnaires will include: 
 
Toronto Alexithymia Scale (TAS-20) (Bagby RM. 2020) 
 
Hamilton Anxiety Rating Scale (HAM-A) (Bech P. 1990) 
 
CogScreen Symbol Digit Coding test (SDC)  (Kay G. 1995) 
 
Montgomery-Asberg Depression Rating Scale (MADRS) (Fantino B., Moore N. 2009) only for patients with a medical history of depression 
 
Conners  Adult ADHD Rating Scale (CAARS) (Walls BD. 2017) only for patients with a medical history of ADHD 
 
The PTSD Checklist for DSM-5 (Blake DD. 1995, Blevins CA. 2015) ony for patients with a medical history of PTSD 
 
Short Form McGill Pain Questionnaire (SF-MPQ) (Melzack R. 1987) only for patients with a medical history of chronic pain 
 
Migraine Disability Assessment Questionnaire (MIDAS) (Lipton RB. 2001) only for patients with a medical history of migraine 
j  Patients will be randomly assigned to either the HB-1 or placebo treatments groups and will be provided with study drug each month while on treatment.  Patients will be instructed to take 
the study drug once a day (QD) nightly at bedtime (QHS) with or without food, at the same time each day with a glass of water. 
k  Patients who discontinue from the study prior to Week 12: End of study visit (EOS) and all EOS assessments should be performed within 7 days following the discontinuation from the 
study. Patients who discontinue study treatment prior to Week 12: Patients may discontinue study treatment and remain in the study. Complete the EOS study visit and all EOS assessments 
within 7 days of study treatment discontinuation. The patient should continue to follow the schedule of assessments through the Safety Follow-Up Phone Call with modified assessments at 
interim visits including Week 12/Visit 6 as follows: 
 
Number of Panic Attacks 
 
C-SSRS (Oquendo MA 2003) 
 
Efficacy Endpoint Questionnaires 
 
Exploratory Endpoint Questionanires (when applicable) 
 
Concomitant Medications 
 
Adverse Event Monitoring 
l  Safety Follow-up Phone Call is performed approximately 7 days after Visit 6/EOS. 
m  Only the PDSS will be repeated at the Week 2 visit. 
n Placebo-Control Reminder Script (PCRS) (Cohen, EA. 2021). The PCRS will be administered immediately prior to administering the PDSS at Visits 3-6. 
O CogScreen Symbol Digit Coding Test (SDC)  (Kay G. 1995); SDC to be done twice at Screening/Visit 1 and no passing score is required. 
 


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TABLE OF CONTENTS 
INVESTIGATOR PROTOCOL APPROVAL ................................................................................2 
SPONSOR PROTOCOL APPROVAL ...........................................................................................3 
CONTACT INFORMATION ..........................................................................................................4 
PROTOCOL SYNOPSIS ................................................................................................................5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................18 
1. 
BACKGROUND ........................................................................................................20 
1.1. 
Unmet Need ................................................................................................................21 
1.2. 
HB-1 for the Treatment of Panic Disorder .................................................................22 
1.3. 
HB-1 ...........................................................................................................................23 
1.4. 
Telmisartan .................................................................................................................23 
1.5. 
Verapamil Hydrochloride ...........................................................................................23 
1.6. 
Study Overview ..........................................................................................................23 
2. 
OBJECTIVES .............................................................................................................25 
2.1. 
Primary Objective .......................................................................................................25 
2.2. 
Exploratory Objective .................................................................................................25 
3. 
ENDPOINTS ..............................................................................................................25 
3.1. 
Safety Endpoints .........................................................................................................25 
3.2. 
Efficacy Endpoints ......................................................................................................25 
3.3. 
Exploratory Endpoints ................................................................................................25 
4. 
STUDY DESIGN AND DESCRIPTION ...................................................................26 
4.1. 
Study Design ...............................................................................................................26 
4.2. 
Justification for Study Design, Dose, and Endpoints .................................................26 
4.3. 
Dosing Frequency .......................................................................................................27 
4.4. 
Monitoring of Adverse Events ....................................................................................27 
4.5. 
Treatment Discontinuation .........................................................................................28 
4.6. 
Study Discontinuation ................................................................................................29 
5. 
STUDY POPULATION .............................................................................................30 
5.1. 
Inclusion Criteria ........................................................................................................30 
5.2. 
Exclusion Criteria .......................................................................................................31 
6. 
STUDY PROCEDURES AND ASSESSMENTS......................................................32 
6.1. 
Screening and Treatment Procedures and Assessments .............................................32 


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6.1.1. 
Informed Consent Form ..............................................................................................32 
6.1.2. 
Inclusion and Exclusion Criteria ................................................................................32 
6.1.3. 
Medical History, Demographics, Neurological and Behavioral Health 
History ........................................................................................................................32 
6.1.4. 
Concomitant Medications and Procedures .................................................................32 
6.1.5. 
Physical Exam ............................................................................................................32 
6.1.6. 
Height, Weight, and BMI ...........................................................................................33 
6.1.7. 
Orthostatic Vital Signs ................................................................................................33 
6.1.8. 
Clinical Laboratory Tests ...........................................................................................34 
6.1.9. 
Study Treatment Administration ................................................................................34 
6.1.10. 
Adverse Events (AEs) .................................................................................................34 
6.1.11. 
Electrocardiogram (ECG) ...........................................................................................34 
6.1.12. 
Weber Test ..................................................................................................................34 
6.1.13. 
Assessments and Questionnaires ................................................................................35 
6.1.13.1. 
Mini International Neuropsychiatric Interview for DSM-5 (MINI) ...........................35 
6.1.13.2. 
Placebo-Control Reminder Script (PCRS) .................................................................35 
6.1.13.3. 
Panic Disorder Symptom Severity Scale (PDSS) .......................................................35 
6.1.13.4. 
Number of Panic Attacks ............................................................................................35 
6.1.13.5. 
Assessment of Overall Sleep Quality .........................................................................35 
6.1.13.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................35 
6.1.13.7. 
Clinical Global Impression-Severity Scale (CGI-S) ...................................................35 
6.1.13.8. 
Quality of Life Enjoyment and Satisfaction Questionnaire Short Form 
(Q-LES-Q-SF) ............................................................................................................36 
6.1.13.9. 
Self Report Leibowitz Anxiety Scale (LSAS) ............................................................36 
6.1.13.10. Toronto Alexithymia Scale (TAS-20) ........................................................................36 
6.1.13.11. Hamilton Anxiety Rating Scale (HAM-A) .................................................................36 
6.1.13.12. Montgomery-Asberg Depression Rating Scale (MADRS) ........................................36 
6.1.13.13. CogScreen Symbol Digit Coding test (SDC) .............................................................36 
6.1.13.14. 
 .........................................................36 
6.1.13.15. The PTSD Checklist for DSM-5 .................................................................................37 
6.1.13.16. Short Form McGill Pain Questionnaire (SF-MPQ) ....................................................37 
6.1.13.17. Migraine Disability Assessment Questionnaire (MIDAS) .........................................37 
6.1.14. 
Safety Follow-Up Phone Call .....................................................................................37 


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6.2. 
Concomitant Medications ...........................................................................................37 
6.2.1. 
Other Concomitant Therapies .....................................................................................37 
6.2.2. 
Contraception and Pregnancy .....................................................................................38 
7. 
HB-1 MATERIALS AND MANAGEMENT ............................................................39 
7.1. 
HB-1 ...........................................................................................................................39 
7.1.1. 
Description of HB-1 ...................................................................................................39 
7.1.2. 
Dosage and Administration ........................................................................................40 
7.1.3. 
Storage and Handling .................................................................................................40 
7.2. 
Drug Accountability ...................................................................................................41 
7.3. 
Assignment to Treatment ............................................................................................41 
7.4. 
Unblinding Procedure .................................................................................................41 
8. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING....................42 
8.1. 
Adverse Events ...........................................................................................................42 
8.1.1. 
Definition of an Adverse Event (AE) .........................................................................42 
8.1.2. 
Definition of Treatment Emergent Adverse Event (TEAE) .......................................42 
8.1.3. 
Definition of Serious Adverse Event (SAE) ...............................................................42 
8.2. 
Procedures for Recording and Reporting Adverse Events .........................................43 
8.2.1. 
Recording Adverse Events .........................................................................................43 
8.2.1.1. 
Relationship to Study Treatment ................................................................................43 
8.2.1.2. 
Adverse Event Severity ..............................................................................................44 
8.2.2. 
Reporting of Serious Adverse Events .........................................................................44 
8.2.2.1. 
Reporting of Serious Adverse Events to Regulatory Authorities and 
Institutional Review Board .........................................................................................44 
9. 
STATISTICAL METHODS .......................................................................................46 
9.1. 
General Considerations ...............................................................................................46 
10. 
STUDY ADMINISTRATION ...................................................................................51 
10.1. 
Good Clinical Practice Statement ...............................................................................51 
10.2. 
Informed Consent (ICF) .............................................................................................51 
10.3. 
Patient Confidentiality ................................................................................................51 
10.4. 
Institutional Review Board Requirements ..................................................................52 
10.5. 
Case Report Forms and Source Documentation .........................................................52 
10.6. 
Sponsor Monitoring ....................................................................................................52 
10.7. 
Quality Assurance .......................................................................................................53 


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10.8. 
Study or Clinical Site Termination .............................................................................53 
10.9. 
Records Retention .......................................................................................................53 
10.10. 
Publications .................................................................................................................54 
11. 
LIST OF REFERENCES ............................................................................................55 
List of Tables 
Table 1: 
Schedule of Assessments ............................................................................................12 
Table 2: 
Subject Specific Stopping Criteria ..............................................................................27 
 
LIST OF FIGURES 
Figure 1: 
HB-1 ...........................................................................................................................21 
Figure 2: 
Study Design ...............................................................................................................26 
Figure 3: 
Structure of Telmisartan .............................................................................................39 
Figure 4: 
Structure of Verapamil Hydrochloride .......................................................................40 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADHD 
Attention Deficit Hyperactivity Disorder 
AE 
adverse event 
AUC 
area under the curve 
CAARS 
 Rating Scale 
CGI-S 
Clinical Global Impression-Severity Scale 
cmax 
maximum serum concentration 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders 5th edition 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EOS 
End of Study 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HAM-A 
Hamilton Anxiety Scale 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
ITT 
Intent-to-treat 
LSAS 
Leibowitz Social Anxiety Scale 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIDAS 
Migraine Disability Assessment Questionnaire 
MINI 
Mini International Neuropsychiatric Interview for DSM-5 
OCD 
Obsessive Compulsive Disorder 
N 
number 
QD 
once a day 
QHS 
nightly at bedtime 
Q-LES-SF 
Quality of Life Enjoyment and Satisfaction Scale  Short Form 
PCRS 
Placebo-Control Reminder Script 
PDSS 
Panic Disorder Symptom Severity Scale 


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Abbreviation 
Definition 
PSQI 
Pittsburgh Sleep Quality Index 
PTSD 
Post-Traumatic Stress Disorder 
PCL 
PTSD Checklist for DSM-5 
PE 
physical examination 
PI 
principal investigator 
QoL 
Quality of life 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDC 
CogScreen Symbol Digit Coding test  
SF-MPQ 
Short Form McGill Pain Questionnaire 
SMC 
Safety Monitoring Committee 
SSRI 
serotonin reuptake inhibitors 
TAS-20 
Toronto Alexithymia Scale 
TEAE 
treatment-emergent adverse event 
W 
week 
WOCBP 
women of childbearing potential 
 


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1. 
BACKGROUND 
New treatments that safely improve whole brain functional connectivity could radically 
transform outcomes for people suffering from Psychiatric Disorders (Tumati S. 2021).  Anxiety 
disorders (ie, Panic Disorder, Social Anxiety Disorder, Generalized Anxiety Disorder, Obsessive 
Compulsive Disorder, Post-traumatic Stress Disorder and Specific Phobia) are a clinically 
diverse group of disorders that have significant pathophysiological overlap.  Anxiety disorders 
commonly feature disequilibrium in functional connectivity.  Specifically, simultaneous 
alterations within more than one functional brain network, such as default mode, salience and 
somatomotor networks, are common to these disorders (Kim Y, Yoon H. 2018).  Anxiety 
disorders also commonly feature dysregulations in both adrenergic and angiotensin systems 
(Winter A. 2019, Killgore W. 2014, Milani A. 2017).  For example, patients with Panic Disorder 
and also patients with Post-Traumatic Stress Disorder display atypical brain connectivity in 
regions that govern autonomic nervous system regulation (Faravelli C. 1997, Rotella F. 2014, 
Reiman E. 1984, Owega A. 2001).  In fact, successful treatment of symptoms for anxiety 
disorders is associated with resolution of multiple atypical patterns of regional cerebral 
connectivity (Zandvakili A. 2020, Lai C. 2013). 
This study introduces HB-1, a fixed dose combination of 96 mg telmisartan and 288 mg 
verapamil, two previously FDA-approved antihypertensives, as a novel therapeutic agent 
targeting symptoms and quality of life (QoL) for patients with Panic Disorder. HB-1 works by 
re-equilibrating functional networks within the telencephalon and the mesencephalon brain 
regions.  HB-1 is a promising treatment for Panic Disorder because Panic Disorder is 
characterized by abnormal physiological stress responses associated with disequilibrium in more 
than one functional brain network. 
This study hypothesizes that, in patients with Panic Disorder, HB-1 demonstrates a comparable 
safety profile compared to the safety profiles of the individual agents; and a statistically 
significant reduction in disease severity, compared to placebo. This study will also examine the 
effects of HB-1 in treating the most commonly experienced co-morbidities in patients diagnosed 
with Panic Disorder. 
These hypotheses are based on real-world clinical observation of significant improvement in 
anxiety and cognitive symptomatology in a diverse group of Neurology & Psychiatry patients 
who received these co-administered medications at a community-based Neuropsychiatry 
specialty practice.  Regarding safety, adverse events were minimal, and systolic and diastolic 
blood pressure did not change significantly before and after an average of nine months of 
treatment observations.  Regarding effectiveness, drastic reductions in symptomatology were 
noted across a broad array of disabling symptoms in patients not only with Panic Disorder but 
also with common co-morbidities.  This hypothesis is also based on an extensive body of 
literature that describes relationships between psychosocial stress, emotional intelligence, 
theories of human motivation, quality of life, the adrenergic system, functional connectivity, 
angiotensin receptors and calcium channels (Lea R. 2019, Zheng Z. 2016, Sagar-Ouriaghli I. 
2018, Keller S. 2003) (see Figure 1). 


