A Phase III, Long-Term, Randomized, Double-blind, Placebo-controlled Trial of Troriluzole in Adult Participants With Spinocerebellar Ataxia.
Phase: PHASE3
Conditions: Spinocerebellar Ataxias, Spinocerebellar Ataxia Type 1, Spinocerebellar Ataxia Type 2, Spinocerebellar Ataxia Type 3, Spinocerebellar Ataxia Type 6, Spinocerebellar Ataxia Type 7, Spinocerebellar Ataxia Type 8, Spinocerebellar Ataxia Type 10
Sponsor: Biohaven Pharmaceuticals, Inc.

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CLINICAL RESEARCH PROTOCOL
DRUG:
Troriluzole
STUDY NUMBER(S):
BHV4157-206
PROTOCOL(S) TITLE:
A Phase III, Long-Term, Randomized, Double-blind, 
Placebo-controlled Trial of Troriluzole in Adult 
Subjects with Spinocerebellar Ataxia
IND NUMBER:
129397
SPONSOR:
Biohaven Pharmaceuticals Inc.
ORIGINAL PROTOCOL DATE:
07AUG2018
VERSION NUMBER:
V09
Incorporates Administrative Letters Dated 
09Oct18;18Mar19; 23Sep19; 28Oct19, 
12Aug20,02Nov20, 09Apr21  
VERSION DATE:
05DEC2022

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Name and Title
Signature Approval
Date
Author/Protocol Writer:
Clinical Operations:
 
Biostatistics:
Regulatory Affairs:

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SUMMARY OF CHANGES1
Version Number
Brief Description of Changes
Page(s) 
Affected/Sections
Date
Original 
Protocol V01 
NA
Aug2018
Protocol V02
1) Exploratory Objective added to 
compare the efficacy of troriluzole 
with placebo on the video-recorded 
administration of the SARA, as 
assessed via central rating
2) Falls diary removed from 
Exploratory Objectives
3) Administrative corrections made to
the Schedule of Assessments to 
ensure footnotes are correct; Falls 
Diary removed from Schedule of 
Assessments, PIFAS removed from 
screening
4) Video equipment added in Study 
Materials section
5) Video recording added
6) Falls Diary Removed
P10, P41
P10, P11, P41
P45, P46, P47, P48, 
P49
P61
P66, P67
P68
21Aug2018
                                                          
1 If higher than v1.0

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Protocol V03
Incorporates 
Administrativ
e Letter dated 
09Oct2018
1) Replaced BHV-4157 with Troriluzole
2) Changed primary outcome measure from 
the SARA to the Modified Functional 
SARA (f-SARA)
3) Revised Secondary and Exploratory 
Objectives and Exploratory Endpoints
4) Revisions made to Phase 2 Clinical Adverse 
Event Profile
5) Added rationale for enriched SCA1 and 
SCA2 genotypes 
6) Modified Schedule of Assessments to 
reflect the changes to secondary and 
exploratory outcome assessments, update 
schedule of pregnancy testing, clarify Early 
Discontinuation Visit, add PK to Extension 
Phase for AEs due to study drug, and 
removed calculation of screening to baseline 
SARA scoring via the IWRS
7) Changed Inclusion/Exclusion criteria to 
reflect f-SARA as opposed to Total SARA 
and also added
8) Added items to study material
9) Clarified who, at site, can administer the S-
STS
10) Rearranged order of Clinical Outcome 
Assessments
11) Changed section 7.5.1 to reflect the change 
from the primary outcome from the mSARA 
to the f-SARA and deleted wording about 
use of central rating.
12) Provided additional detail on Early 
Discontinuation Visit
13) Clarified timing of dosing
14) Added information about independent 
statistician to review randomization
15) Clarifications added to Sample Size.
Throughout 
document
Throughout 
document
Throughout 
document 
Section 1.2.4.2
Section 1.3.3
Section 4.3
Section 5.2 and 5.3
Section 6.1
Section 7.4.9
Section 7.5
Section 7.5.1
Section 8
Section 9.3.4
Section 9.4
Section 11.2
12FEB2019

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16) Clarifications made to Population for 
Analysis
17) Moved up and added clarification to 
Demographic and Baseline Characteristic 
section
18) Changed analysis section to reflect change 
in primary outcome measure to the f-SARA
19) Added section 11.4.3 to adjust statistical 
analysis for Multiplicity for secondary 
endpoints
20) Updated Analysis of Safety section.
21) Added central lab information to Appendix 
19.1
22) Deleted Declaration of Helsinki since 
protocol mentions we are operating under 
current version. Section 19.2 is now 
Appendix II. 
Section 11.3
Section 11.4.1
Section 11.4.2
Section 11.4.3
Section 11.4.5
Appendix 19.1
Appendix 19.2

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V04
Incorporates Administrative Letters Dated 
09Oct18;18Mar19; 23Sep19; 28Oct19.  
The number of randomized subjects has been 
revised from 230 to 210 throughout the 
protocol. 
The protocol was updated to reflect that SCA 1, 
2, and 3 will comprise 80-90% of randomized 
subjects and SCA 6,7,8,and 10 will comprise the 
remainder of subjects. 
The primary and secondary objectives and study 
endpoints have been revised to include all SCAs 
as opposed to just SCA 1 and SCA 2.
Study schematic footnote includes details about 
stratification.
Section 1.2.2.3 updated to reflect that the 
BHV4157-201 Open Label Phase was extended 
to 144 weeks. 
Removed Section 1.3.3 titled Rationale for 
Enriched SCA 1 and SCA 2 Genotype.
Section 1.4 updated research hypothesis.
Section 4.1: Added clarification that, prior to 
down titration, these cases should be discussed 
with the Medical Monitor. 
Table 3. Modified language in Instruction 
Section for Baseline pregnancy testing.
4.3.1 Updated number of screened subjects from 
approximately 375 to 270.
4.3.2 Added details about randomization 
stratification and down titration.
7.4.2 Added clarification about determining 
clinical significance. 
9.2 Updated with permitted temperature 
excursions.
9.3.1 and 9.3.2 Added additional details 
regarding down titration.
07NOV2019

