Clinical trial NCT03017508
Conditions: Social Anxiety Disorder Performance Anxiety
Keywords: Cross-over study Riluzole Double-blind study Speech task Social Anxiety Disorder
Sponsor: Yale University
Start date: 2017-01-01; Completion date: 2021-01-29
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The goal of the current proposal is to examine if sublingual riluzole can reduce anxiety in people with social anxiety disorder during a public speaking task.

Detailed description:
The investigators propose conducting a double-blind, placebo controlled crossover study examining the effects of BHV-0223 on public speaking anxiety. Twenty participants with DSM-5 defined social anxiety disorder and clinically significant public speaking anxiety on the Impromptu Speech Task will be enrolled in a challenge study. Participants will be given BHV-0223 (or placebo) under double-blind crossover conditions 1 hour prior to performing each of 2 impromptu speech tasks. The two study days involving BHV-0223 (or placebo) administration and impromptu speech task will be separated by 2 to 10 days to allow for medication washout. There will be a final follow-up visit 2 to 10 days later to perform a complete Physical exam and do follow-up liver function testing and a Complete Blood Count. Our primary outcome will examine BHV-0223's effects (compared to placebo) on self-rated anxiety during the impromptu speech task. The investigators will also collect physiological measures of anxiety, clinician-rated measures of anxiety, and measures of speech performance as secondary outcomes.

Arms: arm 1: Participants will be given one dose of BHV-0223 (sublingual riluzole) 35mg before performing a 10 minute speech task. Participants will then be assessed every hour for the next three hours. There will be 2 to 10 days of washout period between the randomly assigned arms of the study. arm 2: Participants will be given one dose of an identical looking sublingual placebo before performing a 10 minute speech task. Participants will then be assessed every hour for the next three hours. There will be 2 to 10 days of washout period between the randomly assigned arms of the study.
Interventions: intervention 1: BHV-0223 intervention 2: Placebo
Intervention descriptions: intervention 1: 35mg of sublingual riluzole before performing an anxiety provoking speech task. Participants will then be clinically assessed every hour for 3 hours. intervention 2: a sublingual tablet identical to the active drug will be given before performing an anxiety provoking speech task. Participants will then be clinically assessed every hour for three hours.

Protocol documents:
Prot_SAP_000.pdf: 
 
Title Research Project: Double-Blind, Placebo-Controlled, Single-
Dose Crossover Study Examining the Effects of Sublingual 
Riluzole (BHV-0223) on Public Speaking in Social Anxiety 
Disorder 
Principal Investigator: Michael H. Bloch, MD  
HIC# 1605017768 
Date of Approval: 6/28/2017 VALID THROUGH 7/26/2018 
NTC03017508  
 


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YALE UNIVERSITY
HUMAN INVESTIGATION COMMITTEE
Application to Involve Human Subjects in Biomedical Research 
100 FR1 (2015-2)
SECTION I: ADMINISTRATIVE INFORMATION
Title of Research Project:
Double-Blind, Placebo-Controlled, Single-Dose Crossover Study Examining the Effects of Sublingual 
Riluzole (BHV-0223) on Public Speaking in Social Anxiety Disorder
Principal Investigator: Michael Bloch MD, MS
Yale Academic Appointment: Assistant Professor
Department: Yale Child Study Center
Campus Address: 230 S. Frontage Rd. NIHB 205
Campus Phone:
(203)745-9921
Fax:
(203) 737-5104
Pager:
E-mail: Michael.bloch@yale.edu
Protocol Correspondent Name & Address (if different than PI):
Angeli Landeros-Weisenberger
Campus Phone:
(203)785-7683
Fax:
(203)737-5104
E-mail:
Angeli.landeros@yale.edu
Yale Cancer Center CTO Protocol Correspondent Name & Address (if applicable):
Campus Phone:
Fax:
E-mail:
Business Manager:
Campus Phone :
Fax :
E-mail
tment:
Investigator Interests:
Does the principal investigator, or do any research personnel who are responsible for the design, 
conduct or reporting of this project or any of their family members (spouse or dependent child) 
have an incentive or interest, financial or otherwise, that may affect the protection of the human 
subjects involved in this project, the scientific objectivity of the research or its integrity? Note: 
The Principal Investigator (Project Director), upon consideration of the individual’s role and
Faculty Advisor:(required if PI is a student, 
resident, fellow or other trainee)
NA
Campus Address:
Campus Phone:
Fax:
Pager:
E-mail:


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degree of independence in carrying out the work, will determine who is responsible for the 
design, conduct, or reporting of the research.
See Disclosures and Management of Personal Interests in Human Research  
http://www.yale.edu/hrpp/policies/index.html#COI
 Yes
 No
Do you or does anyone on the research team who is determined by you to be responsible for the 
design, conduct or reporting of this research have any patent (sole right to make, use or sell an 
invention) or copyright (exclusive rights to an original work) interests related to this research 
protocol?
 Yes
 No
If yes to either question above, list names of the investigator or responsible person:
The Yale University Principal Investigator, all Yale University co-investigators, and all Yale 
University individuals who are responsible for the design, conduct or reporting of research must 
have a current financial disclosure form on file with the University’s Conflict of Interest Office. 
Yale New Haven Hospital personnel who are listed as co-investigators on a protocol with a Yale 
University Principal Investigator must also have a current financial disclosure form on file with 
the University’s Conflict of Interest Office. If this has not been done, the individual(s) should 
follow this link to the COI Office Website to complete the form: http://www.yale.edu/coi/
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel.  Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol.
SECTION II: GENERAL INFORMATION
1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research. Choose all that apply:
a. Internal Location[s] of the Study:
Magnetic Resonance Research Center
Yale University PET Center
(MR-TAC)
YCCI/Church Street Research Unit (CSRU) 
Yale Cancer Center/Clinical Trials Office (CTO)
YCCI/Hospital Research Unit (HRU)
Yale Cancer Center/Smilow
YCCI/Keck Laboratories
Yale-New Haven Hospital
Yale-New Haven Hospital—Saint Raphael Campus 
Cancer Data Repository/Tumor Registry
Specify Other Yale Location: Yale Child Study Center


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b. External Location[s]:
APT Foundation, Inc.
Haskins Laboratories 
Connecticut Mental Health Center
John B. Pierce Laboratory, Inc.
Clinical Neuroscience Research Unit (CNRU)
Veterans Affairs Hospital, West Haven 
Other Locations, Specify:
International Research Site
(Specify location(s)):
c. Additional Required Documents (check all that apply):
N/A
*YCCI-Scientific and Safety Committee (YCCI-SSC)
Approval Date:
*Pediatric Protocol Review Committee (PPRC)
Approval Date:
*YCC Protocol Review Committee (YRC-PRC)
Approval Date:
*Dept. of Veterans Affairs, West Haven VA HSS
Approval Date:
*Radioactive Drug Research Committee (RDRC)
Approval Date: 
YNHH-Radiation Safety Committee (YNHH-RSC)
Approval Date: 
Yale University RSC (YU-RSC)
Approval Date: 
Magnetic Resonance Research Center PRC (MRRC-PRC)     Approval Date:
*Nursing Research Committee
Approval Date:
YSM/YNHH Cancer Data Repository (CaDR)
Approval Date: 
Dept. of Lab Medicine request for services or specimens form
Imaging on YNHH Diagnostic Radiology equipment request form (YDRCTO request) found 
at http://radiology.yale.edu/research/ClinTrials.aspx)
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements.
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities. Two years.
3. Research Type/Phase: (Check all that apply)
a. Study Type
Single Center Study 
Multi-Center Study
Does the Yale PI serve as the PI of the multi-site study? Yes
No 
Coordinating Center/Data Management
Other:
b. Study Phase
N/A
Pilot
Phase I
Phase II
Phase III
Phase IV 
Other (Specify)
4. Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more than one category may apply to your research protocol. Definitions for the following 
can be found in the instructions section 4c:


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Clinical Research: Patient-Oriented
Clinical Research: Outcomes and 
Clinical Research: Epidemiologic and Behavioral
Health Services 
Translational Research #1 (“Bench-to-Bedside”)
Interdisciplinary Research 
Translational Research #2 (“Bedside-to-Community”)
Community-Based Research
5. Is this study a clinical trial? Yes
No
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of humans 
to one or more health-related interventions to evaluate the effects on health outcomes.” Health-related 
interventions include any intervention used to modify a biomedical or health-related outcome (for 
example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and 
process-of-care changes). Health outcomes include any biomedical or health-related measures 
obtained in patients or participants, including pharmacokinetic measures and adverse events”
If yes, where is it registered?
Clinical Trials.gov registry 
Other (Specify)
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE.
If this study is registered on clinicaltrials.gov, there is new language in the consent form and compound 
authorization that should be used.
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx 
or contact YCCI at 203.785.3482)
6. Does the Clinical Trials Agreement (CTA) require compliance with ICH GCP (E6)? 
Yes
No
7. Will this study have a billable service? A billable service is defined as any service rendered to 
a study subject that, if he/she was not on a study, would normally generate a bill from either 
Yale-New Haven Hospital or Yale Medical Group to the patient or the patient’s insurer. The 
service may or may not be performed by the research staff on your study, but may be provided by 
professionals within either Yale-New Haven Hospital or Yale Medical Group (examples include 
x-rays, MRIs, CT scans, specimens sent to central labs, or specimens sent to pathology). Notes:
1. There is no distinction made whether the service is paid for by the subject or their insurance 
(Standard of Care) or by the study’s funding mechanism (Research Sponsored). 2. This generally 
includes new services or orders placed in EPIC for research subjects.
Yes
No
If answered, “yes”, this study will need to be set up in OnCore, Yale’s clinical research 
management system, for Epic to appropriately route research related charges. Please contact  
oncore.support@yale.edu


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8.. Are there any procedures involved in this protocol that will be performed at YNHH or one of
its affiliated entities?  Yes
No _X 
If Yes, please answer questions a through c and note
instructions below.  If No, proceed to Section III.
a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform?
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure?
c. Will a novel approach using existing equipment be applied?
If you answered “no” to question 8a, or "yes" to question 8b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol.
Please note that if this protocol includes Yale-New Haven Hospital patients, including patients at 
the HRU, the Principal Investigator and any co-investigators who are physicians or mid-level 
practitioners (includes PAs, APRNs, psychologists and speech pathologists) who may have direct 
patient contact with patients on YNHH premises must have medical staff appointment and 
appropriate clinical privileges at YNHH. If you are uncertain whether the study personnel meet 
the criteria, please telephone the Physician Services Department at 203-688-2615. By signing 
this protocol as a PI, you attest that you and any co-investigator who may have patient contact 
has a medical staff appointment and appropriate clinical privileges at YNHH.
SECTION III: FUNDING, RESEARCH TEAM AND TRAINING
1. Funding Source: Indicate all of the funding source(s) for this study. Check all boxes that apply. 
Provide information regarding the external funding source.  This information should include 
identification of the agency/sponsor, the funding mechanism (grant or contract), and whether 
the award is pending or has been awarded. Provide the M/C# and Agency name (if grant- 
funded).  If the funding source associated with a protocol is “pending” at the time of the 
protocol submission to the HIC (as is the case for most NIH submissions), the PI should note 
“Pending” in the appropriate section of the protocol application, provide the M/C# and 
Agency name (if grant-funded) and further note that University (departmental) funds support 
the research (until such time that an award is made).
PI
Title of Grant
Name of Funding Source
Funding
Funding Mechanism
Michael H. 
Bloch, MD MS
Sublingual Riluzole 
for the Social 
Anxiety Disorder
Biohaven Pharmaceuticals
P
Federal
State
Non Profit 
Industry 
Other For
rofit
Other
I
Grant-M#
Contract# 
Contract Pending
Investigator/Department 
nitiated
Sponsor Initiated 
Other, Specify:


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P
Federal
State
Non Profit 
Industry 
Other For
rofit
Other
I
Grant-M#
Contract# 
Contract Pending
Investigator/Department 
nitiated
Sponsor Initiated 
Other, Specify:
P
Federal
State
Non Profit 
Industry 
Other For
rofit
Other
I
Grant-M#
Contract# 
Contract Pending
Investigator/Department 
nitiated
Sponsor Initiated 
Other, Specify:
IRB Review fees are charged for projects funded by Industry or Other For-Profit Sponsors. 
Provide the Name and Address of the Sponsor Representative to whom the invoice should be 
sent.  Note: the PI’s home department will be billed if this information is not provided.
Send IRB Review Fee Invoice To:
Name: Kimberly Gentile VP, Clinical Operations
Company: Biohaven Pharmaceuticals Inc.
Address: 234 Church Street, Suite #304 
New Haven CT 06510
Tel. 860-690-9543
2. Research Team:  List all members of the research team. Indicate under the affiliation column whether 
the investigators or study personnel are part of the Yale faculty or staff, or part of the faculty or staff 
from a collaborating institution, or are not formally affiliated with any institution. ALL members of 
the research team MUST complete Human Subject Protection Training (HSPT) and Health 
Insurance Portability and Accountability Act (HIPAA) Training before they may be listed on the 
protocol. See NOTE below.
Name
Affiliation: Yale/Other 
Institution (Identify)
NetID
Principal Investigator
Michael H Bloch
Yale
Mhb32
Role:Co-Investigator
Christopher Pittenger
Yale
PITT
Role:Co-Investigator
Angeli Landeros-W.
Yale
Al495
Role:Co-Investigator
Jerome Taylor
Jht28
Role: Study Personnel
Baris Olten, MD
Yale
BO222
Role:Study Personnel
Jessica A. Johnson
Yale
Jaj62


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NOTE: The HIC will remove from the protocol any personnel who have not completed required training. 
A personnel protocol amendment will need to be submitted when training is completed.
SECTION IV:
PRINCIPAL INVESTIGATOR/FACULTY ADVISOR/ DEPARTMENT CHAIR AGREEMENT
As the principal investigator of this research project, I certify that:

The information provided in this application is complete and accurate.

I assume full responsibility for the protection of human subjects and the proper conduct of the 
research.

Subject safety will be of paramount concern, and every effort will be made to protect subjects’ 
rights and welfare.

The research will be performed according to ethical principles and in compliance with all federal, 
state and local laws, as well as institutional regulations and policies regarding the protection of 
human subjects.

All members of the research team will be kept apprised of research goals.

I will obtain approval for this research study and any subsequent revisions prior to my initiating the 
study or any change and I will obtain continuing approval of this study prior to the expiration date 
of any approval period.

I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to 
participants.

I am in compliance with the requirements set by the University and qualify to serve as the 
principal investigator of this project or have acquired the appropriate approval from the 
Dean’s Office or Office of the Provost, or the Human Subject Protection Administrator at 
Yale-New Haven Hospital, or have a faculty advisor.

I will identify a qualified successor should I cease my role as principal investigator and facilitate a 
smooth transfer of investigator responsibilities.
PI Name (PRINT) and Signature
Date
As the faculty advisor of this research project, I certify that:

The information provided in this application is complete and accurate.

This project has scientific value and merit and that the student or trainee investigator has the necessary 
resources to complete the project and achieve the aims.

I will train the student investigator in matters of appropriate research compliance, protection of human 
subjects and proper conduct of research.

The research will be performed according to ethical principles and in compliance with all federal, state and 
local laws, as well as institutional regulations and policies regarding the protection of human subjects.

The student investigator will obtain approval for this research study and any subsequent revisions prior to 
initiating the study or revision and will obtain continuing approval prior to the expiration of any approval 
period.

The student investigator will report to the HIC any serious injuries and/or other unanticipated 
problems involving risk to participants.

I am in compliance with the requirements set forth by the University and qualify to serve as
the faculty 
advisor of this project.

I assume all of the roles and responsibilities of a Principal Investigator even though the student may be 
called a PI.
Advisor Name (PRINT) and Signature
Date


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Department Chair’s Assurance Statement
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a 
sponsoring company, patents, licensure) associated with this research project?
Yes (provide a description of that interest in a separate letter addressed to the HIC.) 
No
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and 
the sponsor of the research project, or its competitor or any interest in any intervention and/or method 
tested in the project that might compromise this research project?
Yes (provide a description of that interest in a separate letter addressed to the HIC) 
No
I assure the HIC that the principal investigator and all members of the research team are qualified by 
education, training, licensure and/or experience to assume participation in the conduct of this research 
trial. I also assure that the principal investigator has departmental support and sufficient resources to 
conduct this trial appropriately.
Chair Name (PRINT) and Signature
Date
Department
YNHH Human Subjects Protection Administrator Assurance Statement
Required when the study is conducted solely at YNHH by YNHH health care providers.
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that:

I have read a copy of the protocol and approve it being conducted at YNHH.

I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest.

The principal investigator of this study is qualified to serve as P.I. and has the support of the hospital 
for this research project.
YNHH HSPA Name (PRINT) and Signature
Date


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SECTION V: RESEARCH PLAN
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested. 
The goal of the current proposal is to examine the acute anxiolytic effects of BHV-0223 
on subjects with social anxiety disorder performing an anxiety-provoking speech task.
2. Background: Describe the background information that led to the plan for this project. 
Provide references to support the expectation of obtaining useful scientific data.

Social Anxiety Disorder is common and causes significant impairment.

First-line treatments for Social Anxiety Disorder are only partially effective. 
Many SAD patients experience little or inadequate symptom relief with 
available treatments.

Riluzole is a glutamate modulating agent that would potentially target a new 
mechanism to treat anxiety.

Riluzole has been shown to reduce anxiety in adults Major Depression, 
Generalized Anxiety Disorder and Obsessive Compulsive Disorder.
Social anxiety disorder (SAD) affects approximately 12.1% of all Americans and 
is defined as a “marked and persistent fear of one or more social situations,” causing 
impairment and distress (1).  SAD typically impairs academic achievement, work 
productivity, social relationships, and results in a significantly poorer quality of life(2).
SAD is associated with subsequent development of depression, alcoholism, and 
cardiovascular disease (1-3).
Roughly one-third to one-half of patients with generalized SAD do not experience 
significant clinical benefit from current evidence-based treatments, such as 
pharmacotherapy with selective serotonin reuptake inhibitors (SSRI) or venlafaxine and 
cognitive behavioral therapy (CBT) (4-7). Failure of anxiety relief in patients with SAD is 
a source of substantial morbidity, distress, and decreases in quality of life.
Several pharmacological treatments are utilized on an as-needed basis because 
of their short-term, potent anti-anxiolytic effects. These pharmacological agents include 
benzodiazepines (which target the gamma-aminobutyric acid-A receptor (GABA-A) and 
beta-blockers (beta adrenergic receptor antagonists) (8, 9). Although, benzodiazepines 
are quite effective at reducing anxiety over the short term (10) in specific situations (e.g. 
flying on an airplane), their side-effects and tolerability currently limit their usefulness in 
many situations (e.g. performance or public-speaking anxiety) (8, 9).  Benzodiazepine 
use is associated with impaired short-term concentration, decreased alertness and 
psychomotor impairment (9, 11).  Chronic benzodiazepine use is further associated with 
physiologic dependence, rebound anxiety on discontinuation and, possibly even 
interference with the efficacy of CBT (one of the first-line treatments for anxiety) (9, 11). 
Beta-blockers, on the other hand, are effective at acutely reducing the peripheral 
physical symptoms of anxiety (e.g. heart palpitations, tremors etc.) but have no effect on


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the cognitive or emotional symptoms of anxiety (9, 10, 12-15).  Novel pharmacological 
treatments are needed to improve patient outcomes with SAD, both chronically to 
reduce symptoms and acutely to reduce impairment during situations where symptoms 
are most likely to be impairing (e.g. public speaking or performance anxiety).
Riluzole is a glutamate-modulating agent that is FDA-approved for the treatment 
of amyotrophic lateral sclerosis.  Riluzole has been documented at physiologically 
realistic drug concentrations to (1) inhibit certain voltage-gated sodium channels 
reducing glutamate release and (2) enhance astrocytic uptake of extracellular 
glutamate. Several uncontrolled trials have suggested the efficacy of riluzole for 
reducing anxiety symptoms in adults with Generalized Anxiety Disorder, Obsessive- 
Compulsive Disorder and Major Depression (16-20). An 8-week, open-label, fixed- 
dose, trial of 18 adults with GAD given riluzole (100mg/day) demonstrated a significant 
improvement over time with riluzole treatment (17).  Sixty-seven percent of adults with 
GAD responded to riluzole treatment (defined as a greater than 50% decrease in HAM-
A) and 44% of subjects had a remission of anxiety symptoms after riluzole treatment 
(HAM-A<8) (17).  No double-blind, placebo-controlled trials of riluzole have been 
conducted in the treatment of patients with primary anxiety disorders.  Riluzole is quite 
well tolerated in psychiatric and ALS population, with nausea and sedation being the 
most common side effects. Elevation of liver function tests is a common occurrence with 
chronic riluzole administration and necessitates periodic monitoring but has been 
without clinical consequences in psychiatric trials with riluzole to date.
Biohaven Pharmaceuticals recently developed BHV-0223, which is a sublingual 
form of riluzole, being investigated for the treatment of ALS. BHV-0223 has several 
advantages over the currently available riluzole formulation in that it (1) avoids first-pass 
metabolism, thereby reducing overall drug burden to the liver and (2) has produced 
subjective reports of relaxing effects when administered to healthy subjects.
3. Research Plan: Summarize the study design and research procedures using non-technical 
language that can be readily understood by someone outside the discipline. Be sure to 
distinguish between standard of care vs. research procedures when applicable, and 
include any flowcharts of visits specifying their individual times and lengths. Describe 
the setting in which the research will take place.

We are proposing a crossover trial in which 20 adults with Social Anxiety 
Disorder with the primary outcome being anxiety on the impromptu speech 
task.

Each subject will be given BHV-0223 (or placebo) under double-blind 
conditions 1-hour before performing the impromptu speech task on 2 
separate study days.

There will be a 2 to 10 day washout period between study days.

There will be a final Follow-up visit 2 to 10 days later to do blood work and 
complete physical exam.


