Clinical trial NCT03829241
Conditions: Generalized Anxiety Disorder
Keywords: Generalized Anxiety Disorder (GAD)
Sponsor: Biohaven Pharmaceuticals, Inc.
Start date: 2019-02-19; Completion date: 2020-05-08
Enrollment: 881 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the efficacy of troriluzole versus placebo in participants with generalized anxiety disorder.

Detailed description:

Arms: arm 1: Randomization phase (Weeks 1 through 8): Participants received troriluzole 100 mg capsules twice daily (BID) orally for up to 8 weeks in the double-blind (DB) randomization phase.

Extension phase (Weeks 9 through 56): Participants, who completed the randomization phase and for whom the investigator believed open-label (OL) treatment could offer an acceptable risk-benefit profile, entered the extension phase and received OL troriluzole capsules (continuing on the same dose and regimen that was taken at the end of the randomization phase) for up to additional 48 weeks. arm 2: Randomization Phase (Weeks 1 through 8): Participants received troriluzole matching placebo capsules BID orally for up to 8 weeks in the DB randomization phase.

Extension Phase (Weeks 9 through 56): Participants, who completed the randomization phase and for whom the investigator believed OL treatment could offer an acceptable risk-benefit profile, entered the extension phase and received OL troriluzole capsules (continuing on the same dose and regimen that was taken at the end of the randomization phase) for up to additional 48 weeks.
Interventions: intervention 1: Troriluzole intervention 2: Placebo
Intervention descriptions: intervention 1: 100 mg capsule intervention 2: Placebo matched to troriluzole

Protocol documents:
Prot_000.pdf: 
BHV4157-207; Clinical Protocol V03
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DRUG:
Troriluzole (BHV4157)
STUDY NUMBER(S):
BHV4157-207
PROTOCOL(S) TITLE:
A Multicenter, Randomized, Double-Blind, Placebo 
Controlled Trial of Troriluzole in Generalized 
Anxiety Disorder
IND NUMBER:
141430
SPONSOR:
Biohaven Pharmaceuticals, Inc
ORIGINAL PROTOCOL 
DATE:
12 Nov 2018
VERSION NUMBER:
V03
Includes Amendment 01, Amendment 02 and 
Administrative Letters 01, 02 and 03
VERSION DATE:
01Aug 2019


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SUMMARY OF CHANGES
Version Number Brief description summary of changes
Date
Version 01 –
Original Draft
NA
20 Nov 2018
Version 02 -
Amendment 01
and Incorporates 
Admin Letter 1
and 2
P12 List of Abreviations:  
-
- added Data Monitoring Committee (DMC) 
-
- added Placebo-Control Reminder Script (PCRS)
Section 2 Study Objectives
-
Removed 4 secondary objectives
-
Moved 3 secondary objectives to exploratory
Section 3 Study Endpoints
-
Removed 4 secondary endpoints
-
Moved 3 secondary endpoints to exploratory
Section 4.3 Table of Assessments
-
added PCRS 
-
added drug dispensing at Week 8 or Rand Phase
-
corrected footnote regarding UDS to reflect test performed at 
Screening and EOS
Section 5.3 Exclusion Criteria
-
changed S-STS reporting period from 12 months to 6 months
Section 7.4.4 Laboratory Assessments
-
f) Urine Drug Screen – removed benzodiazepenes and tricyclic 
antidepressants. Updated frequency of test to Screening and EOS.
Section 7.4.4.2 
-
changed PGX sample collection to Baseline and End of Study (Wk 
8) 
Section 7.5.7
-
Updated the DSST description to clarify that subjects must decode 
the symbols “within 2 minutes”,
Section 11 
-
Miscellaneous statistical updates have been made 
Section 12.1 
-
Added Data Safety Monitoring Committee
Section 17.2 
-
Removed the appendix for the declaration of Helsinki.
Minor administrative corrections have also been made throughout the 
protocol
6-Feb 2019


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Version 03 -
Amendment 01
and 02
Incorporates 
Admin Letter 1, 2 
and 3
Section 4.3 Table of Assessments
-
Lengthened the Extension Phase to 48 Weeks
Study Schematic: Updated to reflect 48 week Extension Phase
Section 5.3: 
4l: Exclusion has been modified to clarify that, in addition to herbal 
medications, use of herbal supplements is excluded within 30 days of 
randomization and during the course of the study.
Section 7.4.4: Laboratory Assessments:
Updated to include serum tests for: 
•B12;
•eGFR;
•amylase; and  
•lipase
As well as urinalysis parameters of:
•appearance
•bilirubin
•color
Section 9.1.2: 
Revised to allow for IP temperature excursions between 150C and 300 C
(590F -860F)
Section 11:
Miscellaneous statistical updates have been made 
Section 11.4.2:
Added clarification based on FDA reveiwer’s comment.
Since the primary intent of this trial is to evaluate the effect of the drug when taken 
as intended in the protocol, a hypothetical strategy will be employed for the 
intercurrent event of treatment/study discontinuation (due to any reason). 
Specifically, the assumption will be that had the subjects not discontinued, their 
efficacy would have been similar to the efficacy of subjects from the same treatment 
group who did not discontinue. For other intercurrent events that do not cause 
treatment/study discontinuation such as modest treatment non-compliance, protocol 
allowed dose adjustments, or initiation or adjustment of concomitant medications 
related to other symptoms all observed values will be used.
Minor administrative corrections have also been made throughout the 
protocol
24-Jul-19


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BHV4157-207
A Multicenter, Randomized, Double-Blind, Placebo Controlled Trial 
of Troriluzole in Generalized Anxiety Disorder
Confidentiality and Investigator Statement
The information contained in this protocol and all other information relevant to troriluzole are 
the confidential and proprietary information of Biohaven Pharmaceutical Holding Company 
Limited, and except as may be required by federal, state or local laws or regulation, may not be 
disclosed to others without prior written permission of Biohaven Pharmaceutical Holding 
Company Limited.
I have read the protocol, including all appendices, and I agree that it contains all of the 
necessary information for me and my staff to conduct this study as described. I will conduct 
this study as outlined herein, in accordance with the regulations stated in the Federal Code of 
Regulations for Good Clinical Practices and International Conference on Harmonization 
guidelines, and will make a reasonable effort to complete the study within the time designated.
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Biohaven Pharmaceutical Holding 
Company Limited. or specified designees. I will discuss the material with them to ensure that 
they are fully informed about Biohaven and the study.
Principal Investigator Name (printed)
Signature
Date
Site Number


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STUDY SUMMARY (SYNOPSIS)
Title:
A Multicenter, Randomized, Double-Blind, Placebo Controlled Trial of
Troriluzole in Generalized Anxiety Disorder
Rationale:
First-line treatment for Generalized Anxiety Disorder (GAD) includes 
cognitive behavior therapy, selective serotonin reuptake inhibitors (SSRIs)
and serotonin norepinephrine reuptake inhibitors (SNRIs). Nonetheless, up 
to 50% of patients have an inadequate response to conventional 
pharmacotherapy[1]. While SSRIs, SNRIs, buspirone and some 
benzodiazepines have been approved for GAD, the majority of patients do 
not have an adequate response to pharmacologic treatment.
The proposed study is based on recent preclinical, clinical, and
neuroimaging studies that implicate glutamatergic hyperactivity in the 
pathogenesis of GAD [2-8]. In addition. the results from a published 
clinical study examining the use of riluzole, a glutamate modulating agent,
suggested efficacy in patients with GAD [2-4].
Troriluzole is a novel glutamate modulating drug that is being developed 
for the potential treatment of GAD.
Troriluzole is a tripeptide prodrug of the glutamate modulating agent 
riluzole that has been optimized for improved bioavailability, 
pharmacokinetics and dosing. Riluzole is currently only indicated for ALS 
and has a number of non-desirable attributes that have limited its clinical 
use. Key limitations of riluzole include:
• Poor oral bioavailability —When riluzole is administered in a tablet 
form, approximately 40% is either not absorbed or is metabolized in the 
liver before reaching systemic circulation. 
• Negative food effect —Riluzole must be taken on an empty stomach, at 
least one hour before or two hours after a meal. Failure to adhere to these 
guidelines results in lower drug levels and potentially decreased 
therapeutic effects.
• Negative effect on liver —Riluzole has been shown to have dose-
dependent liver effects that include elevations on liver function tests. 
Taking riluzole necessitates regular laboratory monitoring of liver 
function. 


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• Pharmacokinetic variability —Due to extensive first-pass metabolism 
and CYP1A2 metabolism.
Troriluzole was developed to address limitations of riluzole that have 
restricted its broader clinical application. Based on the preclinical features of 
troriluzole and data from a completed Phase 1 study of troriluzole, we 
anticipate the clinical pharmacology to offer favorable properties as compared 
to available riluzole: 
1. Troriluzole is expected to have better oral bioavailability;
2. Troriluzole is expected to have no food restrictions imposed;
3. Troriluzole is designed to release riluzole after bypassing first-pass 
metabolism and thus confer lower overall drug burden to the liver, which 
may translate into a better safety and tolerability profile;
4. Troriluzole is expected to have reduced pharmacokinetic variability and be 
dosed only once daily.
As an optimized prodrug of riluzole, the regulatory pathway for troriluzole
will rely on toxicology data with troriluzole in rodents and non-human 
primates, clinical experience with troriluzole in other clinical disorders such 
as spinocerebellar ataxia, and the well-characterized safety experience of 
riluzole, which has been marketed globally for over 20 years and is considered 
safe and well tolerated.
Target 
Population:
Male and female outpatient subjects between the ages of 18 - 65
years, inclusive, with a primary DSM-5 diagnosis of Generalized 
Anxiety Disorder (confirmed by the MINI) who have a Hamilton 
Anxiety Rating Scale (HAM-A) score of 18 or greater at screening 
and baseline.  Additionally, GAD symptoms in subjects had to be 
present for 
year and at least of moderate severity on the Clinical 
Global Impression - Severity of Illness Scale at study entry.
Number of 
Subjects:
Approximately 372 randomized subjects 


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Objectives:
Primary Objectives
The primary objective of the study is to evaluate the efficacy of 
troriluzole compared to placebo after 8-weeks of treatment in subjects
with GAD, as measured by the Hamilton Anxiety Rating Scale 
(HAM-A) scale
Secondary Objectives
•
To assess the safety and tolerability of troriluzole, relative to 
placebo, in subjects with GAD
•
Evaluate the efficacy of troriluzole compared to placebo on 
functional disability as measured by the Sheehan Disability 
Scale (SDS)
•
Evaluate the efficacy of troriluzole compared to placebo on 
global functioning as measured by the Clinical Global 
Impression - Severity Scale (CGI-S)
Exploratory Objectives
•
Evaluate the effects of troriluzole compared to placebo on 
cognitive performance as measured by the Digit Symbol 
Substitution Task (DSST) and the Hopkins Verbal Learning 
Test-Revised (HVLT-R)
•
Evaluate the efficacy of troriluzole compared to placebo on
improvement in global functioning as measured by the Clinical 
Global Impression - Improvement Scale (CGI-I)
•
Evaluate the efficacy of troriluzole compared to placebo on 
depressive symptomatology as measured by the Hamilton 
Depression Rating Scale-17 (HAM-D-17)
•
Evaluate the efficacy of troriluzole compared to placebo on 
anxiety symptoms as measured by the Penn State Worry 
Questionnaire (PSWQ)
•
To characterize the pharmacokinetics of troriluzole based on 
sparse sampling
•
Evaluate correlates of placebo responsiveness by using the 
Clinical Trial and Site Scale-B (CTSS-B) as well as other 
pre-intervention outcome measures and demographic 
information


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Study 
Design:
BHV4157-207 is a Phase III, multicenter, randomized, double-blind, 
placebo-controlled, 2- arm study designed to assess safety, tolerability, and 
efficacy of troriluzole in subjects with Generalized Anxiety Disorder who 
have a Hamilton Anxiety Rating Scale (HAM-A) score of 18 or greater at 
screening and baseline.  Additionally, GAD symptoms in subjects had to be 
Impression Scale-Severity of Illness scale at study entry.
Subjects who qualify will be randomized to receive placebo (BID) or 
troriluzole (100 mg BID).
Dosing will continue for 8 weeks. Eligible subjects will have the
opportunity to continue in a 48 week open label extension phase. Those 
subjects not continuing in the 48 week extension will return to the clinic 
two weeks after discontinuing study medication for a follow-up safety 
visit.
For subjects entering the Extension Phase, their first in-person Extension 
Visit will be four weeks after the Week 8 Randomization Phase visit. 
Subjects will undergo visits every fourth week through Week 12 of this 
phase. Then subjects will undergo visits every 12 weeks up to Week 48 of 
this phase. All subjects will undergo a post study drug termination visit 
two weeks after the last dose of study drug in the Extension Phase.


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STUDY SCHEMATIC*


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TABLE OF CONTENTS
SUMMARY OF CHANGES ............................................................................................ 2 
STUDY SUMMARY (SYNOPSIS).................................................................................. 5
STUDY SCHEMATIC*.................................................................................................... 9
TABLE OF CONTENTS................................................................................................ 10 
LIST OF ABBREVIATIONS......................................................................................... 14 
1
INTRODUCTION AND RATIONALE................................................................. 17 
1.1
BACKGROUND.................................................................................................. 17
1.1.1
GENERALIZED ANXIETY DISORDER (GAD) ..................................... 17
1.1.2
RATIONALE FOR TRORILUZOLE IN THE TREATMENT OF GAD17 
1.1.2.1
PRE-CLINICAL STUDIES ................................................................... 18 
1.1.2.2
CLINICAL EXPERIENCE.................................................................... 18 
1.1.3
POTENTIAL FOR DRUG-DRUG INTERACTIONS.............................. 22
1.1.4
CLINICAL ADVERSE EVENT PROFILE ............................................... 22
1.1.4.1
TRORILUZOLE PHASE I STUDIES.................................................. 23 
1.1.4.2
BHV4157-201:  PHASE 2 CLINICAL ADVERSE EVENT 
PROFILE................................................................................................. 24 
1.1.4.3
RILUZOLE.............................................................................................. 25 
1.1.5
POTENTIAL RISK TO FETAL DEVELOPMENT................................. 27 
1.2
STUDY RATIONALE ........................................................................................ 27 
1.2.1
STUDY DESIGN RATIONALE.................................................................. 27 
1.2.2
DOSE SELECTION...................................................................................... 29 
1.3
RESEARCH HYPOTHESIS.............................................................................. 29 
2
STUDY OBJECTIVES............................................................................................ 30 
2.1
PRIMARY............................................................................................................ 30 
2.2
SECONDARY...................................................................................................... 30 
2.3
EXPLORATORY................................................................................................ 30 
3
STUDY ENDPOINTS.............................................................................................. 31 
3.1
PRIMARY............................................................................................................ 31
3.2
SECONDARY...................................................................................................... 31 
3.3
EXPLORATORY................................................................................................ 31 
4
STUDY PLAN .......................................................................................................... 32 
4.1
STUDY DESIGN AND DURATION ................................................................ 32 
4.2
STUDY SCHEMATIC........................................................................................ 33 
4.3
SCHEDULE OF ASSESSMENTS..................................................................... 34 
4.3.1
SCREENING PHASE................................................................................... 39 
4.3.2
RANDOMIZATION PHASE....................................................................... 39 
4.3.3
EXTENSION PHASE (IF APPLICABLE) ................................................ 39 
4.4
POST STUDY ACCESS TO THERAPY (IF APPLICABLE) ....................... 40 
5
POPULATION......................................................................................................... 40 
5.1
NUMBER OF SUBJECTS ................................................................................. 40 
5.2
INCLUSION CRITERIA ................................................................................... 40 
5.3
EXCLUSION CRITERIA.................................................................................. 41 
5.4
PROHIBITED CONCOMITANT MEDICATION ......................................... 46 
5.5
WOMAN OF CHILDBEARING POTENTIAL .............................................. 49 


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5.6
DEVIATION FROM INCLUSION/EXCLUSION CRITERIA..................... 50 
6
STUDY CONDUCT AND DESCRIPTION OF STUDY PROCEDURES......... 51
6.1
STUDY MATERIALS........................................................................................ 51
7
ELIGIBILITY ASSESSMENTS ............................................................................ 51 
7.1
MINI INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW (MINI) 51 
7.2
SAFER INTERVIEW....................................................................................... 51 
7.3
MEDICAL AND PSYCHIATRIC HISTORY ................................................. 51
7.4
SAFETY ASSESSMENTS ................................................................................. 52
7.4.1
VITAL SIGNS AND PHYSICAL MEASUREMENTS (HEIGHT AND 
WEIGHT) ...................................................................................................... 52 
7.4.2
ELECTROCARDIOGRAM (ECG)............................................................ 52 
7.4.3
PHYSICAL EXAM....................................................................................... 52
7.4.4
LABORATORY ASSESSMENTS .............................................................. 52
7.4.4.1
PHARMACOKINETICS ....................................................................... 53 
7.4.4.3
PREGNANCY TESTING ...................................................................... 54 
7.4.4.4
EVALUATION OF LABORATORY ASSESSMENTS...................... 54 
7.4.5
SHEEHAN SUICIDALITY TRACKING SCALE (SHEEHAN STS)..... 55 
7.5
CLINICAL OUTCOME ASSESSMENTS....................................................... 55 
7.5.1
HAMILTON ANXIETY RATING SCALE (HAM-A).............................. 56 
7.5.2
PLACEBO-CONTROL REMINDER SCRIPT (PCRS)........................... 56 
7.5.3
SHEEHAN DISABILITY SCALE (SDS) ................................................... 56 
7.5.4
CLINICAL GLOBAL IMPRESSION (CGI) ............................................. 57 
7.5.5 
HAMILTON DEPRESSION RATING SCALE 17 ITEM VERSION 
(HAM-D-17).................................................................................................. 57 
7.5.6
PENN STATE WORRY QUESTIONNAIRE (PSWQ)............................. 57 
7.5.7 
COGNITIVE TEST BATTERY ............................................................... 57 
7.5.8 
CLINICAL TRIAL AND SITE SCALE-B (CTSS-B)........................... 57 
8
EARLY DISCONTNUATION OF STUDY .......................................................... 58 
9
STUDY DRUG MANAGEMENT.......................................................................... 58 
9.1
DESCRIPTION OF STUDY DRUG ................................................................. 58 
9.1.1
INVESTIGATIONAL PRODUCT.............................................................. 58 
9.1.2
PACKAGING, SHIPMENT AND STORAGE .......................................... 58 
9.2
DOSE AND ADMINISTRATION..................................................................... 58 
9.2.1
RANDOMIZATION PHASE....................................................................... 58 
9.2.2
EXTENSION PHASE................................................................................... 59 
9.2.3
METHOD OF ASSIGNING PATIENT IDENTIFICATION................... 59 
9.2.4
SELECTION AND TIMING OF DOSE AND ADMINISTRATION...... 60 
9.2.5
DOSE MODIFICATIONS ........................................................................... 60 
9.3
BLINDING AND UNBLINDING...................................................................... 61 
9.4
TREATMENT COMPLIANCE ........................................................................ 61 
9.5
DESTRUCTION AND RETURN OF STUDY DRUG.................................... 61 
10
ADVERSE EVENTS................................................................................................ 62 
10.1
SERIOUS ADVERSE EVENTS ........................................................................ 62 
10.1.1
DEFINITION OF SERIOUS ADVERSE EVENT (SAE) ......................... 62 
10.1.2
DEFINITION OF TERMS........................................................................... 63 
10.1.3
CLASSIFICATION OF ADVERSE EVENTS........................................... 64 


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10.1.4
COLLECTION AND REPORTING SERIOUS ADVERSE EVENTS... 64 
10.1.5
OVERDOSE .................................................................................................. 65
10.1.6
PREGNANCY ............................................................................................... 65
10.1.7
POTENTIAL DRUG INDUCED LIVER INJURY (DILI)....................... 66 
10.2
NON-SERIOUS ADVERSE EVENTS.............................................................. 66 
10.2.1
COLLECTION AND REPORTING OF NON-SERIOUS ADVERSE 
EVENTS......................................................................................................... 66
11
STATISTICS............................................................................................................ 67
11.1
GENERAL PROCEDURES .............................................................................. 67 
11.2
SAMPLE SIZE.................................................................................................... 67 
11.3
POPULATIONS FOR ANALYSIS ................................................................... 67 
11.4
STATISTICAL METHODS .............................................................................. 68
11.4.1
DEMOGRAPHIC AND BASELINE CHARACTERISTICS................... 68
11.4.2
PRIMARY ENDPOINT(S)........................................................................... 68 
11.4.3
SECONDARY AND EXPLORATORY ENDPOINT(S)........................... 69 
11.4.4
ADJUSTMENT FOR MULTIPLICITY..................................................... 69 
11.4.5
MISSING DATA ........................................................................................... 69 
11.4.6
ANALYSIS OF SAFETY ............................................................................. 69 
11.5
SCHEDULE OF ANALYSES............................................................................ 70 
12
ETHICS AND RESPONSIBILITIES .................................................................... 70 
12.1
DATA MONITORING COMMITTEE ............................................................ 71 
12.2
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE..................................................................................................... 71 
12.3
INFORMED CONSENT .................................................................................... 72 
12.4
CASE REPORT FORMS................................................................................... 73 
12.5
RECORDS MANAGEMENT AND RETENTION ......................................... 73 
12.6
SOURCE DOCUMENTATION ........................................................................ 74 
12.7
STUDY FILES AND RECORD RETENTION................................................ 74 
13
AMENDMENTS ...................................................................................................... 74 
14
STUDY REPORT AND PUBLICATIONS ........................................................... 75 
15
STUDY DISCONTINUATION .............................................................................. 75 
16
CONFIDENTIALITY ............................................................................................. 75 
17
APPENDICES.......................................................................................................... 76 
17.1
APPENDIX I - NAMES OF STUDY PERSONNEL........................................ 76 
17.2
APPENDIX II - POTENT AND MODERATE INHIBITORS AND 
INDUCERS OF THE CYP1A2 ENZYME SYSTEM*.................................... 77 
18
REFERENCES CITED........................................................................................... 78 
CLINICAL PROTOCOL APPROVAL FORM........................................................... 80 


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LIST OF TABLES
Table 1: 
Most Frequently Reported Treatment-emergent AEs in Study BHV4157-
201............................................................................................................. 24 
Table 2: 
Schedule of Assessments and Events - Randomization Phase ............ 34 
Table 3: 
Schedule of Assessments and Events - Extension Phase...................... 37 
LIST OF FIGURES
Figure 1: 
Study Schematic ...................................................................................... 33 


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LIST OF ABBREVIATIONS
AE
Adverse Event
ALS
ALT
Amyotrophic Lateral Sclerosis
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BE
Bioequivalence
Bid
Twice a Day
BP
Blood Pressure
BID
BUN
Twice Daily
Blood Urea Nitrogen
CGI-I
CGI-S
Cmax
Clinical Global Impression – Improvement Scale
Clinical Global Impression – Severity Scale
Maximum Plasma Concentration
CNO
Certificate of Non-Objection
CONMED
Concomitant Medication
CRF
Case Report Form
CTSS-B
CYP
DMC
DSM-5
Clinical Trial and Site Scale-B
Cytochrome P450
Data Monitoring Committee
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition
DSST
ECG
Digit Symbol Substitution Scale
Electrocardiogram
GAD
Generalized Anxiety Disorder
GCP
Good Clinical Practice
HAM-A
HAMD-17
HCV
HIV
Hamilton Anxiety Rating Scale
Hamilton Depression Scale 17-Item Version
Hepatitis C Virus
Human Immunodeficiency Virus


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HR
Heart Rate
HRT
HVLT-R
IB
Hormone Replacement Therapy
Hopkins Verbal Learning Test-Revised
Investigator’s Brochure
ICF/IC
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
iv
Intravenous
kg
Kilogram
L
Liters
mg
Milligram
min
Minute
MINI
MRI
mmHg
Mini International Neuropsychiatric Interview
Magnetic Resonance Imaging
Millimeters Mercury
NAA
NDA
NOEL
N-acetylaspartate
New Drug Application
No Observed Effect Level
NOAEL
No Observed Adverse Event Level
OCD
PCP
PK
Obsessive Compulsive Disorder
Phencycledine
Pharmacokinetic
po
By Mouth, Orally
PCRS
PSWQ
qd
Placebo-Control Reminder Script
Penn State Worry Questionnaire
Once Daily
RPR
SAE
Rapid Plasma Reagin
Serious Adverse Event


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SARA
SDS
SNRI
SCA
SSRI
Scale for Assessment and Rating of Ataxia
Sheehan Disability Scale
Selective Norepinephrine Reuptake Inhibitor
Spinocerebellar Ataxia
Selective Serotonin Reuptake Inhibitor
S-STS
ULN
Sheehan Suicidality Tracking Scale
Upper Limit of Normal
USPI
US Package Insert
WOCBP
WHO
Women of Childbearing Potential
World Health Organization


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1
INTRODUCTION AND RATIONALE
1.1
Background
Biohaven Pharmaceuticals, Inc. [Biohaven] is developing a new drug, troriluzole (BHV4157),
for the treatment of neurologic and psychiatric disorders. Troriluzole is a novel and optimized 
prodrug of the glutamatergic agent riluzole. The FDA originally approved riluzole 
(RILUTEK®) 50 mg twice-a-day (NDA #20-599) for the treatment of patients with 
Amyotrophic Lateral Sclerosis (ALS). Riluzole, which is only indicated for ALS, has been 
marketed globally for over 20 years and is considered safe and well tolerated but has a number 
of non-desirable attributes that have limited its clinical use. Troriluzole is a tripeptide prodrug 
of the glutamate modulating agent riluzole that has been optimized for improved 
bioavailability, pharmacokinetics and dosing. The proposed study in GAD is based on recent 
preclinical, clinical and neuroimaging studies that implicate glutamatergic hyperactivity in the 
pathogenesis of GAD[2-8]. Biohaven hypothesizes that the glutamate modulation effects of 
troriluzole may address underlying pathologic brain function that is associated with GAD, and 
thus provide symptomatic benefit in patients suffering from GAD.
1.1.1
Generalized Anxiety Disorder (GAD)
GAD represents a disorder of significant unmet need, affecting approximately 4.3% of the 
population at some point in their life[9] Approximately one-third of cases are considered 
severe.  GAD is a chronic condition characterized by excessive anxiety and worry that is out of 
proportion to actual context and causes significant distress or functional impairment.  Rates of 
full remission have been observed to be low [10], with recovery rates from the index episode of 
less than 60% after a 12-year follow-up. Of those who experienced a recovery, approximately 
half experienced a recurrence within the same observation period [10], over 25% recurring 
within 3 years of remission [11] In clinical studies of approved treatments (SSRIs and SNRIs) 
the rates of remission are typically less than 50%[1]. Patients who experience a partial recovery 
are more vulnerable to relapse [12]. Further, patients with GAD have increased risk of 
cardiovascular disease. The social impact includes increased risk of not marrying, absenteeism 
(average of one week per month), increased risk of suicide, and high healthcare costs. Minimal 
research has been conducted on the treatment of GAD that has not responded to conventional 
therapy. Frequently treatment-resistant patients are adjunctively administered benzodiazepines 
despite the potential for abuse and consequently symptom exacerbation. Based on the unmet 
medical need described above, additional treatments are required for populations with GAD
that has not responded adequately to pharmacotherapy.
1.1.2
Rationale for Troriluzole in the Treatment of GAD
The proposed study is based on recent preclinical, clinical, and neuroimaging studies that 
implicate glutamatergic hyperactivity in the pathogenesis of GAD [2-8] Preclinical data with 
riluzole (the active metabolite of troriluzole) demonstrated rapid acting antianxiety effects in 
multiple preclinical models.  Efficacy was similar to a benzodiazepine comparator but superior 
on cognitive tests [7, 8, 13].