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9.3.5 Two bullets added to clarify how to handle 
tolerability issues and dose titration. 
11.2 Sample size section modified to account 
for changes in randomized subjects.
11.4.2 Primary endpoint section revised.
11.4.5 Added Missing Data section. 
11.4.6 Analysis of Safety section revised.
V05
Added additional window for Week 48 visit in 
order to proactively account for any subjects 
that may potentially be out of visit window due 
to concerns related to COVID-19 pandemic. 
 
Included text throughout document to provide 
instruction in case participants are unable to 
come into the site due to concerns related to 
COVID-19.
Minor typographical errors identified during 
review have been corrected. 
17MAR2020

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V06
Updated length of Open Label Extension Phase 
to 96 Weeks (from 48 Weeks) throughout the 
protocol and on study schematic.
Section 1.2.1 Rational for Troriluzole in the 
Treatment of SCA has been updated. 
Section 1.2.2.2 Clinical Experience has been 
updated based on recent IB information. 
Section 1.2.3 Potential for Drug Drug 
Interactions has been updated based on recent 
clinical trials.
Section 1.2.4 Special Populations is a new 
section added to protocol.
Section 1.3.2 Dose Selection updated to increase 
the Extension Phase of the BHV4157-201 study.
Table 4 Time and Events Schedule – Extension 
Phase is updated for 96 Weeks.
5.4 Prohibited Concomitant Medications 
updated to add information about strong to 
moderate CYP1A2 inhibitors.
7.5.1 Updated to note that video taping of the f-
SARA is not required after Extension Week 48.
9.1.1 Investigational Product updated to add 
description of capsules.
9.4 Blinding and Unblinding section has been 
updated based on most recent Administrative 
Letter.
11.4.5 Missing Data section has been updated. 
19.2 APPENDIX II has been updated based on 
recent findings. 
Clarifications made throughout document 
regarding down titration.
General administrative changes made 
throughout document. 
01MAR2021

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V07
Incorporates revisions from Administrative 
Letter Dated 02Nov20 and 09Apr21.
Study Schematic updated to reflect 144 Weeks 
of Open Label Extension.
 
 
Open Label Extension updated to 144 weeks 
from 96 Weeks.
Pre-Clinical Section updated based on updated 
findings.
Clinical Experience Section updated based on 
most recent Investigator Brochure. 
Phase 2 study information added based on most 
recent Investigator Brochure. 
Potential Drug Drug interaction section updated.
Clinical adverse event profile for troriluzole has 
been updated.  
Clinical adverse event profile for riluzole has 
been updated.  
Updated information regarding elevated liver 
function tests.
Neutropenia section updated.
Time and Events section updated and Extension 
Phase extended to 144 weeks. 
Laboratory Assessment section updated to 
clarify local lab results should be sent to 
Medical Monitor fir review. 
Pregnancy Section updated to specify WOCBP 
will be provided a urine pregnancy test to be 
used in between every three month visits. 
Lost to follow-up section added.
Clarifications added regarding drug destruction. 
Section 9.2; Section 
10.2
Study Summary and 
Section 4.2
Study Summary
Throughout 
Document
Section 1.2.2.1
Section 1.2.2.2
Sections 1.2.2.3 
through 1.2.2.6
Section 1.2.3
Section 1.2.5.1
Section 1.2.5.3
Section 1.2.5.4
Section 1.2.5.5
Table 4
Section 7.4.4
Section 7.4.7
Section 9
Section 10.6
03JAN2022

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BHV4157-206
A PHASE III, LONG-TERM, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED TRIAL OF TRORILUZOLE IN ADULT 
SUBJECTS WITH SPINOCEREBELLAR ATAXIA
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 Pharmaceuticals, 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.
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 Pharmaceuticals or specified 
designees. I will discuss the material with them to ensure that they are fully informed about 
troriluzole and the study.
Principal Investigator Name (printed)
Signature
___________
___________
Date
Site Number