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Overview:
We propose conducting a double-blind, placebo controlled crossover study 
examining the effects of BHV-0223 on public speaking anxiety.  Twenty subjects with 
DSM-5 defined social anxiety disorder and clinically significant public speaking anxiety 
on the Impromptu Speech Task will be enrolled in a challenge study.  Subjects will be 
given BHV-0223 (or placebo) under double-blind crossover conditions 1 hour prior to 
performing each of 2 impromptu speech tasks. The two study days involving BHV-0223 
(or placebo) administration and impromptu speech task will be separated by 2 to 10 
days to allow for medication washout. There will be a final follow-up visit 2 to 10 days 
later to perform a complete Physical exam and do follow-up liver function testing and a 
Complete Blood Count. Our primary outcome will examine BHV-0223’s effects 
(compared to placebo) on self-rated anxiety during the impromptu speech task. We will 
also collect physiological measures of anxiety, clinician-rated measures of anxiety, and 
measures of speech performance as secondary outcomes.
Screening:
A baseline screening assessment to determine study eligibility, clinical ratings, 
and physical health will be conducted at least one week prior to the challenge study.
Medical Assessments
During the screening visit, vital signs (BP, HR: supine, standing X 2-3 min), 
physical exam (including a comprehensive exam of the oral cavity see Appendix 1), and 
clinical laboratory tests (i.e. CBC with differential, complete metabolic panel (CMP) 
(including electrolytes, LFTs, BUN, creatinine and glucose), TFTs, urine drug screen, 
and routine urinalysis) will be completed. A pregnancy test will be given to all females of 
childbearing age enrolled in the study prior to participating in the study sessions. We will 
also perform a visual inspection of the mouth cavity to assess local tolerability before 
and 1 hour after administering study medication on each study day (please see 
appendix document for further details).
Psychiatric Assessments
The SCID (Structured Clinical Interview for DSM disorders) on the screening day 
to verify presence of social anxiety disorder and the absence of other psychiatric 
conditions (psychotic disorders, current substance abuse/dependence etc.). The 
Liebowitz Social Anxiety Scale (LSAS) will be administered to determine that public 
speaking anxiety symptoms are significant enough for inclusion in the trial. The LSAS is 
a rating scale that assesses SAD severity (21) and a 5-item subscale rates public 
speaking fear (22). Psychiatric rating scales examining the severity of anxiety (Hamilton 
Anxiety Rating Scale (HAM-A (23)) and depressive symptoms Hamilton Depression 
Rating Scale (HAM-D) (24) will also be administered. Per FDA guidelines, suicidal 
ideation and behavior will be monitored using the C-SSRS(25) at screening and on 
every visit day.
Intervention:


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Subjects will be given BHV-0223 35mg or placebo in a random order as assigned 
through the CMHC pharmacy with a 2 to 10 day separation between task days.
Randomization will be performed by the CMHC pharmacy.  The identity of the 
treatments will be concealed by the use of study drugs that are identical in packaging, 
labeling, schedule of administration and appearance. Placebo and study drug will be 
prepared in a like fashion in the CMHC pharmacy. Unblinding of a specific patient’s 
randomization assignment will only occur during the study in the case of specific patient 
emergencies.
BHV-0223 is a sublingual, oral-disintegrating tablet containing 35mg of riluzole 
drug substance. BHV-0223 35mg tablets have shown bioequivalence to riluzole 50mg 
administered orally (please see PIND 128411 for further details).  The half-life of BHV- 
0223 is just under 8 hours.  Riluzole is a member of the benzothiazole class of 
medications. Chemically, its molecular formula is C 8 H 5 F 3 N 2 OS and its molecular 
weight is 234.2. The efficacy of riluzole in the treatment of ALS was established in two 
well-controlled studies. Patients randomized to treatment with riluzole showed longer 
time to tracheoctomy or death compared to those treated with placebo. The 
recommended dose of riluzole in the treatment of ALS is 50mg taken every 12 hours (at 
least an hour before, or two hours after, a meal to avoid food-related decreases in 
bioavailability). Riluzole’s mechanism of action in the treatment of ALS is unknown but 
thought to be due to its down-modulation of glutamatergic neurotransmission.
The most commonly observed adverse reactions of riluzole, dosed at 
100mg/day, in placebo-controlled trials were asthenia (19.2%), nausea (16.3%), 
dizziness (3.9%), decreased lung function (10.2%), diarrhea (2.9%), abdominal pain 
(5.1%), pneumonia, vomiting (4.2%), vertigo (1.9%), oral paresthesia, anorexia (3.2%), 
and somnolence (1.9%).  In a study with approximately 4,000 patients given riluzole for 
ALS, three cases of neutropenia were reported within the first two months of treatment.
Rarely, jaundice is a side effect as well.  Riluzole has also been found to cause 
elevations in serum aminotransferase even in patients without a history of liver disease. 
Experience with riluzole in 800 patients with ALS demonstrated that approximately 50% 
of riluzole treated patients experienced at least one ALT/SGPT level above the upper 
limit of normal, 8% had elevations >3x upper limit of normal (ULN), and 2% >5x ULN. 
BHV-0223 may have reduced overall drug burden on the liver as the sublingual 
formulation avoids first-pass metabolism.
Subjects will be asked to come back 2 to 10 days after the second task day to 
perform a complete Physical Exam, Visual examination of the oral cavity, Vital signs 
(BP, HR: supine, standing X 2-3 min), Complete Blood count and Liver function test.
Assessments
Impromptu Speech Behavioral Assessment Test
The impromptu speech BAT will be performed 1 hour after the subject receives 
study medication as outlined in the table below (26-28). Participants will be asked to 
speak about pre-determined topics for 10 minutes to a small audience of research staff


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(27). Patients with more severe social anxiety symptoms are often not able to speak for 
the full 10 minutes and have shorter speech lengths when compared to those with less 
severe social anxiety symptoms (26-28).
VAS-anxiety, State-Trait Anxiety Inventory 
and the Self-Statement during Speech Test (SSPS) (28) will be assessed before and 
after the speech. The Local Tolerability Assessment (Appendix 1) will be performed at 
screening, baseline, 1 hour after receiving the study medication and before discharge.
The Table below shows the assessment schedule for participants enrolling in the trial.
Challenge DAY 1
2-10 day 
washout 
period
Challenge DAY 2
2-10 days
Measure
Screening Baseline
0
1h
2h
3h
Baseline
0
1h
2h
3h
Follow 
up visit
Local  Tolerability Assessment
X
X
X
X
X
X
X
Impromptu Speech Task
X
X
VAS-anxiety
X
X
X
X
X
X
X
X
X
X
X
VAS-speech  performance
X
X
SSPS
X
X
X
X
STAI
X
X
X
X
DSST
X
X
X
X
Immediate and Delayed Word Recall
X
X
X
X
Clinicial-rated  VAS-anxiety
X
X
Clinician rated VAS-speech performance
X
X
LSAS
X
X
X
SCID
X
C-SSRS
X
X
X
Physical Exam with Vital signs (BP, HR: 
supine, standing X 2-3 min) and Visual 
exam of the oral cavity
X
X
X
X
X
X
Blood test
X
X
Urine Test
X
X
X
EKG
X
STUDY MEDICATION ADMINISTRATION
X
X
The rating scales utilized in the trial are detailed in the table below.  Ratings will 
be conducted by raters that are blinded to treatment assignment and will not be present 
during medication administration.
RATING SCALES:
1) Visual Analog Scale (VAS) of Anxiety States: The VAS includes scales for 
anxiety, drowsiness, high, irritability, anger, and sadness. These scales are 100 
mm lines marked by participants at a point corresponding to the apparent 
intensity of the feeling state (0=none, to 100=most ever) (29).  We will also use 
clinician-rated visual analogue scales to measure subject anxiety and speech 
performance during the Impromptu Speech Task.
2) Self-Statement During Public Speaking Scale (SSPS): The SSPS is a rating 
scale used to measure cognitions that occurred during a speech (28).
3) State-Trait Anxiety Inventory (STAI): The STAI is a standardized rating scale of 
trait and state anxiety (30).
4) Digit Symbol Substitution Task (DSST): Digit Symbol Substitution Tasks requires 
the subject to match symbols with their corresponding digit. It consists of 9 digit 
symbols matched with their corresponding numerical digit.  Subjects are asked to 
match as many number-symbol pairs within a 90 second time limit. Performance


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of the DSST has been demonstrated to be impaired by acute treatment with 
benzodiazepines (31).
5) Immediate and Delayed Word Recall Test – In this task, a list of 10 words will be 
repeated 3 times to subjects at a pace of 1 word every 2 seconds.  Immediately 
after presentation of the list and 5 minutes later subjects will be asked to recite as 
many of the words as they can from memory.  Performance on this task has been 
demonstrated to be impaired by acute treatment with benzodiazepines (31).
6) Local Tolerability Assessment: Systematized oral cavity inspection checklist 
(Appendix 1).
7) Columbia-Suicide Severity Rating Scale (C-SSRS) – Assessment of suicidal 
ideation and behavior in clinical and research settings(25)
Statistical Analyses
Assuming that there are no ordering or period effects in the trial, we will use a paired 
t-test to compare ratings of anxiety during the impromptu speech task after BHV-0223 
vs. placebo treatment.  Given a sample size of 20 subjects, assuming a one-sided 
α=0.1, we would have 80% power to detect a treatment effect size=0.5 or greater.  As a 
comparison previous studies of benzodiazepines have demonstrated an effect size of at 
least 0.9 on similar speech paradigms (32).  Our primary measure will be the VAS- 
anxiety after the impromptu speech task (BHV-0223 compared to placebo).  As 
additional secondary measures we will collect (1) subject ratings of speech 
performance, self-statements during public speaking (SSPS) and specific anxiety 
symptoms during speech (STAI); (2) clinical ratings of speech performance; (3) duration 
of speech; (4) assessments of cognition – (DSST and 15 word recall) and 5) side- 
effects.
4. Genetic Testing   N/A
A. Describe
i.
the types of future research to be conducted using the materials, specifying if 
immortalization of cell lines, whole exome or genome sequencing, genome wide 
association studies, or animal studies are planned
ii. the plan for the collection of material or the conditions under which material will 
be received
iii. the types of information about the donor/individual contributors that will be 
entered into a database
iv. the methods to uphold confidentiality
B. What are the conditions or procedures for sharing of materials and/or distributing for 
future research projects?
C. Is widespread sharing of materials planned?
D. When and under what conditions will materials be stripped of all identifiers?