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Figure 1: HB-1
1.1.
Unmet Need
Currently, no FDA-approved treatments for anxiety disorders are designed to improve whole 
brain functional connectivity by targeting the angiotensin and adrenalin systems simultaneously.
This is a critical research gap because anxiety disorders are 1) common, 2) debilitating, 
3) co--morbid and 4) difficult to treat (Cerda M. 2010).  Panic Disorder, for example, is prevalent 
in 6% of primary care patients (Katon W. 1986).  Current FDA-approved treatments, which
target symptomatology using neurotransmitter-specific approaches, are limited due to adverse 
reactions, including abuse potential.  For example, current treatments for Panic Disorder include 
selective serotonin reuptake inhibitors (SSRIs), which have a small to medium effects, and 
benzodiazepines, which are not beneficial for long-term use due to tolerance, dependence, 
cognitive disturbance, and exacerbation of co-morbid mood disorders (Otto M. 1989, Edwards R. 
1980).  Regarding future treatments, the drugs currently being tested for Panic Disorder target 
mechanisms of action similar to currently approved treatments.
Whereas many of the anxiety disorders feature hundreds of novel treatment options in 
development, Panic Disorder represents an important disorder with fewer options in 


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development.  There are few planned or active Phase 2 or 3 studies for the treatment of Panic 
Disorder in adults. 
1.2. 
HB-1 for the Treatment of Panic Disorder  
The Sponsor plans to develop a single dosage formulation therapy of verapamil and telmisartan 
for the treatment of Panic Disorder in adults.  HB-1 contains telmisartan and verapamil, two 
products previously approved by the FDA for the treatment of cardiovascular conditions.  
Telmisartan (Micardis®) was approved by the FDA in 1998 and Verapamil (Verelan® PM) was 
approved in the United States in 1981.  HB-1 is dosed using a specific ratio of verapamil to 
telmisartan which leads to its unique clinical effects.  HB-1 treatment is expected to help patients 
achieve greater reductions in specific symptomatology, faster psychosocial advancement, and 
higher quality of life, with a mechanism of action related to normalization of asymmetric 
cerebral blood flow patterns that cause disability. 
At this time, Honeybrains has conducted an IRB-approved, observational cohort study of a 
diverse group of neurology and psychiatry patients who received combination therapy with 
telmisartan and verapamil from 2019 to March 2020.  The trial included a total of 102 patients, 
ages 18 to 70, with clinically diagnosed panic disorder, social anxiety disorder, ADHD, and other 
co-morbidities such as PTSD, migraine, and/or chronic musculoskeletal pain.  Overall, the 
treatment appeared to significantly reduce symptomatology without causing adverse 
symptomatology or changes to vital signs.  Specifically, the average self-reported symptom 
severity was significantly reduced in eight of the 10 cardinal neuropsychiatric symptoms 
(ie, anxiety, depression, irritability, apathy, body pain, insomnia, headache, cognitive difficulty) 
post treatment compared to baseline.  Effect sizes were largest for anxiety, apathy, cognitive 
difficulty and overall neuropsychiatric disability.  Psychosocial outcomes (NIH Toolbox General 
Life Satisfaction) were significantly better after combination treatment.  Post-treatment systolic 
and diastolic blood pressure measurements did not change significantly from baseline.  The 
effect of combination therapy on vital signs was no different than the effect of individual 
telmisartan or individual verapamil.  The Overall Medical Review of Symptoms score was not 
significantly higher at one month or last observation; in fact, it was lower.  Also, the rate of 
adverse symptoms from combination treatment was similar to known rates of adverse symptoms 
from verapamil and telmisartan.  Importantly, the lateralization of the Weber test, which 
indicates the dominant side of activity of the auditory functional network, changed significantly 
when patients went on or off treatment, suggesting that the mechanisms of action is acting on 
reversible patterns of functional connectivity. 
In summary, this study suggested that in terms of safety HB-1 was well tolerated, with an 
adverse event profile that is no different than those of the individual agents, and as a novel 
therapeutic agent HB-1 is hypothesized to significantly reduce disease severity in patients with 
panic disorder and ADHD.  An extensive body of literature supports the use of this co-
administration and describes relationships between psychosocial stress, the adrenergic system, 
functional connectivity, cerebral blood flow, angiotensin receptors and calcium channels 
(Kikuchi K. 2020, Jennings JR. 2009).  Collectively, findings from the clinical data and from 
prior research suggest that treatments that normalize cerebral blood flow may lead to more 
complete relief of inter-related neuropsychiatric symptoms (anxiety, depression, irritability, body 


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pain, fatigue, headache, apathy, cognitive difficulty, psychosis, insomnia) that are germane to 
different neurological and behavioral health disorders.  
1.3. 
HB-1 
HB-1, a fixed dose combination of 96 mg telmisartan and 288 mg verapamil, two previously 
FDA-approved antihypertensives, is a novel therapeutic agent targeting symptoms and QoL for 
patients with Panic Disorder. HB-1 treatment is expected to help patients achieve greater 
reductions in specific symptomatology, faster psychosocial advancement, and higher QoL, with a 
mechanism of action related to normalization of asymmetric cerebral blood flow patterns that 
cause disability. HB-1 is a new treatment which modulates the brain renin angiotensin system 
(RAS) and adrenergic system simultaneously, resulting in a central hemodynamic that improves 
outcomes in different neuropsychiatric disorders. The use of treatments that target central 
mechanisms common to more than one co-morbidity could radically improve the quality of 
outcomes in neurological and behavioral disorders.  
1.4. 
Telmisartan 
Telmisartan, an angiotensin II type 1 receptor (AT1) blocker, is approved for the treatment of 
hypertension.  The pro-inflammatory properties of angiotensin II as well as its anti-inflammatory 
effects are well-established (Fan X. 2017).  Poor adaptation to stress, alterations in 
cerebrovascular function and excessive brain inflammation play critical roles in the 
pathophysiology of many psychiatric and neurological disorders (Saavedra JM. 2012).  AT1 
blockade may have a therapeutic effect in these types of disorders. 
1.5. 
Verapamil Hydrochloride 
Verapamil is a calcium channel antagonist used in cardiovascular diseases such as hypertension, 
angina, and certain arrythmias.  It is used clinically as a racemic mixture that contains equal 
amounts of (R) verapamil and (S) verapamil.  Its antihypertensive effects result from causing a 
decrease in peripheral vascular resistance.  It specifically blocks the L-type calcium channel 
along with other, lesser characterized, calcium channels (T-, P-, and possibly N- and Q-type Ca 
(2+) channels) (Tfelt-Hansen P. 2009, Dobrev D. 1999). 
P-glycoprotein function, which is involved in verapamil BBB efflux, is associated with several 
neurodegenerative and psychiatric diseases (van Assema DM. 2012).  Measures of psychiatric 
morbidity in patients taking verapamil tended to improve, such as measurements of cognitive 
scores and psychiatric comorbidity scores (Palmer A. 1990).  Multiple studies found verapamil 
to be well tolerated in patients with bipolar disorder with therapeutic effects in mania comparable 
to amitriptyline, prazosin and propranolol (Cipriani A. 2016).  Other psychiatric clinical 
measures have shown significant improvement with verapamil therapy such as the Brief 
Psychiatric Rating Scale (BPRS) and general impression. 
1.6. 
Study Overview 
This multicenter, randomized, double-blind, placebo-controlled trial will assess the safety of HB-
1 and effectiveness of HB-1 versus placebo for the treatment of Panic Disorder.  This study will 
enroll approximately 80 patients who meet DSM-5 criteria for the diagnosis of Panic Disorder 
recruited from approximately eight clinical research sites.  All patients will receive an oral dose 


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of HB-1 or matching placebo once a day.  HB-1 is a proprietary combination of telmisartan and 
verapamil in a once-daily, extended release formulation. 
 
 


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2. 
OBJECTIVES 
2.1. 
Primary Objective 
To determine the safety and efficacy of HB-1 versus placebo in male and female adult patients 
aged 18 to 60 years, inclusive, with Panic Disorder. 
2.2. 
Exploratory Objective 
To compare the effectiveness of HB-1 on Common Neuropsychiatric Co-Morbidities. 
3. 
ENDPOINTS 
3.1. 
Safety Endpoints 
Incidence of Treatment Emergent Adverse Events (TEAEs), clinically significant changes in 
clinical laboratory values, changes in electrocardiogram (ECG), and Columbia Suicide Severity 
Rating Scale (C-SSRS) (Oquendo MA 2003), and orthostatic vital signs. 
3.2. 
Efficacy Endpoints 
 Change in Panic Disorder Symptom Severity Scale (PDSS) (Furukawa T. 2009) - 
primary efficacy endpoint. 
 Number of panic attacks 
 Change in Clinical Global Impression-Severity Scale (CGI-S) (Guy W. 1976) 
 Change in Quality of Life Enjoyment and Satification Questionaire Short Form 
(Q-LES-Q-SF) (Endicott J. 1993) 
 Change in Leibowitz Anxiety Scale (LSAS) (Heimberg R. 1999, Baker S. 2002) 
 Change in Assessment of Overall Sleep Quality -- Question #6 from the Pittsburgh Sleep 
Quality Index (Buysse DJ. 1989) 
3.3. 
Exploratory Endpoints 
 Change in Toronto Alexithymia Scale (TAS-20) (Bagby R. 2020) 
 Change in Hamilton Anxiety Rating Scale (HAM-A) (Bech P. 1990) 
 Change in Montgomery-Asberg Depression Rating Scale (MADRS) (Fantino B., Moore 
N. 2009) only for patients with a medical history of depression 
 Change in CogScreen Symbol Digit Coding test (SDC)  (Kay G. 1995) 
 Change in Conner
 (Walls B. 2017) only for 
patients with a medical history of ADHD 
 Change in The PTSD Checklist for DSM-5 (Blake DD. 1995, Blevins CA. 2015) only for 
patients with a medical history of PTSD 


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 Change in Short Form McGill Pain Questionnaire (SF-MPQ) (Melzack R. 1987) only for 
patients with a medical history of chronic pain 
 Change in Migraine Disability Assessment Questionnaire (MIDAS) (Lipton RB. 2001) 
only for patients with a medical history of migraine 
4. 
STUDY DESIGN AND DESCRIPTION 
4.1. 
Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled trial.  All patients with Panic 
Disorder, with or without specified co-morbidities, who meet all of the inclusion and none of the 
exclusion criteria will be eligible.  Patients and researchers will be blinded to their treatment 
group. 
Approximately 80 patients with Panic Disorder will be enrolled and randomized in a 1:1 ratio to 
HB-1 or placebo using a central randomization. 
The study design is presented in Figure 2.  A schedule of assessments is presented in Table 1. 
 
Figure 2: 
Study Design 
Safety and Effectiveness of HB-1 for Panic Disorder 
 
 
4.2. 
Justification for Study Design, Dose, and Endpoints 
This study was designed as a pragmatic trial because in real-world conditions most panic 
disorder patients have multiple neuropsychiatric co-morbidities and are usually taking one or 
more medications.  Pragmatic trial design was chosen because pragmatic trials are useful to 
Study Recruitment
HB-1
(N=40)
Placebo
(N=40)
Screening/Eligibilty 
Assessment


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address questions related to generalizability and variability in response.  Pragmatic trials can be 
useful to evaluate the effectiveness of an intervention in real-world setting, ie, in patients who 
may not be adherent to treatment and/or who have co-morbid conditions.  Pragmatic trials focus 
on a wide range of outcomes, such as symptoms, mechanisms, functional status, quality of life, 
and costs. 
A pragmatic study design that enables wider inclusion of patients, regardless of whether they 
have co-morbidities, or are already on treatment, was also important in order to increase the 
recruitability of patients (reduce exclusionary criteria).  A pragmatic design is enabled by the fact 
that the drug does not interact with most common psychiatric treatments. 
4.3. 
Dosing Frequency 
HB-1 and placebo are dosed once a day (QD), nightly at bedtime (QHS) with or without food. 
4.4. 
Monitoring of Adverse Events 
Safety will be assessed through the monitoring of Adverse Events (AEs), Treatment Emergent 
Adverse Events (TEAEs), clinical laboratory assessments, ECGs, Columbia Suicide Severity 
Rating Scale (C-SSRS) (Oquendo MA 2003), and orthostatic vital signs.  Patients will be 
monitored for safety from the first dose of HB-1 or placebo at study Week 0 through the Safety 
Follow-up visit. Serious adverse events (SAEs) will be reported immedidately to the sponsor and 
recorded in the eCRF. 
Table 2 below provides guidance on the management of known toxicities that have been 
associated with verapamil or telmisartan monotherapy. If any of the following criteria are met, 
the subject will have study treatment discontinued and the Medical Monitor must be informed 
immediately. Subjects may discontinue study treatment, however, and remain in the study (see 
Section 4.5). The stopping criteria listed below will also be captured as adverse events (see 
Section 8). 
 
Table 2: 
Subject Specific Stopping Criteria 
 
Cardiac Disorders 
Hypotension 
 SBP <90 mmHg and DBP <60 mmHg for three 
consecutive readings 10 minutes apart 
Orthostatic Hypotension 
 Decline of >20mm Hg in systolic or >10 mm Hg 
in diastolic blood pressure after 3 minutes of 
standing. 
New-onset 2nd or 3rd degree 
AV block  
 Grade 1 or higher per CTCAE V5.0* 
Sick sinus syndrome 
 Grade 1 or higher per CTCAE V5.0 
Atrial flutter 
 Grade 1 or higher per CTCAE V5.0 
Atrial fibrillation 
 Grade 1 or higher per CTCAE V5.0 
New-onset bradycardia  
 Resting heart rate below 50  
New-onset tachycardia  
 Resting heart rate above 120 


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Onset of angina pectoris
 Grade 1 or higher per CTCAE V5.0 
Congestive heart failure 
 Grade 1 or higher per CTCAE V5.0 
Pulmonary edema 
 Grade 1 or higher per CTCAE V5.0 
Peripheral edema 
 Grade 2 or higher per CTCAE V5.0 
General Disorders 
Urticaria 
 Grade 2 or higher per CTCAE V5.0 
Hyperkalemia 
 Potassium values that are 2X the ULN for the 
local lab normal refences ranges.  
 Values may be repeated and confirmed. 
Gout exacerbation 
 Hyperuricemia Grade 1 or higher per CTCAE 
V5.0 
 Values may be repeated and confirmed. 
Impaired hepatic function 
 ALT, AST, ALP values that are twice the upper 
or lower limit of local lab normal reference 
range.  
 Values may be repeated and confirmed. 
Impaired renal function 
 Doubling in creatinine value. 
 Values may be repeated and confirmed. 
Thrombocytopenia 
 Platelet count values below 150,000/mL 
 Values may be repeated and confirmed. 
*Common Terminology Criteria for Adverse Events (CTCAE) V5 dated 27Nov2017 
 
Women who are using oral contraceptives will be monitored for adverse events associated with 
overexposure at each study visit. This should include signs and symptoms of myocardial 
infarction, stroke, and venous thromboembolism. 
 
4.5. 
Treatment Discontinuation 
Patients who discontinue from study treatment prior to Week 12/Visit 6 should complete an End 
of Study (EOS) visit. The EOS visit should be conducted within 7 days from the last dose of 
study treatment. Patients may discontinue study treatment and remain in the study. If a patient 
discontinues study treatment for any reason, the patient should continue to follow the schedule of 
assessments through the Safety Follow-Up Phone Call with modified assessments at interim 
visits including Week 12/Visit 6 as follows: 
 Number of Panic Attacks 
 Columbia Suicide Severity Rating Scale (C-SSRS) (Oquendo MA 2003) 
 Efficacy Endpoint Questionairres 
 Exploratory Endpoint Questionanires (when applicable) 
 Concomitant Medications 
 Adverse Event Monitoring 


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Patients will be discontinued from treatment for any of the following reasons: 
 An AE that requires permanent discontinuation of study treatment* 
 Noncompliance to the protocol 
 Investigator decision for any medically appropriate reason or belief that further 
treatment is undesirable or the risk-benefit profile has become unfavorable 
 Patient becomes pregnant 
 Patient lost to follow-up  
 Termination of the study by the Sponsor 
 Voluntary withdrawal of consent by patient  
* 
AEs leading to the discontinuation of study treatment will be followed until resolution, 
resolution to baseline or until the event is considered stable or chronic. 
4.6. 
Study Discontinuation 
Patients are free to withdraw from participation in the study at any time, for any reason, and 
without prejudice.  The Investigator must withdraw any patient from the study if the patient 
withdraws consent and requests to stop participating in the study. 
In the event the patient withdraws from the study, if possible, an End of Study (EOS) Visit 
should occur within 7 days after the last dose of study treatment. Patients may discontinue study 
treatment and remain in the study (see Section 4.5). 