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STUDY SUMMARY
Title: 
A Phase III, Long-Term, Randomized, Double-blind, Placebo-controlled Trial 
of Troriluzole in Adult Subjects with Spinocerebellar Ataxia
Rationale:
Hereditary Spinocerebellar Ataxias (SCA) are disorders of spinocerebellar 
pathology that are characterized clinically by progressive ataxia and are 
attributed to various autosomal dominant genetic mutations. Ataxia, itself, is a 
symptom of loss of control of voluntary body movements and can involve 
unsteady gait, dysarthria, and clumsiness, potentially progressing to the stage of 
difficulty with swallowing and breathing. In patients with SCA, atrophy of the 
cerebellum and sometimes brainstem may be apparent on brain imaging.  
Lifespan is significantly shortened due to complications related to neurologic 
deficits.  Currently, there are no FDA medications approved for this debilitating 
disorder and treatment remains supportive.
In this patient population, prior clinical studies have provided evidence for a 
potential therapeutic role for the glutamate modulating agent riluzole in the 
treatment of hereditary ataxias (1,2).  Troriluzole is a glutamate modulating drug 
that is being developed for eventual commercial use in the treatment of patients 
with SCA.  Troriluzole is a novel tripeptide prodrug of riluzole, optimized for 
improved bioavailability, pharmacokinetics and dosing. Troriluzole was 
designed to be readily cleaved into riluzole once it is in the plasma. In 
nonclinical species, the exposure of troriluzole was found to be less than 1% of 
riluzole exposure. The cleaved moiety of the prodrug is a three amino acid 
peptide that is anticipated to be safe and tolerable as the composite amino acids 
(glycine and sarcosine) are taken up into normal physiological roles in the body. 
Riluzole was first approved in 1995 and the demonstrated safety profile of 
riluzole from over 20 years of global clinical use combined with the nonclinical 
assessments of troriluzole suggests that there are no unwarranted clinical risks 
in advancing troriluzole into clinical trials.  
As a prodrug of riluzole, troriluzole is being developed through the 505(b)(2) 
pathway, a regulatory mechanism that allows the FDA to rely on safety and/or 
efficacy data acquired for a previously approved agent. In the case of troriluzole, 
the 505(b)(2) regulatory pathway will rely on the well-characterized safety 
experience of riluzole. Relevant pharmacologic activities of riluzole, such as 
increasing glutamate transporters (3, 4) or potential activation of small-
conductance calcium-activated potassium
As a prodrug of riluzole, troriluzole is being developed through the 505(b)(2) 
pathway, a regulatory mechanism that allows the FDA to rely on safety and/or 
efficacy data acquired for a previously approved agent. In the case of troriluzole, 
the 505(b)(2) regulatory pathway will rely on the well-characterized safety 
experience of riluzole. Relevant pharmacologic activities of riluzole, such as 
increasing glutamate transporters (3, 4) or potential activation of small-

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conductance calcium-activated potassium channels (5), prompted clinical 
testing in the treatment of ataxia.  Two well-designed academic trials (1, 2) have 
demonstrated preliminary safety and robust efficacy of 50 mg twice per day in 
patients with SCA.  Evidence from these studies suggests that riluzole may 
provide both symptomatic and disease-modifying effects in this patient 
population.  Troriluzole was studied in a randomized, placebo-controlled trial 
in patients with SCA (BHV4157-201). Troriluzole at 140 md QD for eight 
weeks was well tolerated in adult subjects with SCA without any clinically 
significant safety signals or lab abnormalities.  During the ongoing open-label 
extension phase, the safety profile of troriluzole 140 mg QD has been consistent 
with the troriluzole safety profile observed during the randomization phase.
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 (6-9). 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.
Troriluzole was engineered to eliminate the negative food effect, optimize and enhance
the bioavailability, pharmacokinetic profile and dosing schedule, and by-pass first-pass 
metabolism, resulting in lower drug burden on the liver and a better safety and 
tolerability profile. Based on the preclinical features of troriluzole and 
pharmacokinetics from three completed Phase 1 studies, we anticipate the clinical 
pharmacology to offer favorable properties as compared to available riluzole.  To date, 
an ongoing Phase IIb/III study evaluating the safety of troriluzole in patients with SCA 
has shown troriluzole to be safe and well-tolerated in this patient population.
The overall objective of this study is to further evaluate the long-term efficacy 
and safety of troriluzole in adult patients with SCA.
Target 
Population:
Male and female outpatient subjects between the ages of 18 – 75 years, 
inclusive, with a known or suspected diagnosis of the following specific 
hereditary ataxias:  SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, and SCA10.
Number of 
Subjects:
Approximately 210 randomized subjects.  Subjects with SCA1, SCA2, and SCA 
3 genotypes will comprise approximately 80%-90% of the randomized subjects.  
Subjects with SCA6, SCA7, SCA8, and SCA10 genotypes will comprise the 
remainder of the randomized subjects in total.

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Objectives:
Primary Objectives

To compare the efficacy of troriluzole (200 mg once daily) versus placebo 
on ataxia symptoms in subjects with spinocerebellar ataxia (SCA) at 48 
weeks of double-blind treatment as measured by the total score on the 
Modified Functional Scale for the Assessment and Rating of Ataxia [f-
SARA]
Secondary Objectives

To compare the efficacy of troriluzole versus placebo on patient 
impression of benefit via use of the change from baseline in Patient 
Impression of Function and Activities of Daily Living Scale (PIFAS) at 
Randomization Phase Week 48

To compare the efficacy of troriluzole versus placebo on activities of daily 
living as measured by the change from baseline in Activities of Daily 
Living Scale from the Friedreich’s Ataxia Rating Scale (FARS-ADL) at 
Randomization Phase Week 48

To compare the efficacy of troriluzole versus placebo on daily functioning 
as measured by the change from Baseline in Functional Staging for Ataxia 
Scale from the Friedreich’s Ataxia Rating Scale (FARS-FUNC) at 
Randomization Week 48

To assess of the safety and tolerability of troriluzole in subjects with SCA 
during the Randomization and Extension Phases
Exploratory Objectives

To compare the efficacy of troriluzole versus placebo on lower extremity 
mobility and activities as measured by the change from baseline in 
Neurology Quality of Life (Neuro-QOL) Lower Extremity Mobility Scale 
at Randomization Phase Week 48