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E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers 
that connect them to their materials?
i.
How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)?
F. Describe the provisions for protection of participant privacy
G. Describe the methods for the security of storage and sharing of materials
5. Subject Population: Provide a detailed description of the types of human subjects who will 
be recruited into this study.
20 subjects who meet DSM-5 criteria for Social Anxiety Disorder and have a baseline 
LSAS public speaking subscale score>6 will be recruited through the Yale Child Study 
Center. We have experience recruiting subjects with social anxiety disorder through a 
trial examining the effects of ketamine for social anxiety disorder.
6. Subject classification: Check off all classifications of subjects that will be specifically 
recruited for enrollment in the research project. Will subjects who may require additional 
safeguards or other considerations be enrolled in the study? If so, identify the population of 
subjects requiring special safeguards and provide a justification for their involvement.
Children
Healthy
Fetal material, placenta, or dead fetus 
Non-English Speaking
Prisoners
Economically disadvantaged persons 
Decisionally Impaired
Employees
Pregnant women and/or fetuses
Yale Students
Females of childbearing potential
NOTE: Is this research proposal designed to enroll children who are wards of the state as 
potential subjects?
Yes
No (If yes, see Instructions section VII #4 for further 
requirements)


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7. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or 
exclusion?
PATIENTS WITH SOCIAL ANXIETY DISORDER:
Inclusion Criteria:
1) Male or female (post-menopausal, surgically sterile, or negative pregnancy test at 
screening and agreement to utilize an established birth control, including complete 
abstinence, during the testing period) between the age of 18 and 65 yrs.
2) Meet DSM-5 criteria for social anxiety disorder by structured clinical interview (SCID) 
and have a LSAS public speaking subscale score >6.
3) Stable psychiatric medications. Patients must have had stable doses of all 
psychiatric medications for the month prior to treatment and have been on stable 
doses of SSRI and antidepressants for at least 1 month prior to study enrollment. 
As needed benzodiazepine use will be permitted as long as subjects refrain from 
using benzodiazepines for the 48 hours prior to the study.
4) Medically and neurologically healthy on the basis of physical examination, SMAC-20 
(including LFT’s, TFT’s), VDRL, CBC w/ diff, urinalysis, urine toxicology, EKG, and 
medical history. Individuals with stable medical problems that do not have CNS 
effects or interfere with medications administered (e.g., oral hypoglycemics) may be 
included if their medications have not been adjusted in the month prior to entry;
5) Urine toxicology screen negative for drug of abuse.
6) Able to provide written informed consent according to the Yale Human Investigation 
Committee (HIC) guidelines.


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Exclusion Criteria:
1. Positive pregnancy test
2. Breastfeeding females
3. History of substance abuse disorder (ETOH, cocaine, opiates, PCP) within 
the last 6 months or positive urine toxicology on screening (within the 
previous 6 months).
4. History of pervasive developmental disorder or psychotic disorder by DSM-IV- 
TR criteria.
5. Presence of dentures, braces, piercings at the time of dosing, or any physical 
findings in the mouth or tongue that, in the opinion of the Principal 
Investigator, would be likely to interfere with successful completion of the 
dosing procedure.
6. Subjects with a medical condition that might interfere with the physiological 
absorption and motility (ie, gastric bypass, duodenectomy) or gastric bands.
7. Subjects with any clinically significant abnormality or abnormal laboratory test 
results.
8. Subject has a current diagnosis of viral hepatitis (HBsAG or HVC) or a history 
of liver disease.
9. Subject has significant history of seizure disorder other than a single 
childhood febrile seizure (eg. Epilepsy)
10.Subjects using any drugs known to induce or inhibit CYP 1A2 metabolism 
(examples of inducers: rifampin, carbamazepine, etc.; examples of inhibitors: 
fluvoxamine, ciprofloxacin, fluoroquinolones, etc.) within 30 days prior to the 
first study drug administration.
11.Subject with a history of allergic reactions to riluzole or other related drugs.
12.Subject has a history of anaphylaxis, a documented hypersensitivity reaction, 
or a clinically important reaction to any drug.
13.Subject has received another investigational drug or device within the 30 days 
(90 days for biologics) prior to the first dosing or is currently participating in an 
investigational study involving no drug administration.
14.Subject with clinically significant electrocardiogram (ECG) abnormalities 
(QTcF >450 msec) or vital sign abnormalities (systolic blood pressure lower 
than 90 or over 140 mmHg, diastolic blood pressure lower than 50 or over 90 
mmHg, or heart rate less than 50 or over 100 bpm) at Screening or Baseline 
(Day -1).
15.Any reason which, in the opinion of the Principal Investigator, would prevent 
the subject from participating in the study.
8. How will eligibility be determined, and by whom?
Screening: After an initial telephone contact to rule out obvious exclusions from the 
study protocol, potential participants will be scheduled for a screening visit at the Yale 
Child Study Center. A member of our research team will discuss all aspects of this 
research: its purpose, the procedures that will be performed, any/all risks of the 
procedures, possible benefits, and possible alternative treatments. All patients will also


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be informed that the standard of care for patients with SAD who have failed the first line 
treatments [SSRI, SNRI (or alternative SSRI), and CBT] is a trial of a monoamine 
oxidase inhibitor (MAOI), not Riluzole (National Institute for Health and Care Excellence 
2013). The research team will discuss the inclusion and exclusion criteria for the study. 
If patients are considered eligible according to study criteria and if they agree to enroll in 
the study, they will sign the consent forms and schedule a time to go to the CNRU for 
screening visit 2.
Screening visit 2 will occur on the CNRU (may be done directly after Screening Visit 1 
if convenient for the participant), and medical assessments (physical exam, EKG, blood 
draw, and urinalysis), and a battery of psychiatric rating scales will be performed, as 
indicated in Table1 (excluding the SCID which is done during screening visit 1). We will 
also contact the subject’s primary care provider or treating provider to confirm their 
psychiatric history and SAD diagnosis after receiving a signed release form from the 
subject.
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research.
The risks in this study include:
1) drug side effects of riluzole
2) worsening of symptoms
3) blood sampling
4) ratings
5) unanticipated side effects
Drug side effects
BHV-0223 (riluzole) is a member of the benzothiazole class of medications. 
Chemically, its molecular formula is C 8 H 5 F 3 N 2 OS and its molecular weight is 234.2. 
The efficacy of riluzole in the treatment of ALS was established in two, well-controlled 
studies. Patients randomized to treatment with riluzole showed longer delay to 
tracheostomy or death compared to those treated with placebo. The recommended dose 
of riluzole in the treatment of ALS is 50mg taken every 12 hours (at least an hour before, 
or two hours after, a meal to avoid food-related decreases in bioavailability). Riluzole’s 
mechanism of action in the treatment of ALS is unknown but thought to be due to its 
blockade of glutamatergic neurotransmission.
The most commonly observed adverse reactions of riluzole, dosed at 100mg/day, 
in placebo-controlled trials were asthenia (19.2%), nausea (16.3%), dizziness (3.9%), 
decreased lung function (10.2%), diarrhea (2.9%), abdominal pain (5.1%), pneumonia, 
vomiting (4.2%), vertigo (1.9%), oral paresthesia, anorexia (3.2%), and somnolence 
(1.9%). In a study with approximately 4,000 patients given riluzole for ALS, three cases 
of neutropenia were reported within the first two months of treatment.


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Rarely, jaundice is a side effect as well. Riluzole has also been found to cause 
elevations in serum aminotransferase even in patients without a history of liver disease. 
Experience with riluzole in 800 patients with ALS demonstrated that approximately 50% 
of riluzole treated patients experienced at least one ALT/SGPT level above the upper limit 
of normal, 8% had elevations >3x upper limit of normal (ULN), and 2% >5x ULN.
A single non-ALS patient with epilepsy treated with concomitant carbamazepine 
and Phenobarbital experienced marked, rapid elevations of liver enzyme with jaundice 
four months after starting riluzole that returned to normal seven weeks after treatment 
discontinuation.
Riluzole’s effect on liver functioning warrants monitoring of serum LFT levels every 
month during the first 3 months of treatment, every 3 months during the remainder of the 
first year, and periodically thereafter (PDR). Serum LFT levels should be evaluated more 
frequently in patients who develop elevations. Maximum increases in serum ALT usually 
occurred within 3 months after the start of riluzole therapy and were usually transient 
when <5x ULN. In trials, if ALT levels were <5 x ULN, treatment continued and ALT levels 
usually returned to below 2X ULN within 2-6 months. Treatment in studies was 
discontinued if ALT levels exceeded 5x ULN.
Riluzole is contraindicated in patients with a history of severe hypersensitivity 
reactions to riluzole or any of the tablet components. Riluzole should be prescribed with 
caution in patients with current evidence or history of abnormal liver function. Baseline 
elevations of several LFTs (especially bilirubin) should preclude the use of riluzole. 
Riluzole should be used with caution in elderly patients whose hepatic or renal functions 
may be compromised due to age. Females and Japanese patients may possess a lower 
metabolic capacity to eliminate riluzole compared to males and Caucasian populations. 
BHV-0223 may have reduced overall drug burden on the liver as the sublingual 
formulation avoids first-pass metabolism.
Patients should be instructed to report any febrile illness to their physicians. 
Patients should also be warned about the potential for dizziness, vertigo, or somnolence 
and advised not to drive or operate machinery until they have gained sufficient experience 
on riluzole to gauge whether or not it effects their mental or motor abilities. Patients 
treated with riluzole should be discouraged from drinking excessive amounts of alcohol 
as it may increase the risk of serious hepatotoxicity.
Worsening of symptoms
Since Riluzole or placebo is added to the patients’ current medications, the risk of 
symptoms worsening in this study is not significantly greater in this clinical trial than it 
would be if the patient’s medications were changed as part of standard clinical care. 
Furthermore, the acute effects of study medications should dissipate within 8 hours of 
taking the single dose of medication. The only additional risks in this study are potential 
adverse effects of riluzole.


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Blood sampling
As a result of their participation in these studies, subjects will have more blood drawn 
than would be the case in usual clinical practice. Approximately three (3) tablespoons of 
blood will be drawn during the study. Subjects will be instructed to refrain from donating 
blood or participating in research involving blood donation during the study and for the 8 
weeks following the study. Blood sampling may cause pain, bruising and infection. Some 
subjects may faint during blood sampling.
Ratings and Speech Task
Patients may find the battery of behavioral ratings tedious. Additionally, the subjects 
are likely to find the speech task anxiety provoking. Subjects may (and often do) 
discontinue the speech task at any point if they feel excessively uncomfortable. We have 
used this speech tasks in previous task without significant adverse events.
Unanticipated side effects
Although riluzole is an approved drug for the treatment of ALS, its use in patients with 
SAD might be associated with unforeseen risks such as worsening of existing symptoms 
or emergence of new symptoms. All medications can be associated with allergic 
reactions. Any clinical trial involves risks and side effects that cannot be predicted. 
Subjects will be told of any important new information that might affect their decision to 
continue in the study. In addition, the HIC will be notified regularly of any new information 
about the safety of the study medication.
10. Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized.
Conducting the medication administration under supervision of research staff will 
allow closer monitoring for detecting symptom changes or adverse effects. A 
psychiatrist on site will be always emergently available to subjects participating in the 
study to deal with any unanticipated issues that arise. Records will be maintained 
according to FDA Good Clinical Practice guidelines to insure protection of confidentiality 
and security of records.
Drug Side Effects:
Subjects will be closely monitored for any side effects by a study doctor and research 
assistant throughout the medication challenges. Additionally, subjects will be screened 
using physical exam and laboratory assessments to identify any medical conditions that


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may put subjects at increased risk. All female subjects of child bearing age will be 
tested for pregnancy prior to enrollment and if positive excluded from the study.
Blood Sampling:
Experienced clinical research staff will perform blood draws using good clinical 
technique to minimize associated risks.
Ratings and Speech Tasks:
There is minimal risk associated with the questionnaires, clinical assessments and 
speech task.  Clinical research staff will exercise sensitivity when conducting ratings 
and assessments. A study specific MD will be emergently available on site on testing 
days, should unanticipated issues arise.
11. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make 
the final determination of the risk to subjects.) For more information, see the Instructions, 
page 24.
a.
What is the investigator’s assessment of the overall risk level for subjects 
participating in this study?
b.
If children are involved, what is the investigator’s assessment of the overall risk 
level for the children participating in this study?
c.
Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are 
available here http://www.yale.edu/hrpp/forms-templates/biomedical.html  for
i. Minimal risk
ii. Greater than minimal
Moderate Risk DSMP
1. Personnel responsible for the safety review and its frequency:
The principal investigator will be responsible for monitoring the data, assuring protocol 
compliance, and conducting the safety reviews at the specified frequency which must 
be conducted at a minimum of every 6 months (including when re-approval of the 
protocol is sought).  During the review process, the principal investigator (monitor) will 
evaluate whether the study should continue unchanged, require 
modification/amendment, or close to enrollment. Either the principal investigator or the 
IRB have the authority to stop or suspend the study or require modifications.
2. The risks associated with the current study are deemed moderate for the 
following reasons: (choose those that apply)
1. We do not view the risks associated with the sublingual riluzole as minimal.