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Open label data also suggest benefit from the glutamate modulator riluzole in individuals with 
GAD. In a open-label study by Mathew, 12 of 15 patients treated who completed the trial 
responded positively to riluzole on the HAM-A over the 8 week course of the trial[2].  As part 
of this study, subjects received proton magnetic resonance spectroscopy and magnetic 
resonance imaging scans to measure the effect of riluzole on N-acetylaspartate (NAA), which 
is a mitochondrial amino acid considered to be a marker of neuronal integrity.  In general, 
responders showed increases in hippocampal NAA compared to nonresponders and a 
relationship was seen between changes in hippocampal NAA and anxiety symptoms at study 
end compared to baseline [3].   In addition, MRI showed a positive correlation between 
hippocampal volume, NAA concentration and HAM-A improvement [4].  
The tremendous unmet medical need in anxiety disorders combined with favorable clinical 
experience with riluzole to date, warrant the identification and clinical development of an 
optimized formulation of riluzole.  The therapeutic potential of riluzole has been suggested by 
multiple clinical reports and trials on its active metabolite suggesting favorable effects in 
patients with a variety of psychiatric  conditions.
1.1.2.1
Pre-Clinical Studies
Data from preclinical studies support the following findings. Please refer to the IB for 
additional pre-clinical information. 
No activity at a broad screen of enzymes and receptors, including hERG
Toxicology studies in rats and monkeys reveal no novel findings relative to what has been 
reported for riluzole;
Safety pharmacology studies indicate no clinically relevant changes in hERG, 
cardiovascular parameters or respiratory parameters. Minimal changes on neurobehavioral 
parameters at high dose levels are consistent with the known sedative effects of riluzole in 
rats;
No signals for carcinogenicity (negative for Ames assay, in vitro chromosomal aberrations 
and in vivo micronucleus) 
1.1.2.2
Clinical Experience
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The longer-term safety profile of troriluzole is expected to be similar to riluzole based on the 
following: 
Troriluzole is a tripeptide prodrug of riluzole. It readily metabolizes to riluzole and
composite amino acids, sarcosine and glycine. These amino acids are generally non- toxic 
and will be taken up into their normal physiologic role in the body; 
Troriluzole was designed to be stable enough to bypass first-pass metabolism before being 
metabolized.  Performance in healthy volunteers has been similar to what has been 
observed in preclinical species, insofar as the concentrations of troriluzole have been 
negligible compared to active metabolite and time to peak concentration of the active 
metabolite has been delayed relative to troriluzole. In addition, the time to peak 
concentration of the active metabolite (Tmax) is delayed compared to troriluzole.  This 
Tmax is longer than that seen with rilutek tablets.  This PK pattern of delayed time to peak 
riluzole concentration is consistent with diminished first pass liver metabolism.
Troriluzole has no relevant intrinsic receptor activity as tested in 88 ion channels and 
receptors, including hERG; 
Toxicology assessments in two preclinical species reflect no novel safety signals as 
compared to riluzole; 
Troriluzole, dosed between 140-280 mg, contains a comparable molar amount of riluzole as 
found in a 70-140 mg dose of riluzole, well below the 200 mg daily dose of riluzole that has 
been studied in frail subjects with Amyotrophic Lateral Sclerosis where it was found to be 
safely administered and generally well-tolerated.  
1.1.2.2.1
BHV4157 Phase I 
Refer to the Investigators Brochure for detailed and updated information on Phase 1 studies. 
1.1.2.2.2
Troriluzole Phase I - Study BHV4157-101
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1.1.2.2.2.1
Study BHV4157-102
1.1.2.2.2.2
Study BHV4157-103
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1.1.2.2.3
BHV4157 Phase 2 – BHV4157-201
BHV4157-201 was a Phase 2b/3, multicenter, randomized, double-blind, placebo-controlled 
parallel-group study designed to assess the safety, tolerability, and efficacy of troriluzole in 
subjects with spinocerebellar ataxia (SCA). Subjects were randomized to receive troriluzole
(140 mg PO once daily [QD]) or placebo for 8 weeks. A total of 141 subjects were randomized 
into the double-blind randomization phase (71 subjects in the troriluzole 140 mg QD group and 
70 subjects in the placebo group). 
During the double-blind randomization phase, administration of troriluzole at 140 mg QD for 8 
weeks was well tolerated in adult subjects with SCA. There were no deaths reported during the 
randomization phase of this study. Treatment-emergent SAEs were reported for 5 (3.55%) 
subjects, including 4 troriluzole-treated subjects (asthenia, atrial fibrillation, blood creatine 
phosphokinase increased, dehydration, back pain and cerebral infarction), and 1 placebo- 
treated subject (chest discomfort). No clinically meaningful trends in laboratory values were 
identified in this study. No subject had AST or ALT laboratory abnormalities > 3 X ULN. 
Subjects who completed the double-blind randomization phase were offered 96 weeks of open- 
label treatment with troriluzole (140 mg PO QD) in an extension phase. In the first 48-week 
portion of the Extension Phase, subjects who experienced a decline (as defined by 
demonstration of a 2 point or greater decline from baseline on the SARA scale on each of the 
two most recent consecutive visits accompanied by PI impression of clinical worsening) may 
be increased to 280 mg daily.  One hundred and thirty (131) subjects continued into the open-
label extension phase, which is currently on-going.  To date, the preliminary safety profile of 
troriluzole 140 mg QD is consistent with the troriluzole safety profile observed during the 
randomization phase. 
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1.1.3
Potential for Drug-Drug Interactions
Troriluzole: Troriluzole, itself, is not expected to interfere with drug metabolism and its 
cleavage via plasma peptidases renders it unlikely to be affected significantly by liver 
cytochrome P450 inhibitors. Troriluzole has the following known pharmacokinetic/metabolism 
parameters:
Not an inhibitor of CYP3A4, CYP1A2, or CYP2D6
In CYP induction studies:
o
The estimated E
-fold 
induction, respectively;
o
-fold 
induction, respectively; and
o
Troriluzole did not increase CYP3A4 mRNA at doses up to 30
Riluzole Metabolism: Troriluzole metabolizes to riluzole. As per the USPI, riluzole metabolism 
has been assessed in special populations, characterized by hepatic impairment (2 to 3 fold 
increase in AUC with Child-Pugh Scores of A and B), renal impairment (no effect), age (no 
effect), gender (no effect), smokers (20% faster elimination) and race (Japanese compared to 
Caucasians: no effect).
Effect of other drugs on Riluzole metabolism: In vitro studies using human liver microsomal 
preparations suggest that CYP1A2 is the principal isozyme involved in the initial oxidative 
metabolism of riluzole and, therefore, potential interactions may occur when riluzole is given 
concurrently with agents that affect CYP1A2 activity. Potential inhibitors of CYP1A2 (e.g., 
cimetidine, ciprofloxacin, enoxacin, fluvoxamine, methoxsalen, mexiletine, oral 
contraceptives, thiabendazole, vemurafenib, zileuton) could decrease the rate of riluzole 
elimination, while inducers of CYP1A2 (e.g., cigarette smoke, charcoal-broiled food, 
rifampicin, and omeprazole) could increase the rate of riluzole elimination.
Effect of Riluzole on the Metabolism of Other Drugs: CYP1A2 is the principal isoenzyme 
involved in the initial oxidative metabolism of riluzole; potential interactions may occur when 
riluzole is given concurrently with other agents which are also metabolized primarily by 
CYP1A2 (e.g., theophylline, caffeine, and tacrine). Currently, it is not known whether riluzole 
has any potential for enzyme induction in humans.
Clinical drug interaction studies for troriluzole have not been conducted yet.
1.1.4
Clinical Adverse Event Profile
Troriluzole readily metabolizes to riluzole. Therefore, the 20 years’ global clinical experience 
is important to summarize herein.


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1.1.4.1
Troriluzole Phase I Studies
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1.1.4.2
BHV4157-201:  Phase 2 Clinical Adverse Event Profile
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1.1.4.3
Riluzole
Clinical information on riluzole, as reflected in the USPI, is predominantly based on experience 
from approximately 4000 patients given riluzole for ALS. Refer to the US Prescribing 
Information (15) where greater details on the adverse event profile of riluzole can be found.  
The following summarizes relevant information.
Overall, riluzole tablets have been well tolerated in populations with ALS and diverse 
neuropsychiatric conditions that include Major Depressive Disorder (MDD), Generalized 
Anxiety Disorder (GAD) and spinocerebellar ataxia. In randomized controlled trials 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 (16). The published literature on the use of riluzole tablets in 
psychiatric disorders, while generally comprised of case-series, is consistent with this 
tolerability profile.
The most commonly observed AEs associated with the use of riluzole tablets more frequently
than placebo treated patients were:
asthenia;
nausea;
dizziness;
decreased lung function;  
diarrhea;
abdominal pain; 
pneumonia; 
vomiting;
vertigo; 
circumoral paresthesia;
anorexia; and
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somnolence.
Approximately 14% (n = 141) of the 982 individuals with ALS who received riluzole in pre-
marketing clinical trials discontinued treatment because of an adverse experience. Of those 
patients who discontinued due to adverse events, the most commonly reported were: nausea, 
abdominal pain, constipation, and ALT elevations. In a dose response study in ALS patients, 
the rates of discontinuation of RILUTEK for asthenia, nausea, abdominal pain, and ALT 
elevation were dose related. The AEs of asthenia, nausea, dizziness, diarrhea, anorexia, vertigo, 
somnolence, and circumoral paresthesia were dose related. Assessment of pulmonary AEs is 
confounded by the underlying illness, ALS, which is associated with respiratory symptoms.
1.1.4.3.1
Elevations in Liver Function Tests
Troriluzole has not been associated with significant changes in liver function or pathology in 
nonclinical toxicology studies to date, as reflected in the IB. No clinically significant LFT 
changes were observed on study drug in BHV4157-101.  In the ongoing clinical trial in SCA, 
LFTs remain blinded; however, no subjects were required to discontinue study medication due 
to elevated LFTs.  
Riluzole is associated with elevations in aminotransferases that have been reflected in 
monitoring precautions that will be followed within this protocol. 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 X ULN, 
and about 2% of patients will have elevations > 5 X ULN. A single non-ALS patient with 
epilepsy treated with concomitant carbamazepine and phenobarbital experienced marked, rapid 
elevations of liver enzymes with jaundice (ALT 26 X ULN, AST 17 X ULN, and bilirubin 11 
X ULN) four months after starting riluzole; these returned to normal 7 weeks after treatment 
discontinuation. Maximum increases in serum ALT usually occurred within 3 months after the 
start of riluzole therapy and were usually transient when < 5 times ULN. In trials, if ALT levels 
were < 5 times ULN, treatment continued and ALT levels usually returned to below 2 times 
ULN within 2 to 6 months. Treatment in studies was discontinued, however, if ALT levels 
exceeded 5 X ULN, so that there is no experience with continued treatment of ALS patients 
once ALT values exceed 5 times ULN. There were rare instances of jaundice. There is limited 
experience with rechallenge of patients who have had riluzole discontinued for ALT > 5 X 
ULN, but there is the possibility of increased ALT values reoccurring. Therefore, rechallenge is 
not recommended. In post-marketing experience, cases of clinical hepatitis associated with 
riluzole have been reported, including one with fatal outcome.
1.1.4.3.2
Neutropenia
Troriluzole has not been associated with hematologic findings in nonclinical toxicology studies 
to date. In Study BHV4157-101, one subject in the 17.5 mg BID cohort experienced transient 
and mildly decreased white blood cell count after three days of treatment; however, this subject 
evidenced moderate decline during the screening period prior to medication administration.  
The subject’s count increased while on continued study drug and normalized within 6 days 
after onset.


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For riluzole, according to the USPI, rare cases of neutropenia were reported. Among 
approximately 4,000 patients given riluzole for ALS in clinical trials, there were three cases of 
marked neutropenia (absolute neutrophil count less than 500/mm3), all seen within the first 2 
months of riluzole treatment. In one case, neutrophil counts rose on continued treatment. In a 
second case, counts rose after therapy was stopped. A third case was more complex, with 
marked anemia as well as neutropenia and the etiology of both is uncertain. Patients should be 
warned to report any febrile illness to their physicians. The report of a febrile illness should 
prompt treating physicians to check white blood cell counts.
1.1.4.3.3
Interstitial Lung Disease
Troriluzole has not been associated with pulmonary findings in nonclinical toxicology studies 
to date.
For riluzole according to the USPI, rare cases of interstitial lung disease have been reported, 
some of them severe; upon further investigation, many of these cases were hypersensitivity 
pneumonitis. If respiratory symptoms develop such as dry cough and/or dyspnea, chest 
radiography should be performed, and in case of findings suggestive of interstitial lung disease 
or hypersensitivity pneumonitis (e.g., bilateral diffuse lung opacities), riluzole should be 
discontinued immediately. In the majority of the reported cases, symptoms resolved after drug 
discontinuation and symptomatic treatment.
1.1.5
Potential Risk to Fetal Development
Troriluzole has not yet been assessed in fertility and fetal development studies.
As described in the USPI, oral administration of riluzole to pregnant animals during the period 
of organogenesis caused embryotoxicity in rats and rabbits at doses of 27 mg/kg and 60 mg/kg, 
respectively, or 2.6 and 11.5 times, respectively, the recommended maximum human daily 
dose on a mg/m2 basis. Evidence of maternal toxicity was also observed at these doses. When 
administered to rats prior to and during mating (males and females) and throughout gestation 
and lactation (females), riluzole produced adverse effects on pregnancy (decreased 
implantations, increased intrauterine death) and offspring viability and growth at an oral dose 
of 15 mg/kg or 1.5 times the maximum daily dose on a mg/m2 basis. There are no adequate and 
well-controlled studies in pregnant women. Riluzole should be used during pregnancy only if 
the potential benefit justifies the potential risk to the fetus.
1.2
Study Rationale
1.2.1
Study Design Rationale
Troriluzole is a glutamate modulating drug that is being developed for the potential treatment 
of spinocerebellar ataxia (SCA), Obsessive Compulsive Disorder (OCD) and Alzeimer’s 
disease. This protocol represents the first trial of troriluzole in Generalized Anxiety Disorder
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Troriluzole is a novel tripeptide prodrug of the glutamate modulating agent riluzole. The 
proposed study is based on recent preclinical, clinical and neuroimaging studies that implicate 
glutamatergic hyperactivity in the pathogenesis of GAD[2-8]. While troriluzole has yet to be 
studied in GAD, studies with riluzole in populations with GAD provide support for the 
therapeutic potential of troriluzole[2-4]. Trials have also suggested the benefit of riluzole in 
individuals with OCD [17, 18].
Riluzole has several modes of action; prominent among them, are a reduction in glutamate 
outflow due to effects on the excitatory amino acid transporters [19]. Given the evidence for 
the potential role of glutamate in GAD, and that troriluzole is a prodrug of riluzole, it is 
hypothesized that it would be expected to have therapeutic value in GAD as a glutamate 
modulating agent.
Troriluzole was developed to advance upon the limitations of riluzole that have restricted its 
broader clinical application. Riluzole tablets have 60% bioavailability, attributed to high first-
pass metabolism in the liver. This is thought to be related to metabolism by the 
heterogeneously expressed CYP1A2 enzyme, which is also attributable to the high PK 
variability associated with riluzole. In addition, riluzole is associated with reduced exposure 
when taken with meals (i.e., a negative food effect), resulting in the guidance to take riluzole 
within a three hour fast (one hour before or two hours after a meal). Riluzole is also dosed 
twice a day, has dose-dependent effects on liver function tests and the drug substance itself has 
other intrinsic limitations including: very low solubility in water, poor oral palatability, pH 
dependent chemical stability and intense oral numbness if administered directly to the oral 
mucosa.
In an effort to mitigate the aforementioned limitations of riluzole, several classes of prodrugs 
were designed, synthesized, and evaluated in multiple in vitro stability assays to predict in vivo 
drug levels [20]. Troriluzole is a third generation of prodrug development representing 
multiple years of chemistry effort with optimized in vivo and in vitro features based on stability 
while transiting the digestive system, enhanced gastrointestinal absorption, avoidance of first 
pass metabolism, favorable safety pharmacology, metabolic cleavage in the plasma, and 
enhanced pharmacokinetic properties.
Based on the preclinical features of troriluzole, we anticipate the clinical pharmacology to offer 
favorable properties as compared to available riluzole:
Troriluzole is expected to have better oral bioavailability;
Troriluzole is designed to release riluzole after bypassing first-pass metabolism and thus 
confer lower overall drug burden to the liver, which may translate into a better safety and 
tolerability profile as well as reduced pharmacokineticvariability;
Troriluzole is expected to allow for once daily dosing, thus improving medication 
compliance;


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Troriluzole is expected to be readily absorbed in both the fasting and fed states; thus, the 
prodrug is not anticipated to require any special meal restrictions. In contrast, oral riluzole 
tablets require a 3-hour window of fasting around the two daily doses; 
1.2.2
Dose Selection 
1.3 
 Research Hypothesis
Troriluzole monotherapy is associated with superior therapeutic effects as compared to placebo 
over an 8 week treatment period in patients with Generalized Anxiety Disorder. 
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2
STUDY OBJECTIVES
2.1
Primary
The primary objective of the study is to evaluate the efficacy of troriluzole compared to 
placebo after 8-weeks of treatment in subjects with GAD, as measured by the Hamilton 
Anxiety Rating Scale (HAM-A) scale (SIGH-A version).
2.2
Secondary
To assess the safety and tolerability of troriluzole, relative to placebo, in subjects with GAD
Evaluate the efficacy of troriluzole compared to placebo on functional disability as 
measured by the Sheehan Disability Scale (SDS)
Evaluate the efficacy of troriluzole compared to placebo on global functioning as measured 
by the Clinical Global Impression - Severity Scale (CGI-S)
2.3
Exploratory 
Evaluate the effects of troriluzole compared to placebo on cognitive performance as 
measured by the Digit Symbol Substitution Task (DSST) and the Hopkins Verbal Learning 
Test-Revised (HVLT-R)
Evaluate the efficacy of troriluzole compared to placebo on improvement in global 
functioning as measured by the Clinical Global Impression - Improvement Scale (CGI-I)
Evaluate the efficacy of troriluzole compared to placebo on depressive symptomatology as 
measured by the Hamilton Depression Rating Scale-17 (HAM-D-17) scale (SIGH-D
version)
Evaluate the efficacy of troriluzole compared to placebo on anxiety symptoms as measured 
by the Penn State Worry Questionnaire (PSWQ)
To characterize the pharmacokinetics of troriluzole based on sparse sampling
Evaluate correlates of placebo responsiveness by using the Clinical Trial and Site Scale-B
(CTSS-B) as well as other pre-intervention outcome measures and demographic 
information 


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3
STUDY ENDPOINTS
3.1
Primary
Improvement in generalized anxiety disorder is assessed using the change in the Hamilton 
Anxiety Rating Scale (HAM-A) total score from baseline to the end of the double-blind 
phase of the study (Week 8).
3.2
Secondary
Safety and tolerability are assessed using the frequency of unique subjects with: serious 
adverse events; adverse events leading to discontinuation; adverse events judged to be 
related to study medication; and clinically significant laboratory abnormalities that are 
observed during the double-blind phase.
Improvement in functional disability is assessed using the change in the Sheehan Disability 
Scale (SDS) total score from baseline to the end of the double-blind phase. 
Improvement in global clinical condition is assessed using the Clinical Global Impression 
of Severity Scale (CGI-S) at the end of the double-blind phase of the study. 
3.3
Exploratory 
Improvement in cognitive performance is assessed by using the Digit Symbol Substitution 
Test (DSST) and the Hopkins Verbal Learning Test-Revised (HVLT-R) from baseline to 
the end of the double blind phase
Improvement in global clinical condition is assessed using the Clinical Global Impression 
of Improvement Scale (CGI-I) at the end of the double-blind phase of the study. 
Improvement in depressive symptomatology is measured by the change in the Hamilton 
Depression Rating Scale-17 (HAM-D-17) from baseline to the end of the double-blind 
phase
Improvement in anxiety is assessed using the change in the Penn State Worry 
Questionnaire (PSWQ) from baseline to the end of the double blind phase
The pharmacokinetic profile of troriluzole is characterized by blood concentrations 
observed in treated subjects
The Clinical Trial and Site Scale-B (CTSS-B) (total score, subitems, other pre-intervention 
outcome measures and demographics) will be used to characterize correlates of placebo 
responsiveness (as defined by changes on the HAM-A and SDS)


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4
STUDY PLAN
4.1
Study Design and Duration
BHV4157-207 is a Phase III, multicenter, randomized, double-blind, 2-arm placebo- controlled 
parallel-group study designed to assess safety, tolerability, and efficacy of troriluzole in a 
population of patients with Generalized Anxiety Disorder who have a Hamilton Anxiety Rating 
Scale (HAM-A) score of 18 or greater at screening and baseline.  Additionally, GAD
year and at least of moderate severity on the 
Clinical Global Impression - Severity of Illness Scale at study entry.
Qualifying subjects will receive either troriluzole 100 mg BID or Placebo BID during the 
randomization phase of the trial. Dosing will continue for 8 weeks. Subjects will return to the 
clinic two weeks after discontinuing study medication for a follow-up safety visit. In addition, 
subjects completing the Randomization Phase will be offered approximately 48 weeks of open-
label treatment as long as the investigator believes open-label treatment offers an acceptable 
risk-benefit profile. Subjects who agree to enter the Extension Phase will not complete the 
follow-up safety visit and should continue dosing as specified.
Subjects entering the Extension Phase will have their first Extension Visit four weeks after the 
Week 8 Randomization Phase visit. Thereafter, subjects will undergo visits every four weeks 
up through week 12 of the Extension Phase as outlined in Table 2 (Schedule of 
Assessments/Time & Events- Extension Phase). Subjects will then undergo visits every 12 
weeks up to Week 48 of the Extension phase. All subjects will undergo a termination visit two 
weeks after the last dose of study drug.
Subjects entering the Extension Phase will continue with the same dose taken at the end of the 
Randomization Phase. 
Subjects will be assessed at clinic visits per the Schedule of Assessments/Time & Events.


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4.2
Study Schematic
Figure 1:
Study Schematic


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4.3
Schedule of Assessments
Table 2:
Schedule of Assessments and Events - Randomization Phase
Screening Phase a
(2-35 Days)
Treatment Phase (8 Weeks)
End of Week (+/- 2 days)
Follow-up
End of Weekb
(+/- 2 days)
Screen 
Visit a
Baseline Visit a
(Randomization)
2
4
6
8 or Early 
Term
10
Procedure
Eligibility Assessments
Informed Consent (IC)
X
Pharmacogenetic IC
X
Demographic Data 
X
Inclusion/Exclusion 
Criteria
X
X
Medical History c
X
Xc
Prior & Concomitant 
Medication c
X
Xc
X
X
X
X
X
SAFER Interview d
X
Psychiatric Evaluation
Psychiatric History c
X
Xc
Mini International 
Neuropsychiatric Interview 
(MINI)
X
Safety Assessments
Physical Examination
X
X
Vital Signs
X
X
X
X
X
X
X
Physical Measurements 
(weight and height)
X
X
X
Adverse Event 
Assessmentc
X
X
X
X
X
X
X
12 Lead ECG
X
X
X
Laboratory Assessments 
including urinalysis e
X
X
X
X
Serology f
X
Serum Pregnancy Test g
X
X
X
X
X
X
Urine Pregnancy Test g
X
X
X
X
X
Urine Drug Screen h
X
X
Blood Alcohol Test i
X


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Screening Phase a
(2-35 Days)
Treatment Phase (8 Weeks)
End of Week (+/- 2 days)
Follow-up
End of Weekb
(+/- 2 days)
Screen 
Visit a
Baseline Visit a
(Randomization)
2
4
6
8 or Early 
Term
10
Sheehan Suicidality 
Tracking Scale (S-STS) j
X
X
X
X
X
X
X
Pharmacokinetic Sampling
k
X
X
X
Pharmacogenomic 
Sampling
X
X
Clinical Outcome 
Assessments
Hamilton Anxiety Rating 
Scale (HAM-A)
X
X
X
X
X
X
Placebo-Control Reminder 
Script (PCRS)l
X
X
X
X
X
X
Sheehan Disability Scale 
(SDS) m
X
X
X
Hamilton Depression 
Rating Scale (HAM-D-17)n
Xn
X
X
Clinical Global 
Impressions -Improvement 
Scale (CGI-I)
X
X
X
X
Clinical Global 
Impressions-Severity Scale 
(CGI-S)
X
X
X
X
X
X
Penn State Worry
Questionnaire (PSWQ)
X
X
Cognitive Test Battery o
X
X
Clinical Trial and Site 
Scale-B (CTSS-B)
X
Clinical Drug 
Supplies/Study Supplies
Randomization
X
Dispense Study 
Medication p
X
X
X
Drug Accountability
X
X
X
X
Return Unused Study 
Medication
X
X
a Screening/Baseline Phase will be 2 - 35 days. The Baseline Visit may be scheduled but should only occur after 
all screening procedures are complete, patient meets inclusion/exclusion criteria, and lab test and ECG results 
have been received and reviewed by the site. Screening procedures may be performed any time during the 
Screening Phase.  All Screening safety data must be reviewed by a physician prior to randomization into the 
Treatment Phase.
b Only for subjects NOT entering the extension phase, or who discontinue early from the Treatment Phase.
Subjects entering the extension phase will not require the 2-week post dose visit.
c Confirm medical and psychiatric history and update if necessary. Prior & Concomitant medications should be 
captured for the 30 days prior to screening.