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5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
All patients must meet the following criteria for inclusion: 
1. Male or female, aged 18 to 60 years old, inclusive, at the time of informed consent. 
2. Meets DSM-5 Criteria for Panic Disorder. 
3. Documented moderate to severe levels of symptoms at baseline Panic Disorder Severity 
Scale of 13 or above (Furukawa TA. 2009). 
4. Medically stable on current medication regimen for at least 3 months (including PRN 
medications), as determined by clinician. 
5. Willing to remain on current doses of other psychiatric medications throughout the length 
of the trial trial. 
6. Willing and able to safely stop any of the following medications at least 5 days prior to 
Visit 2: Inhibitors or inducers of CYP3A4 (erythromycin, ritonavir, telithromycin, 
rifampin), HMG-CoA Reductase Inhibitors (Simvastatin, Lovastatin, Atorvastatin), Beta 
Blockers (Timolol eyedrops, Metoprolol), Neuromuscular Blocking Agents (curare-like 
and depolarizing), Antihypertensive Agents (Prazosin and vasodilators, angiotensin-
converting enzyme inhibitors, diuretics, beta blockers, alpha agonists), Inhalation 
Anesthetics, Disopyramide, Flecainide, Quinidine, Cimetidine, Lithium, Carbamazepine, 
Phenobarbital, Cyclosporine,, Aliskiren, Ramipril and Ramiprilat, aspirin, Theophylline, 
mTOR inhibitors. 
7. Willing and able to avoid consumption of grapefruit, grapefruit juice and Seville oranges 
within two weeks of screening through the last dose of study treatment. 
8. Willing and able to limit consumption of alcohol to three servings per day defined as: 1 
serving of beer=12 ounces (5% alcohol content); 1 serving of malt liquor=8 ounces (7% 
alcohol content); 1 serving of wine=5 ounces (12% alcohol content); 1 serving of distilled 
spirits=1.5 ounces (40% alcohol content). 
9. Willing and able to avoid concomitant administration of sensitive P-glycoprotein 
substrates (digoxin, fexofenadine, dabigatran etexilate, talinolol, loperamide, vinblastine). 
10. Fluent in English. 
11. Willing to take HB-1. 
12. Willing and able to provide informed consent indicating an understanding of the 
requirements of the study and a willingness to comply with scheduled visits and all study 
procedures. 
13. Female patients must be surgically sterile (or have a monogamous partner who is 
surgically sterile), or be at least 2 years postmenopausal, or commits to use 2 acceptable 
forms of birth control (defined as the use of an intrauterine device (IUD), a barrier 
method with spermicide, condoms, or any form of hormonal contraceptives) for the 
duration of the study and for 4 months following the last dose of study treatment. Male 
patients must be sterile (biologically or surgically) or commit to the use of a reliable 


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method of birth control (condoms with spermicide) for the duration of the study and for 
4 months following the last dose of study treatment .  Individuals who are involved 
exclusively in same-sex relationships are exempt from the birth control requirements but 
must agree to abide by the recommendations if they do engage in a heterosexual 
relationship. 
14. Female patients who are women of childbearing potential (WOCBP) must have a 
negative pregnancy test at Screening within 7 days of dosing with study treatment. 
5.2. 
Exclusion Criteria 
Patients are to be excluded from the study if they meet any of the following criteria: 
1. Severe uncontrolled cardiac disease within 6 months of Screening, including but not 
limited to uncontrolled hypertension, hypotension (defined as below 90/60); unstable 
angina; myocardial infarction (MI) or cerebrovascular accident (CVA). 
2. Any clinically significant electrocardiogram (ECG) abnormalities at screening. 
3. History of atrial flutter, atrial fibrillation or hypertrophic cardiomyopathy. 
4. Inadequate hepatic function defined as total bilirubin >1.5 × the upper limit of normal 
(ULN) ranges of each institution, aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) >3 × the ULN range of each institution. 
5. Inadequate renal function defined as serum creatinine >1.5 × the ULN range of each 
institution and/or eGFR <60. 
6. Any clinically significant abnormalities in clinical laboratory assessments as assessed by 
the investigator. 
7. Any other systemic conditions or organ abnormalities that in the opinion of the 
Investigator may interfere with the conduct and/or interpretation of the current study. 
8. Unable to complete neuropsychological testing. 
9. Diagnosis of Bipolar I, Bipolar II disorder or Schizophrenia. 
10. History of suicidal behaviors including ideation. 
11. Current treatment with doses of benzodiazepines that are outside the FDA-approved 
. 
12. Use of tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) is 
prohibited. 
13. Already on treatment with either telmisartan or verapamil or both. 
14. Documented prior drug allergy to either telmisartan or verapamil. 
15. Documented contraindication to taking telmisartan or verapamil (eg, Duchenne's 
muscular dystrophy, myasthenia gravis). 
16. Documented moderate to severe substance abuse within the last 6 months (recreational 
cannabis use is allowed). 
17. Pregnant or breastfeeding. 


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6. 
STUDY PROCEDURES AND ASSESSMENTS 
Time points for assessments to be collected throughout the study can be found in the Schedule of 
Assessments (Table 1).  A brief description of each assessment can be found below. 
6.1. 
Screening and Treatment Procedures and Assessments 
6.1.1. 
Informed Consent Form 
An ICF must be signed by prospective patients prior to initiating any study-specific procedures. 
Standard of care assessments performed prior to ICF signing may fulfill study eligibility 
requirements if performed within the screening period. 
6.1.2. 
Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria (Section 5.1 and Section 5.2, respectively) will be reviewed for 
each potential patient. Eligibility assessments will include the Mini International 
Neuropsychiatric Interview for DSM-5 (MINI) (Sheehan DV. 1998; Sheehan DV. 1992-2016) 
and Panic Disorder Symptom Severity Scale (PDSS) (Furukawa T. 2009). Eligibility will be 
documented in the electronic case report form (eCRF). 
6.1.3. 
Medical History, Demographics, Neurological and Behavioral Health History 
Complete medical history will be obtained, including demographics, neurological and behavioral 
health information. Demographics will include: Age, Sex, Race, Ethnicity, Education, Gender 
Identity, Lateral Preference Questions, and Parental Education. 
6.1.4. 
Concomitant Medications and Procedures 
At Screening, concomitant medications will be recorded. Assessment of any change in 
concomitant medications or procedures since the last visit will occur at all further patient visits 
through safety follow-up. 
6.1.5. 
Physical Exam  
Physical exams will be conducted at the time points specified in the Schedule of Assessments 
(Table 1).  The physical examination at screening will consist of the following body systems: 
 Head, eyes, ears, nose, and throat exam: inspection, palpation ,and testing, as 
appropriate. 
 Cardiovascular evaluation: Auscultation of the carotid arteries and left anterior 
chest to evaluate heart sounds and possible murmurs. 
 Respiratory assessment: Observation of inspiration and expiration.  Auscultation of 
breath sounds both anterior and posterior chest. 
 Musculosketal assessment: Muscles, bones, and joints are assessed by functional 
grouping using techniques of inspection, palpation, and manipulation while the 
clinician observes responses and reactions. 
 Neurological exam: Observation of mental awareness.  Testing of gross motor 
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 Skin and lymph node check: Skin tone/pallor and lymph nodes are inspected. 
Any abnormal change from the initial screening physical examination must be assessed by the 
investigator as not clinically significant (NCS) or clinically significant (CS) and recorded in the 
source document and eCRF. 
Any CS change after Visit 2, as determined by the investigator, will be recorded as an AE in 
source documentation and on the AE eCRF. 
6.1.6. 
Height, Weight, and BMI 
Height, weight, and BMI will be collected at screening. 
6.1.7. 
Orthostatic Vital Signs 
Orthostatic vital signs check will be performed at the time points specified in the Schedule of 
Assessments (Table 1).  Orthostatic vital signs should include the following steps based up the 
Agency for Healthcare Research and Quality procedure (Tool3F): 
1. Instruct the patient on the process of orthostatic blood pressure measurement and its 
rationale. 
2. Assess by verbal report and observation the patient's ability to stand. 
3. Have patient lie in bed with the head flat for a minimum of 3 minutes. 
4. Measure the blood pressure and the pulse while the patient is supine. 
5. Instruct patient to sit for 1 minute. 
a. Ask patient about dizziness, weakness, or visual changes associated with position 
change. Note diaphoresis or pallor. 
b. Check sitting blood pressure and pulse. 
c. If the patient has symptoms associated with position change or sitting blood 
 90/60, put patient back to bed. 
6. Instruct patient to stand. 
a. Ask patient about dizziness, weakness, or visual changes associated with position 
change. Note diaphoresis or pallor. 
b. If patient is unable to stand, sit patient upright with legs dangling over the edge of 
the bed. 
c. The patient should be permitted to resume a supine position immediately if 
syncope or near syncope develops. 
7. Measure the blood pressure and pulse 3 minutes after patient stands. Support the forearm 
at heart level when taking the blood pressures to prevent inaccurate measurement. 
8. Assist patient back to bed in a position of comfort. 
9. Document vital signs and other pertinent observations on the nursing flowsheet or in the 
medical record. Note all measurements taken and the position of the patient during each 
reading. 
Subtract values 3 minutes after standing (or if patient cannot stand, then sitting) from lying 
values.  
minutes of standing indicates orthostatic hypotension. Clinically significant orthostatic 
hypotension should be treated per standard of care and the Medical Monitor should be contacted. 


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6.1.8. 
Clinical Laboratory Tests 
The following laboratory parameters will be measured at the time points specified in the 
Schedule of Assessments (Table 1) and will be analyzed locally: 
 Pregnancy test should be administered for women of child-bearing potential 
(WOCBP) within 7 days prior to Week 0 and then at each subsequent study visit. 
 Comprehensive Metabolic Panel (CMP): albumin, blood urea nitrogen, calcium, 
carbon dioxide, chloride, creatinine, creatinine phosphokinase, glucose, potassium, 
sodium, total bilirubin, total protein, alanine aminotransferase (ALT), alkaline 
phosphatase (ALP), aspartate aminotransferase (AST) 
 Complete Blood Count (CBC): white blood cell count, red blood cell count, 
hematocrit, hemoglobin, mean corpuscular volume (MCV), mean corpuscular 
hemoglaobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell 
distribution (RDW), platemet cont, mean platelet volume (MPV), Vitamin B12 
 Urinalysis:microscopic examination, specific gravity, pH, protein, glucose, ketones, 
blood and urobilinogen 
6.1.9. 
Study Treatment Administration 
Detailed instructions on the administration of study treatment can be found in Section 7. 
6.1.10. 
Adverse Events (AEs) 
All AEs should be captured on the eCRF from Visit 2/Week 0 through the Safety Follow-up 
visit.  Adverse events considered at least possibly related to study treatment should be followed 
until resolution, return to baseline, or deemed chronic or stable.   
All serious adverse events (SAEs) will be immediately reported to the Sponsor from the time of 
Visit 2/Week 0 (dosing) through the Safety Follow-up/End of Study Visit.  
See Section 8.2 for a full description of the collection and reporting of AEs during this study. 
6.1.11. 
Electrocardiogram (ECG) 
At Visit 1/Screening, Visit 4/Week 4, Visit 5/Week 8 and Visit 6/Week 12 a standard 12-lead 
ECG will be conducted. following an approximate 10-minute rest period in all patients and will 
be interpreted by the Investigator to assess clinical significance. 
6.1.12. 
Weber Test 
A Weber Test will be conducted at Baseline/Visit 2 and Visit 6/Week 12.  The Weber test is a 
test of lateralization of auditory function.  Tap the tuning fork strongly on your palm and then 
 ask the patient 
where they hear the sound.  Normally, the sound is heard in the center of the head or equally in 
both ears.  If there is a conductive hearing loss present, the vibration will be louder on the side 
with the conductive hearing loss.  If the patient does not hear the vibration at all, attempt again, 
 
Weber Test results will be documented on the eCRF. 


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6.1.13. 
Assessments and Questionnaires 
6.1.13.1. Mini International Neuropsychiatric Interview for DSM-5 (MINI) 
The Mini International Neuropsychiatric Interview (MINI) is a brief, structured diagnostic 
interview for the major psychiatric disorders in DSM-5 (Sheehan DV. 1998; Sheehan DV. 1992-
2016).  It is routinely used to assess psychiatric diagnoses in clinical trials. The Standard MINI 
with the additional Attention Deficit Hyperactivity Disorder (ADHD) module will be used at 
Screening. 
6.1.13.2. Placebo-Control Reminder Script (PCRS) 
Placebo-Control Reminder Script (PCRS) (Cohen, EA. 2021) will be administered immediately 
prior to administering the PDSS at Visits 3-6. 
6.1.13.3. Panic Disorder Symptom Severity Scale (PDSS) 
The PDSS is a brief clinician rating scale designed to rate severity and treatment progress in 
individuals diagnosed with Panic Disorder (Furukawa TA. 2009). 
6.1.13.4. Number of Panic Attacks 
1-6. 
The clinician will confirm the reported panic attack(s) meet DSM-5 criteria (APA 2013). 
6.1.13.5. Assessment of Overall Sleep Quality 
sit 2 and Visits 4-6. This is question #6 from the Pittsburgh Sleep Quality Index  
(Buysse DJ. 1989). 
6.1.13.6. Columbia Suicide Severity Rating Scale (C-SSRS) 
The Columbia Suicide Severity Rating Scale (C-SSRS) (Oquendo MA 2003) is a suicidal 
ideation rating scale. The scale identifies behaviors and thoughts that are associated with an 
increased risk of suicidal actions in the future. The C-SSRS Baseline/Screening version will be 
conducted at Screening. The C-SSRS Since Last Visit version will be conducted at each post-
Screening visit, including Baseline. 
If the investigator determines that a patient is at risk of suicide or self-harm, appropriate 
ain mental health evaluation must be 
implemented. Patients who meet criteria will be referred to a local psychiatrist for prompt 
evaluation and also to the National Suicide Prevention Hotline. The patient must immediately be 
discontinued from the study. The event should be recorded as either an AE or SAE as determined 
by the investigator and reported within 24 hours to the Sponsor. 
6.1.13.7. Clinical Global Impression-Severity Scale (CGI-S) 
The CGI-S scale is a tool used by clinicans to assess the severity of illness in relation to the 
clinicans previous experience with other patients with that diagnosis (Guy W. 1976). 


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6.1.13.8.  Quality of Life Enjoyment and Satisfaction Questionnaire Short Form 
(Q-LES-Q-SF) 
The Quality of Life Enjoyment and Satisfaction Scale  Short Form (Q-LES-SF) is a 16-item, 
self-
life. Item scores range from 1 to 5 (Endicott J. 1993). The Total Score is reported as the 
percentage of the maximum possible score (Raw Score  Minimum Possible Score / Maximum 
Possible Score  Minimum Possible Score). 
6.1.13.9. Self Report Leibowitz Anxiety Scale (LSAS) 
The LSAS questionnaire is a self report rating scale used to assess social anxiety in individuals 
and has been validated for use as self-report (Heimberg R. 1999, Baker S. 2002). 
6.1.13.10. Toronto Alexithymia Scale (TAS-20) 
The TAS-20 is a self-administered assessment looking at how one identifies and describes 
emotions (Bagby RM. 2020). 
6.1.13.11. Hamilton Anxiety Rating Scale (HAM-A) 
The Hamilton Anxiety Scale (HAM-A) is a 14-item, clinician-administered scale that 
measuresseverity of anxiety (Bech P. 1990).  Symptoms assessed include those associated with 
mental agitation,psychological distress, and physical complaints related to anxiety.  Items are 
scored along a rangefrom 0 to 4; the Total Score (sum of all item scores) ranges from 0 to 56.  
Higher scores reflectgreater severity of anxiety symptoms. 
6.1.13.12. Montgomery-Asberg Depression Rating Scale (MADRS) 
The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item, clinician 
administered interview assessing severity of depressive symptoms (Fantino B., Moore N. 2009).  
Item scores range from 0 to 6, with the Overall Score (sum of all item scores) ranging from 0  
60.  Higher scores reflect greater severity of depressive symptoms.  This assessment should only 
be administered to patients with a medical history of depression.  
6.1.13.13. CogScreen Symbol Digit Coding test (SDC) 
The CogScreen Symbol Digit Coding test (SDC) is a computer-based digit symbol substitution 
task administered by trained study staff (Kay G. 1995). SDC measures attention, visual scanning, 
working memory, and speed of information processing. 
6.1.13.14. Conners  Adult ADHD Rating Scale (CAARS) 
The Conners  Adult ADHD Rating Scale (CAARS) is a self-report assessment evaluating 
symptoms and behaviors in adults with ADHD (Walls B. 2017). This assessment should only be 
administered to patients with a medical history of ADHD. 