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2. Given the now established safety and validity of the current dose of riluzole in our 
prior work, we do not view the proposed studies as high risk.
Although we have assessed the proposed study as one of moderate risk, the potential 
exists for anticipated and/or unanticipated adverse events, serious or otherwise, to 
occur since it is not possible to predict with certainty the absolute risk in any given 
individual or in advance of first-hand experience with the proposed study methods.
Therefore, we provide a plan for monitoring the data and safety of the proposed study 
as follows:
3. Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and 
attributed to the study procedures / design by the principal investigator (Michael H. 
Bloch, MD) according to the following categories:
a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s). 
b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s). 
c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s). 
d.) Unlikely: Adverse event is likely not to be related to the investigational
procedures(s)/agent(s).
e.) Unrelated: Adverse event is clearly not related to investigational 
procedures(s)/agent(s).
4. Plan for Grading Adverse Events:
The following scale will be used in grading the severity of adverse events noted during 
the study:
1. Mild adverse event
2. Moderate adverse event
3. Severe
5. Plan for Determining Seriousness of Adverse Events: 
Serious Adverse Events:
In addition to grading the adverse event, the PI will determine whether the adverse 
event meets the criteria for a Serious Adverse Event (SAE).  An adverse event is 
considered serious if it:
1. is life-threatening OR
2. results in in-patient hospitalization or prolongation of existing hospitalization OR
3. results in persistent or significant disability or incapacity OR
4. results in a congenital anomaly or birth defect OR
5. results in death OR


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6. based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition, OR
7. adversely affects the risk/benefit ratio of the study
An adverse event may be graded as severe but still not meet the criteria for a Serious 
Adverse Event. Similarly, an adverse event may be graded as moderate but still meet 
the criteria for an SAE. It is important for the PI to consider the grade of the event as 
well as its “seriousness” when determining whether reporting to the IRB is necessary.
6. Plan for reporting Reportable Adverse Events and other unanticipated 
problems involving risks to subjects or others to the IRB
The principal investigator will report the following types of events to the IRB: a) adverse 
events that are serious or life-threatening AND unanticipated (or anticipated but 
occurring with a greater frequency than expected) AND possibly, probably or definitely 
related to the drug/device/intervention; and b) other unanticipated problems involving 
risks to subjects or others.
These adverse events or unanticipated problems involving risks to subjects or others 
will be reported to the IRB in accordance with IRB Policy 710, using the appropriate 
forms found on the website.
7. Plan for reporting adverse events to co-investigators on the study, as 
appropriate the protocol’s research monitor(s), and funding and regulatory 
agencies, and regulatory and decision-making bodies.
For the current study, the following individuals, funding, and/or regulatory 
agencies will be notified (choose those that apply):
xAll Co-Investigators listed on the protocol.
xFood and Drug Administration
The principal investigator (Michael H. Bloch, MD) will conduct a review of all adverse 
events upon completion of every study subject. The principal investigator will evaluate 
the frequency and severity of the adverse events and determine if modifications to the 
protocol or consent form are required.
d. For multi-site studies for which the Yale PI serves as the lead investigator: N/A
i. How will adverse events and unanticipated problems involving risks to subjects or 
others be reported, reviewed and managed?


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ii. What provisions are in place for management of interim results?
iii. What will the multi-site process be for protocol modifications?
12. Statistical Considerations: Describe the statistical analyses that support the study design.
Assuming that there are no ordering or period effects in the trial, we will use a paired 
t-test to compare ratings of anxiety during the impromptu speech task after BHV-0223 
vs. placebo treatment.  Given a sample size of 20 subjects, assuming α=0.05, we 
would have 80% power to detect a treatment effect size=0.58 or greater. As a
comparison previous studies of benzodiazepines have demonstrated an effect size of at 
least 0.9 on similar speech paradigms (32).  Our primary measure will be the VAS- 
anxiety after the impromptu speech task (BHV-0223 compared to placebo).  As 
additional secondary measures we will collect (1) subject ratings of speech 
performance, self-statements during public speaking (SSPS) and specific anxiety 
symptoms during speech (STAI); (2) clinical ratings of speech performance; (3) duration 
of speech; (4) assessments of cognition – (DSST and 15 word recall) and 5) side- 
effects.
We additionally take an interim examination of the efficacy data at the trial after 
10 subjects to evaluate the initial side-effects of the compound and to examine initial 
efficacy. We would consider a treatment effect size of less than 0 (BHV-0223 worsen 
anxiety during the impromptu speech task compared to placebo) as a rationale to stop 
the trial early.
SECTION VI: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND
DEVICES
If this section (or one of its parts, A or B) is not applicable, state N/A and delete the rest of the 
section.
A. DRUGS, BIOLOGICS and RADIOTRACERS
1. Identification of Drug, Biologic or Radiotracer: What is (are) the name(s) of the drug(s) 
biologic(s) or radiotracer(s) being used? Identify whether FDA approval has been granted and for 
what indication(s).
BHV-0223 (riluzole) is a member of the benzothiazole class of medications. Chemically, 
its molecular formula is C 8 H 5 F 3 N 2 OS and its molecular weight is 234.2. Riluzole is 
FDA approved for the treatment of amyotrophic lateral sclerosis (ALS). The mode of action of 
this compound is unknown. Its pharmacological properties include the following, some of 
which may be related to its effect: 1) an inhibitory effect on glutamate release, 2) inactivation 
of voltage-dependent sodium channels, and 3) ability to interfere with intracellular events that 
follow transmitter binding at excitatory amino acid receptors.


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All protocols which utilize a drug, biologic or radiotracer not approved by, but regulated by, the FDA, 
or a radiotracer regulated by the RDRC, must provide the following information:
a. What is the Investigational New Drug (IND) number assigned by the FDA? IND # 130224
b. Who holds the IND?  Michael H. Bloch, MD MS
c. All protocols which utilize a radiotracer not approved by, but regulated by the FDA must 
provide the IND number:  
Alternatively, use of the investigational radiotracer may be under RDRC/RSC oversight: (check 
if appropriate) 
For all investigational radiotracers, attach a copy of the RDRC/RSC application (for 
radioisotopes used in the PET Center, PET Center personnel may complete this step)
Go to http://rsc.med.yale.edu/login.asp?url=myApps.asp.  When you have logged in, complete 
the application and attach a copy to this submission.
Alternatively, an exemption from IND filing requirements may be sought for a clinical 
investigation of a drug product that is lawfully marketed in the United States. If there is no IND and 
an exemption is being sought, review the following categories and complete the category that applies 
(and delete the inapplicable categories):
Exempt Category 1
The clinical investigation of a drug product that is lawfully marketed in the United States can be 
exempt from IND regulations if all of the following are yes:
i. The intention of the investigation is NOT to report to the FDA as a well-controlled study in support 
of a new indication for use or to be used to support any other significant change in the labeling for 
the drug.
Yes
No
ii. The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and 
the intention of the investigation is NOT to support a significant change in the advertising for the 
product.
Yes
No
iii. The investigation does NOT involve a route of administration or dosage level or use in populations 
or other factor that significantly increases the risks (or decreases the acceptability of the risks) 
associated with the use of the drug product.
Yes
No
iv. The investigation will be conducted in compliance with the requirements for institutional (HIC) 
review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50 
and 21 CFR Part 56).      Yes       No
v. The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs.
Yes
No
2. Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might 
influence risks. If this is the first time this drug is being administered to humans, include relevant 
data on animal models.
The clinical safety profile of riluzole has been described in the  US Prescribing 
Information on its use in ALS. This safety information is excerpted herein. Additionally,


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literature reports on the use of riluzole in ALS, psychiatric disorders and other 
indications are summarized.
While the majority of this data is based on chronic administration of riluzole 
tablets at a total oral dose of 100 mg/day, the proposed development plan for BHV-0223 
targets a sublingual dose that is approximately 30% lower (70 mg/day) but is expected 
to achieve exposures bioequivalent to that associated with the RILUTEK dose approved 
for use in ALS. The available safety data on chronic administration of riluzole at a total 
daily dose of 50 mg shows a more favorable safety profile than the recommended daily 
dose of 100 mg (i.e., 50 mg PO BID) – particularly with respect to impact on liver 
enzyme tests. Therefore, with a lessened overall drug burden for BHV-0223 (70 mg per 
day) compared to RILUTEK (100 mg per day), safety is expected similar or better for 
BHV-0223 compared to RILUTEK.
Overall, riluzole tablets have been well tolerated in populations with ALS and 
diverse neuropsychiatric conditions that include Major Depressive Disorder (MDD), 
Obsessive- Compulsive Disorder (OCD) and Generalized Anxiety Disorder (GAD). In 
randomized controlled trials (RCTs) comparing a 100 mg daily dose of riluzole with 
placebo, no AEs occurred at rates greater than 5% and twice that of placebo. The AEs 
occurring greater than 5% and at least 2% more than placebo included asthenia (18% 
vs 12% placebo) and nausea (14% vs 9%). These two AEs showed trends for a dose 
response(33).
The published literature on the use of riluzole tablets in psychiatric disorders, 
while generally comprising of case-series, is consistent with this tolerability profile. Lab 
abnormalities associated with riluzole consist of elevated transaminases that typically 
are below 5x upper limit of normal (ULN) and often resolve while on treatment 
(Bensimon and Doble 2004). Experience with incidents of alanine aminotransferase 
(ALT) increasing >5xULN are limited, insofar as the USPI recommends immediate drug 
discontinuation. Effects on transaminases show a dose response (33). Importantly, total 
daily doses of 50 mg were not associated with increased rates of marked ALT 
elevations (>5xULN) compared to placebo (1.3% vs 2.1%, respectively) and such 
occurrences had a later onset than placebo (median 254 vs 219 days). Total daily 
doses of 100 mg and 200 mg had greater rates of marked ALT elevations than placebo 
and the median occurrence was within 60 days.
Experience from Published Reports
The PubMed database was searched for available reports on clinical use of 
riluzole in patients (e.g., case-series, randomized trials). The search strategy included 
crossing riluzole (as a title or abstract word) with either report type (clinical trial) or “trial” 
(abstract). The publications are summarized in Appendix B. The cumulative data are 
consistent with the current USPI and are described in the following sections.
Clinical reports document the use of riluzole in populations with ALS, Huntington 
Disease, Spinal Cord Injury (SCI), ataxias, Fragile X Syndrome, Spinal Muscular 
Atrophy, Multiple Sclerosis, neuropathic pain, Multiple System Atrophy, Parkinson 
Disease and Irritable Bowel Syndrome. With regards to ALS studies that are not 
reflected in the USPI, the Early Access Programme (34) described the open-label 
experience of 7,916 patients with ALS who were prescribed riluzole tablets for an 
average duration of 202 days. Tolerability was consistent with the USPI. The rate of