To compare the efficacy of troriluzole versus placebo on upper extremity 
function and activities as measured by the change from baseline in 
Neurology Quality of Life (Neuro-QOL) Upper Extremity Scale at 
Randomization Phase Week 48

To compare the efficacy of troriluzole versus placebo on daily fatigue and 
activities as measured by the change from baseline the Neurology Quality 
of Life (Neuro-QOL) Fatigue Scale at Randomization Phase Week 48

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
Change from baseline in Functional Staging for Ataxia (FARS-FUNC) at 
Randomization Phase Week 48

Frequency of subjects with the following adverse events (AEs) identified 
from case report forms: AEs (by severity; by relationship to study drug; 
overall); SAEs; and AEs leading to treatment discontinuation
Exploratory 
Endpoints:

Change from baseline in Neuro-QOL Lower Extremity score at 
Randomization Phase Week 48

Change from baseline in Neuro-QOL Upper Extremity score at 
Randomization Phase Week 48

Change from baseline in Neuro-QOL Fatigue at Randomization Phase 
Week 48

Clinical Global Impression-Global Improvement Scale (CGI-I) at 
Randomization Phase Week 48

Patient Global Impression Scale (PGI) at Randomization Phase Week 48

 

  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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STUDY SCHEMATIC
R, signifies randomization; randomization will be stratified by 3 SCA subgroups: SCA1 & 2; SCA3; and SCA 6, 
7, 8, 10.
* Eligible subjects for the Extension Phase will include those for whom the PI believes extended treatment with 
troriluzole would offer an acceptable risk-benefit profile.
**Subjects will receive 140 mg for the first four (4) weeks and will then be increased to 200 mg for the duration 
of the study.  Down titration will only be temporarily allowed to address tolerability issues.
***Subjects entering the Extension Phase will continue with the same dose taken at the end of the Randomization 
Phase.  Subjects on placebo in the Randomization Phase will be switched in a blinded manner to 140 mg QD for 
the first four weeks and then will be increased to 200 mg QD for the duration of the study.  Down titration after 
the first four weeks of the Extension Phase will only be allowed for tolerability purposes.  All visits after 
Extension Phase Week 4 will be open-label.

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TABLE OF CONTENTS
CLINICAL RESEARCH PROTOCOL ......................................................................................1
CLINICAL PROTOCOL APPROVAL FORM .........................................................................2
SUMMARY OF CHANGES.........................................................................................................4
BHV4157-206..................................................................................................................................5
A PHASE III, LONG-TERM, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED TRIAL OF TRORILUZOLE IN ADULT SUBJECTS WITH 
SPINOCEREBELLAR ATAXIA...................................................................................12
CONFIDENTIALITY AND INVESTIGATOR STATEMENT .............................................12
STUDY SUMMARY....................................................................................................................13
STUDY SCHEMATIC ................................................................................................................18
TABLE OF CONTENTS ............................................................................................................19
LIST OF TABLES.......................................................................................................................23
LIST OF FIGURES.....................................................................................................................23
LIST OF ABBREVIATIONS .....................................................................................................24
1
INTRODUCTION AND RATIONALE.........................................................................26
1.1
Background ......................................................................................................................26
1.1.1
Spinocerebellar Ataxia ....................................................................................................26
1.2
Study Rationale................................................................................................................29
1.2.1
Rationale for Troriluzole in the Treatment of SCA .....................................................29
1.2.2
Pharmacokinetics.............................................................................................................32
1.2.2.1 Pre-Clinical Studies .........................................................................................................32
1.2.2.2 Clinical Experience..........................................................................................................32
1.2.2.3 BHV4157 Phase 2: BHV4157-201 ..................................................................................35
1.2.2.4 BHV4157Phase 2: BHV4157-202....................................................................................35
1.2.2.5 BHV4157 Phase 2: BHV4157-203 ..................................................................................36
1.2.2.6 BHV4157 Phase 2: BHV4157–207..................................................................................36
1.2.3
Potential for Drug-Drug Interactions ............................................................................37
1.2.4
Specific Populations.........................................................................................................38
1.2.5
Clinical Adverse Event Profile........................................................................................38
1.2.5.1 Troriluzole ........................................................................................................................38
1.2.5.2 BHV4157-201:  Phase 2 Clinical Adverse Event Profile ..............................................38
1.2.5.3 Riluzole..............................................................................................................................40
1.2.5.4 Elevations in Liver Function Tests.................................................................................41
1.2.5.5 Neutropenia ......................................................................................................................42
1.2.5.6 Interstitial Lung Disease..................................................................................................43
1.2.6
Potential Risk to Fetal Development..............................................................................43
1.3
Study Rationale................................................................................................................43
1.3.1
Study Design Rationale....................................................................................................43
1.3.2
Dose Selection...................................................................................................................45
1.3.3
Preclinical Pharmacology................................................................................................46
1.4
Research Hypothesis........................................................................................................48
2
STUDY OBJECTIVES....................................................................................................48
2.1
Primary.............................................................................................................................48
2.2
Secondary..........................................................................................................................48
2.3
Exploratory.......................................................................................................................49