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6.1.13.15. The PTSD Checklist for DSM-5 
The PTSD Checklist for DSM-5 (PCL) is a 20-item self-report measure of the DSM-5 symptoms 
of PTSD (Blake D. 1995, Blevins C. 2015). This assessment should only be administered to 
patients with a history of PTSD. 
6.1.13.16. Short Form McGill Pain Questionnaire (SF-MPQ) 
The SF-MPQ is a short self-report assessment evaluating pain using sensory and affective 
subscales from the longer original MPQ assessment (Melzack R. 1987). This assessment should 
only be administered to patients with a medical history of chronic pain. 
6.1.13.17. Migraine Disability Assessment Questionnaire (MIDAS) 
The MIDAS questionnaire is a self-report measure that assesses the impact, level of pain, and 
disability due to an individuals headaches (Lipton R. 2001). This assessment should only be 
administered to patients with a medical history of migraine. 
6.1.14. 
Safety Follow-Up Phone Call 
All patients will have a Safety Follow-Up Phone call approximately 7 days after the last study 
visit (Visit 6 or EOS), unless the patient withdraws from the study prematurely.  During this 
safety follow-up phone call, information on ongoing and new AEs will be collected. 
6.2. 
Concomitant Medications 
6.2.1. 
Other Concomitant Therapies 
Any other medication that is considered necessary for the patient
including 
medications for neuropsychiatric disorders (
, benzodiazepines, stimulant 
medications, antipsychotics, mood stabilizers) and that is not expected to interfere with the 
evaluation of HB-1 may be given at the discretion of the Investigator.  Patients are expected to 
remain stable on their psychiatric medications throughout the duration of the trial.   
Treatment with doses of benzodiazepines that are outside the FDA-
information are excluded. 
The following concomitant medications are also excluded per protocol: Inhibitors or inducers of 
CYP3A4 (erythromycin, ritonavir, telithromycin, rifampin), HMG-CoA Reductase Inhibitors 
(Simvastatin, Lovastatin, Atorvastatin), Beta Blockers (Timolol eyedrops, Metoprolol), 
Neuromuscular Blocking Agents (curare-like and depolarizing), Antihypertensive Agents 
(Prazosin and vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta blockers, 
alpha agonists), Inhalation Anesthetics, Disopyramide, Flecainide, Quinidine, Cimetidine, 
Lithium, Carbamazepine, Phenobarbital, Cyclosporine, Aliskiren, Ramipril and Ramiprilat, 
aspirin, Theophylline, mTOR inhibitors; sensitive P-glycoprotein substrates (digoxin, 
fexofenadine, dabigatran etexilate, talinolol, loperamide, vinblastine); grapefruit, grapefruit juice 
and Seville oranges within two weeks of screening through the last dose of study treatment. 
Additionally, patients are required to limit consumption of alcohol to three servings per day 
defined as: 1 serving of beer=12 ounces (5% alcohol content); 1 serving of malt liquor=8 ounces 


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(7% alcohol content); 1 serving of wine=5 ounces (12% alcohol content); 1 serving of distilled 
spirits=1.5 ounces (40% alcohol content 
 
6.2.2. 
Contraception and Pregnancy 
The effects of HB-1 on conception, pregnancy, and lactation are unknown. 
Note: According to the information available in the Micardis® (telmisartan) label, telmisartan 
belongs to pregnancy categories C (first trimester) and D (second and third trimesters). When 
pregnancy is detected, discontinue telmisartan as soon as possible, as it can cause fetal harm 
when administered to a pregnant woman. 
According to the information available in Verelan® PM (verapamil hydrochloride) label, 
verapamil belongs to pregnancy category C, there are no adequate and well-controlled studies 
in pregnant women. Verapamil should be used during pregnancy only if the potential benefit 
justifies the potential risk to the fetus. Verapamil crosses the placental barrier and can be 
detected in umbilical vein blood at delivery. 
At Screening, all female patients who are not surgically sterile or postmenopausal must agree to 
use at least 2 acceptable methods of birth control (defined as the use of an IUD, a barrier method 
with spermicide, condoms, or any form of hormonal contraceptives,) for the duration of the study 
and for 4 months after the last dose of study treatment. 
At Screening, all male patients who are not sterile (biologically or surgically) must commit to the 
use of a reliable method of birth control (condoms with spermicide) for the duration of the study 
and for 4 months after the last dose of study treatment.  Male patients should not donate sperm 
for 4 months following the last dose of study treatment. 
Individuals who are involved exclusively in same-sex relationships are exempt from the birth 
control requirements but must agree to abide by the recommendations if they do engage in a 
heterosexual relationship. 
Women who are using oral contraceptives will be monitored for adverse events associated with 
overexposure at each study visit. This should include signs and symptoms of myocardial 
infarction, stroke, and venous thromboembolism. 
 


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7. 
HB-1 MATERIALS AND MANAGEMENT 
The Sponsor plans to develop HB-1 as a single dosage formulation of telmisartan and verapamil 
which will be administered orally once a day (QD) nightly at bedtime (QHS) with or without 
food. The Sponsor plans to dose HB-1 at 96 mg telmisartan and 288 mg verapamil with 
extended-release technology to distribute the components as evenly as possible throughout a 24 
hour day.  The proposed dosages to be used in HB-1 are within FDA-approved PK parameters 
[maximum serum concentration (Cmax) and area under the curve (AUC)] and are based on the 
s 
completed observational study. 
7.1. 
HB-1 
7.1.1. 
Description of HB-1 
HB-1 will be supplied as oval, white to off-white dual active pharmaceutical ingredient (API) 
tablet and will be packaged with 35 tablets per HDPE bottle with 1g of desiccants and a child 
resistant closure. 
Telmisartan 
Generic name:  
 
telmisartan (immediate release) 
Chemical name: 
[1,1`-Biphenyl]-2-caboxylic acid, 4`-[(1,4`-dimethyl-2`-propyl[2,6`-bi-
1H-benzimidazol]-1`-yl) methyl]- 
CAS Registry Number:  144701-48-4 
Formula:   
 
C33H30N4O2 
 
Figure 3: 
Structure of Telmisartan 
 
Molecular Weight:  
 
514.62 
Appearance:   
 
White to slightly yellowish crystalline powder 
Solubility: 
Practically insoluble in water, slightly soluble in methanol, 
sparingly soluble in methylene chloride 


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Verapamil Hydrochloride 
Generic name:  
 
verapamil hydrochloride (extended release) 
Chemical name:  
-[3-[[2-(3,4-dimethoxyphenyl)-
ethyl]methylamino]propyl]-3,4-dimethoxy- -(1-methylethyl), 
monohydrochloride 
CAS Registry Number:  52-53-9 
Formula:  
 
C27H36N204 · HCl 
 
Figure 4: 
Structure of Verapamil Hydrochloride 
 
Molecular weight:  
 
491.07 
Appearance:  
 
An almost white, crystalline powder 
Solubility:  
 
Soluble in water, chloroform, and methanol 
7.1.2. 
Dosage and Administration 
All patients will receive an oral dose of HB-1 or matching placebo once a day (QD) nightly at 
bedtime (QHS) with or without food. HB-1 is a proprietary combination of telmisartan and 
verapamil in a once-daily, extended release formulation. 
7.1.3. 
Storage and Handling 
All study drug must be transported, received, stored, and handled in accordance with the 
container or product label, the instructions supplied to the site and its designated pharmacy 
standard operating procedures (SOPs), and applicable regulations.  
Appropriate storage and transportation conditions will be maintained for study treatment from 
the point of manufacture up to delivery to the clinical sites.  All shipments of study treatment 
will include a temperature monitoring device that records required storage conditions for the 
bottles at regular intervals for the entire time the shipment is in transit. 
Upon receipt by the site, the designated site personnel will examine the shipment and 
temperature monitoring devices to verify the study treatment bottles were received in acceptable 
condition.  If not received in acceptable condition, the site must notify their Clinical Research 
Associate and the site should quarantine the study drug until a decision has been made by 
Honeybrains regarding its use.  Once inspected, bottles should be stored at USP Controlled 
Room Temperature Conditions, 20oC to 250C in a locked, limited access area. 


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7.2. 
Drug Accountability 
The Investigator or designee is responsible for taking an inventory of each shipment of drug 
received and comparing it with the accompanying drug order form. All unused drug will be 
retained at the site.  After full drug accountability and reconciliation, the Investigator will 
dispose of any drug at the clinical trial site per site procedures, or if necessary, all drug will be 
returned to the Sponsor or its designee. Disposition of all drug should be documented, including 
any drug that is lost or damaged. 
7.3. 
Assignment to Treatment 
Once enrolled, each patient will be assigned a unique subject identification number.  This 
ghout 
the study.  Once a subject number is assigned, it cannot be reassigned to any other patient.  All 
patients will either be assigned to receive HB-1 or placebo using a central randomization 
system..  Patients and Investigators will be blinded to the study treatment assignment.  
Study treatment will be dispensed to patients in blinded bottles.  Bottle 1 will be dispensed at 
Visit 2/Week 0; patient will bring it back for accountability at Visit 3/Week 2 and will take it 
back home; patient will return Bottle 1 at Visit 4/Week 4 and will be dispensed Bottle 2 (with 
return of Bottle 2 at Visit 5/Week 8); then Bottle 3 will be dispensed at Visit 5/Week 8 (and 
returned at Visit 6/Week 12). 
7.4. 
Unblinding Procedure 
The study drug blind shall not be broken by the Investigator unless information concerning the 
study drug is necessary for the medical treatment of the subject.  All study assessments and 
assignment of causality for AEs should be performed, if possible, prior to unblinding.  In the 
event of a medical emergency, if possible, the medical monitor should be contacted before the 
study drug blind is broken to discuss the need for unblinding. 
For unblinding a subject, the study drug blind can be broken via the central randomization 
system. 
The sponsor must be notified as soon as possible if the study drug blind is broken.  The date, 
time, and reason the blind is broken must be recorded in the source documents and the same 
information (except the time) must be recorded on the eCRF. 
If any site personnel are unblinded, study drug must be stopped immediately and the subject 
must be withdrawn from the study. 
No change should be made to any prior assessments or data of any subject after unblinding of 
his/her treatment assignment. 


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8. 
SAFETY DATA COLLECTION, RECORDING, AND 
REPORTING 
The Medical Monitor will perform an ongoing blinded review of safety and tolerability and will 
advise on whether it is safe to continue study treatment.  Safety will be assessed through the 
monitoring of TEAEs, clinical laboratory assessments, ECG, Columbia Suicide Severity Rating 
Scale (C-SSRS) (Oquendo MA 2003), and orthostatic vital signs. 
8.1. 
Adverse Events  
8.1.1. 
Definition of an Adverse Event (AE) 
An AE is defined as any untoward medical occurrence associated with the use of a drug, or with 
study participation, whether or not consider related to study 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 the medicinal 
product, whether or not considered related to the medicinal product.  
AEs include worsening of a pre-existing medical condition as well as clinically significant 
changes from baseline laboratory values/conditions.  Worsening of the preexisting medical 
condition (eg, diabetes, hypertension) means that it has increased in severity, frequency, and/or 
duration, and/or has an association with a significantly worse outcome.  A pre-existing condition 
that has not worsened during the study is not considered an AE. 
8.1.2. 
Definition of Treatment Emergent Adverse Event (TEAE) 
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to the 
initiation of the drug treatment or any event already present that worsens in either intensity or 
frequency following exposure to the drug treatment. 
8.1.3. 
Definition of Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 Is immediately life-threatening 
 Requires inpatient hospitalization or prolongation of existing hospitalization.  
- 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the ICF (as documented as 
medical history on the eCRF) is not considered an SAE 
- 
Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience, is not considered an SAE 
 Results in persistent or significant disability/incapacity 
 Results in congenital anomaly/birth defect 
 Is considered an important medical event 


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- 
If an AE does not meet one of the serious criteria, but the Investigator or Sponsor 
considers an event to be clinically important, the event could be classified as an SAE 
 
8.2. 
Procedures for Recording and Reporting Adverse Events 
8.2.1. 
Recording Adverse Events 
Patients will be instructed to report all AEs and will be asked a general health status question at 
each study visit.  All AEs and SAEs occurring in patients will be recorded in the eCRF from 
Visit 2/Week 0 through the Saftey Follow-up Visit after the last dose of drug.  An AE will be 
followed until it is either resolved, has returned to baseline, or is determined to be a stable or 
chronic condition.  All SAEs will be processed as outlined in Section 8.2.2. 
At each required visit during the trial, all AEs that have occurred since the previous visit must be 
reviewed by the Investigator.  The Investigator must determine if the AE is serious or 
non-serious. 
The Investigator must assign the following AE attributes: 
 AE diagnosis or syndrome(s) if known 
 If not known at time of the report, record the signs and/or symptoms as AEs and 
provide an updated report with diagnosis when obtained 
 Dates of onset and resolution 
 Severity as defined per protocol 
 Assessment of relatedness to drug 
 Action taken with drug as a result of the AE 
In general, an AE that is the primary cause of subsequent events should be identified by the 
primary cause (eg, for dehydration due to diarrhea, the AE would be diarrhea).  However, AEs 
occurring secondary to an initiating event that are separated in time should be recorded as 
independent events (eg, sepsis secondary to pneumonia, both events should be recorded). 
8.2.1.1. 
Relationship to Study Treatment 
The Investigator must assess whether the AE may be related to study drug or study mandated 
procedure, when applicable. The relationship is defined below: 
 
 None: The event is related to an etiology other than the study product administration (the 
alternative etiology must be documented in the study 
medical record). 
 Remote: The event is unlikely to be related to the study product and likely to be related to 
factors other than study product. 
 