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d The SAFER Interview will be conducted remotely with the subject by a CRO shortly after the screening visit. A
SAFER pass is necessary for randomization.
e Laboratory Tests are not required to be fasting.
fHBsAg, HCV and HIV antibody, RPR
g Serum pregnancy test (b-hcg) conducted at screening and at subsequent visits. Urine pregnancy test conducted 
prior to dosing at baseline and at subsequent visits. The site may test a patient at any time if pregnancy is 
suspected.
h Urine drug test to be conducted at screening and EOS visit and at unscheduled visit at the discretion of the 
investigator.  Reflex confirmatory drug testing will be conducted for all positive urine drug screen samples. The 
urine drug screen must be negative for drugs of abuse including cocaine, amphetamines, barbiturates, 
phencyclidine, cannabis or opioids.
i The blood alcohol level must be < 50 mg/dl.
j Timeframe for S-STS is 6 months prior to Screening and since last visit for subsequent visits.
k Plasma samples for PK will be collected at random at Weeks 2, 6 and 8. Date and time of doses on the day of 
each visit and the day prior will be collected in case report forms along with time of last meal. PK samples should 
also be drawn when there are any SAEs or severe AEs during both the Randomization and Extension Phase of the 
study that are assessed as possibly drug related. Subjects who are able to schedule a morning visit at Weeks 2 and 
6 can be instructed to hold their dose of study drug that morning until after a PK trough sample is obtained, if 
possible and appropriate.
l The PCRS is administered prior to the HAM-A at every visit for every subject. There are unique scripts for each 
phase (Randomization and Extension) please use the appropriate script for each phase and document the time of 
administration of both the PCRS and HAM-A.
m If a subject checks the “not working” box for the Work/School item on the SDS, you MUST check compliance to 
this instruction, before the visit ends.
n HAM-D Item 1 ONLY to be performed at screening.  The full HAM-D is required at all other specified visits.
o The Cognitive Test Battery performance is assessed by using the Digit Symbol Substitution Task (DSST) and the 
Hopkins Verbal Learning Test-Revised (HVLT-R).
p Study Drug will be dispensed at the baseline visit and subsequent visits per visit schedule. Subjects should take 
the first dose the day after the baseline visit. Study drug will be dispensed at Week 8 if subject is deemed eligible 
and agreed to participate in the Extension Phase.


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Table 3:
Schedule of Assessments and Events - Extension Phase
Extension Phase (48 Weeks)
End of Week (+/- 5 days)
Follow-up
End of Week (+/- 2
days)
4
8
12
24
36
48
or Early Term
50
Procedure
Safety Assessments
Physical Examination
X
Vital Signs
X
X
X
X
X
X
X
Physical Measurements 
(weight and height)
X
X
X
X
Adverse Event Assessment
X
X
X
X
X
X
X
Concomitant Medication 
Review
X
X
X
X
X
X
X
12 Lead ECG
X
X
X
X
X
Laboratory Assessments 
including urinalysis
X
X
X
X
X
X
Serum Pregnancy Test a
X
X
X
X
X
X
Urine Pregnancy Testa
X
X
X
X
X
X
Urine Drug Screen b
X
X
X
X
X
X
Sheehan Suicidality 
Tracking Scale (S-STS) c
X
X
X
X
X
X
X
Clinical Outcome 
Assessments
Hamilton Anxiety Rating 
Scale (HAM-A)
X
X
X
X
X
X
Placebo-Control Reminder 
Script (PCRS) d
X
X
X
X
X
X
Sheehan Disability Scale 
(SDS)e
X
X
X
X
X
X
Hamilton Depression Rating 
Scale (HAM-D-17)
X
X
X
X
Clinical Global 
Impressions-Improvement 
Scale (CGI-I)
X
X
X
X
X
X
Clinical Global 
Impressions-Severity Scale 
(CGI-S)
X
X
X
X
X
X
Penn State Worry 
Questionnaire (PSWQ)
X
X
X
X
X
X
Clinical Drug 
Supplies/Study Supplies
Dispense Study Medication
X
X
X
X
X
Drug Accountability
X
X
X
X
X
X
Return Unused Study 
Medication
X
X
X
X
X
X


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a Serum and urine pregnancy tests to be conducted at each visit. The site may test a patient at any time if pregnancy 
is suspected. Subjects will be provided with urine pregnancy tests to take in between the Visit week 12, 24, 36 and 
Visit week 48 office visit. Subjects should be instructed to contact the study doctor if they become pregnant at any 
time during the study. Site should also contact the subject in between the 3-month office visits to remind them of 
the pregnancy testing requirement, as applicable.
bReflex confirmatory drug testing will be conducted for all positive urine drug screen samples.
cTimeframe for S-STS is 6 months prior to Screening and since last visit for subsequent visits.
dThe PCRS is administered with the HAM-A at every visit for every subject. There are unique scripts for each 
phase (Randomization and Extension) please use the appropriate script for each phase and document the time of 
administration of both the PCRS and HAM-A.
eIf a subject checks the “not working” box for the Work/School item on the SDS, you MUST check compliance to 
this instruction, before the visit ends.


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4.3.1
Screening Phase
The Screening Phase will range from a minimum of 2 days to a maximum of 35. The purpose of 
the Screening Visit is to ensure that the appropriate subjects are entered into the trial and remain 
stable during the pre-treatment phase. The investigator will determine that the subject meets 
eligibility criteria and will collect demographic and medical data presenting a full characterization 
of the subject. All attempts should be made to obtain medical and pharmacy records to confirm 
the subject’s medical and medication treatment history. It is estimated approximately 372 subjects 
will enter the randomization phase of the trial.
The SAFER interview will be conducted remotely with the subject by a CRO shortly after 
the screening visit.  A SAFER pass is necessary for the subject to be randomized.
Please refer to the Schedule of Assessments/Time & Events for details on Screening Procedures.
4.3.2
Randomization Phase
Subjects who are determined to be eligible for the study will enter the Randomization Phase. 
Subjects will receive troriluzole (100 mg BID) or placebo (BID) (in a 1:1 ratio).
Dosing will continue for 8 weeks. Subjects will return to the clinic two weeks after discontinuing 
study medication for a follow-up safety visit (unless they are continuing in the Extension Phase).
If subjects have difficulty tolerating BID dosing due to morning dosing of 100 mg (such as 
experiencing sedation) then the investigator may permit the subject to switch to dosing of 200 mg 
at night time only (and document this change in the subject’s records).
Down titration to 100 mg will only be allowed to address tolerability issues and only with medical 
monitor approval. If a subject down titrates they will need to stay on that dose for the duration of 
the Randomization Phase. 
Subjects should take their medication twice a day, doses should be taken in the mornings and 
evenings approximately 12 hours apart.  If tolerability issues arise please refer to Section
9.2.5.
Please refer to the Schedule of Assessments/Time & Events for details on procedures during the 
Randomization Phase. There is a visit window of +/- 2 day visit window during the 
Randomization Phase of the study. It is estimated that approximately 372 subjects will enter this 
phase of the trial.
4.3.3
Extension Phase (if applicable)
Subjects completing the Randomization Phase will be offered approximately 48 weeks of open-
label treatment as long as the PI believes open-label treatment offers an acceptable risk-benefit 
profile. 


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Subjects will have visits in the Extension Phase every four weeks through Week 12 and then 
every 12 weeks thereafter up to Week 48. All subjects will undergo a termination visit two weeks 
after the last dose of study drug.
Subjects entering the Extension phase will continue on the same dose that was taken at the end of 
the Randomization phase.
If subjects have difficulty tolerating BID dosing due to morning dosing of 100 mg (such as 
experiencing sedation) then the investigator may permit the subject to switch to dosing of 200 mg 
at night time only (and document this change in the subject’s records).
Down titration to 100 mg will only be allowed to address tolerability issues. Subjects may be 
rechallenged to increase to 100mg BID during the Extension Phase at the discreation of the 
investigator.
All visits of the Extension Phase will be open-label.
Please refer to the Schedule of Assessments/Time & Events for details on procedures during the 
Extension Phase. There is a visit window of +/- 5 days during the Extension Phase of the study.
4.4
Post Study Access to Therapy (if applicable)
No other study drug access is available after the Extension Phase.
5
POPULATION
5.1
Number of Subjects
Approximately 372 subjects are expected to be randomized in this study.
5.2
Inclusion Criteria
1. Informed Consent
a.
Subjects (or legally acceptable representative as required by the IRB/IEC) must provide a 
written signed informed consent form/forms (IRB/EC specific) prior to the initiation of 
any protocol required procedures.
2. Age and Sex
a.
Male and female outpatient subjects between the ages of 18 - 65, inclusive.
3.
Target Population
a.
Primary diagnosis of generalized anxiety disorder (GAD) either moderate or severe as per 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) as 
confirmed by the MINI at Screening, in addition to a psychiatric evaluation by a board-
certified or Biohaven-approved board-eligible psychiatrist; The duration of illness must be 
1 year;


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b. HAM-A Total Score of 
18 at both Screening and Baseline;
c.
HAM-A anxiety and tension item scores
2 at both Screening and Baseline;
d. CGI-
both Screening and Baseline;
e.
Baseline Visit HAM-A Total Score not more than 30% below the Screening Visit HAM-A
Total Score;
f.
Determined by the investigator to be medically stable at baseline/randomization as 
assessed by medical history, physical examination, laboratory test results, and 
electrocardiogram testing. Subjects must be physically able and expected to complete the 
trial as designed;
g. Minimum of 6 years of education or equivalent to complete necessary scales and 
understand consent forms;
h. Subjects must have adequate hearing, vision, and language skills to perform 
neuropsychiatric testing and interviews as specified in the protocol;
i.
Subjects must be able to understand and agree to comply with the prescribed dosage 
regimens and procedures; report for regularly scheduled office visits; and reliably 
communicate with study personnel about adverse events and concomitant medications; 
j.
It is required that all women of child-bearing potential (WOCBP) who are sexually active 
agree to use two methods of contraception for the duration of the study (i.e. beginning 30 
days prior to baseline and extending to 30 days after the last dose of study drug). 
The two methods should include: 
1. one barrier method (e.g. diaphragm with spermicide, condom with spermicidal 
gel, intrauterine devices, cervical cap); 
2. and one other method. The other method could include hormonal contraceptives 
(e.g. oral contraceptives, injectable contraceptives or contraceptive implant) or 
another barrier method (Section 5.5); 
k. Women of childbearing potential must have a negative serum pregnancy test at 
screening and a negative urine pregnancy test prior to dosing at Baseline; 
l.
It is required that men who are sexually active with WOCBP agree to use two methods of 
contraception for the duration of the study (beginning at first treatment and extending to 
90 days after the last dose of study drug). 
5.3
Exclusion Criteria
1. Target Disease Exceptions
a.
Subjects with a primary DSM-5 psychiatric disorder diagnosis other than GAD 
within the past 6-months. Note: Subjects with a secondary diagnosis of 
comorbid social anxiety disorder or specific phobia are allowed, if in the 
investigator’s judgement, the diagnosis is not sufficiently prominent and 
active so as to confound the assessment of GAD symptoms
b. Subjects should be excluded at screening or baseline if any medical or 
psychiatric condition other than GAD, as specified in the inclusion criteria, 
could predominantly explain or contribute significantly to the subjects’
symptoms or that could confound assessment of GAD symptoms;


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c.
Patients who report a history of inadequate response (per investigator 
judgement) to three (3) or more adequate trials (including current trial) of any 
SSRI or SNRI, at an adequate dose and adequate duration (at least 8 weeks) for 
the treatment of GAD within the 3 years prior to randomization;
d. Current diagnosis of:
i.
Delirium, dementia, amnesic or other cognitive disorder
ii.
Bipolar I or II disorder, 
iii.
Schizophrenia or other psychotic disorders, schizoaffective 
disorder, autism or autistic spectrum disorders, Tourette’s 
disorder, body dysmorphic disorder, hoarding disorder;
iv.
Persistent depressive disorder
v.
Obsessive Compulsive Disorder, Panic Disorder, Post-
Traumatic Stress Disorder, Social Anxiety Disorder or 
Specific Phobia (if primary diagnosis);
e.
Major Depressive Disorder or Unspecified Depressive Disorder within the last 6 
months prior to Screening;
f.
HAM-D-17 item 1 of >1 at Screening or Baseline;
g. HAM-D-17 of > 19 at Baseline;
h. Subjects with clinically significant DSM-5 diagnosis of borderline, antisocial, 
paranoid, schizoid, schizotypal, or histrionic personality disorder based on 
investigator’s clinical judgement if no formal diagnosis;
i.
Subjects experiencing hallucinations, delusions, or any psychotic symptoms in 
the past 3 months prior to Screening;
j.
Any eating disorder within the last 12 months prior to Screening;
k. Acute suicidality in the last 6 months, or suicide attempt or self-injurious 
behavior in the last 6 months prior to Screening;
l.
Score of >0 on the Sheehan Suicidality Tracking Scale for the period of 6
months prior to screening, and at baseline; 
m. Patients who may have received a non-biological investigational agent in any 
clinical trial within 30 days or a biological agent within 90 days prior to 
screening;
n. History of psychosurgery, deep brain stimulation (DBS) or electroconvulsive 
therapy (ECT);
o. Subjects or prisoners who are involuntarily detained or incarcerated for 
treatment of either a psychiatric or physical illness must not be enrolled into the 
study.
2. Medical History Exclusions
a.
History of substance use disorder (drug or alcohol) in the last 12 months (with the 
exception of tobacco) as defined by DSM-5 criteria;


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b. Positive urine drug screening for cannabis (both medical and recreational use of 
cannabis are prohibited; (subjects will be expected to refrain from use during
the period of the study), amphetamines (including MDMA/ecstasy), cocaine, 
barbiturate,  PCP, and/or opiates at screening or  baseline; Note: detectable levels 
of cannabis are exclusionary unless repeat measurements, before randomization, 
demonstrate that the previous test results are no longer present;
c.
Patients with a b
retested prior to randomization, if necessary.
d. Prior or current general medical condition that may confound ability to interpret 
safety and efficacy results as determined by the Investigator;
e.
Clinical history of stroke, TIA, seizure disorder, traumatic brain injury (with 
sequelae).
f.
Patients with a history of Type I or Type II insulin-dependent diabetes mellitus 
(IDDM);
g. Body mass index >40 kg/m2;
h. Active liver disease or a history of hepatic intolerance to medications that, in the 
investigator’s judgment, is medically significant; 
i.
Vitamin B12 or folate deficiency Note: Subjects with a B12 deficiency can 
participate in the study if they are on stable Vitamin B12 replacement for at least 
3 months prior to randomization and their B12 levels are within normal limits 
prior to randomization; 
j.
Hematologic or solid malignancy diagnosis within 5 years prior to screening. 
(Note: Subjects with a history of localized skin cancer, basal cell or squamous 
cell carcinoma, may be enrolled in the study as long as they are cancer free prior 
to randomization). Subjects with other localized cancers (without metastatic 
spread) who have previously completed their course of treatment more than 5
years prior to screening, are not currently receiving treatment and have been in 
remission may be enrolled only if, in the opinion of the investigator, there is no 
expectation for recurrence or further cancer treatment during the study period. 
Antihormonal therapy (e.g., tamoxifen) is allowed if the subject's cancer is in 
remission and the subject is on stable maintenance therapy to reduce their risk of 
recurrence; 
k. Any unstable cardiovascular (includes uncontrolled hypertension), pulmonary, 
gastrointestinal, or hepatic disease 30 days prior to screening;
l.
End-stage cardiovascular disease (e.g., Congestive Heart Failure New York Heart 
Association/CHF NYHA Class III or IV or unstable angina);
m. History of, or current positive rapid plasma reagin [RPR] test and a positive 
confirmatory test;


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n. History of chronic pulmonary disease or chronic pulmonary symptoms;
o. Immunocompromised subjects. Note: Subjects taking a systemic 
immunosuppressive agent may be randomized only if they are on a stable dose, 
have no clinically relevant immunosuppression, and have a white blood count 
(WBC) within normal limits;
p. History of medically significant gastrointestinal (GI) illnesses including:
i.
A current diagnosis of active, peptic ulceration or
gastrointestinal bleeding within the last 6 months and/or  
chronic inflammatory bowel disease at screening;
ii.
A history of any gastrointestinal surgery that impacts the 
absorption of study drug such as gastric bypass or 
reductive surgery;
iii.
Chronic or frequent episodes of loose stools;
q. History or evidence of any medical, neurological or psychological condition that 
would expose the subject to an undue risk of a significant adverse event or 
interfere with assessments of safety and efficacy during the course of the trial as 
determined by the clinical judgment of the investigator;
r.
Women who are pregnant or breastfeeding;
3.
Physical and Laboratory Test Findings
a.
Uncontrolled hypertension at screening (e.g., repeated diastolic 
measurements 
96 mmHg);
b. Diagnosis of hypothyroidism by a screening thyroid stimulating hormone (TSH) 
value > the upper limit of normal (ULN) and free thyroxine (T4) < the lower 
limit of normal (Note: Subjects with history of hypothyroidism may participate 
in the study, provided they are euthyroid on stable thyroid replacement therapy 
for at least 3 months prior to screening, and therapy is expected to remain stable 
during the course of the study;
c.
Hepatic test abnormalities at screening (may be repeated one time for 
confirmation in screening prior to baseline):
i.
Aspartate Aminotransferase (AST), Alanine
Aminotransferase (ALT) or GGT > 1.5 times the upper 
limit of normal; or
ii.
Total bilirubin > 2 times the upper limit of normal (ULN;
unless subject has documented history of Gilbert’s 
Syndrome in which case subject may be enrolled with 
permission of the Sponsor).
d. P-Amylase or Lipase values greater than 1.5 times the upper limit of 
normal at screening (ULN) (may be repeated one time for confirmation in 
screening prior to baseline);
e.
HbA1c > 7.0% at screening;
f.
Pathologic renal findings at screening as defined by the presence of either 
of the following criteria:


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i.
Estimated glomerular filtration rate (eGFR) according to 
the re- expressed abbreviated (four-variable) Modification 
of Diet in Renal Disease (MDRD) Study equation < 30 
ml/min/ 1.73m2; The MDRD estimation is calculated as 
follows: eGFR (mL/min/1.73m2) = 175 x (standardized 
Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if 
Black). [Scr: Standardized serum creatinine];
ii.
g. Hematologic abnormalities at screening:
i.
Hemoglobin < 10 g/dL; or
ii.
WBC < 3.0 x 103/mm3; or
iii.
Platelet count < 100,000/mm3; or
iv.
3
h. Human Immunodeficiency Virus (HIV) positive at screening (indicated by 
positive confirmatory test);
i.
HBsAg or HCV positive at screening;
j.
QTcF (Fridericia) interval 
470 msec during the screening/baseline period 
or uncontrolled arrhythmia or frequent premature ventricular contraction 
(PVCs) (> 5/minute) or Mobitz Type II second or third degree 
atrioventricular (AV) block or left bundle branch block, or right bundle 
branch
evidence of acute or 
sub-acute myocardial infarction or ischemia or other ECG findings that, in 
the investigator’s opinion, would preclude participation in the study;
k.
4.
Prohibited Treatments and/or Therapies
a.
Previous treatment with riluzole;
b. Patients who would likely require prohibited concomitant therapy after 
randomization (Refer to Section 5.4)
c.
Use of a mono-amine-oxidase (MAO) inhibitor is prohibited 30 days prior to 
randomization (baseline visit) and during the study;
d. Patients who have been treated within 7 days or 5 half lives (whichever is longer)
prior to randomization with any other psychotropic medications such as but not 
limited to the following: antipsychotics, antiepileptics (including gabapentin
[Neurontin], pregabalin [Lyrica], cambamazepine [Tegretol], lamotrigine 
[Lamictal], divalproex sodium [Depakote], valproic acid [Depakene], topiramate 
[Topamax]), lithium, diphenhydramine, N-acetylcysteine, ketamine, memantine;
e.
Stimulants are prohibited within 14 days prior to randomization and during the 
study
f.
Patients who have been treated with any antidepressant agents in the 7 days prior 
to Randomization.


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g. Patients who have been treated with fluoxetine (Prozac) in the 30 days prior to 
Randomization;
h. Patients who have been treated with sleeping agents of any kind within seven 
days prior to Randomization; Note: zolpidem, zaleplon, or eszopiclone used as 
sleeping agents, are permitted during the study up to 3 days per week. Subjects 
should be encouraged to avoid taking these medications within 8 hours of 
scheduled efficacy assessments.  See Section 5.4
i.
The use of a depot neuroleptic is prohibited 6 months prior to randomization 
(baseline visit) and during the study;
j.
Use of varenicline (Chantix) is prohibited 30 days prior to randomization 
(baseline visit) and during the randomization phase of the study;
k. Anxiolytic use (including benzodiazepines prn and buspirone) is prohibited
within 7 days of randomization and during the study. For subjects who have 
been on regular, daily benzodiazepine use, benzodiazepine use is prohibited 
30 days prior to randomization and during the study. Note: Low dose 
anxiolytic pre-medications prior to necessary medical diagnostic testing are 
allowed on a prn basis.
l.
Herbal medication and herbal supplement use within 14 days of randomization 
and during the course of the study are prohibited. 
m. Patients receiving psychotherapy (e.g., individual, group, marriage or family 
therapy) unless participation has been regular (e.g., weekly) for at least 3 months 
prior to the Screening Visit and no significant change in frequency is anticipated 
through the Week 8 visit;
n. Transcranial Magnetic Stimulation (TMS) is prohibited within three months 
prior to screening and during the study.
o. Patients taking medications that are CYP1A2 inhibitors or inducers (see 
Appendix II) should not be taking these medications for at least 5 half-lives
prior to randomization and during the study. 
5.4
Prohibited Concomitant Medication
Clinically appropriate dose tapering of prohibited medications may only be done during the 
Screening Phase.
During the course of the study, patients should stay on their usual medication regimes (i.e. those 
not excluded by the protocol) at stable doses.
The use of the following medications are prohibited or restricted as follows:
1) Use of a mono-amine-oxidase (MAO) inhibitor is prohibited 30 days prior to 
randomization (baseline visit) and for the duration of the study;


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2) Patients who have been treated within 7 days or 5 half lives (whichever is longer) prior 
to randomization with any other psychotropic medications such as but not limited to the 
following: antipsychotics, antiepileptics (including gabapentin [Neurontin], pregabalin 
[Lyrica], cambamazepine [Tegretol], lamotrigine [Lamictal], divalprioic acid 
[Depakote], valproic acid [Depakene], topiramate [Topamax]), lithium, 
diphenhydramine, N-acetylcysteine, ketamine, memantine;
3) Stimulants are prohibited within 14 days prior to randomization and during the study.
4) Antidepressant agents are prohibited within the 7 days prior to randomization and during 
the study.
5) Fluoxetine (Prozac) is prohibited within the 30 days prior to randomization and during 
the study.
6) Sleeping agents of any kind within seven days prior to randomization; Note: zolpidem, 
zaleplon, or eszopiclone used as sleeping agents, are permitted during the study, no more 
than 3 days per week.  Note: Subjects should be encouraged to avoid taking these 
medications within 8 hours of scheduled efficacy assessments.
7) The use of a depot neuroleptic is prohibited 6 months prior to randomization 
(baseline visit);
8) Use of varenicline (Chantix) is prohibited 30 days prior to randomization (baseline 
visit) and during the randomization phase of the study;
9) Anxiolytic use (including benzodiazepines prn and buspirone) is prohibited within 7 
days of randomization and during the study.  For subjects who have been on 
regular, daily benzodiazepine use, benzodiazepine use is prohibited 30 days prior to 
randomization and during the study. Note: Low dose anxiolytic pre-medications 
prior to necessary medical diagnostic testing prn are allowed on a prn basis.
10) Herbal over-the-counter preparations or supplements taken to manage symptoms of GAD, 
such as, but not limited to: hypericum perforatum (St. John’s Wort), omega-3 fatty acids, 
S-adenosyl methionine (SAM-e) or kava extracts should not be taken for two weeks prior 
to randomization and during the study.
CYP1A2  Inhibitors and Inducers: Troriluzole should be used with caution with medications 
that are inhibitors or inducers of the CYP1A2 enzyme system due to the potential for drug 
interactions. Subjects should be monitored appropriately when taking a CYP1A2 inhibitor or
inducer. The following medications are prohibited at least 5 half-lives prior to randomization
and during the study (Appendix II): 
o
Strong to moderate CYP1A2 inhibitors which may increase the risk of riluzole 
associated adverse events.
o
Strong to moderate CYP1A2 inducers which may result in decreased efficacy
o
Hepatotoxic drugs (e.g. allopurinol, methyldopa, sulfasalazine) which may increase 
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Oral contraceptives which contain ethinyl estradiol (CYP1A2 inhibitor) are allowed.
Hypnotic Use: New use of hypnotics should be avoided. For the management of persistent 
sleeping difficulties or insomnia, subjects may receive the following medications at no higher 
than the indicated doses, no more than 3 days per week.  Note: Subjects should be encouraged to 
avoid taking these medications within 8 hours of scheduled efficacy assessments:
o
Zolpidem tartrate (Ambien): up to 10 mg at bedtime (HS) as needed (prn);
o
Zolpidem tartrate extended-release (Ambien CR): up to 12.5 mg at HS prn;
o
Zaleplon (Sonata): up to 20 mg at HS prn 
o
Eszopiclone (Lunesta): up to 3 mg at HS prn. 
Low dose anxiolytic pre-medications prior to necessary medical diagnostic testing prn are 
allowed.  Subjects should be encouraged to avoid taking a benzodiazepine the morning of a study 
visit.  Benzodiazepines should not be initiated during the Randomization Phase of the study.
Other medications:  Other medications not explicitly called out herein are allowed during the 
Randomization Phase, provided they (1) have been prescribed for a sufficient duration (at least 30 
days) that the investigator can adequately assess tolerability and deems them to be well-tolerated; 
(2) do not limit subject’s ability to perform key rating scales by the impression of the investigator;
(3) the regimen and dose (± 25%) have been stable for at least 30 days prior to screening and are
not anticipated to change during the Randomization Phase; (4) could not adversely affect 
assessment of safety or efficacy.  
Any medication adjustments or the initiation of new medications are recommended to be 
addressed during the Extension Phase, preferably no sooner than after four weeks of treatment 
during this phase so as not to confound assessment of safety / tolerability.
Lorazepam up to 2 mg/day (or equivalent benzodiazepine) can be used prn during the Extension 
Phase when clinically required per investigator judgement. Subjects should be encouraged to 
avoid taking these medications within 8 hours of scheduled efficacy assessments.
Medications for the short term treatment of intercurrent illness are allowed if needed, provided 
they are not otherwise excluded as noted above.
The generic name (where possible), start date, end date and dosing information for any 
medication (prescriptions or non-prescription) taken within 1 month prior to the screeing visit will 
be recorded in the concomitant medication electronic case report form.
5.4.1
Other Restrictions and Precautions
In order to ensure that appropriate concomitant therapy is administered, it is essential that subjects 
be instructed not to take any medication, either non-prescription or prescription therapy 
prescribed by another physician, without prior consultation with the investigator.