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3
STUDY ENDPOINTS......................................................................................................49
3.1
Primary.............................................................................................................................49
3.2
Secondary..........................................................................................................................49
3.3
Exploratory Outcome Measures.....................................................................................50
3.4
Clinical Lab Test..............................................................................................................50
4
STUDY PLAN..................................................................................................................50
4.1
Study Design and Duration.............................................................................................50
4.2
Study Schematic...............................................................................................................51
4.3
Schedule of Assessments..................................................................................................53
4.3.1
Screening Phase................................................................................................................66
4.3.2
Randomization Phase ......................................................................................................66
4.3.3
Extension Phase................................................................................................................67
4.3.4
Post Study Access to Therapy (if applicable) ................................................................67
5
POPULATION.................................................................................................................67
5.1
Number of Subjects..........................................................................................................67
5.2
Inclusion Criteria.............................................................................................................68
5.3
Exclusion Criteria............................................................................................................69
5.4
Prohibited Concomitant Medications ............................................................................73
5.5
Women of Childbearing Potential..................................................................................75
5.6
Deviation from Inclusion/Exclusion Criteria ................................................................76
6
STUDY CONDUCT.........................................................................................................76
6.1
Study Materials................................................................................................................76
7
ELIGIBILITY ASSESSMENTS ....................................................................................77
7.1
Mini Mental State Examination (MMSE) .....................................................................77
7.2
Neurologic Exam..............................................................................................................77
7.3
Medical History................................................................................................................77
7.4
Safety Assessments...........................................................................................................77
7.4.1
Vital Signs and Physical Measurements (Height and Weight)....................................77
7.4.2
Electrocardiogram (ECG)...............................................................................................78
7.4.3
Physical Exam ..................................................................................................................78
7.4.4
Laboratory Assessments..................................................................................................78
7.4.5
Pharmacogenetic Blood Sample Collection...................................................................79
7.4.6
Pharmacokinetics.............................................................................................................79
7.4.7
Pregnancy Testing............................................................................................................79
7.4.8
Evaluation of Laboratory Assessments..........................................................................80
7.4.9
Sheehan Suicidality Tracking Scale (Sheehan-STS).....................................................81
7.5
Clinical Outcomes Assessments......................................................................................81
7.5.1
The Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA)81
7.5.2
The Patient Impression of Function and Activities of Daily Living  Scale (PIFAS)..83
7.5.3
The Activities of Daily Living Scale from the Friedreich’s Ataxia  Rating Scale 
(FARS-ADL).....................................................................................................................83
7.5.4
The Functional Staging for Ataxia Scale from the Friedreich’s  Ataxia Rating Scale 
(FARS-FUNC)..................................................................................................................83
7.5.5
The Neurology Quality of Life (Neuro-QOL) Lower Extremity Scale (long form)...83
7.5.6
The Neurology Quality of Life (Neuro-QOL) Upper Extremity Scale (long form)...83
7.5.7
The Neurology Quality of Life (Neuro-QOL) Fatigue Scale (long  form) ..................84

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7.5.8
The Clinical Global Impression-Global Improvement Scale (CGI-I).........................84
7.5.9
The Patient Global Impression Scale (PGI) ..................................................................84
8
EARLY DISCONTINUATION OF STUDY.................................................................84
9
LOST TO FOLLOW-UP ................................................................................................84
10
STUDY DRUG MANAGEMENT..................................................................................85
10.1
Description........................................................................................................................85
10.1.1 Investigational Product ...................................................................................................85
10.2
Packaging and Shipment.................................................................................................85
10.3
Dose and Administration.................................................................................................85
10.3.1 Randomization Phase ......................................................................................................85
10.3.2 Extension Phase................................................................................................................86
10.3.3 Method of Assigning Patient Identification...................................................................86
10.3.4 Selection and Timing of Dose Administration...............................................................87
10.3.5 Dose Modifications...........................................................................................................87
10.4
Blinding and Unblinding.................................................................................................88
10.5
Treatment Compliance....................................................................................................89
10.6
Destruction and Return of Study Drug..........................................................................89
11
ADVERSE EVENTS .......................................................................................................89
11.1
Serious Adverse Events ...................................................................................................89
11.1.1 Definition of Serious Adverse Event (SAE)...................................................................90
11.1.2 Definition of Terms..........................................................................................................90
11.2
Collection and Reporting of Serious Adverse Events...................................................91
11.2.1 Overdose ...........................................................................................................................92
11.2.2 Pregnancy .........................................................................................................................93
11.2.3 Potential Drug Induced Liver Injury (DILI) ................................................................93
11.3
Non-Serious Adverse Events...........................................................................................94
11.3.1 Collecting and Reporting of Non-Serious Adverse Events ..........................................94
12
STATISTICS....................................................................................................................94
12.1
General Procedures .........................................................................................................94
12.2
Sample Size.......................................................................................................................95
12.3
Populations for Analysis..................................................................................................95
12.4
Statistical Methods...........................................................................................................95
12.4.1 Demographic and Baseline Characteristics...................................................................95
12.4.2 Primary Endpoint(s)........................................................................................................96
12.4.3 Secondary Endpoint(s) ....................................................................................................96
12.4.4 Adjustment for Multiplicity............................................................................................96
12.4.5 Missing Data.....................................................................................................................97
12.4.6 Analysis of Safety.............................................................................................................97
13
ETHICS AND RESPONSIBILITIES ............................................................................97
13.1
Good Clinical Practice.....................................................................................................97
13.2
Data and Safety Monitoring Board................................................................................98
13.3
Institutional Review Board/Independent Ethics Committee.......................................98
13.4
Informed Consent ............................................................................................................98
13.5
Case Report Forms ..........................................................................................................99
14
RECORDS MANAGEMENT.......................................................................................100
14.1
Source Documentation...................................................................................................101