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ALT increases of > 3xULN and >5xULN was 3.7% and 0.7% respectively – rates that 
were lower than observed in the randomized controlled trials. The lab abnormalities in 
studies on other disorders revealed no novel signals compared to the studies described 
in the USPI; elevations in LFTs were noted. In the study on Huntington Disease (35), 
one subject demonstrated a reversible elevation of
ALT >5xULN after being dosed with 200 mg/day. In the population with acute SCI 
(treated with riluzole within 12 hours of traumatic injury and on a back-drop of other 
common interventions like high-dose steroids), higher reversible elevations in LFTs  
were also observed; however, higher rates of abnormalities were noted prior to 
intervention (9 – 37%) and many of these patients were on medication regimens with 
hepatotoxic potential– thus complicating interpretation of the safety reports from this 
study.
As is suggested from the summary of published data (Appendix B) on the safety 
profile of riluzole to treat not only ALS, but also certain mood, anxiety and behavioral 
conditions, the adverse event profile recorded in these patients does not appear to be 
different either in nature, severity or frequency, to those listed in the currently FDA 
approved USPI for RILUTEK.
Dose Relationship to Safety and Tolerability
Study 301 described in (33) is the only randomized controlled trial that included 
doses of riluzole less than 100 mg/day and, hence, provides data relevant to exposures 
expected for the BHV-0223 program. In this study, 959 patients with ALS were 
randomized to up to 18 months of treatment with either placebo, 50 mg/day riluzole 
(dosed 25 mg PO BID), 100 mg/day riluzole (dosed 50 mg PO BID) and 200 mg/day 
riluzole (dosed 100 mg PO BID). Tolerability as reflected in the most common AEs were 
dose dependent for asthenia, nausea, vomiting, vertigo, somnolence and paresthesias.
Rate of selected AEs by dose
Summary graphic from Bensimon & Doble 2004 (Bensimon and Doble 2004)
Effects on hepatic lab parameters also demonstrate a dose dependent pattern. 
The rate of marked ALT elevations (≥5xULN) were lower in the 50 mg daily dose group 
(1.3%) than the placebo (2.1%), 100 mg daily dose group (3.8%) or 200 mg daily dose 
group (3.3%). Mean time to onset of marked ALT elevation distinguished placebo (219


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days) and the 50 mg daily dose group (255 days) from the 100 mg (51 days) and 200 
mg (42 days) daily dose groups. This pattern suggests a potential threshold 
phenomenon for impact on transaminases.
Dose relationship of rate of ALT effects
Summary graphics from Bensimon & Doble 2004 (36). The left panel indicates the proportion of 
study subjects demonstrating ALT elevations by dose. The right panel indicates the mean time to first 
observation of any ALT ≥ 5xULN.
The USPI provides a warning on Liver Injury for riluzole and proscribes specific 
monitoring of liver chemistries. Lab abnormalities associated with riluzole consist of 
elevated transaminases. These elevations are typically below 5xULN and often resolve 
while on treatment (36). Experience with incidents of ALT increasing >5xULN are 
limited, insofar as the USPI recommends immediate drug discontinuation. A dose- 
response is seen for elevations in transaminases within the available documentation on 
riluzole (33). Total daily doses of 50 mg were not associated with increased rates of 
marked ALT elevations (>5xULN) compared to placebo (1.3% vs 2.1%, respectively) 
and such occurrences had a later onset than placebo (median 254 vs 219 days). Total 
daily doses of 100 mg and 200 mg had greater rates of marked ALT elevations than 
placebo and the median occurrence was within 60 days. This pattern of adverse hepatic 
effects is consistent with observations that drugs associated with doses of at least 50


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mg per day have a significantly greater propensity for liver injury and the associated 
incidents of liver injury are more serious (37).
While few cases of markedly elevated transaminases have been cited in the 
literature in association with elevated total bilirubin (38-40) (as well as the USPI), the 
outcomes in these cases were non-fatal and noted to be readily resolving. Further, 
interpretation of these cases is confounded by limited details and complicating factors. 
For example, the case cited in the USPI involves a subject with epilepsy treated with 
riluzole at doses up to 250 mg/day and who was on multiple concomitant medications 
(e.g., phenobarbital and carbamazepine) and who also had mildly elevated alkaline 
phosphatase and gamma-GT levels at baseline (Details noted in RILUTEK SBA).
In the course of the clinical development program for BHV-0223, the Sponsor 
intends to adhere to laboratory monitoring guidelines for LFTs that are described in the 
USPI for all subjects on chronic dosing. In addition, a complete baseline examination  
will assess predisposition for hepatic illness (e.g., hepatitis serologies, baseline 
abnormalities, concomitant medications, alcohol usage). We would welcome any advice 
that the Review Division would be prepared to offer in regard to additional assessments.
Safety Data from the Phase 1 Study BHV223-101
There were no drug-related SAEs reported in BHV-223-001. Additionally, no 
patients discontinued treatment due to drug-related AEs. BHV-0223 had good mouth 
palatability with expected mild and transient oral paresthesias. The vast majority of 
subjects rated the oral parathesias as mild and not bothersome, with few patients 
considering the numbness to be “somewhat” bothersome. The PI deemed all cases of 
paresthesias as mild. All cases of oral parathesias were transient and resolved. Overall, 
the preliminary results suggest that the SL formulation of riluzole is well tolerated and 
associated with mild, transient and not bothersome oral paresthesias. The Sponsor 
believes that the potential safety benefits on hepatic function, ease of administration for 
patients with dysphagia and potential to avoid the negative food effect associated with 
the generic tablet formulation outweigh any mild and transient oral numbness 
associated with the API.
FDA-approved Labeling
The current FDA-approved labeling for riluzole includes three Warnings:
•
Liver injury (causing elevated levels of liver enzymes serum transaminase 
[ALT/SGPT]; [AST/SGOT], bilirubin, and/or gamma-glutamate transferase [GGT] 
levels). Experience in almost 800 ALS patients indicates that about 50% of riluzole- 
treated patients will experience at least one ALT/SGPT level above the upper limit of 
normal, about 8% will have elevations > 3 × ULN, and about 2% of patients will have 
elevations > 5 × ULN.
•
Neutropenia (causing one portion of your white blood cell test results are 
considered abnormal, and this can make you more prone to infections). Among 
approximately 4000 patients given riluzole for ALS, there were three cases of marked 
neutropenia (absolute neutrophil count less than 500/mm3), all seen within the first 2 
months of riluzole treatment.
•
Interstitial lung disease (causing dry cough and/or difficulty breathing). Cases of 
interstitial lung disease (see ADVERSE REACTIONS) have been reported in patients


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treated with riluzole, some of them severe; upon further investigation, many of these 
cases were hypersensitivity pneumonitis.
Additionally, per the Riluzole label, Riluzole has been shown to impaired fertility when 
administered to male and female rats prior to and during mating at an oral dose of 15 
mg/kg or 1.5 times the maximum daily dose on a mg/m2 basis.
3. Source: a) Identify the source of the drug or biologic to be used.
BHV-0223 will be obtained from the CMHC pharmacy and supplied by Biohaven 
Pharmaceutical Inc.
b) Is the drug provided free of charge to subjects?
Yes
No 
If yes, by whom?
Biohaven Pharmaceutical Inc.
4. Storage, Preparation and Use: Describe the method of storage, preparation, stability information, 
and for parenteral products, method of sterilization and method of testing sterility and 
pyrogenicity.
Check applicable Investigational Drug Service utilized:
YNHH IDS
Yale Cancer Center
CMHC Pharmacy
West Haven VA
PET Center
None
Other:
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in 
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.
5. Use of Placebo:
Not applicable to this research project
If use of a placebo is planned, provide a justification which addresses the following:
a.Describe the safety and efficacy of other available therapies. If there are no other 
available therapies, state this.
Several pharmacological treatments are utilized on an as-needed basis because 
of their short-term, potent anti-anxiolytic effects. These pharmacological agents include 
benzodiazepines (which target the gamma-aminobutyric acid-A receptor (GABA-A) and 
beta-blockers (beta adrenergic receptor antagonists)(8, 9).  Although, benzodiazepines 
are quite effective at reducing anxiety over the short term (12) in specific situations (e.g. 
flying on an airplane), their side-effects and tolerability currently limit their usefulness in 
many situations (e.g. performance or public-speaking anxiety)(9, 10).  Benzodiazepine 
use is associated with impaired short-term concentration, decreased alertness and 
psychomotor impairment (9, 11).  Chronic benzodiazepine use is further associated with 
physiologic dependence, rebound anxiety on discontinuation and, possibly even 
interference with the efficacy of CBT (one of the first-line treatments for anxiety) (9, 11). 
Beta-blockers, on the other hand, are effective at acutely reducing the peripheral


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physical symptoms of anxiety (e.g. heart palpitations, tremors etc.) but have no effect on 
the cognitive or emotional symptoms of anxiety (9, 10, 12-15).  Novel pharmacological 
treatments are needed to improve patient outcomes with SAD, both chronically to 
reduce symptoms and acutely to reduce impairment during situations where symptoms 
are most likely to be impairing (e.g. public speaking or performance anxiety).  A placebo 
is given on a single-study day in addition to the subject’s regular medications in order to 
provide an adequate comparison condition to assess BHV-0223’s efficacy.
b.
State the maximum total length of time a participant may receive placebo while on the study.
Placebo will be given for 1 dose.
c.
Address the greatest potential harm that may come to a participant as a result of receiving 
placebo.
Since Placebo is added to the patients’ current medications, the risk of symptoms 
worsening when patients are receiving placebo in this study is not significantly greater in 
this clinical trial than it would be if the patients had not received the placebo and 
continued their current medication.
d. Describe the procedures that are in place to safeguard participants receiving placebo.
If a patient has worsening of symptoms, the patient will be offered inpatient or 
outpatient therapy and/or additional pharmacological treatments as clinically indicated.
6. Use of Controlled Substances:
Will this research project involve the use of controlled substances in human subjects?
Yes
No  See HIC Application Instructions to view controlled substance listings.
If yes, is the use of the controlled substance considered:
Therapeutic: The use of the controlled substance, within the context of the research, has the 
potential to benefit the research participant.
Non-Therapeutic: Note, the use of a controlled substance in a non-therapeutic research study 
involving human subjects may require that the investigator obtain a Laboratory Research License. 
Examples include controlled substances used for basic imaging, observation or biochemical 
studies or other non-therapeutic purposes. See Instructions for further information.
7. Continuation of Drug Therapy After Study Closure
Not applicable to this project
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended?
Yes   If yes, describe the conditions under which continued access to study drug(s) may apply 
as well as conditions for termination of such access.
No
If no, explain why this is acceptable.