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Patients should not undergo any elective medical procedure without prior consultation with the 
Investigator.  An elective procedure (minor surgery, dental surgery, orthopedic surgery etc…) that 
might require hospitalization or anesthesia should be deferred until after the study whenever 
clinically appropriate.
5.5
Woman of Childbearing Potential
Women of childbearing potential (WOCBP) include any female who has experienced menarche 
and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, 
or bilateral oophorectomy) or is not postmenopausal. Post-menopausal is defined as:
o
Amenorrhea greater than or equal to 12 consecutive months without another cause and a 
documented serum follicle stimulating hormone (FSH) level > 35mIU/mL or;
o
Woman with irregular menstrual periods and a documented serum follicle stimulating 
hormone (FSH) level > 35mIU/mL or;
o
NOTE: FSH level testing is not required for women greater than or equal to 62 years old 
with amenorrhea of greater than or equal to one year;
o
Woman on hormone replacement therapy (HRT).
The requisite drug interaction studies to determine the interaction of troriluzole with oral 
contraceptives have not been completed to date. It is therefore not possible to determine the 
efficacy of oral contraceptives as an effective method of contraception for WOCBP who are 
participating in this study. Oral estrogen and progestin hormonal contraceptives as a sole method 
of contraception are therefore prohibited. It is required that all WOCBP use two methods of 
contraception for the duration of the study (i.e. beginning at 30 days prior to baseline) through 30
days after the last dose of study drug. The two methods should include one barrier method (e.g. 
diaphragm with spermicidal gel, condom with spermicidal gel, intrauterine devices, cervical cap) 
and one other method. The other method could include oral contraceptives (e.g. oral 
contraceptives, injectable contraceptives or contraceptive implant) or another barrier method.
Any male who has a female partner of WOCBP has to avoid becoming pregnant while 
participating in this study. If male subjects are sexually active and not vasectomized for at least 6 
months, and if the subject’s female partner is not surgically sterile or is not post- menopausal, 
then one of the following accepted methods of contraception should be used throughout the study 
and for 90 days after the last study drug administration:
o
Simultaneous use of male condom, and for the female partner, hormonal contraceptives 
(e.g., birth control pills, implants, patch, depot injection, used since at least 4 weeks) or 
intra-uterine contraceptive device (placed since at least 4 weeks) before sexual 
intercourse;
o
Simultaneous use of male condom, and for the female partner, diaphragm with 
intravaginally applied spermicide.


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5.6
Deviation from Inclusion/Exclusion Criteria
Any significant event that does not comply with the inclusion exclusion criteria, study conduct, or 
study procedures will be documented as a deviation. Deviations will be documented and reported 
through the clinical monitoring of the trial. Deviations will be reported to the IRB/EC at the 
frequency required by your IRB/EC. There will be no protocol exceptions granted by the Sponsor 
for Inclusion/Exclusion criteria.


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6
STUDY CONDUCT AND DESCRIPTION OF STUDY PROCEDURES
6.1
Study Materials
The sponsor will provide investigational product which will include troriluzole (100 mg) capsules
and matching placebo.
Sites will also be provided with a Regulatory binder, and IWRS Manual. Source document 
creation is the responsibility of the site. Instructions on all specimens collected will be provided 
by a central laboratory.
All sites will use an Electronic Data Capture (EDC) tool to submit study data. Electronic Case 
Report Forms (eCRFs) will be prepared for all data collections.
Sites will be provided with a Biohaven approved protocol and any amendments.
The investigator will be required to have a centrifuge, a secure locked cabinet or similar (for drug 
storage) as well as appropriate containers and dry ice for shipment and storage of blood and 
plasma samples. Enough dry ice, when indicated, should be utilized to allow samples to arrive at 
their designated laboratory in a frozen state.
7
ELIGIBILITY ASSESSMENTS
7.1
MINI International Neuropsychiatric Interview (MINI)
The MINI is a structured interview for the diagnosis of psychiatric disorders that will be 
conducted at screening to confirm the diagnosis of GAD and assess for the presence of other 
major psychiatric conditions.
7.2
SAFER Interview
The SAFER Interview is a structured interview conducted remotely by a CRO (telephone call 
to subject) shortly after the screening visit is completed to confirm the diagnosis, treatment 
history and GAD severity. A SAFER pass is necessary for randomization. This will be 
conducted by trained personnel who are qualified psychiatrists and psychologists. Additional 
details about this interview will be provided in the Informed Consent Form.
7.3
Medical and Psychiatric History
A full medical history will need to be obtained at the screening visit. This will include but is not 
limited to: smoking history, cardiovascular disease, patient history of GAD and other psychiatric 
history.


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7.4
Safety Assessments
Safety and tolerability will be evaluated by report of adverse events (AE) and by evaluation of 
abnormalities and clinically significant changes in physical examinations, ECGs, vital signs, and 
laboratory tests.
7.4.1
Vital Signs and Physical Measurements (Height and Weight)
Sitting vital sign measurements (temperature, blood pressure, and heart rate) will be recorded 
during the scheduled visits as specified in the Schedule of Assessments/Time & Events and as 
medically necessary.
Body weight and height will be recorded at scheduled visits. The following guidelines will aid in 
the standardization of these measurements:
1. The site should attempt to use the same scale to weigh a given subject throughout the study;
2. Scales should be calibrated and zeroed just prior to each subject’s weigh-in session.
7.4.2
Electrocardiogram (ECG)
A 12-Lead ECG will be recorded during the scheduled visits as specified in the Schedule of 
Assessments/Time & Events and as medically necessary.
7.4.3
Physical Exam
Subjects will undergo a complete physical exam in both the Randomization and Extension Phase 
of the study. The Physical Exam should include at least the following components: HEENT 
(head, eyes, ears, nose, and throat), neck, lymph nodes, lungs, cardiovascular, abdomen, skin, and 
musculoskeletal evaluation by the Principal Investigator or a medically qualified delegate.  If a 
subject is discontinued for any reason, an attempt should be made to conduct a final physical 
exam.
7.4.4
Laboratory Assessments
Laboratory testing will include the following:
a) Hematology: hemoglobin, hematocrit, platelets, CBC with differential and absolute 
neutrophil count
b) Serum Chemistry: sodium, potassium, chloride, calcium, ALT, AST, LDH, alkaline 
phosphatase, GGT, phosphorous, bicarbonate, CPK, total protein, albumin, total bilirubin 
(if greater than 2 mg/dl bilirubin will be fractionated), glucose, creatinine, BUN, uric acid, 
and pregnancy testing (WOCBP). Additionally, at screening, total cholesterol, LDL, HDL, 
triglycerides, folate, HbA1c, TSH, T4, B12, eGFR, P-Amylase, and Lipase;
c) Urinalysis: macroscopic examination, pH, specific gravity, ketones, nitrites, urobilinogen, 
leukocyte esterase, protein, creatinine, glucose, and occult blood will be performed during 
the scheduled visits as specified in the Schedule of Assessments/Time & Events and as 


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medically necessary. If blood, protein, or leukocytes, are positive microscopic 
examination will be performed on abnormal findings;
d) Serum pregnancy test will be conducted at screening, baseline and all scheduled 
visits. Urine pregnancy tests will be performed prior to dosing at baseline and at 
scheduled visits, at study visits where lab assessments are not performed, or at the 
discretion of the Investigator. Subjects will be provided with urine pregnancy tests to take 
in between the Week 12, Week 24, Week 36 and Week 48 office visits during the 
Extension Phase;
e) HBsAg, HCV, HIV antibody detection, and RPR (reflex testing will be done for any 
positive RPR) will be performed at screening.
f)
Urine Drug Screen for cannabis (medical and recreational), amphetamines (including
MDMA/ecstasy), cocaine, barbiturate, PCP and opiates at screening and EOS visit. Reflex 
confirmatory testing will be conducted on all positive urine drug screen samples.
g) Blood alcohol level.
Any lab value outside of the normal range must be brought to the attention of a physician 
(Investigator or Sub-Investigator) at the site. The Investigator will indicate whether or not a 
flagged value is of clinical significance in the source document. In addition, if warranted repeat 
labs can be drawn.
7.4.4.1
Pharmacokinetics
A pharmacokinetic sample will be collected at Week 2, Week 6, and Week 8 of the
Randomization Phase. Subjects should take their dose at their routine time on the days of these 
visits. Date and time of doses on the day of each visit and the day prior will be collected in case 
report forms along with time of last meal for entry into the eDC system. Subjects who are able to 
schedule a morning visit for Week 2 and Week 6 can be instructed to hold their dose of study 
drug that morning until after a PK trough sample is obtained, if possible and appropriate.
Additionally, PK samples should be drawn if there are any SAEs in either the Randomization or 
Extension Phase of the study that are assessed as possibly drug-related or severe AEs that could 
be drug-related.
7.4.4.2
Pharmacogenetics
A pharmacogenetics blood sample will be obtained at baseline and end of study (Week 8 
Randomization Phase) for possible future exploratory analysis investigating how genetic variation 
may determine troriluzole efficacy and safety. All subjects will sign a pharmacogenomics ICF 
indicating whether they are consenting to or not consenting to provide a pharmacogenetic blood 
sample. All subjects will be informed that consenting to provide a blood sample for 
pharmacogenetic analysis is optional and does not affect participation in the study.
DNA samples will be stored indefinitely from subjects who have provided written informed 
consent unless a written request for destruction of the sample is provided by the subject to the site 
which conducted the Biohaven-sponsored clinical trial. This written request provided by the 
subject requesting destruction of the subject’s pharmacogenetic samples should be provided by 
the site to the sponsor.


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7.4.4.3
Pregnancy Testing
Pregnancy testing should be performed on all women of childbearing potential (WOCBP) during 
both the Randomization Phase and Extension Phase of the study. Refer to the Schedule of 
Assessments/Time & Events for detailed time points in which serum pregnancy tests and urine 
pregnancy tests are required. Urine pregnancy testing may also be done at the discretion of the 
Investigator at any time during the study. Subjects should not continue in the study if the 
pregnancy test is positive at any time.
7.4.4.4
Evaluation of Laboratory Assessments
The management of abnormal LFTs are described herein. Scheduled LFTs (ALT, AST, bilirubin, 
alkaline phosphatase) at Week 4 and through Week 48 visits (see Schedule of Assessments for 
details) will be evaluated by a physician or other qualified medical personnel.
If AST or ALT values are between 3x ULN and <5x ULN, the Investigator will medically 
evaluate the subject. Medical assessment of the subject can include the following:
Must include repeat LFT assessments (ALT, AST, total and direct bilirubin, alkaline
phosphatase, PT, aPTT, INR) within 1 week and follow until resolution. The frequency of the 
repeat tests will be clinically based on trajectory of change (e.g., improving, stable vs 
increasing). These tests can be performed either at a local, or preferably, central lab
Assessment of AEs, usage of concomitant medications, exposure to potential hepatic toxins, 
risk factors for hepatitis or alcoholic liver disease
Based on overall clinical presentation (severity and extent of lab abnormalities; rate of change 
of lab values), additional evaluations (as outlined under the scenario of ALT/AST > 5xULN) 
may be considered.
If any visit shows ALT or AST>5x ULN, the Investigator will assess this as a potential SAE. The 
subject will be managed as appropriate, including:
Study medication must be discontinued immediately
Bring subject in for physical exam and evaluation.
o
Assess for right heart failure, hypotension, and signs/symptoms of alcohol abuse
o
Assess for exposure to toxic dietary/herbal supplements and/or prescriptions drugs that are 
associated with hepatic effects, such as acetaminophen;
o
Assess for potential exposure to environmental toxins
o
Evaluate for abdominal pain, splenomegaly, hepatomegaly


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Repeat LFTs (AST, ALT, total and direct bilirubin, alkaline phosphatase) as soon as possible, 
with either a local lab or preferably central lab; and, follow to resolution;
Order other labs tests to rule-out other causes of lab abnormalities and to assess extent of 
hepatic effects
o
coagulation factors (PT, aPTT, INR)
o
Hepatitis A, B and C serologies
o
Epstein-Barr virus serology
Assess AEs
Consider gall bladder or ductal imaging studies if presentation suggests potential for gall 
stones.
Entry into the Extension Phase requires continued impression that open-label treatment offers an 
acceptable risk-benefit profile. If lab abnormalities in the Randomization Phase are potentially 
clinically significant then treatment with study drug in the Extension Phase should not begin until 
such labs near normal limits or in the case of elevated transaminases (ALT or AST) are within 3x 
ULN. If results from the scheduled Week 8 assessment show emergence of potentially clinically 
significant lab abnormalities and the subject has already started open-label troriluzole, then labs 
must be repeated and the investigator, based on clinical impression concerning the nature and 
severity of results, may decide to continue troriluzole. In the case of AST or ALT > 5 x ULN, re-
challenge with study drug will not be allowed.
7.4.5
Sheehan Suicidality Tracking Scale (Sheehan STS)
The Sheehan STS (S-STS) is a prospective, clinician administered rating scale that contains 16 
questions to track both treatment-emergent suicidal ideation and behaviors[21, 22]. The S-STS 
will be completed on a paper form at the site. At the screening visit, the recall period for 
completing the S-STS is 6 months prior; at all other visits, the recall period for completing the S-
STS is since the last visit. Subjects who have a S-STS score > 0 should be evaluated by the 
investigator.  If the investigator determines that a subject is at risk of suicide or self-harm, 
appropriate measures to ensure the subject’s safety and obtain mental health evaluation must be 
implemented. The subject must immediately be discontinued from the study. The event should be 
recorded as either an AE or SAE as determined by the investigator and reported within 24 hours 
to the Sponsor.
7.5
Clinical Outcome Assessments
Training will be provided for all clinical outcome assessments through either didactic, video 
certification, and/or online training.  
The order of the tests should include the administration of the HAM-A prior to other clinical / 
safety outcome assessments, followed by the other clinical outcome assessments.


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7.5.1
Hamilton Anxiety Rating Scale (HAM-A)
The HAM-A is a clinician-administered scale used extensively in research and clinical practice to 
both rate severity of GAD and to monitor improvement during treatment. It is designed to rate the 
severity of anxiety as well as the type of symptoms in patients with GAD. The HAM-A will be 
utilized as the primary efficacy assessment of the patient’s level of anxiety and must be 
administered utilizing a structured interview guide, the Structured Interview Guide for the 
Hamilton Anxiety Scale (SIGH-A) [23].
The scale consists of 14 items. Each item is scored on a scale of 0 (not present) to 4 (severe) with 
a total score range of 0-56.  Subscale scores can be calculated for psychic anxiety factor (sum of 
HAM-A items anxious mood, tension, fears, insomnia, concentration, depressed mood, and 
behavior at interview), and somatic anxiety factor (sum of HAM-A items somatic muscular, 
somatic sensory, cardiovascular, respiratory, gastrointestinal, genitourinary and autonomic 
symptoms).
Raters must be trained and pre-approved by sponsor or sponsor representative (i.e. CRO) to rate 
subjects on the HAM-A. Raters must complete training and receive their certification prior to 
administering the HAM-A to study subjects. 
7.5.2
Placebo-Control Reminder Script (PCRS)
The Placebo-Control Reminder Script (PCRS) is a statement read by a clinician to a subject prior 
to every administration of the HAM-A throughout the study. It is intended to provide a 
standardized method for educating subjects on what it means to be in a placebo-controlled study, 
expectations regarding clinical benefit, and how to interact with study staff, to minimizing the 
placebo effect.
7.5.3
Sheehan Disability Scale (SDS)
The Sheehan Disability Scale (SDS) is a patient-rated measure of functional disability in domains 
of work, social and family life. The SDS has demonstrated sensitivity to treatment effects in 
numerous randomized controlled trials in populations with varied diagnoses (70).  The assessment 
is a three item questionnaire measuring disease-related disruption of work, social life and family 
life.  Respondents evaluate impairment on an 11 point scale from 0 -10 with anchor definitions. 
The 3 items can also be summed into a single dimensional measure of global functional 
impairment that rages from 0 (unimpaired) to 30 (highly impaired).
Subjects may indicate that item 1 of the SDS (Work/School) is not applicable to them by 
checking a box labeled “I have not worked / studied at all during the past week for reasons 
unrelated to the disorder.” For these subjects item 1 of the SDS is not scored. However, subjects 
that were unable to work or study due to reasons related to the disorder must complete item 1.
If a subject checks the “not working” box for the Work/School item, you MUST check 
compliance to this instruction, before the visit ends.


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7.5.4
Clinical Global Impression (CGI)
Subjects will be rated on the seven-point Severity of Illness (CGI-S) and Global 
Improvement (CGI-I) scales of the CGI.  The CGI-S is rated during the screening phase as a 
screening assessment to determine eligibility for entry into the study.  
A Sponsor approved rater, preferably a psychiatrist, should administer the CGI.  All efforts 
should be made to ensure that the same clinician administers the CGI-S and CGI-I for a 
given patient.  Notation in the subject’s study records should substantiate the CGI ratings.
7.5.5
Hamilton Depression Rating Scale 17 Item Version (HAM-D-17)
The HAM-D 17 score, derived from the Structured Interview Guide for the Hamilton Depression 
Rating Scale (SIGH-D) will be used as a secondary assessment of the patient’s level of 
depression.  
Although the HAM-D consists of  21 items, the scoring is based on the first 17. Eight items 
are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine are scored from 0-
2.
7.5.6
Penn State Worry Questionnaire (PSWQ)
The Penn State Worry Questionnaire (PSWQ) is a self-administered, 16-item, Likert-type scale 
designed to measure worry. Possible range of scores is 16-80.  Each item is scored 1-5.  Items 1, 
3, 8, 10 and 11 are reversed scored.
7.5.7
Cognitive Test Battery
The Cognitive Test Battery will consist of the Digit Symbol Substitution Task (DSST) and the 
Hopkins Verbal Learning Test-Revised (HVLT-R).
The DSST requires that subjects fill in a series of symbols correctly coded withing 2 minutes.
The higher the score the better the performance.  
The Hopkins Verbal Learning Test-Revised (HVLT-R) is one test with a set of six forms intended 
to measure verbal learning and memory in individuals ages 16 and older. The six forms of the 
HVLT-R are designed to allow frequent, rapid retesting. Each test includes a list of 12 nouns; the 
examiner reads the list to the examinee, who repeats as many words as remembered, in any order. 
This process is repeated three times; 20-25 minutes later, examinees are asked again to recall as 
many words as possible; for the final task, the examiner reads a list of 24 words (including the 12 
words from the list) and asks the examinee after each whether the word was on the list [24].
7.5.8
Clinical Trial and Site Scale-B (CTSS-B)
The Clinical Trial and Site Scale-B (CTSS-B) is a scale to assess potential domains associated 
with placebo response.  The scale is a patient reported assessment and consists of 26 items.   
Items 1-24 are rated on a scale from 1 (“Completely Disagree”) to 9 (“Completely Agree”).  


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Items 25 and 26 are rated on a scale of 1 (“Very much better”) to 7 (“Very much worse”).  The 
CTSS-B is a modified version of an assessment developed by Feltner et al. [25].
8
EARLY DISCONTNUATION OF STUDY
All subjects who discontinue study treatment early should complete the 2-Week Post Dose Visit. 
The only exception to this requirement is when a subject withdraws consent for all study 
procedures or loses the ability to consent freely (i.e. is imprisoned or involuntarily incarcerated 
for the treatment of either a psychiatric or physical illness).
9
STUDY DRUG MANAGEMENT
9.1
Description of Study Drug
9.1.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined as follows:
A pharmaceutical form of an active substance or placebo being tested or used as a reference in a 
clinical study, including products already with a marketing authorization but used or assembled 
(formulated or packaged) in a way different from the authorized form, or used for an unauthorized 
indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to the local regulations. It 
is the responsibility of the investigator to ensure that the investigational product is only dispensed 
to study patients. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
In this protocol, the investigational products are: troriluzole capsules 100 mg and matching 
placebo.
9.1.2
Packaging, Shipment and Storage
Clinical Trial Materials should be stored at controlled temperature between 200C and 250 C (680F
-770F), with excursions permitted between 150C and 300 C (590F -860F), in a secure, temperature 
controlled, limited access area. The medications will be stored in a locked, environmentally-
controlled medication room with restricted access. Container(s) will bear a label containing at 
least the name of the study drug, lot and/or batch number and storage conditions.
9.2
Dose and Administration
9.2.1
Randomization Phase
During the randomization phase, all subjects will be randomized to receive troriluzole 100 mg 
BID or placebo BID.


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It is recommended that all patients ingest study drug twice per day (BID) once in the morning and 
once in the evening (approximately 12 hours apart).  Study drug can be taken without regard to 
meals. 
If subjects have difficulty tolerating BID dosing due to morning dosing of 100 mg (such as 
experiencing sedation) then the investigator may permit the subject to switch to dosing of 200 mg 
at night time only (and document this change in the subject’s records).
Down titration to 100 mg will only be allowed to address tolerability issues and only with medical 
monitor approval. If a subject down titrates they will need to stay on that dose for the duration of 
the Randomization Phase. 
9.2.2
Extension Phase
Subjects completing the Randomization Phase will be offered approximately 48 weeks of 
troriluzole treatment as long as the PI believes open-label treatment offers an acceptable risk-
benefit profile. Subjects who agree to enter the Extension Phase will receive open-label 
troriluzole. Subjects entering the Extension phase will continue on the same dose that was taken 
at the end of the Randomization phase. Subjects will continue to ingest study drug twice per day 
(BID) once in the morning and once in the evening (approximately 12 hours apart).  Study drug 
can be taken without regard to meals.
If subjects have difficulty tolerating BID dosing due to morning dosing of 100 mg (such as 
experiencing sedation) then the investigator may permit the subject to switch to dosing of 200 mg 
at night time only (and document this change in the subject’s records).
Down titration to 100 mg will only be allowed to address tolerability issues. Subjects may be 
rechallenged to increase to 100mg BID during the Extension Phase at the discreation of the 
investigator.
All visits of the Extension Phase will be open-label.
9.2.3
Method of Assigning Patient Identification
The investigator or designee will need to access an Interactive Web-based Response System 
(IWRS) in order to register each subject in each study phase. Initially the investigator or designee 
will enter the subject into the study at the Screening Visit after informed consent is obtained and a 
subject number is assigned. After completion of all screening evaluations, all eligible subjects 
will be randomized via IWRS at the Baseline Visit, in a 1:1 ratio to receive either placebo (BID)
or troriluzole (100 mg BID). Treatment assignments will be obtained by the investigator (or 
designee) via the IWRS system.
Investigational sites will access the IWRS at each scheduled IP dispensing visit throughout the 
Randomization Phase to dispense drug. The IWRS system will assign specific bottle numbers for 
all blinded study drug to be dispensed to the subject. Once a bottle has been assigned it cannot be 
dispensed to another study subject.