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14.2
Study Files and Record Retention................................................................................101
15
AMENDMENTS ............................................................................................................101
16
STUDY REPORT AND PUBLICATIONS .................................................................101
17
STUDY DISCONTINUATION ....................................................................................102
18
CONFIDENTIALITY ...................................................................................................103
19
REFERENCES...............................................................................................................104
20
APPENDICES................................................................................................................109
20.1
APPENDIX I – Names of Study Personnel..................................................................109
20.2
APPENDIX II – Potent and Moderate Inhibitors and Inducers of the CYP1A2 
Enzyme System...............................................................................................................110

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LIST OF TABLES
Table 1: 
Genetic and Clinical Features of Common SCAs.............................................29
Table 2: 
Most Frequently Reported Treatment-emergent AEs in Study BHV4157-
201..........................................................................................................................40
Table 3: 
Schedule of Assessments and Events – Randomization Phase ........................53
Table 4: 
BHV4157-206 SCA Time & Events Schedule - Extension Phase ....................57
LIST OF FIGURES
Figure 1: 
Genetic mechanisms in hereditary ataxias ........................................................28
Figure 2:
Schematic representation on the mechanism of action of riluzole ..................47
Figure 3: 
Study Schematic...................................................................................................51

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LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
bid
Twice Daily
big-ET
Proendothelin-1
BP
Blood Pressure
BUN
Blood Urea Nitrogen
Cmax
Maximum Plasma Concentration
CNO
Certificate of Non-Objection
CONMED
Concomitant Medication
CRF
Case Report Form
DSMC
Data and Safety Monitoring Committee
ECG
Electrocardiogram
FEV1
Forced Expiratory Volume 
GCP
Good Clinical Practice
HR
Heart Rate
ICF
Informed Consent Form
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
IRB
Institutional Review Board

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iv
Intravenous
kg
Kilogram
L
Liters
mg
Milligram
min
Minute
mmHg
Millimeters Mercury
NOEL
No Observed Effect Level
NOAEL
No Observed Adverse Event Level
NO
Nitric Oxide
PK
Pharmacokinetic
po
By Mouth, Orally
qd
Once Daily
SAE
Serious Adverse Event
ULN
Upper Limit of Normal
WHO
World Health Organization

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1
INTRODUCTION AND RATIONALE
1.1
Background
Hereditary Spinocerebellar Ataxias (SCA) are disorders of spinocerebellar pathology that are 
characterized clinically by progressive ataxia and are attributed to various autosomal dominant 
genetic mutations. Ataxia, itself, is a symptom of loss of control of voluntary body movements 
and can involve unsteady gait, dysarthria, and clumsiness, potentially progressing to the stage of 
difficulty with swallowing and breathing. Atrophy of the cerebellum and sometimes brainstem
may be apparent on brain imaging.  The diagnosis of a spinocerebellar ataxia requires the 
exclusion of acquired, non-genetic causes of ataxia, including alcoholism, vitamin deficiencies, 
multiple sclerosis, vascular disease, tumors, and paraneoplastic disease. A definitive diagnosis 
requires genetic testing or occurrence within kindred. Lifespan is significantly shortened due to 
complications related to neurologic deficits. There are currently no FDA approved medications 
for the treatment of SCA.
Troriluzole is being developed for the treatment of SCA. Troriluzole is a novel pro-drug 
formulation of the generic drug riluzole. The FDA originally approved riluzole (RILUTEK®) 50 
mg tablets, on December 12, 1995 (NDA #20-599) for “the treatment of patients with 
amyotrophic lateral sclerosis. Riluzole extends survival and/or time to tracheostomy.” Based 
upon preclinical evidence and results from two academic health center randomized controlled 
trials examining the use of riluzole in hereditary cerebellar ataxias, troriluzole is being developed 
for SCA through the 505(b)(2) pathway, a regulatory mechanism that allows the FDA to rely on 
safety and/or efficacy data acquired for a previously approved agent. In the case of troriluzole, 
the 505(b)(2) regulatory pathway will rely on the well-characterized safety experience of 
riluzole, which has been marketed globally for over 20 years and is considered safe, well 
tolerated. Biohaven hypothesizes that the pleiotropic effects of riluzole (e.g., enhanced glutamate 
transporter activity and selective potassium channel activation) may target mechanisms 
underlying pathologic cerebellar function that is associated with SCA, and thus provide benefit 
in patients suffering from SCA - for whom there is no approved treatment.
1.1.1
Spinocerebellar Ataxia
Hereditary ataxias may transmit via multiple mechanisms such as autosomal dominant, 
autosomal recessive, X-linked and mitochondrial. Figure 1 provides an overview on the 
classification of genetic ataxias. Autosomal dominant hereditary ataxias include a group called 
the spinocerebellar ataxias (SCAs) (Figure 1). Most dominant mutations are associated with 
pathologic protein function due to expanded polyglutamine repeats. These aberrant proteins form 
toxic aggregates and damage neurons, leading to apoptosis.
The overlapping pathology leads to shared features among the SCAs. For example, they are 
associated with spinocerebellar degeneration, which is often observable on brain imaging.
In addition, symptom presentation among the SCA subtypes share many common, prominent 
features: slowly progressive, symmetrical, midline and appendicular ataxia with dysmetria 
(i.e., loss of accuracy); dysdiadochokinesis (loss of rhythm as in difficulty performing alternating 