 Possible: There is an association between the event and the administration of drug, and 
there is a plausible mechanism for the event to be related to the study product; but there 


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may also be alternative etiology, such as characteristics of the 
clinical status or 
underlying disease. 
 Probable: There is an association between the event and the administration of drug, there 
is a plausible mechanism for the event to be related to the study product, and the event 
could not be reasonably explained by known characteristics of the 
clinical status 
or an alternative etiology is not apparent. 
 Definite: There is an association between the event and the administration of drug, there is 
a plausible mechanism for the event to be related to the study product and causes other 
than drug have been ruled out and/or the event re-appeared on re-exposure to drug. 
8.2.1.2. 
Adverse Event Severity 
The Investigator will assess the Grade of the AE using the criteria below:  
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
 Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL) 
 Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL 
 Grade 4: Life-threatening consequences; urgent intervention indicated 
 Grade 5: Death related to AE 
Note: it is important to distinguish between SAEs and severe AEs. Severity is a measure of 
intensity, whereas seriousness is classified by the criteria based on the regulatory definitions as 
described in Section 8.1.3 above. 
8.2.2. 
Reporting of Serious Adverse Events 
SAEs will be reported to the sponsor immediately and recorded on the appropriate eCRF and 
SAE Report Form within 24 hours of the Investigator
experience does not appear to be related to drug, from the Visit 2/Week 0 through the Safety 
Follow-up visit after the last dose of study drug. 
The initial SAE eCRF must be as complete as possible, including details of the current illness 
and SAE, and an assessment of the relationship between the event and drug.  Additional 
information relating to a previously reported SAE must also be reported within 24 hours of the 
Investigator
 The Investigator may also be asked, by the 
Sponsor or designee, to provide clarifications or additional information. 
8.2.2.1. 
Reporting of Serious Adverse Events to Regulatory Authorities and Institutional 
Review Board 
The Sponsor or designee will determine expectedness of 
 product for each reported 
SAE based on the appropriate reference safety information per local requirements.  The Sponsor 


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or designee shall notify regulatory authorities of serious, unexpected, and related AEs or other 
AEs, per local requirements.  
The Sponsor or designee shall notify the Investigator of serious, related, and unexpected AE(s) 
submitted to the regulatory agencies, per local country requirements.  
The Investigator will notify the appropriate IRB of serious, related, and unexpected AE(s), or 
significant risks to patients, per local country requirements.  The Investigator must keep copies 
of all AE information on file, including correspondence with the Sponsor or IRBs. 


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9. 
STATISTICAL METHODS 
9.1. 
General Considerations 
This is a multicenter, randomized, double-blind placebo-controlled trial. All patients will be 
randomized in a 1:1 ratio to receive an oral dose of HB-1 or matching placebo once a day.  Study 
data will be provided in listings and sorted by patient number, study period, and assessment time.  
The study results will be displayed using descriptive summary tables and inferential analyses 
completed as described below.  Summaries will be displayed by treatment group for all tables.  
For measurements that have multiple intermediate visits, results for observed data will be 
summarized for each time point. 
Standard numeric descriptive statistics include number of patients or records observed (N), 
mean, standard deviation (std), median, minimum (min), and maximum (max) values. Standard 
categorical descriptive statistics include the count and percentages of patients with a level of the 
variable summarized.  Hypothesis tests will assess the null hypothesis that there is no difference 
between HB-1 and placebo treatment arms.  Testing will be done at the 0.05 alpha-level.  Any 
confidence intervals provided will be at 95% confidence. 
All summaries, statistical analyses, and individual patient data listings described below will be 
completed using Version 9.4 or later of the SAS Statistical Analysis System (SAS Institute, Inc. 
Cary, NC). 
Additional details regarding estimands, including handling of intercurrent events will be 
provided in a separate statistical analysis plan (SAP) to be finalized prior to completion of the 
study and unblinding. 
Determination of Sample Size 
A sample size of 80 patients is planned for the study to be randomized in a 1:1 ratio of active to 
control.   
Assuming a standard deviation of 4.5 in the PDSS, 80 patients will provide for in excess of 95% 
power to detect a difference in the mean change (from baseline) in the PDSS score of 3.75 at an 
alpha-level of 0.05 at 12 weeks. This corresponds to a 50% reduction in mean PDSS scores on 
HB-1 and a 25% reduction in mean PDSS scores on placebo, assuming baseline mean PDSS 
scores of 15 for both groups. 
In addition, with respect to adverse events, the study has approximately 95% power to detect at 
least one patient with an event that occurs in 7.2% of patients in either treatment group. 
Analysis Populations 
Analyses will be performed comparing treatment groups for each of the following populations: 
All Patients  all patients who sign informed consent and are assigned a unique patient 
identification number. 
Intent-to-Treat (ITT)  all patients who are successfully randomized to either the HB-1 or control 
treatment groups. This will be the primary population used for efficacy analyses. Patients will be 
analyzed according to randomized treatment group. 


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Safety Population  patients who are randomized and receive at least one dose of study drug.  
This will be the primary population used to summarize all safety data.  Safety summaries will be 
based on the treatment that patients actually receive. 
Handling of Missing Data 
Data may be missing either because an assessment is not completed or if patients have 
withdrawn consent from further participation in the study. Additional details for handling 
missing data will be dependent on the extent of missing data and will be specified in the SAP. 
Adjustments of Multiplicity 
To control for multiplicity of select analyses, a hierarchical approach will be used to test the 
following endpoints in order, each at the 0.05 alpha-level.  These endpoints are 1) PDSS 
(primary efficacy endpoint), 2) mean number of panic attacks, 3) CGI-S.  Irrespective, of the 
significance of these specific measures, planning for future studies will be based on the totality 
of safety and efficacy data and nominal p-values will be reported for all inferential tests.  
Interim Analyses 
Interim analyses are not planned for this study. 
Patient Disposition 
Patient disposition will be summarized for the All Patients population and summarized by 
treatment group and overall for all patients.  The number and percentage of patients who are 
screened, screen-failed, randomized, and completed the treatment period, follow-up period, or 
discontinued the study (including reasons for discontinuation) will be presented. 
Demographics and Baseline Characteristics 
Demographics information will be summarized using descriptive statistics. For gender, race, and 
ethnicity the summarization of those categorical values will be performed using percentages and 
frequency.  Age, height, weight, and BMI will be summarized using descriptive statistics as total 
number of patient observed (n), mean, median, minimum, and maximum.  Listings and 
summaries of demographics, baseline characteristics, and medical history, will be summarized 
by treatment group for the Safety population. 
Extent of Exposure to Study Medications and Treatment Compliance 
All patients will receive an oral dose of HB-1 or matching placebo once a day for a total of 
12 weeks.  One (1) bottle will be dispensed to the patient at Visits 2, 4 and 5.  Study drug 
accountability will be performed at Visits 3  6 and study drug bottles will be returned at Visits 
4-6. 
Drug exposure and compliance will be summarized by treatment for the safety population. Drug 
exposure (in days) will be calculated as: last dose date - first dose date + 1.  Exposure will be 
summarized as a continuous variable for the treatment period.  Percent compliance will be 
calculated by visit and overall for the treatment period.  Compliance will be summarized as a 
continuous variable. 
 


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Prior and Concomitant Therapies
All patients with Panic Disorder, with or without co-morbidities will be eligible, as long as they 
are stable on their current psychiatric medications for at least three months as determined by 
Investigator and are willing to remain on current doses of other psychiatric medications 
throughout the length of the trial.  Concomitant medications will be summarized categorically by 
treatment group for the safety population by visit and overall for the treatment period. 
Efficacy and Exploratory Analyses 
All efficacy and exploratory analyses shall be conducted by treatment group on the ITT 
population.  These endpoints are based on measurement scales collected over the visits of the 
study.  Each of the scales may have domains or subdomains.   
A mixed model repeated measures (MMRM) approach, with fixed effects for treatment, visit, the 
treatment-by-visit interaction, baseline, baseline-by-visit, will be used to analyze continuous 
endpoints.  The outcome is the change from baseline to each on-treatment time point. All 
protocol-scheduled time points will be included in the model. The model will use the 
unstructured or Toeplitz (whichever has a better fit by AICC value) within-subject variance-
covariance matrix. The denominator degrees of freedom will be according to the method of 
Kenward-Roger.  The estimated least square (LS) means and their standard errors as well as the 
estimated treatment effect (differences between treatments at each time point) will be 
summarized by treatment. In addition, the 95% confidence intervals of the LS means and the 
difference between treatments, p-values for treatment comparisons will be provided. For 
endpoints without a baseline measurement, baseline and the visit-by-baseline interaction will be 
omitted from the model. The primary analysis timepoint will be at 12 weeks.  
Efficacy Endpoint Analyses 
Scales of interest Panic Disorder are the: 
 Panic Disorder Symptom Severity Scale (PDSS) (Furukawa TA. 2009) 
 Number of panic attacks 
 Clinical Global Impression-Severity Scale (CGI-S) (Guy W. 1976) 
 Quality of Life Enjoyment and Satisfaction Questionaire Short Form (Q-LES-Q-SF) 
(Endicott J. 1993) 
 Self-Reported Leibowitz Anxiety Scale (LSAS) (Heimberg R. 1999, Baker S. 2002) 
 Assessment of Overall Sleep Quality
Question #6 from the Pittsburgh Sleep Quality 
Index (Buysse DJ. 1989) 


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Exploratory Endpoint Analyses
The objective of all exploratory endpoints is to compare the effectiveness of HB-1 versus 
placebo on common neuropsychiatric comorbidities.  Analyses will be conducted in the same 
manner as efficacy endpoints.  The questionnaires which will be used for exploratory endpoints 
include: 
 Toronto Alexithymia Scale (TAS-20) (Bagby RM. 2020) 
 
 Hamilton Anxiety Rating Scale (HAM-A) (Bech P. 1990) 
 Montgomery-Asberg Depression Rating Scale (MADRS) (Fantino B., Moore N. 2009) 
only for patients with a medical history of depression 
 
 CogScreen Symbol Digit Coding test (SDC)  (Kay G. 1995) 
 
) (Walls B. 2017) only for patients with a 
medical history of ADHD 
 The PTSD Checklist for DSM-5 (Short Form McGill Pain Questionnaire (SF-MPQ) 
(Blake D. 1995, Blevins C. 2015) only for patients with a medical history of PTSD 
 Migraine Disability Assessment Questionnaire (MIDAS) (Lipton R. 2001) only for 
patients with a medical history of migraine 
 Short Form McGill Pain Questionnaire (SF-MPQ) (Melzack R. 1987) only for patients 
with a history of chronic pain. 
Safety Analyses 
Safety endpoints include TEAEs, clinical laboratory abnormalities, changes in ECG, and 
orthostatic vital signs between treatment groups.  C-SSRS (Oquendo MA 2003) results will be 
provided in a listing.  All summaries of safety and tolerability will be performed on data from the 
safety population using descriptive statistics only unless otherwise specified. 
Adverse Events 
All adverse events will be summarized descriptively by group without comparison between the 
groups.  An overall summary of aderse events should be provided to the show the the number 
and percentage of patients with at least one TEAEs, at least one serious TEAEs, at least one drug 
related event, and at least one serious drug-related event.  The total number of each event type 
will also be summarized along the severity and relatedness distribution of all events. 
Summaries of the number and percentage of patients in the safety population with at least one 
adverse event, classified according to preferred term and/or body system using the current 
version of the Medical Dictionary for Regulatory Activities (MedDRA) will be provided for the 
following types of AEs: 
 TEAEs 
 Drug Related TEAEs 
 SAEs 


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 Drug Related SAEs 
 AEs by severity (mild, moderate, severe, life-threatening, death) 
 AEs by relationship (not related, remote, possible, probable, definite) 
Clinical Laboratory Evaluations 
Clinical laboratory results will be collected at screening and at each visit specified in the 
Schedule of Assessments table.  Clinical laboratory test results for pregnancy, comprehensive 
metabolid panel, complete blood count, and urinalysis, will be summarized by treatment group 
and presented in tabular and graphic formats where appropriate.  Descriptive summaries of the 
change from baseline calculations will be provided along with 95% CIs for the mean change 
from baseline within each group will be provided, but no formal statistical tests are planned 
between treatment groups.  Any abnormal finding or clinically significant changes will be 
captured as AEs. 
Vital Signs and ECGs 
Vital signs check and ECGs will be performed at the time points specified in the Schedule of 
Assessments.  Vital signs parameters (including blood pressure and pulse rate after 3 minutes of 
lying flat in a supine position; followed by blood pressure and pulse rate after standing for 
3 minutes) and ECG results will be summarized by treatment group and presented in tabular and 
graphic formats where appropriate.  Descriptive summaries of the change from baseline 
calculations will be provided along with 95% CIs for the mean change from baseline to detect 
potentially significant changes in vital sign values or ECG results.  ECG abnormalities will be 
summarized by timepoint and for post-baseline assessments, the number and percentage of 
patients with new abnormalities will be summarized. 
Physical Examinations 
Physical examination findings will be listed for each patient at each assessment time point as 
specified in the Schedule of Assessments.  Any abnormal change from the initial screening 
physical examination must be assessed by the investigator as not clinically significant or 
clinically significant and recorded in the source document and eCRF.  Clinically significant new 
findings and adverse changes in physical examination findings will be captured as AEs or 
pretreatment events.  Body systems which will be inspected for physical examinaions include: 
head, eyes; ears, nose, throat; cardiovascular system; respiratory system; musculoskeletal 
system; neurological exam; skin; lymph nodes. 


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10. 
STUDY ADMINISTRATION 
10.1. 
Good Clinical Practice Statement 
This study is to be performed in accordance with the protocol, the Declaration of Helsinki, the 
International Conference on Harmonisation (ICH) Harmonised Tripartite Guideline for Good 
Clinical Practice (GCP) E6 (R2), and all applicable local laws and regulatory requirements. 
10.2. 
Informed Consent (ICF) 
The Sponsor or designee will provide a sample patient informed consent form (ICF) for 
modification, as appropriate, by the Investigator.  The ICF must include all elements required by 
ICH and GCP and must adhere to the IRB/IEC requirements and the ethical principles that have 
their origin in the Declaration of Helsinki. 
The Investigator or designee will explain the nature of the study, its purpose and associated 
procedures, the expected duration, and the potential risks involved to the patient prior to 
enrollment.  The Investigator or designee will obtain written, informed consent.  The patient will 
have ample time and opportunity to ask questions and will be informed about the right to 
withdraw from the study at any time without any disadvantage and without having to provide a 
reason for this decision.  Following the discussion regarding the study, a patient will be asked if 
they are willing to sign and personally date a statement of informed consent.  Only if the patient 
voluntarily agrees to sign the informed consent statement and has done so, may he/she enter the 
study. A copy of the signed and dated ICF will be provided to the patient.  The original signed 
 
The ICF and any other written information provided to the patients will be revised whenever 
important new information becomes available that may be relevant to the patient
there is an amendment to the protocol which necessitates a change to the content of the patient
informed consent.  The Investigator will inform the patients of changes in a timely manner and 
will ask the patients to confirm continuation of their participation in the study by their signature 
on the revised ICF (if applicable).  Any written ICF and written information must receive the 
approval/favorable opinion of the IRB in advance of use.  Any additional approvals from the 
initial ICF should be forwarded to the Sponsor. 
10.3. 
Patient Confidentiality 
The written ICF will explain that study data will be stored in a database, maintaining 
confidentiality in accordance with national data legislation.  All data processed by the Sponsor or 
its representative(s) will be identified by patient number and study code. 
The written ICF will also explain that for data verification purposes, authorized representatives 
of the Sponsor, a regulatory authority, and an IRB may require direct access to parts of the 
hospital or clinic records relevant to the study that include the patient
 
The Investigator must ensure that the patient
documents submitted to the Sponsor, patients should not be identified by their names, but by 
their assigned patient number and study code.  Documents not for submission to the Sponsor, 
such as signed ICF, should be maintained in strict confidence by the Investigator. 