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Once a subject completes the Randomization Phase or if a subject is discontinued early from the 
study, the investigator or designee must access the IWRS to discontinue the patient from 
participation in the study or to indicate that the subject will continue into the Extension Phase.
Subjects who complete 8 weeks of treatment in the Randomization Phase may be eligible for an 
Extension Phase of the study. The investigator or designee must access the IWRS to enter the 
subject in the Extension Phase. Investigational sites will access the IWRS at each IP dispensing
visit throughout the Extension Phase to dispense drug.
Study medication will be assigned via the IWRS system in the Randomization and Extension 
Phase. Sites will be responsible for recording the bottle numbers dispensed to the subject on the 
Drug Accountability Form provided in the Regulatory Binder, as well as ensure appropriate 
documentation of dispensation in the subject’s medical record. Once a subject completes the 
Extension Phase or if a subject is discontinued early from the Extension Phase of the study, the 
investigator or designee must access the IWRS to document the discontinuation of the subject 
from participation in the study.
9.2.4
Selection and Timing of Dose and Administration
During the randomization phase of the study, subjects will be randomized to receive placebo 
(BID) or troriluzole (100 mg BID). Open label BHV -4157 will be provided during the extension 
phase. Study Drug will be dispensed at the baseline visit. Subjects should take the first dose the 
day after the baseline visit.  Study medication should be administered twice per day (BID) once in 
the morning and once in the evening (approximately 12 hours apart).
9.2.5
Dose Modifications
Randomization Phase:  Subjects will receive 100 mg BID or Placebo BID for eight (8) weeks.
If subjects have difficulty tolerating 100 mg BID dosing (such as experiencing sedation) then the 
investigator may permit the subject to switch to dosing of 200 mg at night time or morning only 
(and document this change in the subject’s records).
Down titration to 100 mg once daily (QD) will only be allowed to address tolerability issues and 
only with medical monitor approval. If a subject down titrates to 100 mg QD they will need to 
stay on that dose for the duration of the Randomization Phase.
Extension Phase: Subjects entering the Extension phase will continue on the same dose that was 
taken at the end of the Randomization phase. Subjects receiving placebo in the randomization 
phase will be switched in a blinded manner to 100 mg BID or 100 mg QD.  Subjects who enter 
the Extension Phase on 100 mg QD due to tolerability issues can be rechallenged to increase to 
100 mg BID based on investigator judgement.
For subjects who do not tolerate their study treatment the investigator may permit them to switch 
to night time dosing (200 mg QD at night) if there is reason to believe that may help tolerability. 
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and this switch in dosing time does not result in acceptable tolerability then dosing should be 
discontinued. 
9.3
Blinding and Unblinding
Blinding is critical to the integrity of this clinical study. However, in the event of a medical 
emergency or pregnancy in an individual subject, in which knowledge of the investigational 
product is critical to the subject’s management, the blind for that patient may be broken by the 
treating physician.
Before breaking the blind of an individual subject’s treatment, the investigator should have 
determined that the information is necessary, i.e., that it will alter the subject’s immediate 
management. In many cases, particularly when the emergency is clearly not investigational 
product related, the problem may be properly managed by assuming that the subject is receiving 
active product without the need for unblinding. Unblinding will be managed via the IWRS 
system.
A pharmacokineticist, IWRS vendor, and pharmacovigilance role may be unblinded before data 
are unblinded for the primary endpoint and all subjects complete the Randomized Phase of the 
study. Except as noted above, other members of the BHV research team will remain blinded. For 
purposes of the DMC, periodic analysis will be carried out by the unblinded safety biostatistics 
team independent and firewalled from the team directly involved with the design and primary 
analysis of the trial.  A report will be prepared for the DMC as outlined in the DMC charter.
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt to 
preserve the blind is made.
9.4
Treatment Compliance
Responsible study personnel will dispense the study drug. Accountability and compliance 
verification should be documented in the subject’s study records.
Subjects will be counseled on the importance of taking the study drug as directed at all study 
visits. If poor compliance continues, (i.e., multiple missed doses resulting in less than 80% overall 
compliance during the Randomization and Extension Phase), discontinuation of the subject from 
the trial should be considered and discussed with the Sponsor.
9.5
Destruction and Return of Study Drug
All unused and/or partially used study drug can be sent back to the drug depot for destruction 
only after being inspected and reconciled by the responsible BHV Study monitor or the sponsor’s 
designee.
If it is site policy to destroy study drug on site, it is the investigator’s responsibility to ensure that 
arrangements have been made for the disposal, procedures for proper disposal have been 
established according to the applicable regulations, guidelines and institutional procedures, and 
appropriate records of the disposal have been documented. The unused study drugs can only be 


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destroyed after being inspected and reconciled by the responsible BHV Study monitor or the 
sponsor’s designee.
10 ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient or clinical investigation patient administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding for example) symptom, or disease temporally associated with the use 
of the investigational product, whether or not considered related to the investigational product.
Adverse events can be spontaneously reported or elicited during an open-ended questioning, 
examination, or evaluation of a patient. In order to prevent reporting bias, patients should not be 
questioned regarding the specific occurrence of one or more AEs. The collection of non-serious 
AE information should begin at the initiation of study drug.
10.1
Serious Adverse Events
There are two types of adverse events, Serious Adverse Events (SAE) and Non-Serious Adverse 
Events (AEs).
10.1.1
Definition of Serious Adverse Event (SAE)
A SAE is any event that meets any of the following criteria at any dose:
Death;
Life-threatening;
Inpatient hospitalization or prolongation of existing hospitalization;
Persistent or significant disability/incapacity;
Congenital anomaly/birth defect in the offspring of a subject who received troriluzole;
Other: Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such events are (but not limited to):
o
Intensive treatment in an emergency room or at home for allergic bronchospasm;
o
Blood dyscrasias or convulsions that do not result in inpatient hospitalization;
o
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o
Potential drug induced liver injury (see section 10.1.7).
10.1.2
Definition of Terms
Mild: Is usually transient and may require only minimal treatment or therapeutic
intervention. The event does not generally interfere with usual activities of daily living.
Moderate: Is usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no significant or 
permanent risk of harm to the subject.
Severe: Interrupts usual activities of daily living, significantly affects clinical status, or may 
require intensive therapeutic intervention.
Life threatening: An AE is life threatening if the subject was at immediate risk of death from the 
event as it occurred; i.e., it does not include a reaction that if it had occurred in a more serious 
form might have caused death. For example, drug induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life threatening even though drug induced 
hepatitis can be fatal.
Hospitalization: AEs requiring hospitalization should be considered SAEs. Hospitalization for 
elective surgery or routine clinical procedures that are not the result of an AE (e.g., elective 
surgery for a pre-existing condition that has not worsened) need not be considered AEs or SAEs. 
If anything untoward is reported during the procedure, that occurrence must be reported as an AE, 
either 'serious' or 'non-serious' according to the usual criteria.
In general, hospitalization signifies that the subject has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician's office or outpatient setting. When in doubt as to 
whether 'hospitalization' occurred or was necessary, the AE should be considered serious.
The following hospitalizations are not considered SAEs in BHV clinical studies (but may be 
considered non-serious AEs):
A visit to the emergency room or other hospital department <24 hours that does not result in 
an admission (unless considered “important medical event” or event that is life threatening);
Elective surgery, planned prior to signing consent;
Admissions as per protocol for a planned medical/surgical procedure;
Routine health assessment requiring admission (i.e., routine colonoscopy);
Admission encountered for another life circumstance that carries no bearing on health and 
requires no medical intervention (i.e., lack of housing, care-giver respite, family 
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Disability/incapacitating: An AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the subject's ability to carry out normal life functions. 
10.1.3
Classification of Adverse Events
The severity of all AEs must be recorded in the eCRF and on the SAE Form, if applicable. The 
severity or intensity of an AE refers to the extent to which it affects the subject’s daily activities. 
The severity of events should be graded as mild, moderate or severe.  
The Investigator’s assessment of an AEs relationship to study drug is part of the documentation 
process but is not a factor in determining what is or is not reported in the study. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported. The relationship 
or association of the study drug in causing or contributing to the AE will be characterized as 
either not related or related. 
10.1.4
Collection and Reporting Serious Adverse Events
Following the patient’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specific procedures. All SAEs must be collected that occur during the screening period 
and within 30 days of discontinuation of dosing. The investigator should report any SAE 
occurring after these time periods that is believed to be related to study drug or protocol-specific 
procedures. 
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness. 
If the investigator believes that an SAE is not related to the study drug, but is potentially related 
to the conditions of the study (such as a withdrawal of previous therapy or a complication related 
to study procedure), the relationship should be specified in the narrative section of the SAE 
Report Form. 
SAEs, whether related or not related to study drug, overdose, potential drug induced liver injury 
and pregnancies must be reported within 24 hours of the Investigator becoming aware of the 
event. For this study we will be capturing SAEs through electronic data capture (EDC) and on the 
SAE form. 
The Investigator is responsible for reporting all SAEs and all Other Important Medical Events 
to 
 immediately via telephone, upon observing or learning of the event. 
 will then 
immediately notify the Biohaven Medical Monitor of the event.  The SAE form must then be 
submitted to 
 within one working day. The Investigator is responsible for submitting all 
applicable events to the Independent Review Board (IRB) as per the IRB’s reporting 
requirements. Additionally, the Investigator, or designated staff, is responsible for entering the 
SAE information in the Electronic Data Capture (EDC) system (i.e.: event term, start stop dates, 
causality, severity).  
CCI
CCI
CCI


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Additionally, any serious adverse experience must be reported immediately or no later than 24 
hours after awareness of the event to the 
 department. 
The Serious Adverse Event Report Form (SAERF) should be submitted to 
 by facsimile 
(FAX). 
Reports can be made by telephone via the Safety Hotline Number below if a SAERF cannot be 
immediately submitted.
For any questions relating to SAEs, please contact the Medical Monitor via telephone:
SAE Telephone Contact: Dr. 
If only limited information is initially available, follow-up reports are required. If an ongoing 
SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours of the Investigator becoming 
aware of the updated information using the same procedure used for the transmission of the initial 
SAE and the same event term should be used. 
All SAEs should be followed to resolution or stabilization. 
10.1.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of the product 
that is considered both excessive and medically important. All occurrences of overdose 
(suspected or confirmed and irrespective of whether or not it involved troriluzole) must be 
communicated to Biohaven or a specified designee within 24 hours of the Investigator becoming 
aware of the updated information and be fully documented as an SAE. Details of any signs or 
symptoms and their management should be recorded including details of any antidote(s) 
administered.
10.1.6
Pregnancy
If following initiation of the investigational product, it is subsequently discovered that a study 
patient is pregnant or may have been pregnant at the time of the investigational product exposure, 
including during at least 6 half-lives after the product administration, the investigational product 
will be permanently discontinued in an appropriate manner (i.e., dose tapering if necessary for 
patient safety). Protocol-required procedures for the study will be discontinued and the follow up 
must be performed on the patient unless contraindicated by the pregnancy (i.e., x-ray studies). 
Other appropriate pregnancy follow-up procedures should be considered if indicated. 
Sites should instruct patients to contact the investigator if they become pregnant during the course 
of the study. The investigator must immediately notify 
 of the event within 24 hours of the 
Investigator becoming aware of the information. The site must complete a Pregnancy Report 
CCI
CCI
CCI
CCI
PPD
PPD
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Form. Follow up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable offspring information must also be reported on a 
Pregnancy Report Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
10.1.7
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of the initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs as per Section 10.1.4.
Potential drug induced liver injury is defined as:
Aminotransferases (AT) (ALT or AST) elevation > 3 times the upper limit of normal (ULN);
 
 
AND
Total bilirubin (TBL) > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase); 
AND
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
If any potential DILI is identified and meets the criteria above, the Biohaven Medical Monitor 
should immediately be contacted for further instruction on dosing adjustments and whether the 
patient must discontinue from the trial and appropriate follow up requirements. 
10.2
Non-serious Adverse Events
A non-serious adverse event is an AE not classified as serious.
10.2.1
Collection and Reporting of Non-Serious Adverse Events
The collection of non-serious AE information should begin at the initiation of study drug.
Non-serious adverse events should be followed until conclusion or stabilization, or reported as 
SAEs if they become serious. Follow-up is also required for non-serious AEs that cause 
interruption or discontinuation of study drug or those that are present at the end of study 
treatment.
The following laboratory test abnormalities should be captured on the non-serious AE CRF page 
or SAE Report Form (paper or electronic) as appropriate: 
Any laboratory test result that is clinically significant or meets the definition ofan SAE;
CCI


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Any laboratory abnormality that required the patient to have the study drug discontinued or
interrupted;
Any laboratory abnormality that required the patient to receive specific corrective therapy.
11 STATISTICS
Detailed plans for analysis will be summarized in a separate Statistical Analysis Plan document, 
to be written and approved prior to database unblinding. A summary of statistical aspects of the 
design and intended analysis is provided here
11.1
General Procedures
Categorical variables are tabulated with counts and percentages. Continuous variables are 
summarized with univariate statistics (e.g., n, mean, standard error, median, minimum and 
maximum).  
For the calculation of descriptive statistics of observed data, subjects must have a baseline value 
to be evaluable for endpoints based on values and changes from baseline over time.
Tabulations of the following endpoints present the number of unique subjects with an event: 
protocol deviations; non-study medications; adverse events; and laboratory abnormalities. Thus, 
for these endpoints, multiple occurrences of the same event are counted only once per subject.
Unless otherwise specified, the randomization phase and the open-label extension phase will be 
analyzed separately. For subjects receiving troriluzole during both phases, summary statistics will 
be provided for data from both phases combined.
11.2
Sample Size
The sample size for this study will be approximately 372 randomized subjects.
From a review of generalized anxiety disorder by Hidalgo[26], data from 7 adult studies 
(treatment duration between 4 to 12 weeks) provided the standard deviation for change from 
baseline ranging from 6.0 to 8.7; the average standard deviation was 7.4. 
With an expected Week 8 difference between treatment groups to be 2.5 points on the HAM-A
total scale, 372 subjects provide 90% power based on a 2-sample t-test with a common standard 
deviation of 7.4. The previous is based on an assumption of no premature discontinuations, if 
premature discontinuations occur at a rate of up to 25%, the power to detect a 2.5 point difference 
may be as low as 80%.
11.3
Populations for Analysis
The following analysis sets are defined for this protocol:


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o
Enrolled subjects: Patients who signed an informed consent form and were assigned a 
Patient Identification number (PID)
o
Randomized subjects: Enrolled subjects who received a treatment assignment from the 
Interactive Web Response System (IWRS).
o
Treated subjects: Enrolled subjects who received at least 1 dose of blinded study therapy 
(troriluzole or placebo) or open-label troriluzole.
o
Modified Intent to Treat (mITT) subjects: Randomized subjects that received at least one 
dose of blinded study therapy and provided at least one post-baseline efficacy assessment 
during the randomization phase
11.4
Statistical Methods
11.4.1
Demographic and Baseline Characteristics
Tabulations of demographic and baseline characteristics will be made for all treated subjects. A 
separate set of tabulations will be made for subjects enrolled but not randomized.
Demographic information will be summarized descriptively by treatment group and overall (i.e., 
treatment groups combined).
11.4.2
Primary Endpoint(s)
As the primary objective of this study is based on the evaluation of severity of patients’ 
symptomology, the estimand for the primary endpoint will be the effect due to the initially 
randomized treatments if taken as directed, a de jure efficacy estimand.  The target population 
will be the mITT population. The primary endpoint will be the change from baseline in the HAM-
A score, troriluzole relative to placebo, at Week 8 of the randomization phase. This treatment 
effect will be summarized as the difference in change from baseline in the HAM-A between the 
groups receiving troriluzole and placebo. 
Since the primary intent of this trial is to evaluate the effect of the drug when taken as intended in 
the protocol, a hypothetical strategy will be employed for the intercurrent event of treatment/study 
discontinuation (due to any reason). Specifically, the assumption will be that had the subjects not 
discontinued, their efficacy would have been similar to the efficacy of subjects from the same 
treatment group who did not discontinue. For other intercurrent events that do not cause 
treatment/study discontinuation such as modest treatment non-compliance, protocol allowed dose 
adjustments, or initiation or adjustment of concomitant medications related to other symptoms all 
observed values will be used.
The change from baseline in the HAM-A score, will be analyzed using Mixed Model for 
Repeated Measures (MMRM).  The model will include treatment, visit and the treatment-by-visit 
interaction as fixed effects, and the baseline value of the HAM-A and baseline Ham-A by visit 
interaction as covariates. The covariance structure will be initially specified as unstructured.  If 
the model fails to converge, then a Huynh-Feldt structure may be used, followed by an AR(1) 


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structure. The troriluzole and placebo groups will be compared at the end of the double-blind 
phase using a single degree of freedom contrast, with Kenwood-Rogers degrees of freedom, and 
significance assessed at a two-sided alpha level of 0.05.  Sensitivity analyses will include, but not 
limited to a multiple imputation method employing a jump to reference method. Details of these 
analyses are provided in the statistical analysis plan.
Additional analyses on the HAM-A Scale will included analysis of the change from baseline 
Psychic Anxiety and Somatic Anxiety subscales as well as analyses of the percentage of HAM-A
responders and remitters.  Response is defined a a 50% or greater reduction in the HAM-A Total 
Score from baseline to endpoint.  Remission is defined as a HAM-A Total Score <= 7 at Weeks 6
and 8. Details of these analyses are provided in the statistical analysis plan.
11.4.3
Secondary and Exploratory Endpoint(s)
Continuous change-from-baseline efficacy endpoints will be analyzed using the same 
methodology as the primary endpoint.  Further details on the secondary and exploratory analyses 
are provided in the SAP.
11.4.4
Adjustment for Multiplicity
Type 1 error will be controlled for the primary and secondary efficacy endpoints by testing them 
with a gate-keeping procedure. The primary endpoint will be tested at a two-sided alpha level of 
0.05. If this test is significant, then the secondary efficacy endpoints will be tested using 
Hochberg’s procedure.  If the test of the primary endpoint is not significant, then the unadjusted 
p-values for the secondary endpoints will be presented only for descriptive purposes, and no 
conclusions will be drawn from this result
No attempt will be made to adjust for multiplicity when testing the exploratory endpoints. Any 
exploratory endpoints subjected to significance testing are evaluated at an unadjusted two-sided 
alpha level of 0.05.
11.4.5
Missing Data
Studies similar to the randomized phase of this study showed ~25% of the subjects fail to 
complete the blinded randomized portion of the study[27][28]. Hence, we expect a similar rate of 
discontinuation during the randomized phase of this study. As part of sensitivity analyses for the 
primary and secondary endpoints, the missing data will be multiply imputed for the primary 
endpoint using reference methods (e.g. jump to reference). Further details on the handling of 
missing data, including for the SDS, are provided in the statistical analysis plan.
11.4.6
Analysis of Safety
The investigators determine the intensity of AEs and the relationship of AEs to study therapy. The 
investigators’ terms are coded and grouped by system organ class using the latest version of the 
Medical Dictionary for Regulatory Activities (MedDRA) available. AEs will be presented by 
system organ class and preferred term, ordered by the overall frequency of events.  If a subject 


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had an adverse event with different intensities over time, then only the greatest intensity is 
reported in a study phase.
The frequencies of the following safety events are summarized by treatment group and overall for 
treated subjects:  SAEs; all AEs, non-serious AEs; AEs by intensity; AEs by relatedness and 
clinically relevant laboratory abnormalities.
Graphical and tabular displays of on-treatment liver function test results are provided
11.5
Schedule of Analyses
This study will be monitored by a Data Safety Monitoring Board which will review interim 
summaries of the data during the trial. Please see section 12.1 for details.
An initial analysis of the data will be conducted after the last subject completes their Week 8 visit.  
This will only include analyses of efficacy data from the double-blind phase of the study, 
however safety analyses will include data from double-blind as well as the extension phase.
A final analysis of the study will be completed after the last subject completes their last study 
visit. This will summarize all efficacy data collected in the open-label phase, and summarize all 
safety, laboratory and other data collected through the entire study.
Additional analyses may be conducted during the open-label phase of the study to support 
regulatory and administrative requirements. 
12 ETHICS AND RESPONSIBILITIES
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
Good Laboratory Practice (GLP) and all applicable regulations, including the Federal Food, Drug 
and Cosmetic Act, U.S. applicable Code of Federal Regulations (title 21), any IEC requirements 
relative to clinical studies. The study will also be conducted in compliance with the 
recommendations laid down in the most recent version of the Declaration of Helsinki, with the 
exception that registration of such Phase 1 trials in a publicly accessible database is not 
mandatory.
This study will be conducted in compliance with the protocol. The protocol and any amendments 
and the patient informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All serious breaches must be reported to Biohaven (or designee) immediately. A Serious breach is 
a breach of the conditions and principles of GCP in connection with the study or protocol, which 
is likely to affect, to a significant degree, the safety or physical or mental integrity of the patients 
of the study or the scientific value of the study.
Study personnel involved in conducting this study will be qualified by education, training, and 
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This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment).
12.1
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) will be utilized for this study. The DMC 
will review the safety of all patients enrolled in trials on an regular basis. 
The DMC will review the protocol, and will identify the data parameters and format of the 
information to be regularly reported.  The DMC will meet in person or by conference call 
approximately quarterly. The DMC will typically receive reports with data by treatment group 
(e.g. blinded group A, group B etc.) or, if requested by the DMC, completely unblinded. 
Based on the review of safety data, the DMC will make recommendations regarding the conduct 
of the study to the clinical team. These may include continuing the study as designed, amending 
safety monitoring procedures, modifying the protocol or the informed consent form, or 
recommending the termination of the study.  
For purposes of the DMC, data analysis will be carried out by the unblinded safety biostatistics 
team independent and firewalled from the team directly involved witht the study design and 
primary analyses, and a report will be prepared for the DMC.
For further details please refer to the DMC charter.
12.2
Institutional Review Board/Independent Ethics Committee
The Investigators agree to provide the IEC with all appropriate documents, including a copy of 
the protocol/amendments, ICFs, advertising text (if any), Investigator’s brochure (if any) and any 
other written information provided to study subjects. The trial will not begin until the 
Investigators have obtained the IEC favorable written approvals for the above-mentioned study 
documents. A properly executed written ICF shall be read, signed, and dated by each subject prior 
to entering the trial or prior to performing any study procedure. The original signed and dated ICF 
will be kept at the Investigator site and a copy will be given to the subject.
In the event that the protocol is amended, the revised protocol must be approved by the IEC prior 
to its implementation, unless the changes involve only logistical or administrative aspects of the
trial. If a revised ICF is introduced during the study, each subject’s further consent must be 
obtained. The new version of the ICF must be approved by the IEC, prior to subsequently 
obtaining each subject’s consent.
The Principal investigator and the Sponsor’s representative must sign the protocol and its 
amendments (if any) before initiating the study.
It is the Sponsor’s responsibility to submit the protocol and its amendments (if any), and the ICFs 
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12.3
Informed Consent
Investigators must ensure that patients, or, in those situations where consent cannot be given by 
patients, their legally acceptable representatives, are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate.
Biohaven (or designee) will provide the investigator with an appropriate (i.e., Global or Local) 
sample informed consent form which will include all elements required by ICH, GCP and 
applicable regulatory requirements. The sample informed consent form will adhere to the ethical 
principles that have their origin in the Declaration of Helsinki.
Before the potential subject has undergone any study-related screening procedures, the nature of 
the study and the potential risks associated with it will be explained to the subject, and the subject 
will be given an opportunity to ask questions to his or her satisfaction. After the questions are 
answered, but before proceeding further, the subject must read and sign a written informed 
consent form. This signed informed consent form will be reviewed and approved by an IRB/IEC, 
revisions to the protocol and informed consent form will be reviewed and approved by the 
IRB/IEC, a copy retained in the Study Master File, and the date and time the subject signed the 
form will be entered in his or her CRF. The subject will be provided with a copy of his or her 
signed and dated informed consent form.
If informed consent is initially given by a patient’s legal guardian or legally acceptable 
representative, and the patient subsequently becomes capable of making and communicating their 
informed consent during the study, then the consent must additionally be obtained from the 
patient.
The informed consent form must also include a statement that Biohaven and its representatives 
and regulatory authorities may have direct access to patient records.
The rights, safety, and well-being of study patients are the most important considerations and 
should prevail over interests of science and society.
A separate ICF will be obtained for the collection of blood for pharmacogenetic samples for 
possible future exploratory analysis investigating how genetic variation may determine troriluzole
efficacy and safety. All subjects will sign a pharmacogenomics ICF indicating whether they are 
consenting to or not consenting to provide a pharmacogenetic blood sample. All subjects will be 
informed that consenting to provide a blood sample for pharmacogenetic analysis is optional and 
does not affect participation in the study. The investigator or the investigator’s designee is 
responsible for verifying the patient’s consent prior to obtaining the pharmacogenetic blood 
sample.
The approval of the pharmacogenetic ICF may occur separately from the consent form for other 
study related procedures and assessments. In instances were IRB approval for pharmacogenetics 
samples is not obtained, samples for genetic analysis will not be collected.


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DNA samples will be stored indefinitely from subjects who have provided written informed 
consent unless a written request for destruction of the sample is provided by the subject to the site 
which conducted the Biohaven-sponsored clinical trial. This written request provided by the 
subject to the site requesting destruction of the subject’s pharmacogenetic samples should be 
provided by the site to the sponsor.
12.4
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation of each study patient. Data 
reported on the CRF that are derived from source documents must be consistent with the source 
documents or the discrepancies must be explained.
Electronic CRFs will be prepared for all data collections fields when EDC is being used.
The confidentiality of records that could identify patients must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator must retain a copy of the CRFs including records of changes and corrections. If 
EDC is being used, signatures will be obtained electronically and a copy of the electronic CRFs 
will be provided (or the data from the CRFs) for future reference.
12.5
Records Management and Retention
In accordance with the principles of GCP and GLP, the study may be inspected by regulatory 
authorities, the Sponsor and CRO. The Sponsor is entitled to access information about the status 
of the study and to review the original documents of the study.
The investigator must retain all study records and source documents for the maximum required by 
the applicable regulations and guidelines, or institution procedures or for the period of time 
specified by the sponsor, whichever is longer. The investigator must contact the Sponsor prior to 
destroying any records associated with this study.
Biohaven will notify the investigators when the study files for this study are no longer needed.
If the investigator withdraws from the study (i.e., retirement, relocation), the records shall be 
transferred to a mutually agreed upon designee.  Notice of such transfer will be given in writing to 
Biohaven.
It is the responsibility of the investigator to ensure that the current disposition record of 
investigational product (those supplied by the sponsor) is maintained at each study site where the 
study drug is inventoried and dispensed. Records or logs must comply with applicable regulations 
and guidelines and should include:
o
Amount of study drug received and placed in storage area;
o
Label ID number or batch number or Kit number as specified for the protocol;


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o
Amount dispensed to and returned from each patient;
o
Amount transferred to another area or site for dispensing or storage if applicable;
o
Amount of drug lost or wasted;
o
Amount destroyed at the site if applicable;
o
Amount returned to sponsor, if applicable;
o
Retained samples for bioavailability/bioequivalence, if applicable;
o
Record of dates and initials of personnel responsible for IM dispensing and accountability.
12.6
Source Documentation
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent for all subjects on study.
If source documents are created to support the collection of study information, this must be 
retained with the other pertinent medical record for each patient for verification of data points, 
unless otherwise instructed by the Sponsor or designee to enter data directly on the CRF.
12.7
Study Files and Record Retention
The CRO will utilize the Sponsor’s Electronic Trial Master File (eTMF) for the purposes of this 
study. The Sponsor does not require original documents that have already been scanned and 
entered into the eTMF system be forwarded to the Sponsor. Any original documents (i.e. 1572, 
signed financial disclosure, signed ICF, etc.) will be retained in the regulatory binder at the study 
site. The CRO will do a final TMF reconciliation to ensure all study files and regulatory 
documents have been correctly uploaded to the TMF prior to the close or termination of the study. 
Any materials or documents to support the clinical trial outside of the eTMF (i.e. rater training 
tapes) should be maintained by the CRO. The Sponsor will be contacted to determine whether the 
study documents/materials that are retained outside of the TMF will be forwarded to the Sponsor, 
destroyed or kept at CRO or at another facility for a longer period of time at the Sponsor's
expense.
13 AMENDMENTS
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Biohaven. A protocol change intended to eliminate an apparent immediate hazard 
to subjects may be implemented immediately, provided the IRB/IEC is notified within 5 days.
Any permanent change to the protocol must be handled as a protocol amendment. The written 
amendment must be submitted to the IRB/IEC and the investigator must await approval before 
implementing the changes. Biohaven will submit protocol amendments to the appropriate 
regulatory authorities for approval.


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If in the judgment of the IRB/IEC, the investigator, and/or Biohaven, the amendment to the 
protocol substantially changes the study design and/or increases the potential risk to the subject 
and/or has an impact on the subject's involvement as a study participant, the currently approved 
written informed consent form will require similar modification. In such cases, informed consent 
will be renewed for subjects enrolled in the study before continued participation.
14 STUDY REPORT AND PUBLICATIONS
Biohaven is responsible for preparing and providing the appropriate regulatory authorities with 
clinical study reports according to the applicable regulatory requirements. The publication policy 
of Biohaven is discussed in the investigator's Clinical Research Agreement.
15 STUDY DISCONTINUATION
Both Biohaven and the Principal Investigator reserve the right to terminate the study at the 
investigator’s site at any time. Should this be necessary, Biohaven or a specified designee will 
inform the appropriate regulatory authorities of the termination of the study and the reasons for its 
termination, and the Principal Investigator will inform the IRB/IEC of the same. In terminating 
the study, Biohaven and the Principal Investigator will assure that adequate consideration is given 
to the protection of the subjects’ interests.
16 CONFIDENTIALITY
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is gained from Biohaven. However, authorized regulatory officials, IRB/IEC personnel, Biohaven 
and its authorized representatives are allowed full access to the records.
Identification of subjects and CRFs shall be by initials, screening and treatment numbers only. If 
required, the subject's full name may be made known to an authorized regulatory agency or other 
authorized official.
Biohaven may approve the sharing of de-identified data from this study to be made available to 
researchers for the purpose of advancing the understanding of neurologic or psychiatric illness,
rating scales, or trial methodology for the affected population. In any publication of this data, 
confidentiality of individual subjects will be protected.