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movements); decreased speed of eye movements that affect eye gaze (including nystagmus and 
diplopia); abnormalities of speech (dysarthria); difficulty swallowing; hand/foot incoordination 
(limb ataxia); abnormal station; and, abnormal gait. Notably, there can also be significant clinical 
variation in the order and/or extent of symptom expression between mutations, within a common 
mutation, and even within kindred that shares the same genotype. Non-cerebellar involvement 
may also occur in many SCA subtypes (e.g., cognition, pyramidal, extrapyramidal, motor 
neuron, peripheral nerve or macular involvement).
Signs and symptoms of SCA typically begin in early adulthood but can appear anytime from 
childhood to late adulthood; SCAs are degenerative and progress over a number of years. The 
severity of the disability and related mortality depends on type of ataxia, the age of onset of 
symptoms, and other factors that are poorly understood at this time. It is common for subsequent 
generations to experience earlier onset and more extensive disease, attributable to the 
phenomenon of “anticipation” whereby mutation length (e.g., polyglutamine triplet) expands 
over successive generations.
The typical clinical course of SCAs may be described, as follows. Balance and coordination are 
affected first. Incoordination of hands, arms, and legs, and slurring of speech are other common, 
early symptoms. Over time, individuals with SCA may develop numbness, tingling, or pain in 
the arms and legs (sensory neuropathy), uncontrolled muscle tensing (dystonia), muscle wasting 
(atrophy), and muscle twitches (fasciculations).
Walking becomes difficult and is characterized by walking with feet placed further apart to 
compensate for poor balance. Impaired coordination of the arms and hands affects the ability to 
perform tasks requiring fine motor control such as writing and eating. Rarely, rigidity, tremors, 
and involuntary jerking movements (chorea) have been reported in people who have been 
affected for many years.
Slow eye movements can be seen in some forms of ataxia, including weakness in the muscles 
that control eye movement (ophthalmoplegia). As time goes on, ataxia can affect speech and 
swallowing. Finally, individuals with SCA may also have difficulty processing, learning, and 
remembering information (cognitive impairment).
With the production of abnormal proteins, the affected nerve cells eventually begin to function 
poorly and ultimately degenerate. As SCA progresses, muscles become decreasingly 
coordinated, causing ataxia symptoms to become more pronounced.

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 1:
Genetic mechanisms in hereditary ataxias
Genetic mechanisms in hereditary ataxias. Autosomal dominant ataxias include the spinocerebellar ataxias (SCAs), 
dentatorubral pallidoluysian atrophy (DRPLA), and the episodic ataxias (EAs). Autosomal recessive ataxias include 
Friedreich ataxia (FA), fragile X–associated tremor-ataxia syndrome (FXTAS), and ataxia-telangiectasia (AT). Two 
distinctive modes of autosomal dominant inheritance are observed in some, but not all, SCAs. In one of these (blue 
in figure), there is pathologic expansion of a CAG trinucleotide repeat in the coding region of an affected gene, 
which is translated into an abnormally long polyglutamine (PolyQ) tract within the protein (eg, SCA1, 2, 3, 6, 7, 8, 
12, or 17). In the other (brown in figure), there is pathologic expansion of a tri- or pentanucleotide repeat in 
noncoding regions (NCRs) of the protein, which, although not translated, interferes with protein function (eg, SCA8, 
10, or 31). Two autosomal recessive ataxias, FA and FXTAS, also involve trinucleotide repeats in noncoding 
regions 1.
The most common SCAs include type 1, 2, 3, 6, 7, 8 and 10. SCA1 produces gait ataxia, limb 
ataxia, and dysarthria, with brainstem involvement but little cognitive abnormality. SCA2 is 
notable for the association of ataxia and dysarthria with slow saccadic eye movements and 
polyneuropathy. SCA3 (Machado-Joseph disease) is accompanied by eyelid retraction, reduced 
blinking, external ophthalmoplegia, dysarthria, dysphagia, and sometimes parkinsonism or 
peripheral neuropathy. SCA6 is comparatively less severe, progresses more slowly, is more 
limited to cerebellar involvement than other SCAs, and has a later age of onset. SCA7 is 
distinguished by retinal degeneration leading to blindness, in addition to ataxia. Overall, there is 
significant symptom overlap among these SCAs. The shared symptomatic manifestations of the 
SCAs may reflect common pathology affecting cerebellar purkinje cell fibers.

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Table 1:
Genetic and Clinical Features of Common SCAs
Disease
Gene
Protein
Repeat
Features in addition to Ataxia
SCA1
ATXN1
Ataxin-1
CAG
10–25% of dominant ataxias; spasticity, 
polyneuropathy, ophthalmoparesis, dysarthria, 
pyramidal and extrapyramidal signs
SCA2
ATXN2
Ataxin-2
CAG
Neuropathy, ophthalmoparesis, extrapyramidal 
features, dysarthria, pyramidal signs, dementia
SCA3
(Machado- Joseph 
Disease)
ATXN3
Ataxin-3
CAG
25% of dominant ataxias, spasticity, 
neuropathy, extrapyramidal features, dysarthria, 
pyramidal signs,dementia
SCA6
CACNA1A
Alpha-1a 
Calcium 
Channel
CAG
20% of dominant ataxias; dysarthria, 
nystagmus, posterior column signs, dysarthria, 
and sometimes mild pyramidal signs
SCA7
ATXN7
Ataxin-7
CAG
Olivopontocerebellar atrophy and syndrome of 
retinal degeneration, hearing loss, 
ophthalmoplegia, spasticity, generational 
anticipation, dysarthria, and pigmentary 
maculopathy
SCA8
ATXN8
Ataxin-8
CTA/CTG
Slowly progressive sensory neuropathy, 
spasticity, known rapid infantile variant, 
dysarthria, pyramidal and extrapyramidal signs, 
dementia
SCA10
ATXN10
Ataxin-10
ATTCT
Seizures, personality change, ataxia, dysarthria, 
and sometimes mild pyramidal signs
[Adapted from Clinical Neurology 9th Edition and Adams and Victor’s Principles Neurology 10th Edition]
1,2
1.2
Study Rationale
1.2.1
Rationale for Troriluzole in the Treatment of SCA
Treatment for hereditary ataxias is supportive and no medications have been approved by the 
FDA for this condition. Recent evidence suggests that riluzole may provide both symptomatic 
and disease-modifying therapeutic effects. Troriluzole is a tripeptide prodrug of riluzole 
developed for improved bioavailability, pharmacokinetics and dosing. Since the active moiety of 
troriluzole is riluzole and circulating exposure of troriluzole is expected to be negligible (i.e., less 
than 1% the Cmax and AUC of riluzole as observed in Phase I), the safety of troriluzole is 
expected to be similar to riluzole. Currently, treatment for SCA focuses on targeting specific 
clinical features such as tremor, parkinsonism, dystonia, spasticity, urinary urgency, sleep 
pathology, fatigue and depression. Rehabilitative efforts (physical, occupational and speech 