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10.4. 
Institutional Review Board Requirements 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an institutional review board (IRB) at each clinical trial site.  The 
Principal Investigator must submit written approval from the IRB to the Sponsor before he or she 
can enroll any patient into the study. 
The Principal Investigator is responsible for informing the IRB of any amendment to the 
protocol.  In addition, the IRB must approve all advertising used to recruit patients for the study.  
The protocol must be re-approved by the IRB annually or as required by the IRB, regulations, 
and guidelines. 
Progress reports and notifications of SAEs will be provided to the IRB according to regulations 
and guidelines. 
10.5. 
Case Report Forms and Source Documentation 
eCRFs will be provided for the recording of all data.  The Principal Investigator or designee will 
record data from all observations, tests, and assessments specified in the protocol on the eCRFs 
provided by the Sponsor. 
As used in this protocol, the term CRF should be understood to refer to either a paper form or an 
electronic data record or both, depending on the data collection method used in this study. 
A CRF is required and should be completed for each included subject.  The completed original 
CRFs are the sole property of Honeybrains and should not be made available in any form to third 
parties without written permission from Honeybrains. 
The Investigator has ultimate responsibility for the collection and reporting of all clinical, safety 
and laboratory data entered on the CRFs and any other data collection forms (source documents) 
and ensuring that they are accurate, authentic / original, attributable, complete, consistent, 
legible, timely (contemporaneous), enduring and available when required.  The CRFs must be 
signed by the investigator or by an authorized staff member to attest that the data contained on 
the CRFs is true.  Any corrections to entries made in the CRFs, and /or source documents must 
be dated, initialed and explained (if necessary) and should not obscure the original entry.  
In most cases, the source documents are the hospital's or the physician's subject chart. In these 
cases, data collected on the CRFs must match the data in those charts.  In some cases, the CRF, 
or part of the CRF, may also serve as source documents.  In these cases, a document should be 
, as well as at Honeybrains and clearly identify those data that 
will be recorded in the CRF, and for which the CRF will stand as the source document. 
10.6. 
Sponsor Monitoring 
Before the first patient signs consent to participate in the study, a representative of the Sponsor 
will perform a qualification visit (either in person or remotely) to: 
 Determine the adequacy of the facilities 
 Discuss with the Investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to the protocol and the responsibilities of the Sponsor 


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 Confirm that the Investigator(s) (and other personnel involved with the study) have 
not invoked sanctions or demonstrated any scientific misconduct or fraud 
During the conduct of the study, a representative of the Sponsor will have regular contact with 
the clinical trial site, and have regular visits (either in person or remotely) with the clinical site 
to: 
 Provide information and support the Investigator 
 Confirm that the facilities remain acceptable 
 Confirm that the study team is adhering to the protocol, data are being accurately 
recorded in the eCRFs, and the study drug is being properly maintained and 
accountability records are current 
 Perform source data verification with access to all original clinical records for each 
patient 
10.7. 
Quality Assurance 
In compliance with GCP and regulatory requirements, the Sponsor, a third party on behalf of the 
Sponsor, regulatory agencies or IRB may conduct quality assurance audits at any time during or 
following a study.  The Investigator must agree to allow auditors direct access to all study-related 
documents, including source documents, and must agree to allocate his or her time and the time 
of his or her study staff to the auditors in order to discuss findings and issues. 
10.8. 
Study or Clinical Site Termination 
The Sponsor, or designee, reserves the right to terminate the study or a clinical trial site at any 
time.  Conditions that may warrant termination of the study include, but are not limited to: 
 The discovery of an unexpected, serious, or unacceptable risk to patients enrolled in 
the study 
 The decision on the part of the Sponsor to suspend or discontinue testing the study 
treatment 
 Failure of the Investigator to comply with GCP 
 Submission of knowingly false information from the clinical trial site to the Sponsor 
or regulatory authorities 
 Insufficient adherence to protocol requirements 
If terminating the study, the Sponsor and the Investigator(s) will assure that adequate 
consideration is given to the protection of the patient
 
10.9. 
Records Retention 
All correspondence related to this clinical study should be kept in appropriate study files. 
Records of patients, source documents, eCRFs, drug inventory, IRB, and Sponsor 
correspondence pertaining to this study must be kept on file.  All study documents must be kept 
secured for a period of 2 years after a marketing application is approved for drug, or until 2 years 


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after shipment and delivery of the drug for investigational use is discontinued or as long as 
required by local regulations, whichever is longer.  There may be other circumstances for which 
the Sponsor is required to maintain study records and, therefore, the Sponsor should be contacted 
prior to removing or relocating study records for any reason. 
10.10. 
Publications 
Publication by the clinical trial site(s) of any data from this study must be carried out in 
accordance with the Clinical Trial Agreement. 
 
 


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26. Saavedra JM. Angiotensin II AT1 Receptor Blockers Ameliorate Inflammatory Stress: A 
Beneficial Effect for the Treatment of Brain Disorders. Cell Mol Neurobiol. 2012 July ; 
32(5): 667 681. doi:10.1007/s10571-011-9754-6. 
27. Cipriani A, Saunders K, Attenburrow M-J, Stefaniak J, Panchal P, Stockton S, Lane TA, 
Tunbridge EM, Geddes JR, and Harrison PJ. A Systematic Review of Calcium Channel 
Antagonists in Bipolar Disorder and Some Considerations for their Future Development. 
Molecular Psychiatry (2016) 21, 1324-1332. 
28. Dobrev D, Milde AS, Andreas K, and Ravens U. The Effects of Verapamil and Diltiazem 
on N-, P- and Q-type Calcium Channels Mediating Dopamine Release in rat Striatum. 
British Journal of Pharmacology (1999) 127, 576-582. 
29. van Assema DM, Lubberink M, Bauer M, van der Flier WM, Schuit RC, Windhorst AD, 
Comans EFI, Hoetjes NJ, Tolboom, N, Langer O, Muller M, Scheltens P, Lammertsma 
AA, and van Berckel BNM. Blood-Brain Barrier P-
Disease. Brain 2012: 135; 181 189. 


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CONFIDENTIAL  
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30. Tfelt-Hansen P, and Tfelt-Hansen J. Verapamil for Cluster Headache. Clinical 
Pharmacology and Possible Mode of Action. Headache 2009;49:117-125. 
31. Fan X, Song X, Zhao M, Jarskog LF, Natarajan R, Shukair N, Freudenreich O, 
Henderson DC, and Goff DC. The Effect of Adjunctive Telmisartan Treatment on 
Psychopathology and Cognition in Patients with Schizophrenia. Acta Psychiatr Scand. 
2017 November ; 136(5): 465 472. doi:10.1111/acps.12799. 
32. Otto MW, Tuby KS, Gould RA, McLean RY, Pollack MH. An Effect-Size Analysis of 
the Relative Efficacy and Tolerability of Serotonin Selective Reuptake Inhibitors for 
Panic Disorder. Am J Psychiatry. 2001 Dec;158(12):1989-92. doi: 
10.1176/appi.ajp.158.12.1989. 
33. Edwards RA, Medlicott RW. Advantages and Disadvantages of Benzodiazepine 
Prescription. N Z Med J. 1980 Nov 12;92(671):357-9. 
34. Lea RG, Davis SK, Mahoney B, Qualter P. Does Emotional Intelligence Buffer the 
Effects of Acute Stress? A Systematic Review. Front Psychol. 2019 Apr 17;10:810. doi: 
10.3389/fpsyg.2019.00810. eCollection 2019. 
35. Zheng Z, Gu S, Lei Y, Lu S, Wang W, Li Y, Wang F. Safety Needs Mediate Stressful 
Events Induced Mental Disorders. Neural Plast. 2016;2016:8058093. doi: 
10.1155/2016/8058093. Epub 2016 Sep 21. 
36. Sagar-Ouriaghli I, Lievesley K, Santosh PJ. Propranolol for Treating Emotional, 
Behavioural, Autonomic Dysregulation in Children and Adolescents with Autism 
Spectrum Disorders. Psychopharmacol. 2018 Jun;32(6):641-653. doi: 
10.1177/0269881118756245. Epub 2018 Feb 27.PMID: 29484909. 
37. Keller S, Frishman WH. Neuropsychiatric Effects of Cardiovascular Drug Therapy. 
Cardiol Rev. 2003 Mar-Apr;11(2):73-93. doi: 
10.1097/01.CRD.0000053453.89776.2D.PMID: 12620132. 
38. Katon W. Panic Disorder: Epidemiology, Diagnosis, and Treatment in Primary Care. J 
Clin Psychiatry. 1986 Oct;47 Suppl:21-30.PMID: 3531189 Review. 
39. .Jennings JR, Zanstra Y. Is the Brain the Essential in Hypertension? Neuroimage. 2009 
Sep;47(3):914-21. doi: 10.1016/j.neuroimage.2009.04.072. Epub 2009 May 
4.PMID: 19410005  


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40. Endicott J., Nee J., Harrison W., Blumenthal R. Quality of Life Enjoyment and 
Satisfaction Questionnaire: A New Measure. Psychopharmacol Bull. 1993;29(2):321-
6.PMID: 8290681 
41. Tool 3F: Orthostatic Vital Sign Measurement. Content last reviewed January 2013. 
Agency for Healthcare Research and Quality, Rockville, MD. 
https://www.ahrq.gov/patient-safety/settings/hospital/fall-prevention/toolkit/orthostatic-
vital-sign.html 
42. Bech P. Psychometric developments of the Hamilton scales: the spectrum of depression, 
dysthymia, and anxiety. Psychopharmacol Ser. 1990;9:72-9. doi: 10.1007/978-3-642-
75373-2_9.PMID: 2204923  
43. Kay G. Cogscreen Aeromedical Edition Professional Manual. Psychological Assessment 
Resources, Inc.; Odessa, FL: 1995. 
44. Fantino B., Moore N. The self-reported Montgomery-Asberg Depression Rating Scale is 
a useful evaluative tool in Major Depressive Disorder. BMC Psychiatry. 2009 May 
27;9:26. doi: 10.1186/1471-244X-9-26.PMID: 19473506  
45. American Psychiatric Association (2013). Diagnostic and statistical manual of mental 
disorders, fifth edition (DSM-5).  American Psychiatric Publishing: Washington, DC. 
46. Oquendo M. A., Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility 
and limitations of research instruments. In M.B. First [Ed.] Standardized Evaluation in 
Clinical Practice, pp. 103 -130, 2003. 
47. Buysse D.J., Reynolds C.F., Monk T.H., Berman S.R., & Kupfer D.J. (1989). The 
Pittsburgh Sleep Quality Index (PSQI): A new instrument for psychiatric research and 
practice. Psychiatry Research, 28(2), 193-213. 
48. Cohen E.A., Hassman H.H., Ereshefsky L. et al. Placebo response mitigation with a 
participant-focused psychoeducational procedure: a randomized, single-blind, all placebo 
study in major depressive and psychotic disorders. Neuropsychopharmacol. 46, 844 850 
49. . Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Amorim P, Janavs J, Weiller E, 
Hergueta T, Baker R, Dunbar G: The Mini International Neuropsychiatric Interview 
(M.I.N.I.): The Development and Validation of a Structured Diagnostic Psychiatric 
Interview. J. Clin Psychiatry, 1998;59(suppl 20): 22-33. 
http://www.psychiatrist.com/JCP/article/Pages/1998/v59s20/v59s2005.aspx 


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50. Sheehan, D.V. (1992 - 2016). Mini International Psychiatric Interview, English Version 
7.0.2 for DSM-5. Harm Research Institute. 
 

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN 
Protocol: HB-001 
SAFETY AND EFFICACY OF HB-1 FOR PANIC DISORDER: A MULTICENTER, 
RANDOMIZED, DOUBLE BLINDED, PLACEBO CONTROLLED TRIAL 
 
SPONSOR: 
Honeybrains Biotech 
 
 
515 W 20th St, Ste 4e 
 
 
New York, NY 10011 
 
PRODUCT: 
HB-1 
 
AUTHORS: 
Kavita Gohil, Ph.D., Jeffrey Finman, Ph.D. 
 
DATE:   
08 August 2022 
 
STATUS:  
Version 1.2 
 
 




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SPONSOR COMPANY REPRESENTATIVE  
DOCUMENT REVIEWED AND APPROVED BY: 
SIGNATURE: 
DATE: 
NAME: Alon Seifan, MD, MS 
DEPARTMENT/TITLE: Chief Medical Officer, Honeybrains Biotech 
8/18/2022


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1 TABLE OF CONTENTS 
2 
AMENDMENT HISTORY ............................................................................. 6 
3 
LIST OF ABBREVIATIONS ............................................................................ 7 
4 
INTRODUCTION ....................................................................................... 10 
5 
STUDY OBJECTIVES .................................................................................. 10 
5.1 
Primary Objective ............................................................................................................. 10 
5.2 
Exploratory Objective ....................................................................................................... 10 
6 
STUDY DESIGN ........................................................................................ 10 
6.1 
Duration of Study .............................................................................................................. 10 
6.2 
Number of Participants ..................................................................................................... 10 
6.3 
Design ................................................................................................................................ 10 
6.4 
Study Schema .................................................................................................................... 11 
6.5 
Schedule of Events ............................................................................................................ 12 
6.6 
Treatment ......................................................................................................................... 14 
6.7 
Randomization .................................................................................................................. 14 
6.8 
Assessments ...................................................................................................................... 14 
6.9 
Efficacy .............................................................................................................................. 15 
6.9.1 Primary and Secondary Efficacy Endpoints ...................................................................... 15 
6.9.2 Exploratory Endpoints ....................................................................................................... 15 
6.10 
Safety ................................................................................................................................ 15 
6.10.1 Safety endpoints ............................................................................................................... 15 
6.10.2 Adverse Events .................................................................................................................. 15 
6.10.3 Laboratory Assessments ................................................................................................... 16 
6.11 
Stopping Criteria ............................................................................................................... 16 
7 
STATISTICAL ANALYSES ........................................................................... 17 
7.1 
General Considerations..................................................................................................... 17 
7.2 
Study Day and Visit Window Definitions .......................................................................... 17 
7.3 
Analysis Populations ......................................................................................................... 18 
7.4 
Sample Size Determination ............................................................................................... 18 
7.5 
Treatment Groups ............................................................................................................. 19 
7.6 
Statistical Hypothesis Tests ............................................................................................... 19 
7.7 
Missing Data ...................................................................................................................... 19 
7.8 
Multiplicity Adjustments ................................................................................................... 19 
7.9 
Interim Analysis ................................................................................................................. 20 
7.10 
Endpoints and Estimands .................................................................................................. 20 
7.11 
Efficacy and Exploratory Analyses .................................................................................... 20 
7.11.1 Primary and Secondary Efficacy Endpoints ...................................................................... 20 
7.11.2 Exploratory Endpoints ....................................................................................................... 21 
7.11.3 Subgroup Analyses ............................................................................................................ 21 
7.12 
Safety Analyses ................................................................................................................. 21 
7.12.1 Adverse Events .................................................................................................................. 21 
7.12.2 Clinical Laboratory Evaluations ......................................................................................... 22 


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7.13 
Vital Signs .......................................................................................................................... 22 
7.14 
Electrocardiograms ........................................................................................................... 22 
7.15 
Physical Examinations ....................................................................................................... 22 
8 
CHANGES FROM PROTOCOL .................................................................... 22 
9 
REFERENCES ............................................................................................ 22 
 
 
 


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2 AMENDMENT HISTORY 
Not applicable. 
 