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Study participants cannot be given study drug at study completion in the absence 
of an approved open-label study as recommend by the FDA in response to an initial IND 
request. This is a proof-of-concept study to determine if sublingual riluzole is helpful on a 
single time basis for speech anxiety.
B. DEVICES
1.
Are there any investigational devices used or investigational procedures performed at Yale- 
New Haven Hospital (YNHH) (e.g., in the YNHH Operating Room or YNHH Heart and 
Vascular Center)?  ☐Yes   ☒No
If Yes, please be aware of the following requirements:
a.
A YNHH New Product/Trial Request Form must be completed via EPIC: Pull down the 
Tools tab in the EPIC Banner, Click on Lawson, Click on “Add new” under the New 
Technology Request Summary and fill out the forms requested including the “Initial 
Request Form,” “Clinical Evidence Summary, “ and attach any other pertinent 
documents. Then select “save and submit” to submit your request; and
e.   Your request must be reviewed and approved in writing by the appropriate YNHH 
committee before patients/subjects may be scheduled to receive the investigational device 
or investigational procedure.
2. What is the name of the device to be studied in this protocol? 
Has this device been FDA approved?
Yes
No
If yes, state for what indication.
3. Background Information: Provide a description of previous human use, known risks, and 
any other factors that might influence risks. If this is the first time this device is being used in 
humans, include relevant data on animal models.
4. Source:
a) Identify the source of the device to be used.
b) Is the device provided free of charge to subjects?
Yes
No
5.  What is the PI’s assessment of risk level (significant or non-significant) associated with the 
use of the device?
Significant Risk (SR) Device Study: A study of a device that presents a potential for serious 
risk to the health, safety, or welfare of a participant and 1) is intended as an implant; 2) is used in 
supporting or sustaining human life; or otherwise prevents impairment of human health; 3) is of 
substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents


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impairment of human health; or 4) otherwise presents a potential for serious risk to the health, 
safety, or welfare of a participant.
Significant Risk Devices require an Investigational Device Exemption (IDE) issued by the FDA. 
What is the IDE number assigned by the FDA?
Did the FDA approve this IDE as Category A (experimental/investigational) or as Category B
(non-experimental/investigational)? 
Who holds the IDE?
Non-Significant Risk (NSR) Device Study: A study of a device that does not meet the 
definition for a significant risk device and does not present a potential for serious risk to the health, 
safety, or welfare of participants.  Note that if the HIC concurs with this determination, an IDE is 
not required.
6. Abbreviated IDE or Exempt IDE: There are abbreviated requirements for an IDE and 
there also are exemptions to the requirement for an IDE. See the criteria in the HIC 
Application Instructions, Section VI.B.4 at  
http://www.yale.edu/hrpp/resources/docs/100FR1aHICProtocol_Application_Instructions5-   
25-11.pdf to determine if these pertain to this study.
Abbreviated IDE or Exempt IDE – If criteria set forth in the HIC Application Instructions 
are met, copy and paste the completed relevant section from the Instructions into this application.
7.
Investigational device accountability:
a.
State how the PI, or named designee, ensures that an investigational device is used only in 
accordance with the research protocol approved by the HIC, and maintains control of the 
investigational device as follows:
Maintains appropriate records, including receipt of shipment, inventory at the 
site, dispensation or use by each participant, and final disposition and/or the return of the 
investigational device (or other disposal if applicable):
Documents pertinent information assigned to the investigational device (e.g., date, quantity, batch 
or serial number, expiration date if applicable, and unique code number):
Stores the investigational device according to the manufacturer's recommendations with respect to 
temperature, humidity, lighting, and other environmental considerations:
Ensures that the device is stored in a secure area with limited access in accordance with applicable 
regulatory requirements:
Distributes the investigational device to subjects enrolled in the IRB-approved protocol:
SECTION VII: RECRUITMENT/CONSENT AND ASSENT PROCEDURES
1. Targeted Enrollment: Give the number of subjects:
a.
targeted for enrollment at Yale for this protocol
20


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b.
If this is a multi-site study, give the total number of subjects targeted across all 
sites 
2. Indicate recruitment methods below.  Attach copies of any recruitment materials that will be used.
Flyers
Internet/Web Postings
Radio
Posters
Mass E-mail Solicitation
Telephone
Letter
Departmental/Center Website
Television
Medical Record Review
Departmental/Center Newsletters
Departmental/Center Research Boards
Web-Based Clinical Trial Registries
Newspaper
YCCI Recruitment database
Clinicaltrials.gov Registry (do not send materials to HIC)
Other (describe):
3.
Recruitment Procedures:
a.
Describe how potential subjects will be identified.
Patients with Social Anxiety Disorder in the Yale Center for Anxiety and Mood Disorders 
Clinic will be recruited for this study. Additionally, some subjects will respond to the contact 
phone number on the clinicaltrials.gov trial listing, flyers, or postings on the departmental 
website/YCCI recruitment database. We will also reach out to local providers and leaders of 
local social anxiety groups by letter to inform them of our study.  Lastly, we will recruit subjects 
from a list of subjects who expressed interest and/or participated in a trial examining ketamine 
for Social Anxiety Disorder.
b. Describe how potential subjects are contacted.
Clinicians will be informed about the opportunity and asked to inform their patients about 
the opportunity if appropriate. Potential subjects interested in the trial will initiate first contact 
with the study recruitment coordinator or another member of the research team.
c.
Who is recruiting potential subjects?
Co-investigators Angeli Landeros-Weisenberger and Jerome Taylor, MD will inform 
clinicians at the clinic about the opportunity and may ask patients directly if they are seeing the 
patients clinically.
4. Screening Procedures
a.
Will email or telephone correspondence be used to screen potential subjects for 
eligibility prior to the potential subject coming to the research office?
Yes
No
b. If yes, identify below all health information to be collected as part of screening and 
check off any of the following HIPAA identifiers to be collected and retained by the 
research team during this screening process.
HEALTH INFORMATION TO BE COLLECTED:
A brief psychiatric and medical history will be collected during telephone screening 
including Axis I diagnoses, medical and neurologic diagnoses, as well as recent 
medication and psychotherapy changes. All information will be stored in locked 
cabinets/password protected computer in an office that is locked. Information that will


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breach subject confidentiality will not be shared. Rather, data will only be released upon 
written consent of the subject and will be available for review by the Yale human 
Investigation Committee. We will hold paper files for seven years at which point they will 
be destroyed.
HIPAA identifiers:
Names
All geographic subdivisions smaller than a State, including: street address, city, county, precinct, zip codes and their 
equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly-available data from 
the Bureau of the Census: (1) the geographic unit formed by combining all zip codes with the same three initial digits contains 
more than 20,000 people, and (2) the initial three digits of a zip code for all such geographic units containing 20,000 or fewer 
people is changed to 000.
Telephone numbers 
Fax numbers
E-mail addresses
Social Security numbers 
Medical record numbers
Health plan beneficiary numbers 
Account numbers
All elements of dates (except year) for dates related to an individual, including: birth date, admission date, discharge 
date, date of death, all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages 
and elements may be aggregated into a single category of age 90 or older
Certificate/license numbers
Vehicle identifiers and serial numbers, including license plate numbers 
Device identifiers and serial numbers
Web Universal Resource Locators (URLs) 
Internet Protocol (IP) address numbers
Biometric identifiers, including finger and voice prints  
Full face photographic images and any comparable images
Any other unique identifying numbers, characteristics, or codes
5. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject?
Yes, all subjects
Yes, some of the subjects 
No
If yes, describe the nature of this relationship.
Some of the subjects might be recruited from the outpatient service at the Yale Child 
Study Center.  Dr. Bloch and Dr. Taylor currently work as providers in the clinic.  Subjects will 
be informed that participation or lack of participation in this study will not affect the clinical 
care they receive at the clinic.
6. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization 
for either the entire study, or for recruitment purposes only. Note: if you are collecting PHI as part of 
a phone or email screen, you must request a HIPAA waiver for recruitment purposes.)


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Choose one:
□For entire study
☒ For recruitment purposes only
□For inclusion of non-English speaking subject if short form is being used
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data;
ii. If requesting a waiver of signed authorization, describe why it would be 
impracticable to obtain the subject’s signed authorization for use/disclosure of this 
data;
We are requesting a waiver of HIPAA authorization for recruitment purposes 
only. Subjects will be initially recruited through clinicians at Yale Child Study Center and 
the clinicaltrials.gov registry. We will need to use PHI such as name, telephone number 
and email addresses to schedule initial screening interviews. It would be impractical to 
coordinate initial subject enrollment and recruitment without this data.
Signed authorization is impractical because initial screening of patients recruited 
through clinicaltrials.gov or clinician referral may occur over the telephone or email.
By signing this protocol application, the investigator assures that the protected 
health information for which a Waiver of Authorization has been requested will not 
be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject 
name, purpose, date, recipients, and a description of information provided.  Logs are to be 
forwarded to the Deputy HIPAA Privacy Officer.
7. Required HIPAA Authorization: If the research involves the creation, use or disclosure of 
protected health information (PHI), separate subject authorization is required under the 
HIPAA Privacy Rule. Indicate which of the following forms are being provided:
Compound Consent and Authorization form 
HIPAA Research Authorization Form
8. Consent Personnel: List the names of all members of the research team who will be obtaining 
consent/assent.
Michael H. Bloch MD, MS 
Christopher Pittenger MD, PhD 
Jerome Taylor MD
Angeli Landeros-Weisenberger MD 
Jessica A. Johnson, BS
Baris Olten, MD


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9. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will 
be obtained, including parental permission or surrogate permission and the steps taken to ensure 
subjects’ independent decision-making.
•The research team (PI, his designee or research coordinator) will explain the study to 
the patient.
•Understanding of the study will be tested using a brief questionnaire (see consent form) 
of the key elements of the study.
•Every attempt will be made to include spouses, significant others, and family in the 
consent process.
•The research team will discuss the patient’s participation in the study with the patient’s 
psychiatric primary clinician. The clinician’s opinion about the patient’s participation and 
ability to provide informed consent will be documented.