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17 APPENDICES 
17.1
APPENDIX I - Names of Study Personnel
Sponsor:
Biohaven Pharmaceutical Holding Company Limited
c/o Biohaven Pharmaceuticals, Inc.
New Haven, CT 06510
Medical Monitor 
and Medical 
Monitor Back-up: 
Biohaven Pharmaceuticals, Inc.  
New Haven, Connecticut 06510 
Biohaven Pharmaceuticals, Inc. 
New Haven, Connecticut 06510
Biohaven Pharmaceuticals, Inc. 
New Haven, Connecticut 06510 
Clinical 
Research
Organizations:
  
PPD
PPD
PPD
PPD PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
CCI
PPD
PPD
PPD


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17.2
APPENDIX II - Potent and Moderate Inhibitors and Inducers of the CYP1A2 
Enzyme System*
CYP1A2 Potent and Moderate Inhibitors
Amiodarone
Artemisinin
Atazanavir
Cimetidine
Ciprofloxacin
Efavirenz
Enoxacin
Fluoroquinolones
Furafylline
Interferon
Methoxsalen
Mexiletine
Mibefradil
Tacirne
Thiabendazole
Ticlopidine
Vemurafenib
Zileuton
CYP1A2 Potent and Moderate Inducers
Barbiturates
Beta-naphthoflavone
Carbamazepine
Insulin
Methylcholanthrene
Modafinil
Nafcillin
Omeprazole
Primidone
Rifampin
*This list is not exhaustive.  


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18 REFERENCES CITED
1.
Rickels, K., et al., Remission of generalized anxiety disorder: a review of the paroxetine 
clinical trials database. J Clin Psychiatry, 2006. 67(1): p. 41-7.
2.
Mathew, S.J., et al., Open-label trial of riluzole in generalized anxiety disorder. American 
Journal of Psychiatry, 2005. 162: p. 2379-2381.
3.
Mathew, S.J., et al., Hippocampal N-acetylaspartate concentration and response to 
riluzole in generalized anxiety disorder. Biol Psychiatry, 2008. 63(9): p. 891-8.
4.
Abdallah, C.G., et al., A pilot study of hippocampal volume and N-acetylaspartate (NAA) 
as response biomarkers in riluzole-treated patients with GAD. Eur 
Neuropsychopharmacol, 2013. 23(4): p. 276-84.
5.
Sugiyama, A., et al., Administration of riluzole into the basolateral amygdala has an 
anxiolytic-like effect and enhances recognition memory in the rat. Behavioural brain 
research, 2017. 327: p. 98-102.
6.
Sugiyama, A., et al., Administration of riluzole to the basolateral amygdala facilitates fear 
extinction in rats. Behav Brain Res, 2018. 336: p. 8-14.
7.
Sugiyama, A., et al., Riluzole produces distinct anxiolytic-like effects in rats without the 
adverse effects associated with benzodiazepines. Neuropharmacology, 2012. 62(8): p. 
2489-98.
8.
Sugiyama, A., et al., Systemic administration of riluzole enhances recognition memory 
and facilitates extinction of fear memory in rats. Neuropharmacology, 2015. 97: p. 322-8.
9.
Kessler, R.C., et al., Twelve-month and lifetime prevalence and lifetime morbid risk of 
anxiety and mood disorders in the United States. International Journal of Methods in 
Psychiatric Research, 2012. 21(3): p. 169-184.
10.
Bruce, S.E., et al., Influence of psychiatric comorbidity on recovery and recurrence in 
generalized anxiety disorder, social phobia, and panic disorder: a 12-year prospective 
study. American Journal of Psychiatry, 2005. 162(6): p. 1179-1187.
11.
Yonkers, K.A., S.E. Bruce, and M.B. Keller, Chronicity, relapse, and illness--course of 
panic disorder, social phobia, and generalized anxiety disorder: findings in men and 
women from 8 years of follow-up. Depression and Anxiety, 2003. 17(3): p. 173-179.
12.
Pollack, M.H., Refractory generalized anxiety disorder. Journal of Clinical Psychiatry, 
2009. 70(suppl 2): p. 33-38.
13.
Sasaki-Hamada, S., et al., Riluzole does not affect hippocampal synaptic plasticity and 
spatial memory, which are impaired by diazepam in rats. J Pharmacol Sci, 2013. 122(3): 
p. 232-6.
14.
Chandu, B.R., et al., Quantitative estimation of riluzole in human plasma by LC-ESI-
MS/MS and its application to a bioequivalence study. Analytical and Bioanalytical 
Chemistry, 2010. 398: p. 1367-1374.
15.
Ristori, G., et al., Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-
controlled pilot trial. Neurology, 2010. 74(10): p. 839-45.
16.
Romano, S., et al., Riluzole in patients with hereditary cerebellar ataxia: a randomised, 
double-blind, placebo-controlled trial. Lancet Neurol, 2015. 14(10): p. 985-91.
17.
Coric, V., et al., Riluzole augmentation in treatment-resistant obsessive-compulsive 
disorder: an open-label trial. Biological Psychiatry, 2005. 58: p. 424-428.
18.
Emamzadehfard, S., et al., Riluzole in augmentation of fluvoxamine for moderate to severe 
obsessive-compulsive disorder: Randomized, double-blind, placebo-controlled study.
Psychiatry Clin Neurosci, 2016. 70(8): p. 332-41.


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19.
Pittenger, C., et al., Riluzole in the treatment of mood and anxiety disorders. CNS Drugs, 
2008. 22(9): p. 761-786.
20.
McDonnell, M.E., et al., Riluzole prodrugs for melanoma and ALS: design, synthesis, and 
in vitro metabolic profiling. Bioorg Med Chem, 2012. 20(18): p. 5642-8.
21.
Sheehan, D.V., et al., Comparative Validation of the S-STS, the ISST-Plus, and the C-
SSRS for Assessing the Suicidal Thinking and Behavior FDA 2012 Suicidality Categories.
Innov Clin Neurosci, 2014. 11(9-10): p. 32-46.
22.
Sheehan, D.V., J.M. Giddens, and I.S. Sheehan, Status Update on the Sheehan-Suicidality 
Tracking Scale (S-STS) 2014. Innov Clin Neurosci, 2014. 11(9-10): p. 93-140.
23.
Shear, M.K., et al., Reliability and validity of a structured interview guide for the 
Hamilton Anxiety Rating Scale (SIGH-A). Depress Anxiety, 2001. 13(4): p. 166-78.
24.
Brandt, J., The Hopkins Verbal Learning Test: Development of a New Memory Test with 
Six Equivalent Forms. Clinical Neuropsychologist, 1991. Vol. 5(2): p. 125-142.
25.
Feltner, D.E., et al., Clinical evaluation of the Daily Assessment of Symptoms-Anxiety 
(DAS-A): a new instrument to assess the onset of symptomatic improvement in generalized 
anxiety disorder. CNS Neurosci Ther, 2009. 15(1): p. 12-8.
26.
Hidalgo, R.B., L.A. Tupler, and J.R. Davidson, An effect-size analysis of pharmacologic 
treatments for generalized anxiety disorder. J Psychopharmacol, 2007. 21(8): p. 864-72.
27.
Durgam, S., et al., Efficacy and Safety of Vilazodone in Patients With Generalized Anxiety 
Disorder: A Randomized, Double-Blind, Placebo-Controlled, Flexible-Dose Trial. J Clin 
Psychiatry, 2016. 77(12): p. 1687-1694.
28.
Coric, V., et al., Multicenter, randomized, double-blind, active comparator and placebo-
controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized 
anxiety disorder. Depress Anxiety, 2010. 27(5): p. 417-25.


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CLINICAL PROTOCOL APPROVAL FORM
Protocol Title: A Multicenter, Randomized, Double-Blind, Placebo Controlled Trial of Troriluzole in 
Generalized Anxiety Disorder
Study No: BHV4157-207 
Draft Original Protocol Date: 16 Nov 2018
Protocol Version No: V03
Protocol Version Date: 01 Aug 2019
This study protocol was subject to critical review and has been approved by the appropriate 
protocol review committee of the sponsor.  The information contained in this protocol is 
consistent with:
-
The current risk-benefit evaluation of the investigational product. 
-
The moral, ethical and scientific principles governing clinical research as set out in the 
Declaration of Helsinki, and principles of GCP as described in 21 CFR parts 50, 54, 56 
and 312 and according to applicable local requirements. 
-
The Investigator will be supplied with details of any significant or new findings, including 
adverse events, relating to treatment with the investigational product. 
Name and Title
Signature Approval
Date
Author/Protocol Writer:
Biohaven Pharmaceuticals
(I confirm, QC completed for required elements)
Clinical Operations:
 
 
Biohaven Pharmaceuticals
Biostatistics:
Biohaven Pharmaceuticals
Medical Lead:
 
 
Biohaven Pharmaceuticals
Regulatory Affairs:
Biohaven Pharmaceuticals
PPD
PPD
PPD
PPDPPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

SAP_001.pdf: 
Confidentiality 
This document is confidential and proprietary property of Biohaven Pharmaceuticals and to be used only as 
authorized by Biohaven Pharmaceuticals.  No part is to be reproduced, disclosed to others, or quoted without prior 
written authorization from Biohaven Pharmaceuticals. 
Biohaven Pharmaceuticals 
 
Protocol BHV4157-207 
 
A Multicenter, Randomized, Double-Blind, Placebo Controlled Trial of 
Troriluzole in Generalized Anxiety Disorder  
 
Statistical Analysis Plan 
Final Version 1.1
Date: 22 January 2020


 
SIGNATURE PAGE
Protocol Title: 
A Multicenter, Randomized, Double-Blind, Placebo 
Controlled Trial of Troriluzole in Generalized Anxiety 
Disorder 
Sponsor:
Biohaven Pharmaceuticals, Inc.
Protocol Number: 
BHV4157-207 
Document Version/Date: 
V1.1/22 January 2020 (Final) 
Author:                                      
 
 
 
Signature:____________________________________ 
Date:________________________________________ 
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein.  I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidances and guidelines.
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments.  All changes to the 
planned analyses will be described in the clinical study report (CSR).
Sponsor Signatories: 
 
 Biohaven 
Pharmaceuticals 
Signature:____________________________________ 
Date:________________________________________ 
 
 
 Biohaven 
Pharmaceuticals  
Signature:____________________________________ 
Date:________________________________________ 
PPD
PPD
CCI
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Biohaven Pharmaceuticals                                
Protocol BHV4157-207
Confidential   
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3
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................2
TABLE OF CONTENTS.............................................................................3
ABBREVIATIONS......................................................................................5
INTRODUCTION AND OBJECTIVES OF ANALYSIS .........................7
Introduction.........................................................................7
Objectives of Statistical Analysis......................................7
STUDY DESIGN...................................................................................8
Synopsis of Study Design..................................................8
Randomization Methodology.............................................8
Unblinding...........................................................................8
Figure 1: Study Schematic............................................................9
Efficacy, Safety, and Other Variables................................9
2.4.1. Primary Endpoint................................................................9
2.4.2. Secondary Endpoints.........................................................9
2.4.3. Exploratory Endpoints .......................................................9
SUBJECT POPULATIONS ................................................................11
Population Definitions......................................................11
Protocol Deviations ..........................................................11
STATISTICAL METHODS..................................................................12
Sample Size Justification.................................................12
General Statistical Methods and Data Handling ............12
4.2.1. General Methods...............................................................12
4.2.2. Computing Environment..................................................13
4.2.3. Adjustments for Covariates and Stratification...............13
4.2.4. Multiple Comparisons/Multiplicity...................................13
4.2.5. Subpopulations.................................................................13
4.2.6. Discontinuations, Dropouts, and Loss to Follow-up.....13
4.2.7. Missing, Unused, and Spurious Data..............................14
4.2.7.1.
Efficacy.........................................................................14
4.2.7.2.
Safety............................................................................14
4.2.8. Visit Windows ...................................................................15


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Protocol BHV4157-207
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4
Analysis Periods and Study Phases ...............................16
Planned Analyses .............................................................17
Subject Disposition ..........................................................17
Demographic and Baseline Characteristics ...................18
Efficacy Evaluation...........................................................18
4.7.1. Primary Endpoint..............................................................18
4.7.1.1.
Hamilton Anxiety Rating Scale...................................18
4.7.2. Secondary Efficacy Endpoints ........................................21
4.7.2.1.
Sheehan Disability Scale ............................................21
4.7.2.2.
Clinical Global Impression-Severity Scale ................21
4.7.3. Exploratory Efficacy Endpoints.......................................22
4.7.3.1.
Digit Symbol Substitution Task..................................22
4.7.3.2.
Hopkins Verbal Learning Test - Revised...................23
4.7.3.3.
Clinical Global Impression-Improvement Scale........23
4.7.3.4.
Hamilton Depression Rating Scale ............................24
4.7.3.5.
Penn State Worry Questionnaire................................24
4.7.3.6.
Clinical Trial and Site Scale-B ....................................25
Pharmacokinetic Evaluations ..........................................26
Safety and Other Analyses ..............................................26
4.9.1. Extent of Exposure and Compliance to Study 
Treatment ..........................................................................26
4.9.2. Adverse Events.................................................................28
4.9.3. Laboratory Data ................................................................29
4.9.4. Physical Examination.......................................................31
4.9.5. Vital Signs and Physical Measurements.........................31
4.9.6. Electrocardiogram ............................................................31
4.9.7. Concomitant Medications ................................................32
4.9.8. Sheehan-Suicidality Tracking Scale................................32
4.9.9. Subjects Identified for Narratives....................................32
REFERENCES ...................................................................................34
APPENDIX 1............................................................................................35


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Protocol BHV4157-207
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5
ABBREVIATIONS 
Abbreviation
Definition 
AE
Adverse event 
ALP
Alkaline phosphatase 
ALT
Alanine aminotransferase 
ANCOVA 
Analysis of covariance
AST
Aspartate aminotransferase 
BID
Twice daily 
BQL
Below limit of quantification
BUN
Blood urine nitrogen 
CGI-I
Clinical Global Impression-Improvement scale 
CGI-S
Clinical Global Impression-Severity scale 
CTCAE 
Common Technical Criteria for Adverse Events 
CI
Confidence interval
CPK
Creatine phosphokinase  
CRF
Case report form
CSR
Clinical study report
CTSS-B
Clinical Trial and Site Scale-B
DAIDS 
Division of Acquired Immunodeficiency Syndrome
DILI
Drug induced liver injury 
DMC
Data monitoring committee 
DB
Double-blind 
DSST
Digit symbol substitution scale 
ECG
Electrocardiogram 
eDISH
Evaluation of drug-induced serious hepatotoxicity 
GAD
Generalized anxiety disorder
HAM-A
Hamilton Anxiety Rating Scale
HAM-D 17
Hamilton Depression Scale 17-Item Version
HbA1c
Hemoglobin A1c 
HBsAg 
Hepatitis B surface antigen 
HCV
Hepatitis C virus
HDL
High-density lipoprotein 
HIV
Human immunodeficiency virus 
HVLT-R
Hopkins Verbal Learning Test-Revised 
GGT
Gamma-glutamyl transferase  
ICH
International Conference on Harmonisation


Biohaven Pharmaceuticals                                
Protocol BHV4157-207
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6
Abbreviation
Definition 
IWRS
Interactive web response system
LDH
Lactate dehydrogenase  
LDL
Low-density lipoprotein 
LOCF
Last observation carried forward
LSMeans
Least square means 
MAR
Missing at random 
mITT
Modified intent-to-treat
MCMC
Markov chain Monte Carlo 
MedDRA
Medical Dictionary for Regulatory Activities
MINI
Mini International Neuropsychiatric Interview
MMRM
Mixed model for repeated measures 
MNAR 
Missing not at random
NC=F 
Non-completer equals failure
NTF
Note to file
OL
Open-label 
PID
Patient identification number
PCRS
Placebo-Control Reminder Script  
PK
Pharmacokinetic
PRSS
Placebo Response Screening Scale
PSWQ 
Penn State Worry Questionnaire
PT
Preferred term
ROC
Receiver Operating Characteristic
RPR
Rapid plasma reagin
SAE
Serious adverse event
SAP 
Statistical analysis plan 
SD
Standard deviation
SDS 
Sheehan Disability Scale 
SE
Standard error 
SI
Standard International
SIGH-D
Structured Interview Guide for the Hamilton Depression Rating Scale
SOC
System organ class
S-STS
Sheehan Suicidality Tracking Scale 
TSH
Thyroid-stimulation hormone 
ULN
Upper limit of normal 
WHO-DD
World Health Organization-Drug Dictionary 
 


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INTRODUCTION AND OBJECTIVES OF ANALYSIS
Introduction
This document presents the statistical analysis plan (SAP) for Biohaven Pharmaceuticals, 
Protocol BHV4157-207: A Multicenter, Randomized, Double-blind, Placebo Controlled Trial of 
Troriluzole in Generalized Anxiety Disorder, version 3.0, dated August 2, 2019. 
It contains the analysis details and methodology to answer the study objectives, including 
planned summary tables, by-subject listings, and figures, which will provide the basis for the 
results section of the clinical study report (CSR). Operational aspects related to collection and 
timing of planned clinical assessments are not repeated in this SAP unless relevant to the 
planned analyses.
Objectives of Statistical Analysis
Primary Objective
The primary objective of the study is to evaluate the efficacy of troriluzole compared to 
placebo after 8-weeks of treatment in subjects with generalized anxiety disorder (GAD), 
as measured by the Hamilton Anxiety Rating (HAM-A) Scale
Secondary Objectives
To assess the safety and tolerability of troriluzole, relative to placebo, in subjects with 
GAD
Evaluate the efficacy of troriluzole compared to placebo on functional disability as 
measured by the Sheehan Disability Scale (SDS)
Evaluate the efficacy of troriluzole compared to placebo on global functioning as 
measured by the Clinical Global Impression - Severity (CGI-S) Scale 
Exploratory Objectives
Evaluate the effects of troriluzole compared to placebo on cognitive performance as 
measured by the Digit Symbol Substitution Task (DSST) and the Hopkins Verbal 
Learning Test-Revised (HVLT-R)
Evaluate the efficacy of troriluzole compared to placebo on improvement in global 
functioning as measured by the Clinical Global Impression - Improvement Scale (CGI-I)
Evaluate the efficacy of troriluzole compared to placebo on depressive symptomatology 
as measured by the Hamilton Depression Rating Scale-17 (HAM-D-17)
Evaluate the efficacy of troriluzole compared to placebo on anxiety symptoms as 
measured by the Penn State Worry Questionnaire (PSWQ)
To characterize the pharmacokinetics of troriluzole based on sparse sampling
Evaluate correlates of placebo responsiveness by using the Clinical Trial and Site Scale-
B (CTSS-B) as well as other pre-intervention outcome measures and demographic 
information


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Protocol BHV4157-207
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8
STUDY DESIGN
Synopsis of Study Design
BHV4157-207 is a Phase III, multicenter, randomized, double-blind, placebo-controlled, 2-arm 
study designed to assess safety, tolerability, and efficacy of troriluzole in subjects with GAD 
who have a HAM-A score of 18 or greater at screening and baseline. Additionally, GAD 
symptoms in subjects had to be present for at least 1 year and at least of moderate severity on 
the CGI-S scale at study entry.
Subjects who qualified were randomized to receive placebo (BID) or troriluzole (100 mg BID) 
for 8 weeks of double-blind (DB) treatment. Eligible subjects also had the opportunity to 
continue in a 48-week open-label (OL) extension phase. Those subjects not continuing in the 
48-week extension returned to the clinic 2 weeks after discontinuing study medication for a 
follow-up safety visit.
For subjects entering the extension phase, their first in-person extension visit occurred 4 weeks 
after the Week 8 randomization phase visit. Subjects underwent visits every four weeks through 
Week 12 of this phase. Then subjects underwent visits every 12 weeks until Week 48 of the 
extension phase. All subjects underwent a post study drug termination visit 2 weeks after the 
last dose of study drug in the extension phase.
Figure 1 illustrates the study schematic.
Randomization Methodology
After completion of all screening evaluations, all eligible subjects were randomized in a 1:1 
ratio to receive either placebo (BID) or troriluzole (100 mg BID).  Treatment assignments were
obtained by the investigator (or designee) via the interactive web response system (IWRS).
Unblinding
Blinding is critical to the integrity of this clinical study. However, in the event of a medical 
emergency or pregnancy, in which knowledge of the investigational product is critical to the 
subject’s management, the blind for that subject may be broken by the treating physician. 
Before breaking the blind of an individual subject’s treatment, the investigator should have 
determined that the information is necessary, i.e., that it will alter the subject’s immediate 
management. In many cases, particularly when the emergency is clearly not related to the 
investigational product, the problem may be properly managed by assuming that the subject is 
receiving active product without the need for unblinding. Unblinding will be managed via the 
IWRS. 
A pharmacokineticist, IWRS vendor, and pharmacovigilance role may be unblinded before data 
are unblinded for the primary endpoint and all subjects complete the randomization phase of the 
study. Except as noted above, other members of the Biohaven research team will remain 
blinded. For purposes of the data monitoring committee (DMC), periodic analysis will be 
carried out by the unblinded safety biostatistics team independent and firewalled from the team 
directly involved with the design and primary analysis of the trial. A report will be prepared for 
the DMC as outlined in the DMC charter and abbreviated SAP. 
In cases of accidental unblinding, contact the medical monitor and ensure every attempt to 
preserve the blind is made.


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Figure 1: Study Schematic
*Eligible subjects are those subjects who complete the randomization phase and for whom the 
investigator believes OL treatment offers an acceptable risk-benefit profile.
Efficacy, Safety, and Other Variables
2.4.1.
Primary Endpoint
Improvement in GAD is assessed using the change in the total HAM-A score from 
baseline to the end of the randomization phase (Week 8)
2.4.2.
Secondary Endpoints
Safety and tolerability are assessed using the frequency of unique subjects with: 
o
Serious adverse events (SAEs)
o
Adverse events (AEs) leading to discontinuation
o
AEs judged to be related to study medication
o
Clinically significant laboratory abnormalities that are observed during the 
randomization phase
Improvement in functional disability is assessed using the change in the total SDS 
score from baseline to the end of the randomization phase (Week 8)
Improvement in global functioning is assessed using the CGI-S at the end of the 
randomization phase (Week 8)
2.4.3.
Exploratory Endpoints
Improvement in cognitive performance is assessed using the DSST and HVLT-R from 
baseline to the end of the randomization phase (Week 8)


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Improvement in global functioning is assessed using the CGI-I at the end of the 
randomization phase (Week 8)
Improvement in depressive symptomatology is measured by the change in the HAM-D-
17 from baseline to the end of the randomization phase (Week 8)
 Improvement in anxiety symptoms is assessed using the change in the PSWQ from 
baseline to the end of the randomization phase (Week 8) 
 The pharmacokinetic profile of troriluzole is characterized by blood concentrations 
observed in treated subjects  
 The CTSS-B (total score, subitems, other pre-intervention outcome measures and 
demographics) will be used to characterize correlates of placebo responsiveness (as 
defined by change from baseline on the HAM-A and SDS)  
 


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SUBJECT POPULATIONS
Population Definitions
The following populations will be evaluated and used for presentation and analysis of the data:
Enrolled subjects: Patients who signed an informed consent form and were assigned a 
patient identification number (PID)
Randomized subjects: Enrolled subjects who received a treatment assignment from the 
IWRS
Treated subjects in the randomization phase: Enrolled subjects who received at least 1 
dose of blinded study therapy (troriluzole or placebo) 
Treated subjects in the extension phase: Treated subjects in the randomization phase 
who received at least 1 dose of troriluzole in the OL extension phase
DB and OL troriluzole treated subjects: Enrolled subjects who received at least 1 dose of 
DB or OL troriluzole during the entire study
Modified intent-to-treat (mITT) subjects in the randomization phase: Randomized 
subjects who received at least 1 dose of blinded study therapy (troriluzole or placebo), 
and provided a non-missing baseline assessment and at least 1 non-missing post-baseline 
efficacy assessment during the randomization phase
mITT subjects in the extension phase: mITT subjects in the randomization phase who 
provided at least 1 non-missing efficacy assessment during the extension phase
DB and OL troriluzole mITT subjects: Randomized subjects who received at least 1 dose 
of DB or OL troriluzole, and provided a non-missing baseline assessment and at least 1
non-missing post-baseline efficacy assessment during the entire study
Protocol Deviations
Any significant event that does not comply with the inclusion/exclusion criteria, study conduct
(e.g., inadequate informed consent), or study procedures (e.g., use of prohibited medications as 
defined by the protocol; improper breaking of the blind) will be documented as a major
deviation. 
The sponsor, or designee, will be responsible for producing the final protocol deviation file 
(formatted as a Microsoft Excel file), which will be finalized prior to database lock. This file 
will include site, subject ID, deviation date, deviation type, status (major vs. minor), and a 
description of the protocol deviation.
All major protocol deviations will be tabulated for the randomization and extension phases, 
separately, and all deviations will be presented in a by-subject listing.


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STATISTICAL METHODS
Sample Size Justification
The sample size for this study will be approximately 372 randomized subjects.
From a review of GAD by Hidalgo et al. (2007), data from 7 adult studies (treatment duration 
between 4 to 12 weeks) provided the standard deviation (SD) for change from baseline ranging 
from 6.0 to 8.7; the average SD was 7.4.
With an expected Week 8 difference between treatment groups to be 2.5 points on the total 
HAM-A score, 372 subjects provide 90% power based on a 2-sample t-test with a common SD
of 7.4. The previous calculation is based on an assumption of no premature discontinuations; if 
premature discontinuations occur at a rate of up to 25%, the power to detect a 2.5 point 
difference may be as low as 80%.
General Statistical Methods and Data Handling
4.2.1.
General Methods
All output will be incorporated into Microsoft Excel or Word files, sorted and labeled according 
to the International Conference on Harmonization (ICH) recommendations, and formatted to the 
appropriate page size(s). Tabulations will be produced by randomized treatment group and 
overall, unless otherwise specified.  
Categorical variables will be tabulated with counts and percentages.  Continuous variables will 
be summarized with univariate statistics (e.g. n, mean, SD, median, minimum, and maximum).
The minimum and maximum will be presented with the same precision as the data, the mean 
and percentiles will be presented with the precision of the data + 1 decimal place, and the SD 
will be presented with the precision of the data + 2 decimal places. P-values < 0.0001 will be 
presented as “<0.0001”. Otherwise, p-values will be presented to 4 decimal places.
Tabulations of the following endpoints present the number of unique subjects with an event: 
protocol deviations, non-study medications, AEs, and laboratory abnormalities.  Thus, for these 
endpoints, multiple occurrences of the same event are counted only once per subject.
Unless otherwise specified, data collected from the randomization and extension phases will be 
analyzed separately.  For subjects receiving troriluzole during the DB and OL phases, summary 
statistics will be provided for data from both phases combined.
By-subject listings will display “Site-Subject ID (Age/Sex/Race)” stacked together in the same 
column using the following conventions: 
Age at informed consent will be displayed truncated to an integer. 
Sex will be displayed abbreviated as “F” for female and “M” for male. 
Race will be displayed abbreviated as “A” for Asian”, “B” for Black or African American, 
“I” for American Indian or Alaska Native, “M” for multiple, “N” for Native Hawaiian or 
Other Pacific Islander, and “W” for White.
A footnote will describe the abbreviations as applicable. Subjects who reported more than one 
race will be counted only once in the “Multiple” category.  Missing age, sex, or race will be 
displayed as a single blank space. 