 


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3 LIST OF ABBREVIATIONS 
Abbreviation  
Definition  
ADHD  
Attention Deficit Hyperactivity Disorder  
AE  
Adverse Event  
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
CAARS  
Conners’ Adult ADHD Rating Scale  
CBC 
Complete Blood Count 
CGI-S  
Clinical Global Impression-Severity Scale  
CI 
Confidence Interval 
CMP 
Comprehensive Metabolic Panel 
CS 
Clinically Significant 
C-SSRS  
Columbia Suicide Severity Rating Scale  
CTCAE  
Common Terminology Criteria for Adverse Events  
DBP 
Diastolic Blood Pressure 
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders 5th 
edition  
ECG  
Electrocardiogram  
eCRF  
Electronic Case Report Form  
EOS  
End of Study  
FDA  
Food and Drug Administration  
GCP  
Good Clinical Practice  
GLP  
Good Laboratory Practice  
HAM-A  
Hamilton Anxiety Scale  
ICF  
Informed Consent Form  
ICH  
International Conference on Harmonization  
ITT  
Intent-to-Treat  
LS 
Least Squares 


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Abbreviation  
Definition  
LSAS  
Leibowitz Social Anxiety Scale  
MADRS  
Montgomery-Asberg Depression Rating Scale  
MAR 
Missing at Random 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Affairs 
MIDAS  
Migraine Disability Assessment Questionnaire  
MINI  
Mini International Neuropsychiatric Interview for DSM-5  
MMRM 
Mixed Model Repeated Measures 
MNAR 
Missing Not at Random 
MPV 
Mean Platelet Volume 
NCS 
Not Clinically Significant 
PCRS  
Placebo-Control Reminder Script  
PDSS  
Panic Disorder Symptom Severity Scale  
PE  
Physical Examination  
PI  
Principal Investigator  
PSQI  
Pittsburgh Sleep Quality Index  
PT 
Preferred Term 
PTSD  
Post-Traumatic Stress Disorder  
QD  
Once a Day  
QHS  
Nightly at Bedtime  
Q-LES-Q-SF  
Quality of Life Enjoyment and Satisfaction Scale 
Questionnaire – Short Form  
RDW 
Red Cell Distribution 
SAE  
Serious Adverse Event  
SAP  
Statistical Analysis Plan  
SBP 
Systolic Blood Pressure 
SDC  
CogScreen Symbol Digit Coding  


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Abbreviation  
Definition  
SF-MPQ  
Short Form McGill Pain Questionnaire  
SOC 
System Organ Class 
STD 
Standard Deviation 
TAS-20  
Toronto Alexithymia Scale  
TEAE  
Treatment-Emergent Adverse Event  
TLFs 
Tables, Figures, and Listings 
ULN 
Upper Lower Normal 
WOCBP  
Women of Childbearing Potential  
 
 
 


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4 INTRODUCTION 
This statistical analysis plan (SAP) describes the planned statistical analysis to be conducted for 
the study entitled “Safety and Efficacy of HB-1 for Panic Disorder: A Multicenter, Randomized, 
Double-Blind, Placebo-Controlled Trial” version 4.0, dated 02 December, 2021. Mock shells will 
be produced as a separate working document to facilitate programming of Tables, Figures, and 
Listings (TFLs) according to SAP. The SAP is to be interpreted in conjunction with the protocol. 
5 STUDY OBJECTIVES 
5.1 PRIMARY OBJECTIVE 
To determine the safety and efficacy of HB-1 versus placebo in male and female adult patients 
aged 18 to 60 years, inclusive, with Panic Disorder. 
5.2 EXPLORATORY OBJECTIVE 
To explore the effectiveness of HB-1 on Common Neuropsychiatric Co-Morbidities. 
6 STUDY DESIGN 
6.1 DURATION OF STUDY 
The study will consist of 12-week treatment period and a one-week post- treatment period for 
safety follow-up.  
6.2 NUMBER OF PARTICIPANTS 
Approximately 80 patients with Panic Disorder will be enrolled and randomized (using central 
randomization) in a 1:1 ratio of active treatment to control at approximately 8-10 clinical 
research sites in the United States.  
6.3 DESIGN 
This is a multicenter, randomized, double-blind, placebo-controlled trial. All patients with Panic 
Disorder, with or without specified co-morbidities, who meet all of the inclusion and none of 
the exclusion criteria will be eligible. Patients and researchers will be blinded to their treatment 
group. Approximately 80 patients who meet DSM-5 criteria for the diagnosis of Panic Disorder 
will be recruited at approximately 8-10 clinical research sites.  
HB is a single fixed dose formulation of Verapamil (288 mg) and Telmisartan (96 mg) (extended-
release formula) developed for the treatment of Panic Disorders. Patients meeting all inclusion 
criteria and none of the exclusion criteria, will receive an oral dose of HB-1 or matching placebo 
once a day (QD) nightly at bedtime (QHS) with or without food. Once enrolled, each patient will 
be assigned a unique subject identification number. This number will be recorded on the patient’s 
electronic case report form (eCRF) pages and used to identify the patient throughout the study. 
An Informed Consent Form (ICF) must be signed by prospective patients prior to initiating any 
study-specific procedures. Inclusion and exclusion criteria will be reviewed for each potential 


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patient. Eligibility assessments will include the Mini International Neuropsychiatric Interview for 
DSM-5 (MINI) and Panic Disorder Symptom Severity Scale (PDSS). Eligibility will be documented 
in the electronic case report form (eCRF). Complete medical history will be obtained, including 
demographics, neurological and behavioral health information. At Screening, concomitant 
medications will be recorded with height, weight, and BMI. Physical exams and orthostatic vital 
signs checks will be conducted at the time points specified in the Schedule of Assessments 
(Table 1). A decline of ≥20mm Hg in systolic or ≥10 mm Hg in diastolic blood pressure after 3 
minutes of standing indicates orthostatic hypotension. Clinically significant orthostatic 
hypotension should be treated per standard of care and the Medical Monitor should be 
contacted. 
Any abnormal change from the initial screening physical examination (PE) must be assessed by 
the investigator as not clinically significant (NCS) or clinically significant (CS) and recorded in the 
source document and electronic case report form (eCRF). 
Any clinically significant (CS) change after Visit 2, as determined by the investigator, will be 
recorded as an adverse event (AE) in source documentation and on the AE eCRF. 
At Visit 1/Screening, Visit 4/Week 4, Visit 5/Week 8 and Visit 6/Week 12 a standard 12-lead 
Electrocardiogram (ECG) will be conducted. following an approximate 10-minute rest period in 
all patients and will be interpreted by the Investigator to assess clinical significance. 
A Weber Test will be conducted at Baseline/Visit 2 and Visit 6/Week 12. The Weber Test is a 
test of lateralization of auditory function. Weber Test results will be documented on the eCRF. 
6.4 STUDY SCHEMA 
 


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6.5 SCHEDULE OF EVENTS 
Table 1: 
Schedule of Assessments 
 
Screening  
Baseline 
Treatment Period 
Safety Follow-up 
Procedure or Assessment 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6/ 
EOS Visitk  
Safety Follow-upl 
Study Week 
Week - 1 
Week 0  
Week 2 
Week 4 
Week 8 
Week 12 
Week 13 
Visit Windows 
V2 within 7 days of V1 
+/- 3 days 
Informed Consent  
X 
 
 
 
 
 
 
Medical History and Demographicsa 
X 
 
 
 
 
 
 
Eligibility Assessment  
X 
 
 
 
 
 
 
Number of Panic Attacksb 
X 
X 
X 
X 
X 
X 
 
Columbia Suicide Severity Rating Scalec 
X 
X 
X 
X 
X 
X 
 
Clinical Laboratory Assessmentsd 
X 
X 
X 
 
 
X 
 
Physical Exam 
X 
 
 
X 
X 
X 
 
Height/Weight/BMI 
X 
 
 
 
 
 
 
Urine Pregnancy Teste 
X 
X 
X 
X 
X 
X 
 
Screening Questionnaires (3)f 
X 
 
 
 
 
 
 
Orthostatic Vitalsg 
X 
X 
X 
X 
X 
X 
 
12-Lead ECG  
X 
 
 
X 
X 
X 
 
CogScreen Symbol Digit Coding Test o 
X 
 
 
 
 
 
 
Weber Test 
 
X 
 
 
 
X 
 
Placebo-Control Reminder Script (PCRS)n 
 
 
X 
X 
X 
X 
 
Efficacy Endpoint Questionnaires (5)h 
 
X 
Xm 
X 
X 
X 
 
Exploratory Endpoint Questionnaires (8)i 
 
X 
 
 
 
X 
 
Study Treatment Dispensation/Return/ 
Accountability j 
 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
Adverse Event Monitoring 
 
X 
X 
X 
X 
X 
X 
Safety Follow-up Phone Call 
 
 
 
 
 
 
Xl 


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a  Demographics will include: Age, Sex, Race, Ethnicity, Education, Gender Identity, Lateral Preference Questions, and Parental Education 
b  Number of Panic Attacks. The clinician will ask the patient “How many panic attacks have you had in the last week?” and will confirm the reported panic attack(s) meet DSM-5 
criteria (APA 2013). 
c Columbia Suicide Severity Rating Scale (C-SSRS) (Oquendo MA 2003). At screening, use the Screening/Baseline C-SSRS; at subsequent visits, use the Since Last Visit C-SSRS. 
d  Clinical laboratory assessments will include a comprehensive metabolic panel, CBC including Vitamin B12, urinalysis. 
e  Urine pregnancy test to be administered for women of child-bearing potential (WOCBP) within 7 days prior to Week 0, at Baseline/Week 0, and  at each subsequent study visit 
f  Screening Questionnaires will include: Mini International Neuropsychiatric Interview for DSM-5 (MINI) (Sheehan, DV. 1998; Sheehan, DV. 1992-2016), the Clinical Global 
Impression-Severity Scale (CGI-S) (Guy W. 1976), and the Panic Disorder Symptom Severity Scale (PDSS) (Furukawa TA. 2009). 
g  Orthostatic vital signs should be obtained per Section 6.1.7 in the protocol. 
h  Efficacy Endpoint Questionnaires will include: 
• 
Panic Disorder Symptom Severity Scale (PDSS) (not repeated at Week 0) (Furukawa TA. 2009) 
• 
Clinical Global Impression-Severity Scale (CGI-S) (not repeated at Week 0) (Guy W. 1976) 
• 
Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) (Endicott J. 1993) 
• 
Self-Report Leibowitz Anxiety Scale (LSAS) (Heimberg RG. 1999, Baker SL. 2002) 
• 
Assessment of Overall Sleep Quality -- Question #6 from the Pittsburgh Sleep Quality Index (Buysse DJ. 1989) 
i  Exploratory Endpoint Questionnaires will include: 
• 
Toronto Alexithymia Scale (TAS-20) (Bagby RM. 2020) 
• 
Hamilton Anxiety Rating Scale (HAM-A) (Bech P. 1990) 
• 
CogScreen Symbol Digit Coding test (SDC)  (Kay G. 1995) 
• 
Montgomery-Asberg Depression Rating Scale (MADRS) (Fantino B., Moore N. 2009) only for patients with a medical history of depression 
• 
Conners’ Adult ADHD Rating Scale (CAARS) (Walls BD. 2017) only for patients with a medical history of ADHD 
• 
The PTSD Checklist for DSM-5 (Blake DD. 1995, Blevins CA. 2015) only for patients with a medical history of PTSD 
• 
Short Form McGill Pain Questionnaire (SF-MPQ) (Melzack R. 1987) only for patients with a medical history of chronic pain 
• 
Migraine Disability Assessment Questionnaire (MIDAS) (Lipton RB. 2001) only for patients with a medical history of migraine 
j  Patients will be randomly assigned to either the HB-1 or placebo treatments groups and will be provided with study drug each month while on treatment.  Patients will be 
instructed to take the study drug once a day (QD) nightly at bedtime (QHS) with or without food, at the same time each day with a glass of water. 
k  Patients who discontinue from the study prior to Week 12: End of study visit (EOS) and all EOS assessments should be performed within 7 days following the discontinuation 
from the study. Patients who discontinue study treatment prior to Week 12: Patients may discontinue study treatment and remain in the study. Complete the EOS study visit 
and all EOS assessments within 7 days of study treatment discontinuation. The patient should continue to follow the schedule of assessments through the Safety Follow-Up 
Phone Call with modified assessments at interim visits including Week 12/Visit 6 as follows: 
• 
Number of Panic Attacks 
• 
C-SSRS (Oquendo MA 2003) 
• 
Efficacy Endpoint Questionnaires 
• 
Exploratory Endpoint Questionnaires (when applicable) 
• 
Concomitant Medications 
• 
Adverse Event Monitoring 
l   Safety Follow-up Phone Call is performed approximately 7 days after Visit 6/EOS. 
m  Only the PDSS will be repeated at the Week 2 visit. 
n  Placebo-Control Reminder Script (PCRS) (Cohen, EA. 2021). The PCRS will be administered immediately prior to administering the PDSS at Visits 3-6. 
O  CogScreen Symbol Digit Coding Test (SDC)  (Kay G. 1995); SDC to be done twice at Screening/Visit 1 and no passing score is required. 


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6.6 TREATMENT 
Once enrolled, each patient will be assigned a unique subject identification number. This 
number will be recorded on the patient’s eCRF pages and used to identify the patient 
throughout the study. Once a subject number is assigned, it cannot be reassigned to any other 
patient. 
6.7 RANDOMIZATION 
All patients will either be assigned to receive HB-1 or placebo using a central randomization 
system. Patients and Investigators will be blinded to the study treatment assignment. 
Study treatment will be dispensed to patients in blinded bottles. Bottle 1 will be dispensed at 
Visit 2/Week 0; patient will bring it back for accountability at Visit 3/Week 2 and will take it 
back home; patient will return Bottle 1 at Visit 4/Week 4 and will be dispensed Bottle 2 (with 
return of Bottle 2 at Visit 5/Week 8); then Bottle 3 will be dispensed at Visit 5/Week 8 (and 
returned at Visit 6/Week 12). 
6.8 ASSESSMENTS 
Assessments and questionnaires included are:  
• Mini International Neuropsychiatric Interview for DSM-5 (MINI) at screening 
• Placebo-Control Reminder Script (PCRS) at Visits 3-6 
• Panic Disorder Symptom Severity Scale (PDSS)  
• Number of Panic Attacks at Visits 1-6 
• Assessment of Overall Sleep Quality at Visit 2 and Visits 4-6 
• Columbia Suicide Severity Rating Scale (C-SSRS) at screening and each post screening 
visit including Baseline 
• Clinical Global Impression-Severity Scale (CGI-S)  
• Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF)  
• Leibowitz Social Anxiety Scale (LSAS)  
• Toronto Alexithymia Scale (TAS-20)  
• Hamilton Anxiety Rating Scale (HAM-A)  
• Montgomery-Asberg Depression Rating Scale (MADRS)  
• CogScreen Symbol Digit Coding test (SDC)  
• Conners’ Adult Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale (CAARS)  
• Post-Traumatic Stress Disorder (PTSD) Checklist for DSM-5 
• Short Form McGill Pain Questionnaire (SF-MPQ) 
• Migraine Disability Assessment Questionnaire (MIDAS) 


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6.9 EFFICACY 
6.9.1  PRIMARY AND SECONDARY EFFICACY ENDPOINTS 
• Change in Panic Disorder Symptom Severity Scale (PDSS)- primary efficacy endpoint. 
• Number of panic attacks 
• Change in Clinical Global Impression-Severity Scale (CGI-S)  
• Change in Quality-of-Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-
Q-SF)  
• Change in Leibowitz Social Anxiety Scale (LSAS)  
• Change in Assessment of Overall Sleep Quality -- Question #6 from the Pittsburgh Sleep 
Quality Index  
6.9.2  EXPLORATORY ENDPOINTS 
• Change in Toronto Alexithymia Scale (TAS-20)  
• Change in Hamilton Anxiety Rating Scale (HAM-A)   
• Change in Montgomery-Asberg Depression Rating Scale (MADRS) only for patients with 
a medical history of depression  
• Change in CogScreen Symbol Digit Coding test (SDC)  
• Change in Conners’ Adult ADHD Rating Scale (CAARS) only for patients with a medical 
history of ADHD  
• Change in the PTSD Checklist for DSM-5 only for patients with a medical history of PTSD  
• Change in Short Form McGill Pain Questionnaire (SF-MPQ) only for patients with a 
medical history of chronic pain  
• Change in Migraine Disability Assessment Questionnaire (MIDAS) only for patients with 
a medical history of migraine 
6.10 SAFETY 
6.10.1 SAFETY ENDPOINTS 
Incidence of Treatment Emergent Adverse Events (TEAEs), clinically significant changes in 
clinical laboratory values, changes in electrocardiogram (ECG), and Columbia Suicide Severity 
Rating Scale (C-SSRS), and orthostatic vital signs. 
6.10.2 ADVERSE EVENTS 
All AEs should be captured on the eCRF from Visit 2/Week 0 through the Safety Follow-up visit. 
Adverse events considered at least possibly related to study treatment should be followed until 
resolution, return to baseline, or deemed chronic or stable. 
All serious adverse events (SAEs) will be immediately reported to the Sponsor from the time of 
Visit 2/Week 0 (dosing) through the Safety Follow-up/End of Study Visit. 