Subject will be given a copy of the signed consent form
10. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed.
Protocol does not involve subjects with limited decision making capacity
11. Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the same 
format that they will be given to subjects.
Adult consent form.
12. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. If enrollment of these subjects is anticipated, 
translated copies of all consent materials must be submitted for approval prior to use.
Protocol does not involve non-English speaking subjects.
12(a) As a limited alternative to the above requirement, will you use the short form* for 
consenting process if you unexpectedly encounter a non-English speaking individual interested 
in study participation and the translation of the long form is not possible prior to intended 
enrollment?
YES ☐ NO ☒


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Note* If more than 2 study participants are enrolled using a short form translated into the same 
language, then the full consent form should be translated into that language for use the next time 
a subject speaking that language is to be enrolled.
Several translated short form templates are found on our website
at: http://www.yale.edu/hrpp/forms-templates/biomedical.html. If the translation of the short 
form is not available on our website, then the translated short form needs to be submitted to the 
IRB office for approval via amendment prior to enrolling the subject. Please review the 
guidance and presentation on use of the short form available on the HRPP website.
If using a short form without a translated HIPAA Research Authorization Form, please 
request a HIPAA waiver in the section above.
13. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or 
a full waiver of consent, depending on the study. If you will request either a waiver of consent, 
or a waiver of signed consent for this study, complete the appropriate section below.
Not Requesting a consent waiver 
Requesting a waiver of signed consent 
Requesting a full waiver of consent
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6)
Requesting a waiver of signed consent for Recruitment/Screening only
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research?
Yes
No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
Yes
No
OR
c. Does the research activity pose greater than minimal risk?
Yes If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity
No
AND
d. Does the research include any activities that would require signed consent in a non- 
research context?
Yes
No
Requesting a waiver of signed consent for the Entire Study (Note that an information 
sheet may be required.)
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research? 
Yes
No


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b. Does a breach of confidentiality constitute the principal risk to subjects? 
Yes
No
OR
c. Does the research pose greater than minimal risk?
Yes If you answered yes, stop. A 
waiver cannot be granted.
No
AND
d. Does the research include any activities that would require signed consent in a non- 
research context?
Yes
No
B. Full waiver of consent: (No consent from subjects will be obtained for the activity.)
Requesting a waiver of consent for Recruitment/Screening only
a. Does the research activity pose greater than minimal risk to subjects?
Yes If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity
No
b. Will the waiver adversely affect subjects’ rights and welfare?
Yes
No
c. Why would the research be impracticable to conduct without the waiver?
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date?
Requesting a full waiver of consent for the Entire Study (Note: If PHI is 
collected, information here must match Section VII, question 6.)
If requesting a full waiver of consent, please address the following:
a. Does the research pose greater than minimal risk to subjects? 
Yes If you answered yes, stop. A waiver cannot be granted.
No
b. Will the waiver adversely affect subjects’ rights and welfare?
Yes
No
c. Why would the research be impracticable to conduct without the waiver?
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date?
SECTION VIII: PROTECTION OF RESEARCH SUBJECTS
Confidentiality & Security of Data:
a.
What protected health information (medical information along with the HIPAA identifiers) 
about subjects will be collected and used for the research?
PHI about subjects will include name, age, diagnosis, medical record data, results 
of physical examination including EKG information, laboratory tests, psychiatric rating 
scores, and performance on psychiatric tests (impromptu speech and attention bias 
tests). The urine toxicology results will be placed in the research study record. The subject


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will have a medical record at CMHC. Since the baseline urine toxicology and lab results 
will be collected during a visit at CMHC, the results of this test will become part of the 
CMHC medical record. This will be disclosed to the subject in the consent form and the 
investigator has obtained a Certificate of Confidentiality to protect all sensitive information 
connected with this study.
b. How will the research data be collected, recorded and stored?
All study ratings completed during study visits, histories obtained at screening and 
medical records pertaining to study procedures are secured in locked files and stored on 
password-protected computers. Since this is an investigator-initiated study, the PI and 
study team will develop Clinical Research Forms (CRFs) for this study. These forms will 
be labeled with a unique random study code that cannot identify the patient. The key 
linking the code to the subject’s identifiable information will be kept in an electronic excel 
file which is kept in a password protected file, on a password protected computer on the 
secure Yale server. A paper copy of this “master file” will be kept in a locked file cabinet 
as noted above. This master file will be kept separately from any coded data so that the 
identity of the participant will not be disclosed. Information which is required to be part of 
the medical record will be filed into the CMHC medical record. If a medical record has not 
been created, one will be created with this visit. The results of the medical and psychiatric 
evaluations conducted as part of this research will be available to clinicians caring for the 
subject unless the participant requests otherwise. The Yale Human Investigation 
Committee may review records of this research. In the case of published reports of this 
study, the identities of all participants will be protected.
c.
How will the digital data be stored?
CD
DVD
Flash Drive
Portable Hard 
Drive
Secured Server
Laptop Computer
Desktop Computer
Other
d.
What methods and procedures will be used to safeguard the confidentiality and security of 
the identifiable study data and the storage media indicated above during and after the subject’s 
participation in the study?
All of the information obtained from subjects in this research study will be locked 
clinic files or on a password protected server to insure confidentiality. Also, the methods 
utilized include storing identified data separately from that which need not be identified, 
storing medical records according to CMHC policy, and utilizing a secure server.
Do all portable devices contain encryption software?
Yes
No
If no, see http://hipaa.yale.edu/guidance/policy.html
e.
What will be done with the data when the research is completed? Are there plans to destroy 
the identifiable data? If yes, describe how, by whom and when identifiers will be destroyed. If 
no, describe how the data and/or identifiers will be secured.
Data will be kept in a locked filing cabinet whose access is only obtainable by study 
personnel and electronic clinical data will be kept on a password protected server. The PI 
will  also  conduct  periodic  assessments  to  ensure  that  confidentiality  provisions


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established at the onset of the study are maintained throughout the study and during data 
analysis. Additionally, all staff involved in the handling of subject data are/or will be trained 
on the requirements of HIPAA Privacy Rule and Human Subject Protection. If the PI 
should leave Yale, the PI will collaborate with his Department Chair and Faculty Advisor 
to ensure that proper and continued protection of individually identifiable information and 
protected health information continues.
After a period of five years these files will be destroyed by ITS approved methods 
or de-identified to protect subject confidentiality. All identifiable data will be destroyed by 
Dr. Bloch when the research is completed. Paper will be shredded via the confidential 
CMHC bins and all electronic files will be deleted or edited so that there is no identifiable 
information.
Impromptu speeches will be videotaped during the study. The subject has the right 
to request a copy of the video after the whole trial is completed, however, they will not 
have the right to edit the videos. The videotapes can be destroyed at any point in time 
upon request by the subject, otherwise, they will be kept for 5 years. After that time they 
will be destroyed or de-identified.
f. Who will have access to the protected health information (such as the research sponsor, the 
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and Safety 
Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and de-identified 
data)
In addition to study investigators, members of the HIC, the study sponsor, and 
the FDA may have access to study data.
g. If appropriate, has a Certificate of Confidentiality been obtained?
A Certificate of Confidentiality has been obtained to protect the drug toxicology 
results. Where possible, information will be destroyed that may link the subject to illicit 
drug use. Since a CMHC chart will need to be created for these subjects by virtue of their 
visit to the site, there is a concern that these results could be traced back to the subject. 
Subjects who test positive on the toxicology test will not be able to participate in this 
protocol. Subjects will be encouraged to seek treatment for their substance use, as 
appropriate.
h.
Are any of the study procedures likely to yield information subject to mandatory reporting 
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview -incidents 
of child abuse, elderly abuse, etc.). Please verify to whom such instances will need to be reported.
Although considered unlikely to be encountered, limits to confidentiality such as 
mandatory reporting requirements for abuse of children or the elderly will be complied 
with.
SECTION IX: POTENTIAL BENEFITS


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Potential Benefits: Identify any benefits that may be reasonably expected to result from the 
research, either to the subject(s) or to society at large. (Payment of subjects is not considered a 
benefit in this context of the risk benefit assessment.)
There may be no direct benefit from a subject’s participation in this study. The 
potential benefits to society of these investigations are considerable. SAD continues to 
be a major public health problem with tragic cost to the individual, the family, and the 
community. The present study may improve our understanding of SAD by providing a 
pharmacologic rationale for developing novel treatments.
SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.
Alternatives: What other alternatives are available to the study subjects outside of the research?
The subject may discuss other non-research treatments for SAD with their 
practitioner or remain on their current standard of care regiment. This will include a 
discussion of pharmacologic, psychosocial, and somatic treatments.
2.
Payments for Participation (Economic Considerations): Describe any payments that will be 
made to subjects, the amount and schedule of payments, and the conditions for receiving this 
compensation.
Participants will be paid $50.00 for the screening visit; $100 for each of the study 
challenge days and $50 for the follow-up visit; for a total of $300.00 cash upon 
completion of the study.  We will be able to reimburse up to $200.00 in travel and lodging if 
you are traveling from greater than 50 miles distance, receipts will be required to issue 
reimbursement checks.
3.
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the study that 
will be provided at no cost to subjects.
The study drugs and all medical procedures in this research study will be provided free 
of charge to the participants. There are no charges for the study visits, including the 
cost of parking on challenge days and transportation and lodging up to $200 for 
subjects traveling from a greater than 50 miles distance.
4.
In Case of Injury: This section is required for any research involving more than minimal risk.
a.
Will medical treatment be available if research-related injury occurs? If a physical injury or 
illness occurs as a direct result of participation in this study, study physicians and nursing 
personnel will be provided emergency medical care and ensure that research participants receive 
prompt evaluation and medical treatment as necessary. In severe cases this may involve a 
transfer to Yale-New Haven Hospital emergency room. The cost of treatment for any such injury


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or illness will not be paid for through the study and will be the responsibility of the research 
participant.
a.
Where and from whom may treatment be obtained?
In the event of a significant medical emergency the participant will be transported 
to Yale New Haven Hospital. Should there be adverse psychiatric effects as a result of 
the study they will receive either inpatient treatment on the CNRU at CMHC or as an 
outpatient from the Yale Child Study Center.
b. Are there any limits to the treatment being provided?
In the unlikely event that any psychiatric care more intensive than regular clinic 
visits and a couple of nights of observation on the CNRU is required as a direct result of 
participation in this study, study personnel will provide emergent care and stabilization. 
Longer observation on the CNRU and more frequent clinic visits, if necessary in the 
short term may also be provided. If longer-term psychiatric care is required, beyond 
what is normally provided by a research clinic, then study personnel will provide 
referrals and otherwise endeavor to assist participants in arranging such care.
c.
Who will pay for this treatment?
Since this is an investigator initiated study, the study’s investigators will provide 
additional short-term inpatient hospitalization that is needed to provide emergent care 
and stabilization following any adverse psychiatric events. Longer-term psychiatric care 
to alleviate a participant’s symptoms below their severity when entering the study or 
medical treatments provided at other facilities will be billed to the participant or the 
participant’s insurance company. Participants do not give up any of their legal rights by 
signing the consent forms.
d. How will the medical treatment be accessed by subjects?
As part of the study protocol, participants will be systematically asked about any 
adverse events they experience and their SAD symptom severity by study personnel. 
They will also be instructed to inform study personnel if they believe they have suffered 
an adverse event or worsening of their SAD symptoms as a result of the protocol.


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APPENDIX 1
Local Tolerability Assessment
A local tolerability assessment will be performed at baseline and 1 hour after study medication 
administration on study days 1 and 2. Any alteration of the appearance of the tongue, palate and 
buccal mucosa space will be recorded. Oral tolerability assessment will include:
Any history of dysphagia (difficulty swallowing), dysgeusia (the distortion of the sense of taste) 
or burning, stinging or tingling sensation of the mouth.
Systematic examination of the oral cavity for any signs of erythema, swelling or ulceration 
(ulcers which are white, small, punched out lesions of epithelial surfaces of the mouth) of the 
mucosa.
Also check for stomatitis (inflammation and infection of the oral mucosa), gingivitis 
(inflammation of the gums leading to erythema, swelling and bleeding), xerostomia (a dry 
mouth) or staining of mucosa.
• Areas to be inspected:
- Right palate area
- Left palate area
- Right sublingual area
- Left sublingual area
- Right upper buccal area
- Right lower buccal area
- Left upper buccal area
- Left lower buccal area
• Severity Grading Scale: 
Grade 0: Normal mucosa
Grade 1: Localized mucosal erythema and/or irritation without ulceration
Grade 2: Generalized erythema and/or irritation and induration without ulceration
Grade 3: Ulceration, with or without any other combination of signs.


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