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Note that “(Age/Sex/Race)” will not be displayed in listings of randomization scheme and 
codes, batch numbers, or demographics.
4.2.2. 
Computing Environment 
All statistical analyses will be performed using SAS statistical software (Version 9.4). Medical 
history and AEs will be coded using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA) at the time of database lock. Concomitant medications will be 
coded using World Health Organization Drug Dictionary (WHO-DD, Sep2016).
Clinically significant laboratory abnormalities will be identified as Grade 3 to 4 laboratory test 
results graded according to numeric laboratory test criteria in Common Technical Criteria for 
Adverse Events (CTCAE) version 5.0 (2017) if available; otherwise according to Division of 
Acquired Immunodeficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events Corrected version 2.1 (2017). 
4.2.3. 
Adjustments for Covariates and Stratification 
The randomization was not stratified. The analysis of the primary endpoint and other continuous 
change from baseline efficacy endpoints will be adjusted by the baseline value of the endpoint
as a covariate in statistical models.  
4.2.4. 
Multiple Comparisons/Multiplicity 
Type 1 error will be controlled for the primary and secondary efficacy endpoints by testing them
with a gate-keeping procedure.  The primary endpoint, change from baseline in the total HAM-
A score at Week 8, will be tested at a 2-sided alpha level of 0.05.  If this test is significant, then 
the secondary efficacy endpoints will be tested using Hochberg’s procedure, in which the p-
values from the test of each secondary endpoint will be ranked from lowest to highest, and all 
tests for the null hypothesis of each secondary endpoint with a p-value less than the test with the 
highest p-value below its critical p-value (defined as 0.05/(k-j+1) where j is the rank of the test 
and k is the total number of tests) can be rejected.   
If the test of the primary endpoint is not significant, then the unadjusted p-values for the 
secondary endpoints will be presented only for descriptive purposes, and no conclusions will be 
drawn from these results. 
No attempt will be made to adjust for multiplicity when testing the exploratory endpoints.  Any 
exploratory endpoints subjected to significance testing are evaluated at an unadjusted 2-sided 
alpha level of 0.05 and are presented for descriptive purposes only.  
4.2.5. 
Subpopulations 
The subgroups of interest for this study are gender (female, male) and race (Asian, Black or 
African American, White, and all other races combined).  Only descriptive summaries will be 
provided for the primary and secondary endpoints for each subgroup.
4.2.6. 
Discontinuations, Dropouts, and Loss to Follow-up 
Subjects who discontinue from the study will not be replaced.


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4.2.7.
Missing, Unused, and Spurious Data
4.2.7.1. Efficacy 
Unless otherwise noted, efficacy analyses will be based on observed data only. Studies similar 
to the randomization phase of this study showed ~25% of the subjects fail to complete the 
blinded randomized portion of the study (Durgam et al. 2016; Coric et al. 2010). Hence, we 
expect a similar rate of discontinuation during the randomization phase of this study.  
For the principal analysis of efficacy for primary, secondary and exploratory endpoints, no 
imputation will be performed on missing data following discontinuation from study.  In some 
cases missing items will be imputed (see individual scale sections below).   
Sensititivity analyses using multiple imputation (MI) will be conducted on the primary and 
secondary endpoints using a jump to reference and copy reference approach to assess the impact 
of the missing at random (MAR) assumption (see Section 4.7.1.1).  
For efficacy analyses, partial or missing dates will not be imputed. The relative study days, 
where determined, will be calculated for full dates only.  
4.2.7.2. Safety 
Adverse Events 
If the start date/time of an AE is partially or completely missing, the date/time will be compared 
as far as possible with the date/time of the start of administration of study drug. The AE will be 
assumed to be treatment-emergent if it cannot be definitively shown that the AE did not occur or 
worsen during the treatment-emergent period (worst case approach).  
The following general rules will be used:
 If the start time of an AE is missing but the start date is complete, an AE will only be 
excluded as being treatment-emergent if the start date is before the date of study drug 
administration or if the stop date/time is before study drug administration.  
 If the start time and day are missing but the start month and year are complete, an AE 
will only be excluded as being treatment-emergent if the start month/year is before the 
month/year of study drug administration or if the stop date/time is before study drug 
administration.  
 If the start day and month are missing but the start year is complete, an AE will only be 
excluded as being treatment-emergent if start year is before the year of study drug 
administration or if the stop date/time is before study drug administration.  
 If the start date is completely missing, an AE will be considered treatment-emergent 
unless the stop date/time is before study drug administration. 
Non-Study Medications 
All non-study medications will be assumed to be both a prior and concomitant medication 
unless the start or stop dates definitively exclude that the medication was taken during either or 
both prior or during study treatment.  
  


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Prior medications are defined as those medications taken before study drug start. A medication 
will be excluded as a prior medication:  
If the start date is on or after the first day of study medication
If the start day is missing but the start month and year are complete, a medication will 
not be considered as prior if the start month/year are after the month/year of the start 
date of study drug administration  
If the start day and month are missing but the start year is complete, a medication will 
not be considered as prior if start year is after the year of the start of study drug 
administration 
Concomitant medications during the randomization and/or extension phases are defined as those 
medications taken during either phase. A medication will be excluded as a concomitant 
medication for a given phase: 
 If the start date is after the last day of study medication for that phase or the end date is 
before the first day of study medication
 If the start day is missing but the start month and year are complete, a medication will 
not be considered as concomitant if the start month/year are after the month/year of the 
end date of study drug administration for that phase
 If the start day and month are missing but the start year is complete, a medication will 
not be considered as concomitant if start year is after the year of the end date of study 
drug administration for that phase 
 If the stop day is missing but the stop month and year are complete, a medication will be 
not considered as concomitant if the stop month/year are before the month/year of the 
start of study drug administration for that phase 
 
If the stop day and month are missing but the stop year is complete, a medication will be 
not considered as concomitant if stop year is before the year of the start of study drug 
administration for that phase
4.2.8. 
Visit Windows 
The protocol-specified visit window is ± 2 days during the randomization phase and ± 5 days
during the extension phase of the study; however, analysis windows will be adjusted in an 
attempt to include all data. Refer to Table 1 for details on the analysis visit windows.   
If a subject has more than one record within an analysis window, the latest record in the window
will be used in the analysis.  In the case of a tie, the earlier record will be used. 


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Table 1:     Analysis Visit Windows
Evaluation
Protocol-Specified 
Day
Protocol-Specified 
Interval
Analysis-Specified 
Interval
Randomization Phase
Week 2
Day 14
Day 12-16
Day 2-21
Week 4*
Day 28
Day 26-30
Day 22-35
Week 6
Day 42
Day 40-44
Day 36-49
Week 8*
Day 56
Day 54-58
Day 50-70
Extension Phase**
Ext. Week 4
Ext. Day 28
Ext. Day 23-33
Day 1-35
Ext. Week 8
Ext. Day 56
Ext. Day 51-61
Day 36-70
Ext. Week 12
Ext. Day 84
Ext. Day 79-89
Day 71-126
Ext. Week 24 
Ext. Day 168
Ext. Day 163-173
Day 127-210
Ext. Week 36
Ext. Day 252
Ext Day 247-257
Day 211-294
Ext. Week 48
Ext. Day 336
Ext Day 331-341
Day 295-364
Note: For the randomization phase, the baseline assessment is defined as the last available assessment on or before 
the first day of the randomization phase study drug; for the extension phase, the baseline assessment is defined as 
the last available assessment on or before the first day of extension phase study drug. For any troriluzole summaries 
(DB and/or OL), the baseline assessment is defined as the last available assessment on or before the first day of 
troriluzole treatment.
*For the SDS, the analysis-specified interval is Day 2-42 for Week 4 and Day 43-70 for Week 8 (unlike other 
endpoints, there is no SDS assessment at Week 2 or Week 6 visit of the randomization phase). For the SDS Week 8 
assessment, the last available observation within Day 43-63 will be used; if there are no other observations in this 
window, then the last observation within Day 64-70 will be used. For all other Week 8 assessments, the last 
available observation within Day 50-63 will be used; if there are no other observations in this window, then the last 
observation within Day 64-70 will be used. 
**Relative to randomization phase Week 8 visit.
Analysis Periods and Study Phases
Analysis periods and study phases are defined as follows:
Screening phase: to include all assessments on or before the first day of study drug. 
On-treatment in the randomization phase: to include all assessments after first day of DB 
study drug in the randomization phase and up to the first day of OL study drug in the 
extension phase (for subjects entering the extension phase) or last day of the randomization 
phase study drug + 30 days. 
o
On-treatment laboratory/ECG/vital sign abnormalities in the randomization phase: 
to include any abnormality with an assessment date after the first day of of DB 
study drug
o
Treatment-emergent AEs (TEAEs) in the randomization phase: to include any AE 
with an onset date on or after the first day of DB study drug
On-treatment in the extension phase: to include all assessments after the first day of OL 
study drug in the extension phase until the last day of study drug + 30 days. 


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o
On-treatment laboratory/ECG/vital sign abnormalities in the extension phase: to 
include any abnormality with an assessment date after the date of the first dose of 
OL study drug
o
TEAEs in the extension phase: to include any AE with an onset date on or after the 
first day of OL study drug. If an AE onset date occurs on the last day of 
randomization treatment and the first day of OL study drug dosing (i.e., dosing 
overlap), then the AE will be attributed to both the randomization and extension 
phases.
On-treatment in the study: to include any troriluzole treatment (DB or OL), and all 
assessments after the first day of troriluzole treatment and last day of troriluzole treatment + 
30 days. 
o
On-treatment laboratory abnormalities/ECG/vital sign in the study: to include any 
abnormality with an assessment date/time after the date/time of the first dose of 
DB or OL study drug (troriluzole)
o
TEAEs in the study: to include any AE with an onset date on or after the first dose 
of DB or OL study drug (troriluzole)
Planned Analyses
Multiple safety meetings with the DMC will be held throughout the study and prior to database 
lock. Safety results will be presented in open and closed formats per the request of the DMC. 
Only DMC members and the unblinded statistical team will have access to the partially 
unblinded data.
In addition, the analysis for the primary endpoint will be conducted after the last subject 
completes their Week 8 visit or discontinues from the randomization phase. The study will be 
unblinded and will include all data from the randomization phase of the study, but will not 
include summaries of efficacy data accumulated from the extension phase.
A final analysis of the study will be completed after the last subject completes their last study 
visit.  This analysis will summarize all efficacy data collected in the OL extension phase as well 
as all safety, laboratory, and other data collected thoughout the entire study. Change from 
baseline will be based on the extension baseline for all analyses conducted during the extension 
phase, unless otherwise specified. Extension baseline is defined as the last assessment prior to 
the start of the extension phase.
Additional analyses may be conducted during the extension phase to support regulatory and 
administrative requirements. 
Subject Disposition
A summary of subject disposition will be tabulated for all enrolled subjects by treatment group 
and overall, including:
Number of enrolled subjects who signed the informed consent form
Number of enrolled subjects excluded from the study and reason for exclusion (e.g., 
Exclusion 1a, Inclusion 1a)
Number of randomized subjects


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Number of treated subjects in the randomization phase
Number of mITT subjects in the randomization phase
Number of subjects who completed the randomization phase
Number of subjects who prematurely withdrew from the randomization phase and 
reasons for withdrawal
Number of subjects who entered the extension phase
Number of treated subjects in the extension phase
Number of mITT subjeects in the extension phase
Number of subjects who completed the extension phase
Number of subjects who withdrew from the extension phase and reasons for withdrawal
A by-subject listing of study completion information for both the randomization and extension 
phases, including the reason for withdrawal, if applicable, will be presented.
Demographic and Baseline Characteristics
Tabulations of demographic and baseline characteristics, including medical and psychiatric 
history, and the Mini International Neuropsychiatric Interview (MINI) will be made for all 
treated subjects in the randomization phase by treatment group and overall. 
Demographic and other baseline data will also be provided in by-subject listings.
Efficacy Evaluation
Unless otherwise noted, all efficacy analyses will be conducted on mITT subjects in the 
randomization and extension phases. All efficacy data will be included in listings by subject, 
treatment group, and visit (as applicable). Randomization and extension phase data will be 
shown within the same listing unless otherwise specified.
4.7.1.
Primary Endpoint
4.7.1.1.
Hamilton Anxiety Rating Scale 
The HAM-A is a clinician-administered scale used extensively in research and clinical practice 
to both rate severity of GAD and to monitor improvement during treatment. It is designed to rate 
the severity of anxiety as well as the type of symptoms in patients with GAD. The scale consists 
of 14 items. Each item is scored on a scale of 0 (not present) to 4 (severe) with a total score 
range of 0-56. Subscale scores can be calculated for psychic anxiety factor (sum of HAM-A 
items: anxious mood, tension, fears, insomnia, concentration, depressed mood, and behavior at 
interview) and somatic anxiety factor (sum of HAM-A items: somatic muscular, somatic 
sensory, cardiovascular, respiratory, gastrointestinal, genitourinary, and autonomic symptoms).
Each subscale will be calculated, provided there is no more than 1 item missing, as the mean of 
the available items multiplied by 7. The subscale scores are summed to create a total score 
ranging from 0 – 56 to indicate overall severity.
As the primary objective of this study is based on the evaluation of severity of patients’ 
symptomology, the estimand for the primary endpoint will be the effect due to the initially 
randomized treatments if taken as directed, a “de jure” or “hypothetical” efficacy estimand. The 


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primary endpoint will be the change from baseline in the total HAM-A score, troriluzole relative 
to placebo, at Week 8 of the randomization phase. This treatment effect will be summarized as 
the difference in the change from baseline in the total HAM-A score between the treatment 
groups.  
Since the primary intent of this trial is to evaluate the effect of the drug when taken as intended 
in the protocol, a hypothetical strategy will be employed for the intercurrent event of 
treatment/study discontinuation (due to any reason). Specifically, the assumption will be that 
had the subjects not discontinued, their efficacy would have been similar to the efficacy of 
subjects from the same treatment group who did not discontinue. For other intercurrent events 
that do not cause treatment/study discontinuation such as modest treatment non-compliance, 
protocol allowed dose adjustments, or initiation or adjustment of concomitant medications 
related to other symptoms, all observed values will be used. 
The change from baseline in the total HAM-A score through Week 8 will be analyzed using a 
Mixed Model for Repeated Measures (MMRM). The model will include treatment, visit (Weeks 
2, 4, 6, and 8), and the treatment-by-visit interaction as fixed effects, and baseline total HAM-A 
score and baseline-by-visit interaction as covariates. Repeated measurements are made on each 
subject.  The covariance structure for within-subject error (“R” Matrix) will be initially 
specified as unstructured. If the model fails to converge, then a Huynh-Feldt structure may be 
used, followed by an AR(1) structure. Error degrees of freedom will be calculated using 
Kenward-Roger approximation if an unstructured covariance structure fits appropriately; 
otherwise, a sandwich estimator will be utilized to estimate the covariance structure and degrees 
of freedom will be calculated using the between-within method. 
Least Square Means (LSMeans) for the change from baseline for each treatment group will be 
derived for Weeks 2, 4, 6, and 8.  These estimates will be presented with degrees of freedom, 
standard errors (SEs), and 2-sided 95% confidence intervals (CIs).  The difference in change 
from baseline between the treatment groups will also be derived for the same visits, and 
presented with degrees of freedom, SEs, 2-sided 95% CIs, and p-values. 
The subscores  of the HAM-A (i.e., psychic anxiety and somatic anxiety) will be analyzed using 
methodology similar to the total score.  
Descriptive statistics for the total HAM-A score and subscale scores and the change from 
baseline in the total HAM-A score and subscale scores will be presented by visit for the 
randomization and extension phases, separately. In addition, the total HAM-A score and change 
from baseline (from randomization baseline) will be summarized with descriptive statistics for 
the DB and OL troriluzole mITT subjects originally randomized to DB troriluzole. 
Sensitivity Analyses 
The following sensitivity analyses will be conducted to support the principal analysis for the 
randomization phase: 
 Responder analysis with “response” defined as at least 50% reduction in the total HAM-
A score from baseline to Week 8.  
Remission analysis with “remission” defined as a total HAM-A score <=7 at both Weeks 
6 and 8.  


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Multiple imputation (MI) analyses using referenced-based imputation methods as 
described below
In the responder and remitter analysis, non-completers will be treated as failures (NC=F). The 
data will be evaluated with a Fisher’s exact test with a 2-sided alpha level of 0.05 by treatment 
group.  Success rates for each treatment group will be presented with exact (Clopper-Pearson) 
95% CIs. The responder analysis will be supported by a cumulative probability graph, showing 
both treatment groups, with change from baseline on the abscissa (x-axis) and cumulative 
probability on the ordinate (y-axis). In addition, the non-completers (NC=F) will be presented as 
a distinct point mass to the left of the cumulative probability curve with a single bar for each 
treatment group representing the proportion of subjects who are non-completers.  
The principal analysis of the total HAM-A score, based on a MMRM analysis model, assumes 
data are MAR and subjects who discontinue study medication prematurely have a response 
profile for the remainder of the randomization phase similar to subjects who completed the 8 
weeks of the randomization phase (an analysis of a “de jure” or “hypothetical” based estimand). 
In order to explore the impact of these assumptions, a sensitivity analysis will be conducted 
where subjects who discontinue troriluzole prematurely have a response profile similar to those 
subjects on placebo using both a jump to reference and copy reference approach. These analyses 
use “defacto” estimands and are based on the methods described in Carpenter et al. (2013) and 
implemented in the SAS Macros provided by the DIA Working Group section of the 
missingdata.org.uk website. 
Mean changes from baseline in the total HAM-A score will be analyzed based on data observed 
while the subject remains on study as well as data imputed using MI methodology for time 
points at which no value was observed. MI will be performed under the assumption of MAR and 
will be implemented in two steps. In the first step, a parameter-estimation model is fitted 
assuming MAR by a Markov chain Monte Carlo (MCMC) procedure in SAS with starting 
values based on fitting an MMRM model with the MIXED procedure.  In the second step, an 
imputation model, which uses the parameters estimated in part 1, calculates predicted values for 
each pattern of withdrawal.  Any intermediate missing values are imputed first assuming MAR, 
and then missing not at random (MNAR); part of the model is used to impute values for trailing 
missing values (e.g., after subject withdrawals from study). The MNAR part of the imputation 
will use a profile based on the estimated profile of the reference arm (placebo) to impute values 
after withdrawal for subjects in the troriluzole arm. In the case of the jump to reference 
approach, the mean response distribution after withdrawal will be used; and for the copy 
reference approach, the whole distribution, both before and after withdrawal, is assumed to 
come from the placebo arm. Subjects in the placebo arm will use the profile under MAR. 
For each analysis, the imputed data will consist of 1000 imputed data sets (using a MCMC 
length of 100). Both the parameter-estimation model and the imputation model will include 
treatment, visit (Weeks 2, 4, 6, and 8), and the treatment-by-visit interaction as fixed effects, and 
baseline total HAM-A score and baseline-by-visit interaction as covariates.  
For each imputed dataset, the change from baseline for the total HAM-A score at Week 8 will 
be based on observed and imputed data. An analysis of covariance (ANCOVA) model will be 
used with the baseline score as a covariate, and treatment groups will be compared at Week 8 
based on the LSMean difference between troriluzole and placebo in each of the imputed data 
sets. Results from the analysis of each imputed data set (i.e., LSMean treatment differences and 


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SEs) will be combined using Rubin’s imputation rules to produce a pooled LSMean estimate of 
treatment difference, 95% CI, and a pooled p-value for the test of the null hypothesis of no 
treatment effect. 
Subgroup Analyses 
Descriptive statistics for the total HAM-A score, and change from baseline, will be tabulated by 
visit for the randomization phase for the following subgroups:
Gender (Female, Male)
 Race (Asian, Black or African American, White, and all other races combined)
4.7.2.
Secondary Efficacy Endpoints
4.7.2.1. Sheehan Disability Scale  
The SDS is assessed in 3 domains: work/school (0-10), social life (0-10), and family life (0-10). 
The score from each domain will be summed into a single dimensional measure of global 
functional impairment that ranges from 0 (unimpaired) to 30 (highly impaired). If the subject 
has not worked or studied for reasons unrelated to GAD, then the total score will be missing. All 
3 domains must be non-missing for the total SDS score to be calculated.
The change from baseline in the total SDS score will be analyzed using a MMRM model, 
similar to the analysis described in Section 4.7.1.1.  The model will include fixed effects for 
treatment, visit (Weeks 4 and 8), and the treatment-by-visit interaction, and the baseline total 
SDS score and visit-by-baseline interaction as covariates for the randomization phase only. 
Descriptive statistics for the total SDS score (and individual items) and the change from 
baseline in the total SDS score (and individual items) will be presented by visit for the 
randomization and extension phases, separately. 
Sensitivity Analyses 
Sensitivity analyses will be conducted to support the principal analysis for the randomization 
phase. The MAR assumption for the MMRM analysis will be assessed by MI analyses using 
referenced-based imputation methods in the same manner as the primary endpoint (see Section 
4.7.1.1). The parameter-estimation model and the imputation model will include treatment, visit 
(Weeks 4 and 8), and the treatment-by-visit interaction as fixed effects, and baseline total SDS
score and baseline-by-visit interaction as covariates.  
Subgroup Analyses
Descriptive statistics for the total SDS score, and change from baseline, will be tabulated by 
visit for the randomization phase for the subgroups defined by: 
 Gender (Female, Male) 
 Race (Asian, Black or African American, White, and all other races combined)
4.7.2.2. Clinical Global Impression-Severity Scale 
The secondary endpoint, the clinician global impression of severity via the CGI-S, will be 
summarized by visit for the randomization and extension phases, separately. The number and 
percentage of subjects in each category will be summarized: normal, not at all ill; borderline ill; 
mildly ill; moderately ill; markedly ill; severely ill; and among the most extremely ill patients. 


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In addition, the CGI-S scores will be transformed into numeric values ranging from 1 to 7 (1 
indicating “normal, not at all ill” and 7 indicating “among the most extremely ill patients”). 
Descriptive statistics for the CGI-S score and the change from baseline will be presented by visit 
for the randomization and extension phases, separately.  
The change from baseline in the CGI-S score will also be analyzed using a MMRM analysis 
model, similar to the analysis described in Section 4.7.1.1. The model will include fixed effects 
for treatment, visit (Weeks 2, 4, 6, 8), and the treatment-by-visit interaction, and the baseline 
CGI-S score and visit-by-baseline CGI-S score interaction as covariates.   
Sensitivity Analyses 
Sensitivity analyses will be conducted to support the principal analysis for the randomization 
phase. The MAR assumption for the MMRM analysis will be assessed by MI analyses using 
referenced-based imputation methods in the same manner as the primary endpoint (see Section 
4.7.1.1). The parameter-estimation model and the imputation model will include treatment, visit 
(Weeks 2, 4, 6, and 8), and the treatment-by-visit interaction as fixed effects, and baseline total 
CGI-S score and baseline-by-visit interaction as covariates.  
Subgroup Analyses 
Descriptive statistics for the total CGI-S score, and change from baseline, will be tabulated by 
visit for the randomization phase, for the subgroups defined by:
 Gender (Female, Male) 
 Race (Asian, Black or African American, White, and all other races combined)
4.7.3. 
Exploratory Efficacy Endpoints 
4.7.3.1. Digit Symbol Substitution Task  
Improvement in cognitive performance will be assessed by the DSST at baseline and Week 8 of 
the randomization phase. The DSST requires that subjects fill in a series of symbols within 90 
seconds. The number of symbols correctly coded is derived as the number completed minus the
number of symbols incorrectly coded. The higher the score, the better the performance. 
The change from baseline to Week 8 in the number of symbols correctly coded will be analyzed 
with an univariate analysis of covariance (ANCOVA).  The model will contain treatment group 
as a fixed effect and the baseline score as a covariate.  The covariate adjusted difference in the 
change from baseline between the troriluzole and placebo groups will be tested at a 2-sided 
alpha level of 0.05.  Covariate adjusted LSMeans, model based SEs, degrees of freedom, and 2-
sided 95% CIs will be presented for each treatment group and for the difference between the 
treatment groups.
The above ANCOVA model will be repeated for observed cases at Week 8 and using last 
observation carried forward (LOCF).  Covariate adjusted LSMeans, model based SEs, degrees 
of freedom, and 2-sided 95% CIs will be presented for each treatment group and for the 
difference between the treatment groups.
Descriptive statistics for the the number of symbols correctly coded (including baseline) and 
change from baseline will be summarized by treatment group and visit for the randomization 
phase. 