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6.10.3 LABORATORY ASSESSMENTS 
The following laboratory parameters will be measured at the time points specified in the 
Schedule of Assessments and will be analyzed locally:  
• Pregnancy test should be administered for women of child-bearing potential (WOCBP) 
within 7 days prior to Week 0 and then at each subsequent study visit.  
• Comprehensive Metabolic Panel (CMP): albumin, blood urea nitrogen, calcium, carbon 
dioxide, chloride, creatinine, creatinine phosphokinase, glucose, potassium, sodium, 
total bilirubin, total protein, alanine aminotransferase (ALT), alkaline phosphatase (ALP), 
aspartate aminotransferase (AST)  
• Complete Blood Count (CBC): white blood cell count, red blood cell count, hematocrit, 
hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), 
mean corpuscular hemoglobin concentration (MCHC), red cell distribution (RDW), 
platelet count, mean platelet volume (MPV), Vitamin B12  
• Urinalysis: microscopic examination, specific gravity, pH, protein, glucose, ketones, 
blood and urobilinogen  
6.11 STOPPING CRITERIA 
Table 2: 
Subject Specific Stopping Criteria 
Cardiac Disorders 
Hypotension  
• SBP <90 mmHg and DBP <60 mmHg for 
three consecutive readings 10 minutes 
apart  
Orthostatic Hypotension  
• Decline of >20mm Hg in systolic or >10 mm 
Hg in diastolic blood pressure after 3 
minutes of standing.  
New-onset 2nd or 3rd degree AV 
block  
• Grade 1 or higher per CTCAE V5.0*  
Sick sinus syndrome  
• Grade 1 or higher per CTCAE V5.0  
Atrial flutter  
• Grade 1 or higher per CTCAE V5.0  
Atrial fibrillation  
• Grade 1 or higher per CTCAE V5.0  
New-onset bradycardia  
• Resting heart rate below 50  
New-onset tachycardia  
• Resting heart rate above 120  
Onset of angina pectoris 
• Grade 1 or higher per CTCAE V5.0 
Congestive heart failure 
• Grade 1 or higher per CTCAE V5.0 
Pulmonary edema 
• Grade 1 or higher per CTCAE V5.0 
Peripheral edema 
• Grade 1 or higher per CTCAE V5.0 
Pulmonary edema 
• Grade 2 or higher per CTCAE V5.0 


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General Disorders 
Urticaria 
• Grade 2 or higher per CTCAE V5.0 
Hyperkalemia 
• Potassium values that are 2X the ULN for 
the local lab normal refences ranges. 
• Values may be repeated and confirmed. 
Gout exacerbation  
• Hyperuricemia Grade 1 or higher per CTCAE 
V5.0  
• Values may be repeated and confirmed. 
Impaired hepatic function  
• ALT, AST, ALP values that are twice the 
upper or lower limit of local lab normal 
reference range. 
• Values may be repeated and confirmed. 
Impaired renal function  
• Doubling in creatinine value.  
• Values may be repeated and confirmed.  
Thrombocytopenia  
• Platelet count values below 150,000/mL 
• Values may be repeated and confirmed. 
*Common Terminology Criteria for Adverse Events (CTCAE) V5 dated 27Nov2017 
7 STATISTICAL ANALYSES 
7.1 GENERAL CONSIDERATIONS 
All analysis dataset preparations and statistical analyses will be performed using SAS® version 
9.4 or higher. Study data will be provided in listings and sorted by patient number, study 
period, and assessment time. The study results will be displayed using descriptive summary 
tables and inferential analyses completed as described below. Summaries will be displayed by 
treatment group for all tables. For measurements that have multiple intermediate visits, results 
for observed data will be summarized for each time point. 
Standard numeric descriptive statistics include number of patients or records observed, mean, 
standard deviation, median, minimum, and maximum values. Standard categorical descriptive 
statistics include the count and percentages of patients.  
7.2 STUDY DAY AND VISIT WINDOW DEFINITIONS 
The baseline assessment from which to include baseline in the analysis model and for the 
calculation of change scores for all efficacy endpoints is defined as last assessment prior to the 
first dose of study treatment.  
Data obtained during unscheduled and early discontinuation visits will be allocated to the 
scheduled visit corresponding to the visit window in which they fall in as specified in Table 3. 


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Data will be analyzed based on the nominal visits and nominal time points. If the data from the 
nominal visit or time point is missing, data from unscheduled visits or an early discontinuation 
visit for the same nominal visit or time point will be used.  
If multiple visits among unscheduled or early termination assessments fall in the same visit 
window or time point, the non-missing assessment closest to target time point will be selected 
for analysis. If multiple values are the same number of days away from the target study day, 
then the latter value will be used. In the unlikely event an unscheduled or early discontinuation 
visit, associated with a particular visit window, falls either prior to the actual previous nominal 
visit date or after the subsequent nominal visit date, it will not be used. 
The first date on which subject receives study treatment is defined as Study Day 1. Study days 
for other visits will be calculated as follows: 
Before Study Day 1 visit:  
Study Day = date of assessment – date of Study Day 1. 
On or after Study Day 1 visit:  Study Day = date of assessment – date of Study Day 1 + 1. 
The target study days of Visits are summarized below.  
Table 3: 
Time Windows for Assessments (unscheduled and early discontinuation visits) 
7.3 ANALYSIS POPULATIONS 
Analyses will be performed comparing treatment groups for each of the following populations:  
• All Patients – all patients who sign informed consent and are assigned a unique patient 
identification number.  
• Intent-to-Treat (ITT) – all patients who are successfully randomized to either the HB-1 or 
control treatment groups. This will be the primary population used for efficacy analyses. 
Patients will be analyzed according to randomized treatment group. 
• Safety Population – patients who are randomized and receive at least one dose of study 
drug. This will be the primary population used to summarize all safety data. Safety 
summaries will be based on the treatment that patients receive. 
7.4 SAMPLE SIZE DETERMINATION 
Assuming a standard deviation of 4.5 for the PDSS, 80 patients will provide more than 95% 
power to detect a difference in the mean change (from baseline) in the PDSS score of 3.75 at an 
Scheduled Visit 
Number 
Nominal Visit (label) 
Time Window (day) 
Target Time Point 
(day) 
1 
Screening 
≤ -1 
≤ -1 
2 
Visit 2 (Baseline/Day 1) 
1 
1 
3 
Visit 3 (Week 2) 
2 to 21 
14 
4 
Visit 4 (Week 4) 
22 to 42 
28 
5 
Visit 5 (Week 8) 
43 to 70  
56 
6 
Visit 6 (Week 12) 
71 to < Safety Follow-up Visit 
84 


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alpha-level of 0.05 at 12 weeks. This corresponds to a 50% reduction in mean PDSS scores on 
HB-1 and a 25% reduction in mean PDSS scores on placebo, assuming baseline mean PDSS 
scores of 15 for both groups. 
In addition, with respect to adverse events, the study has approximately 95% power to detect 
at least one patient with an event that occurs in 7.2% of patients in either treatment group. 
7.5 TREATMENT GROUPS 
The analyses will be conducted by treatment group: 
• HB-1  
• Placebo 
7.6 STATISTICAL HYPOTHESIS TESTS 
The hypotheses for testing the primary analysis are:  
Ho: μa = μp  vs.  Ha: μa ≠ μp 
where μa is the mean change from baseline to Week 12 in the PDSS for the HB-1 arm and μp is 
the mean change from baseline to week 12 in the placebo arm. 
Testing will be done at the 0.05 alpha-level. Any confidence intervals (CI) provided will be at 
95% confidence. 
7.7 MISSING DATA 
Data may be missing either because an assessment is not completed or if patients have 
withdrawn consent from further participation in the study. To minimize missing data, 
participants who may discontinue treatment, but do not withdraw consent from further 
participation are expected to continue in the study, with primary and key secondary efficacy 
assessments conducted.  
The approach to handling missing data for the primary endpoint and key secondary endpoints is 
dependent upon the extent of missing data and potential reasons for missingness. Therefore, 
prior to database lock, an assessment of missing data will be conducted to determine potential 
reasons for missingness, where missing data will be considered missing not at random (MNAR), 
unless sufficient evidence is available to reasonably conclude the data is missing at random 
(MAR). 
The mixed model analysis is considered valid under a missing at random assumption, however 
alternative approaches such as multiple imputation using within-treatment group imputation, 
control-based imputation and a tipping point analysis with a within-treatment imputation will 
be considered if a sufficient amount of missing data are present and considered potentially 
MNAR.     
7.8 MULTIPLICITY ADJUSTMENTS 
To control for multiplicity of select analyses, Hochberg’s procedure will be used to test the 
protocol designated primary endpoint (PDSS) as well as the key secondary endpoint CGI-S, 


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which are not expected to be negatively correlated. Accordingly, if the largest p-value among 
these two endpoints (at the primary time point) does not exceed 0.05, then both endpoints will 
be considered statistically significant. If the largest p-value exceeds 0.05 and the smallest p-
value does not exceed 0.025, then the endpoint with the smaller p-values will be considered 
statistically significant. This provides control of the familywise error rate at α = 0.05 such that 
either of the 2 endpoints statistically significant according to the above procedure will 
constitute a successful efficacy outcome for the trial. 
Irrespective of the significance of these specific measures, planning for future studies will be 
based on the totality of safety and efficacy data and nominal p-values will be reported for all 
inferential tests. 
7.9 INTERIM ANALYSIS 
Interim analyses are not planned for this study. 
7.10 ENDPOINTS AND ESTIMANDS 
Endpoints are based on measurement scales collected over the visits of the study. Each of the 
scales may have domains or subdomains. The treatment policy strategy is planned for all 
intercurrent events.   
7.11 EFFICACY AND EXPLORATORY ANALYSES 
7.11.1 PRIMARY AND SECONDARY EFFICACY ENDPOINTS 
• Panic Disorder Symptom Severity Scale (PDSS)- primary efficacy endpoint 
• Number of panic attacks – key secondary endpoint 
• Clinical Global Impression-Severity Scale (CGI-S) – key secondary endpoint  
• Quality-of-Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF)  
• Leibowitz Social Anxiety Scale (LSAS)  
• Assessment of Overall Sleep Quality -- Question #6 from the Pittsburgh Sleep Quality 
Index  
The primary analysis of efficacy will be performed using the ITT population. The change from 
baseline to in PDSS will be compared between HB-1 and placebo using Mixed Model Repeated 
Measures (MMRM) model using SAS mixed procedure with repeated measures. The model will 
include the fixed effect of treatment, visit, the treatment-by-visit interaction, baseline, 
baseline-by-visit. The outcome will be the change from baseline to each on-treatment time 
point. All protocol-scheduled time points will be included in the model. The model will use the 
unstructured or Toeplitz (whichever has a better fit by AICC value) within-subject variance-
covariance matrix. The denominator degrees of freedom will be according to the method of 
Kenward-Roger. The estimated least square (LS) means and their standard errors as well as the 
estimated treatment effect (differences between treatments at each time point) will be 
summarized by treatment. In addition, the 95% CIs of the LS means and the difference between 
treatments, p-values for treatment comparisons will be provided. The primary analysis 


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timepoint will be at 12 weeks. Secondary endpoints will be analyzed similarly. For endpoints 
without a baseline measurement, baseline and the visit-by-baseline interaction will be omitted 
from the model. 
7.11.2 EXPLORATORY ENDPOINTS 
Analyses will be conducted in the same manner as for the primary efficacy endpoint. In some 
cases, the analysis population will be restricted to only those patients with the underlying 
condition, as noted (e.g., MADRS, only for patients with a medical history of depression), The 
questionnaires which will be used for exploratory endpoints are referenced in Section 6.9.2. 
Safety endpoints include TEAEs, clinical laboratory abnormalities, changes in ECG, and 
orthostatic vital signs between treatment groups. C-SSRS results will be provided in a listing. All 
summaries of safety and tolerability will be performed on data from the safety population using 
descriptive statistics only unless otherwise specified. 
7.11.3 SUBGROUP ANALYSES 
All efficacy analyses will be repeated for the subgroup of participants not concurrently being 
treated with benzodiazepines prior to enrollment. 
7.12 SAFETY ANALYSES 
7.12.1 ADVERSE EVENTS 
All AEs will be coded to System Organ Class (SOC) and Preferred Term (PT) using the most up-
to-date version of the Medical Dictionary for Regulatory Affairs (MedDRA) at the time of data 
reporting.  
Pre-treatment adverse events are defined as AEs that started after signing the informed 
consent form up to the start of study medication. Pre-treatment AEs will be listed. 
A TEAE is defined as any untoward medical event not present prior to the initiation of the study 
treatment, or any event already present which worsens either in intensity or frequency 
following the exposure to the study treatment. 
Summaries of the number and percentage of patients in the safety population with at least one 
adverse event, classified according to preferred term and/or body system using the current 
version of the MedDRA will be provided for the following types of AEs: 
• TEAEs 
• Drug Related TEAEs 
• SAEs 
• Drug Related SAEs 
• AEs by severity (mild, moderate, severe, life-threatening, death) 
• AEs by relationship (not related, remote, possible, probable, definite) 


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7.12.2 CLINICAL LABORATORY EVALUATIONS 
Clinical laboratory results will be collected at screening and at each visit specified in the 
Schedule of Assessments table. Clinical laboratory test results for pregnancy, comprehensive 
metabolic panel, complete blood count, and urinalysis, will be summarized by treatment group 
and presented descriptively. Descriptive summaries of the change from baseline will be 
provided along with 95% CIs within each group.  
7.13 VITAL SIGNS 
Vital signs check will be performed at the time points specified in the Schedule of Assessments. 
Vital signs parameters (including blood pressure and pulse rate after 3 minutes of lying flat in a 
supine position; followed by blood pressure and pulse rate after standing for 3 minutes) results 
will be summarized by treatment group and presented descriptively. Descriptive summaries of 
the change from baseline calculations will be provided along with 95% CIs for the mean change 
from baseline to detect potentially significant changes in vital sign values.  
7.14 ELECTROCARDIOGRAMS 
ECGs will be performed at the time points specified in the Schedule of Assessments. ECG results 
will be summarized by treatment group and presented in tabular and graphic formats where 
appropriate. ECG abnormalities will be summarized by timepoint and for post-baseline 
assessments, the number and percentage of patients with new abnormalities will be 
summarized. 
7.15 PHYSICAL EXAMINATIONS 
Physical examination findings will be listed for each patient at each assessment time point as 
specified in the Schedule of Assessments. 
8 CHANGES FROM PROTOCOL 
Hochberg’s procedure is now used to control the familywise error rate for the primary endpoint 
and the key secondary endpoints of the number of panic attacks and the CGI-S. In addition, 
subgroup analyses of efficacy endpoints are added for participants who are not receiving 
concomitant benzodiazepines at baseline.  
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