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4.7.3.2.
Hopkins Verbal Learning Test - Revised
Improvement in cognitive performance will also be assessed by the HVLT-R at baseline and 
Week 8 of the randomization phase. The HVLT-R is one test within a set of six alternate forms 
intended to measure verbal learning and memory in individuals ages 16 and older. Each test 
includes a list of 12 nouns; the examiner reads the list to the examinee, who repeats as many 
words as remembered, in any order. This process is repeated three times (trials); 20-25 minutes 
later, examinees are asked again to recall as many words as possible; for the fourth trial, the 
examiner reads a list of 24 words (including the 12 words from the list) and asks the examinee 
after each whether the word was on the list.  
When scoring the HVLT-R, the four trials are combined to calculate the following summary 
scores: 
1. Total recall score: Sum of the total correct responses for Trials 1, 2, and 3 
2. Delayed recall score: Total number of correct responses 20-25 minutes later 
3. Percent retention score: Calculated by dividing the delayed recall score by the higher 
score of Trials 2 and 3 x 100 
4. Recognition Discrimination Index: Total number of true positives – total number of false 
positives from Trial 4 
The change from baseline to Week 8 in each of the above summary scores (i.e., total recall 
score, delayed recall score, percent retention score, and recognition discrimination index) will 
be analyzed with an univariate ANCOVA.  The model will contain treatment group as a fixed 
effect and the baseline score as a covariate.  The covariate adjusted difference in the change 
from baseline between the troriluzole and placebo groups will be tested at a 2-sided alpha level 
of 0.05.  Covariate adjusted LSMeans, model based SEs, degrees of freedom, and 2-sided 95% 
CIs will be presented for each treatment group and for the difference between the treatment 
groups. 
The above ANCOVA models will be repeated for observed cases at Week 8 and using LOCF.  
Covariate adjusted LSMeans, model based SEs, degrees of freedom, and 2-sided 95% CIs will 
be presented for each treatment group and for the difference between the treatment groups.
Descriptive statistics for the total recall score, delayed recall score, percent retention score, and 
recognition discrimination index (including baseline) and change from baseline will be 
summarized by treatment group and visit for the randomization phase.
4.7.3.3. Clinical Global Impression-Improvement Scale 
Subjects will be rated on the 7-point global improvement scale of the CGI-I. Improvement in 
global functioning will be summarized descriptively by visit for the randomization and 
extension phases, separately. The number and percentage of subjects in each category will be 
summarized: very much improved, much improved, minimally improved, no change, minimally 
worse, much worse, and very much worse. 
In addition, the CGI-I scores will be transformed into numeric values ranging from 1 to 7 (1 
indicating “very much improved” and 7 indicating “very much worse”). Descriptive statistics 
for the CGI-I score will be presented by visit for the randomization and extension phases, 
separately. 


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The transformed CGI-I score will also be analyzed using a MMRM analysis model, similar to 
the analysis described in Section 4.7.1.1. The model will include fixed effects for treatment, 
visit (Weeks 2, 4, 6, and 8), and the treatment-by-visit interaction, and the baseline CGI-S score 
and visit-by-baseline CGI-S score interaction as covariates.   
4.7.3.4. Hamilton Depression Rating Scale  
The HAM-D 17 score, derived from the Structured Interview Guide for the Hamilton 
Depression Rating Scale (SIGH-D), will be used to assess the patient’s level of depression at 
baseline and Week 8 of the randomization phase and Weeks 12 and 24 of the extension phase. 
Although the HAM-D consists of 21 items, the scoring is based on the first 17. Eight items are 
scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine items are scored on a 
3-point scale, ranging from 0 to 2. The total score will be calculated, provided there is no more 
than 2 items missing among either the 8 items with a 5-point scale or the 9 items with a 3-point 
scale, as the sum of the mean of the available items in each group (5-point scale or 3-point 
scale) multiplied by the number of items in that group.  
The change from baseline to Week 8 in the total HAM-D 17 score will be analyzed with an 
ANCOVA.  The model will contain treatment group as a fixed effect and the baseline score as a 
covariate.  The covariate adjusted difference in the change from baseline between the troriluzole 
and placebo groups will be tested at a 2-sided alpha level of 0.05.  Covariate adjusted LSMeans, 
model based SEs, degrees of freedom, and 2-sided 95% CIs will be presented for each treatment 
group and for the difference between the treatment groups.
The above ANCOVA model will be repeated for observed cases at Week 8 and the LOCF 
endpoint.  Covariate adjusted LSMeans, model based SEs, degrees of freedom, and 2-sided 95% 
CIs will be presented for each treatment group and for the difference between the treatment 
groups. 
Descriptive statistics for the total HAM-D 17 score (including baseline) and the change from 
baseline in the total HAM-D 17 score will be presented by visit for the randomization and 
extension phases, separately.  
4.7.3.5. Penn State Worry Questionnaire  
The PSWQ is a self-administered 16-item scale designed to measure worry at baseline at Week 
8 of the randomization phase and Weeks 4, 8, 12, and 24 of the extension phase. Possible range 
of scores is 16 - 80. Each item is scored on a 5-point likert-type scale, ranging from 1 to 5. 
Items 1, 3, 8, 10 and 11 are reversed scored. The total PSWQ score will be calculated, provided
there is no more than 4 items missing, as the mean of the non-missing items (after reverse 
scoring) multiplied by 16. 
The change from baseline to Week 8 in the total PSWQ score will be analyzed with a univariate 
ANCOVA.  The model will contain treatment as a fixed effect and the baseline score as a 
covariate.  The covariate adjusted difference in the change from baseline between troriluzole
and placebo groups will be tested at a 2-sided alpha level of 0.05.  Covariate adjusted LSMeans, 
model based SEs, degrees of freedom, and 2-sided 95% CIs will be presented for each treatment 
group and for the difference between the treatment groups.
The above ANCOVA model will be repeated for observed cases at Week 8 and the LOCF 
endpoint.  Covariate adjusted LSMeans, model based SEs, degrees of freedom, and 2-sided 95% 


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CIs will be presented for each treatment group and for the difference between the treatment 
groups.
Descriptive statistics for the total PSWQ score (including baseline) and change from baseline 
will be summarized by treatment group and visit for the randomization and extension phases, 
separately. 
4.7.3.6. Clinical Trial and Site Scale-B 
The CTSS-B is a scale administered at baseline to assess potential domains associated with 
placebo response. The scale is a patient reported assessment and consists of 26 items. Items 1-24 
are rated on a scale of 1 (“Completely Disagree”) to 9 (“Completely Agree”). Items 25 and 26 
are rated on a scale of 1 (“Very much better”) to 7 (“Very much worse”). The scale has been 
adapted from the Placebo Response Screening Scale (PRSS) presented by Feltner et al. (2009). 
A total score will be calculated from the same items identified in the 20-item score established 
in their article (i.e., items 1-18, 26 and 27). If at least 80% of items are non-missing (no more 
than 4 items are missing), scale scores will be calculated by translating each item to a 0–100 
scale (after reverse-scoring as necessary) and taking an average of the non-missing items. 
To identify study subjects who demonstrated improvement over the course of the study, three 
different responder definitions will be used:
1. HAM-A Responder: responders defined as subjects who achieved at least 50% reduction 
in the total HAM-A score from baseline to Week 8
2. Combination Responder 1: responders defined as subjects who (a) achieved 50% 
reduction in the total HAM-A score from baseline to Week 8, or (b) indicated ‘‘Very
much improved,” ‘‘Much improved,” or ‘‘Minimally improved” on the CGI-I (Guy, 
1976) at Week 8  
3. Combination Responder 2: responders defined as subjects who (a) achieved 50% 
reduction in the total HAM-A score from baseline to Week 8 or (b) were rated ‘‘Very 
much improved” or ‘‘Much improved” on the CGI-I at Week 8
To assess their ability to correctly identify placebo responders (as defined by the three responder 
definitions above), the 20-item CTSS-B score will be assesed using marginal probability 
Receiver Operating Characteristic (ROC) curves based on data from subjects in the placebo 
group. Concordance values, equivalent to the area under the ROC curve and estimated as the 
probability of agreement between predicted and observed responses, will be computed as 
measures of overall accuracy. The ROC curves will also be used to identify a cut score that
maximizes both sensitivity and specificity based on the placebo data in this trial. Sensitivity (y-
axis) and 1-specificity (x-axis) will be plotted for each of the responder definitions. 
Using both the newly calculated cut-score and the cut-score of 50 based on Feltner et al. (2009), 
analyses by subgroups defined by the cutpoint will be conducted using the MMRM model, 
similar to the analysis described in Section 4.7.1.1, to compare troriluzole vs. placebo at Week 8 
on the change from baseline in the total HAM-A score based on mITT subjects in the 
randomization phase with a 20-item total CTSS-B score. This analysis will be repeated for the 
change from baseline in the total SDS score at Week 8.
Descriptive statistics for the 20-item total CTSS-B score and each item on the CTSS-B will be 
provided by treatment group and overall.  


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In addition, the correlation of other pre-intervention outcome measures (including the additional 
items from the CTSS-B) and demographic characteristics with placebo responsiveness may also 
be explored.
Pharmacokinetic Evaluations
All PK analyses will be conducted on treated subjects. A PK sample will be collected at Weeks
2, 6, and 8 of the randomization phase. Additionally, PK samples should be drawn if there are 
any SAEs or severe AEs during the randomization or extension phase of the study that are 
assessed as possibly drug related. Date/time of last dose prior to the PK draw will be collected 
on the CRF along with the date/time of last meal.  Subjects who are able to schedule a morning 
visit for Weeks 2 and 6 can be instructed to hold their dose of study drug that morning until after 
a PK trough sample is obtained, if possible and appropriate.
Individual concentrations will be summarized by visit for the randomization phase. Plasma 
concentrations below the limit of quantification (BQL) will be considered to be 0 concentration.  
Missing values will not be imputed. 
Individual plasma concentration data will also be displayed in a listing.
Safety and Other Analyses
Safety and other analyses will be conducted on treated subjects. For randomization phase 
outputs, treated subjects in the randomization phase will be used; for extension phase outputs, 
treated subjects in the extension phase will be used; and for the combined phase outputs, DB 
and OL troriluzole treated subjects will be used. All incidence table denominators require the 
subject to have received treatment in that phase and have at least one measurement on-treatment
(see section 4.3). All safety and other data will be listed for the entire study with screening, 
randomization, and extension phase data presented together. 
Safety outcome measures include: exposure, AEs, laboratory assessments, physical 
examinations, vital signs, physical measurements, ECGs, concomitant medications, and the S-
STS.
4.9.1.
Extent of Exposure and Compliance to Study Treatment
Subjects received placebo (BID) or troriluzole (100 mg BID) during the randomization phase. 
Subjects who completed 8 weeks of treatment in the randomization phase may also be eligible 
for the OL extension phase. The first day of dosing is the first exposure to study drug (at least 
one dose of study drug) whereas the last day of dosing is the last exposure to study drug (at least 
one dose of study drug), whether in the randomization, extension, or combined phases.
Randomization Phase
The extent of subject exposure (treatment duration) in the randomization phase will be 
quantified as the number of days on DB study medication (placebo or troriluzole) and measured 
from the time the subject received the first dose of study medication until the time the subject 
received the last dose, either at the end of 8 weeks of treatment or withdrawal from the DB
randomization phase (i.e., total days on randomized study medication = last dose date of DB
randomized study medication – first dose date of DB randomized study medication + 1). 
Treatment duration includes missed dose days.


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The extent of subject exposure (total days on study medication) will also be calculated for each 
subject by counting days where the number of tablets taken was >0 (i.e., treatment duration of 
DB study medication – number of days a subject missed both doses of the DB randomized study 
medication). If a subject took at least one dose of DB study medication on a study day, then the 
subject will be counted as having been exposed to study medication on that day.
In addition to treatment duration and total days on study medication, percent (%) compliance 
will be calculated and summarized as follows: total days on study medication during the 
randomization phase / treatment duration of DB study medication  × 100. 
The number of subjects on-treatment and their average daily dose will also be summarized by 
each week (7-day intervals) of the randomization phase. If a subject took at least one dose of 
study medication during the 7-day interval, then the subject will be considered as exposed to 
study medication during that week. Average daily dose is calculated as the total number of 
tablets taken during the interval / number of days on-treatment during the interval. 
The extent of exposure will also be summarized with a Kaplan-Meier plot by treatment group. 
The proportion of treated subjects on randomized study medication (y-axis) versus weeks (x-
axis). Subjects continuing in the extension phase should be censored on the last day of 
randomized study medication. 
Extension Phase
The extent of subject exposure (treatment duration) in the extension phase will be quantified as 
the number of days on OL troriluzole study medication (troriluzole) and measured from the time 
the subject received the first dose of troriluzole study medication in the extension phase until the 
time the subject received the last dose in the extension phase (i.e., total days on OL troriluzole 
study medication = last dose date of OL troriluzole study medication – first dose date of OL 
troriluzole study medication + 1). Treatment duration includes missed dose days. 
The extent of subject exposure (total days on study medication) will also be calculated by 
counting days where the number of tablets taken was > 0 (i.e., treatment duration of OL study 
medication – number of days a subject missed both doses of the extension phase study 
medication). If a subject took at least one dose of OL troriluzole study medication on a study 
day, then the subject will be counted as having been exposed to study medication on that day.
In addition to treatment duration and total days on study medication, percent (%) compliance 
will be calculated and summarized as follows: total days on study medication during the 
extension phase / treatment duration of OL troriluzole study medication × 100.  
The number of subjects on-treatment and their average daily dose will also be summarized by 2 
week (or 14-day) intervals of the extension phase. If a subject took at least one dose of study 
medication during the 14-day interval, then the subject will be considered as exposed to study 
medication during that 2 week period. Average daily dose is calculated as the total number of 
tablets taken during the interval / number of days on-treatment during the interval. 
Combined Phases
For the combined phase data, the extent of subject exposure (overall treatment duration) will be 
quantified as the number of days on troriluzole study medication during the entire study and 
measured from the time the subject received the first dose of troriluzole study medication until 
the time the subject received the last dose (i.e., total days on DB or OL troriluzole during the 


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study = last dose date of troriluzole study medication – first dose date of troriluzole study 
medication + 1). 
The extent of subject exposure (total days on study medication) will also be calculated for each 
subject by counting days where the number of tablets taken was  > 0 (i.e., overall treatment 
duration – number of days a subject missed both doses of DB or OL troriluzole study 
medication). If a subject took at least one dose of DB or OL troriluzole study medication on a 
study day, then the subject will be counted as having received study medication on that day. 
In addition to overall treatment duration and total days of study medication, overall percent (%) 
compliance will be calculated and summarized as follows: total days on DB or OL troriluzole 
study medication / overall treatment duration  × 100. 
The number of subjects on-treatment and their average daily dose will also be summarized by 2 
week (or 14-day) intervals for the entire study. If a subject took at least one dose of study 
medication during the 14-day interval, then the subject will be considered as exposed to study 
medication during that 2 week period. Average daily dose is calculated as the total number of 
tablets taken during the interval / number of days on-treatment during the interval. 
Study drug administration and compliance will be listed in by-subject listings. 
4.9.2. 
Adverse Events 
Adverse events will be coded using MedDRA and displayed in tables and listings by system 
organ class (SOC) and preferred term (PT).
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined as any AE that developed, worsened, or became serious 
after first dose of study treatment.   
The number and percentage of subjects with the following AEs will be summarized by 
treatment group and overall for the randomization and extension phases, separately, as well as 
overall for the DB and OL troriluzole treated subjects: 
 TEAEs,  
 TEAEs related to treatment,   
 Serious TEAEs,  
 TEAEs leading to discontinuation of study treatment,  
 TEAEs by higest severity (mild, moderate, severe), and 
 TEAEs related to treatment by highest severity (mild, moderate, severe) 
 TEAEs indicating potential Interstitial Lung Disease (using Standardized MedDRA 
Queries (SMQ) Interstitial Lung Disease including Eosinphilic Pneumonia and 
Hypersensitivity Pneumonitis) 
In the above tabulations, each subject will be counted only once (i.e., the most related or severe 
occurrence) for each PT and the corresponding incidence rates in the descriptive analysis, 
regardless of the number of episodes. No formal hypothesis-testing of AE incidence rates will 
be performed.   
All AEs occurring pre-treatment and during the entire study will be listed with a flag 
designating which phase the AE had onset in (i.e., screening, randomization, or extension 


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phase). Additional listings will be provided including deaths, SAEs, and AEs leading to 
discontinuation of study drug.
4.9.3. 
Laboratory Data 
Clinical laboratory evaluations include:
Hematology: hemoglobin#, hematocrit, platelet count#, absolute basophil count, 
absolute eosinophil count, absolute lymphocyte count#, absolute monocyte count, 
absolute neutrophil count#, white blood cell (WBC) count#, red blood cell (RBC) count
 Serum chemistry: sodium#, potassium#, chloride, calcium#, lactate dehydrogenase# 
(LDH), phosphorous, bicarbonate#, creatine kinase#, total protein, albumin#, glucose@, 
creatinine#, blood urine nitrogen (BUN), uric acid@. Additionally, total cholesterol#, 
low-density lipoprotein@ (LDL), high-density lipoprotein (HDL), triglycerides#, folate, 
HbA1c, P-Amylase or Lipase, thyroid-stimulating hormone (TSH), and T4 will be 
collected at screening and provided in listings only. 
 Liver function: alanine aminotransferase# (ALT), aspartate aminotransferase# (AST), 
alkaline phosphatase# (ALP), gamma-glutamyl transferase (GGT), total bilirubin# 
(TBILI)  
 Urinalysis: macroscopic examination (appearance, color), pH, specific gravity, ketones, 
nitrites, bilirubin, urobilinogen, leukocyte esterase, protein@, glucose@, occult blood, 
and microscopic examination (if blood, protein, or leukocytes are positive) 
 Other: HBsAg, hepatitis C virus (HCV), human immunodeficiency virus, HIV antibody 
detection, rapid plasma reagin (RPR; and reflex testing if positive) will be performed at 
screening; urine drug screen for cannabinoids, amphetamines, cocaine metabolites, 
barbiturates, phencyclidine, ecstasy, oxycodone, and opiates (and reflex confirmatory 
testing if positive urine drug screen samples) at screening and end of study; blood 
alcohol level; all other test results to be provided in listings only 
 Serum and urine pregnancy tests; these results will be provided in a listing  
Clinical laboratory values will be expressed using conventional (US) and standard international 
(SI) units. In the event of repeat values within the same analysis visit, if any measurement has 
an abnormal result, then that measurement will be used for the presentation in by-visit tables.  If 
none of the measurements is abnormal, or all of them are abnormal, the latest measurement in 
the analysis visit interval will be used for presentation in by-visit tables.  All measurements will 
be presented in listings along with the normal range (if applicable) and considered for 
evaluation of potential drug induced liver injury (DILI) and abnormalities.  
The observed value and change from baseline will be summarized for hematology and serum 
chemistry tests (including liver function) in both conventional and SI units for treated subjects 
in the randomization and extension phases. 
Tests marked with “#” will be graded according to CTCAE version 5.0 (2017) and tests marked 
with “@” will be graded according to DAIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events Corrected version 2.1 (2017). The number and percentage of subjects 
with at least one on-treatment laboratory assessment by grade will be summarized by treatment 
group (regardless of baseline) for the randomization and extension phases, separately, as well as 
overall for the DB and OL troriluzole treated subjects.


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In addition, the shift from baseline for laboratory abnormalities (based on either normal limits or 
grading, where available) will be tabulated by grade (if applicable), visit, and the overall 
minimum and maximum observed for treated subjects in the randomization and extension 
phases. The shift tables will only include subjects with a baseline assessment and at least one 
on-treatment assessment.
For the liver function tests, the shift from baseline will also be presented by visit and to the 
maximum observed abnormality for treated subjects in the randomization and extension phases. 
Shift tables will only include treated subjects with an assessment for the specific test of interest 
at baseline and on-treatment. Baseline is defined as the last available assessment on or before 
the first day of study treatment. 
For ALT and AST, the following categories will be used to summarize the shift from baseline 
based on the upper limit of normal (ULN):  
 
ULN  
 
 ULN 
 
 
 >5x ULN 
For ALP, the following categories will be used to summarize the shift from baseline:  
 
 
 
 
 
 
 >2.5x ULN 
For  GGT, the following categories will be used to summarize the shift from baseline:  
 
ULN 
 
 >2.5x ULN 
For TBILI, the following categories will be used to summarize the shift from baseline:  
 
 
 
 >2.0x ULN 
An evaluation of drug-induced serious hepatotoxicity (eDISH) scatter plot will display the 
maximum TBL ratio of value to ULN on the y-axis versus the maximum ALT ratio of value to 
ULN on the x-axis, where the maxima is not necessarily concurrent, for treated subjects in the 
randomization phase and DB and OL troriluzole treated subjects. Both axes will be on the log10 
scale. Ratios < 0.1 x ULN will be set to 0.1. Sample sizes in the legend will represent subjects 
with paired ratios. A horizontal reference line will be placed at 2 x ULN, and a vertical 


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reference line will be placed at 3 x ULN. The lower left quadrant will be labeled “Normal 
Range”, the upper left quadrant will be labeled “Hyperbilirubinemia”, the lower right quadrant 
will be labeled “Temple’s Corollary”, and the upper right quadrant will be labeled “Possible 
Hy’s Law Range.”  
Additional listings will be presented for the following: 
 All abnormal laboratory values considered potentially clinically significant (i.e., CTCAE 
Grade 3 or 4) for the randomization and extension phases combined 
 Subjects with a maximum value of ALT or AST >3x ULN or a maximum total bilirubin 
value >2x ULN observed at any point during the entire study, but not necessarily on 
concurrent visits 
4.9.4. 
Physical Examination 
Results of the physical examination will be included as a listing. 
4.9.5. 
Vital Signs and Physical Measurements 
The observed value and change from baseline in vital signs and physical measurements will be 
summarized at each visit for the randomization and extension phases, separately.  In addition, 
the number and percentage of subjects who meet the following criteria will be summarized:
 Systolic Blood Pressure: <90 mmHg, >140 mmHg, >160 mmHg 
 Diastolic Blood Pressure: <50 mmHg, >90 mmHg, >100 mmHg 
 Pulse Rate: <60 bpm, >100 bpm
 
 
Temperature: >38.0 °C, <36.0 °C
The number and percentage of subjects meeting these criteria will be summarized for the 
randomization and extension phases, separately, as well as the DB and OL troriluzole treated 
subjects. A subject listing of vital signs and physical measurements will identify abnormal 
assessments using the above criteria. 
4.9.6. 
Electrocardiogram 
Descriptive statistics for ECG interval data (e.g., QRS, PR, QT, QTcF) and ventricular heart rate 
will be reported by visit for the randomization and extension phases, separately. In addition, the 
number and percentage of subjects who meet the following criteria will be summarized for the 
randomization and extension phases, separately, as well as the DB and OL troriluzole treated
subjects:
At least one post-baseline QTcF > 450 ms, >480 ms, and >500 ms
At least one post-baseline QTcF change from baseline >= 30 ms to < 60 ms 
At least one post-baseline QTcF change from baseline >= 60 ms
A subject listing of ECG results will identify abnormal QTcF assessments using the above 
criteria.


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4.9.7.
Concomitant Medications
Concomitant medications will be coded using the WHO-DD, Sep2016. Results will be tabulated 
by Anatomic Therapeutic Class (ATC2) and PT for treated subjects in the randomization and 
extension phases, separately. See Section 4.2.7.2 for the derivation of prior and concomitant 
medications. 
All prior and concomitant medications will be listed.
4.9.8.
Sheehan-Suicidality Tracking Scale 
The S-STS is a prospective, self-reported rating scale that contains 16 questions to track both 
treatment-emergent suicidal ideation and behaviors. In the event the subject is unavailable, the 
S-STS clinician-administered rating scale will be completed that contains 6 yes/no questions. 
Self-reported S-STS scores are calculated as follows:
 Ideation subscale score: Sum of scores (0 – 4) for Questions 2 – 11 
 Behavior subscale score: Sum of scores (0 – 4) for Questions 1a, (highest of 12 or any 
row of 16), (highest of 14 or any row of 15), 17, and 20 
 Total score: Sum of the ideation and behavior subscale scores
The self-reported S-STS ideation subscale, behavior subscale, and total score will be 
summarized as the change from baseline (i.e., <-1, -1, no change, 1, >1) at each visit and the
maximum score observed.  For any troriluzole exposure (DB or OL phase), the summary will be 
based on the maximum score observed any time on troriluzole. 
All S-STS data will be listed.
4.9.9. 
Subjects Identified for Narratives 
A safety narrative will be prepared for each subject who received at least one dose of study drug 
and experienced the following events (regardless of relationship to study drug): 
 All deaths on-treatment and post-treatment through the end of the study 
SAEs on-treatment, which includes up to 30 days after the last dose of study drugy; SAEs 
that occur > 30 days (i.e., during the follow-up period) will be included per the clinical 
judgment of the Biohaven medical monitor 
 All premature discontinuations of study drug due to AEs (either identified through “action 
taken” or “end of treatment status”)
 The following on-treatment events of special interest: 
o Neutropenia based on laboratory results and defined as minimum absolute neutrophil 
count < 500 per mm3  
o LFT abnormalities: 
 ALT or AST > 3x ULN  
 ALT or AST > 3x ULN, and serum total bilirubin  2x ULN  


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o Interstitial lung disease Standardized MedDRA Query (SMQ) including eosinophilic 
pneumonia and hypersensitivity pneumonitis  
These select events are described in the current version (v2) of the Biohaven Safety Narrative 
Scope for BHV-4157 (troriluzole). Because select events may be subject to change, updates to 
the list of events or selection algorithms after database lock may be described in a Note to File 
(NTF) rather than amending the SAP.
A by-subject listing of safety narrative subject identifiers will be presented for all DB and OL 
troriluzole treated subjects with the select events as described above. 


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REFERENCES
Carpenter, J.R., Roger, J.H., and Kenward, M.G. (2013). Analysis of longitudinal trials with 
protocol deviation: A Framework for Relevant, Accessible Assumptions, and Inference via 
Multiple Imputation. J Biopharmaceutical Statistics, 6 (23), 1352 – 1371.
Coric, V., et al. (2010). Multicenter, randomized, double-blind, active comparator and placebo-
controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety 
disorder. Depress Anxiety, 27(5): 417-25.
Durgam, S., et al., (2016). Efficacy and Safety of Vilazodone in Patients With Generalized 
Anxiety Disorder: A Randomized, Double-Blind, Placebo-Controlled, Flexible-Dose Trial. J 
Clin Psychiatry. 77(12): 1687-1694. 
Feltner, D., Hill, C., Lenderking, W., Williams, V., and Morlock, R. (2009). Development of a 
patient-reported assessment to identify placebo responders in a generalized anxiety disorder 
trial. J Psychiatric Research. 43: 1224-1230.
Guy, W (1976). ECDEU Assessment Manual for Psychopharmacology. U.S. Department of 
Health, Education, and Welfare, National Institute of Mental Health, Psychopharmacology 
Research Branch. Retrieved from http://www.archive.org/details/ecdeuassessmentm1933guyw
Hidalgo, R.B., Tupler, L.A., and Davidson, J.R. (2007). An effect-size analysis of 
pharmacologic treatments for generalized anxiety disorder. J Psychopharmacology, 21(8): 864-
72.


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APPENDIX 1
Table 2:
Schedule of Assessments – Randomization Phase


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Table 3:
Schedule of Assessments – Extension Phase


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