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therapies) are employed to mitigate the impact of the core ataxia on mobility, speech and 
swallowing.
 
 
 
 
 
 
 
 7,8.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Study BHV4157-201:  BHV4157-201 is a Phase 2b/3 randomized, double-blind, placebo-
controlled trial of troriluzole in adult subjects with SCA. The study was comprised of an 8-week 
randomization phase, followed by a 48-week open-label phase. An additional 96 weeks of open 
label was initiated, based on encouraging preliminary data at 1 year.  Patients experienced a gap 
in troriluzole dosing for a range of up to 12 months prior to initiation of this additional open label 
extension during which they were off troriluzole.
In the primary analysis from the 8-week Randomization Phase of the trial, troriluzole did not 
differentiate from placebo on the primary outcome, change in the total score on the Scale for 
Assessment and Rating of Ataxia (SARA) at Week 8.  Significant variability in the SARA scale 
was observed in the trial, as well as a higher than expected placebo response rate.  Nonetheless, 
post-hoc analyses, chosen based on reducing rating variability, showed trends favoring 
troriluzole over placebo on the SARA.  
The on-going, open-label, 192-week Extension Phase of BHV4157-201 has high participation 
rates and interim analysis of data from subjects who have completed up to 96 weeks of treatment 
demonstrate stability of SARA scores from baseline.  After up to 96 weeks of open-label 
treatment with troriluzole, the mean change from baseline in total SARA score (mean 
change±SE) was 0.3 ± 0.30.  Patients who had a gap in troriluzole treatment (3 weeks to 
12 months) while awaiting approval of the protocol extension showed a greater than 1 point 
worsening during the off-treatment period.  This worsening increased with longer duration off 
troriluzole. Improvements in total SARA score were observed after re-initiation of troriluzole 
therapy.  The observed changes suggest an attenuation of disease progression in patients treated 
with troriluzole for up to 3 years, including up to a 1-year gap in dosing during which patients 
declined, versus the expected rate of decline in the SARA in untreated patients of approximately 
1-2 points per year, based on cumulative natural history data9.  These trends are consistent with 
the results from two prior studies (discussed above) using the active metabolite of troriluzole 7,8.

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1.2.2
Pharmacokinetics
1.2.2.1
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;

Preliminary 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); 

More extended riluzole concentrations compared to oral doses of riluzole, as exemplified by 
the rat data. This is consistent with data suggesting the main route of prodrug cleavage is 
mediated by serum-based enzymes; 

Troriluzole is stable in saliva and crosses the buccal membrane (pig model), hence 
supporting testing for sublingual absorption in the clinic; 

 
1.2.2.2
Clinical Experience
Detailed information is available in the current version of the Investigator Brochure. Troriluzole 
has been observed to be well tolerated with no clinically relevant safety signals identified in the 
completed and ongoing clinical studies. The current troriluzole clinical program includes Phase 1 
PK studies in normal healthy volunteers (BHV4157-101, BHV4157-102, BHV4157-103, 
BHV4157-104, BHV4157-105, BHV4157-106, BHV4157-107 and BHV4157-108), Phase 2 or 3 
studies in subjects with SCA (BHV4157-201, BHV4157- 206), OCD (BHV4157-202), AD 
(BHV4157-203) and GAD (BHV4157-207). Overall, the PK and safety profile from the Phase 1 
studies support the investigation of troriluzole at doses of 280 mg QD in Phase 2. 
Several clinical studies, each with a double-blind phase with the potential for eligible subjects to 
enroll into an extension phase with open label troriluzole treatment, are ongoing or have been 
completed in the various indications noted above. A study is assessing efficacy in subjects with 
SCA randomized to 8 weeks of treatment with either troriluzole or placebo and up to 48 weeks 
of open label treatment with troriluzole. A study is assessing efficacy in subjects with OCD who 
were randomized to treatment with either troriluzole or placebo for 12 weeks with the option to 
enroll into an open label expanded extension phase through 96 weeks if eligible. A study is 
assessing subjects with AD randomized for 48 weeks to either troriluzole or placebo and up to 48 

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weeks of open label treatment with troriluzole. A study was completed of subjects with GAD 
randomized for 8 weeks to either troriluzole or placebo and up to 48 weeks of open label 
treatment with troriluzole. Please reference the current IB for further details. 
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 pharmacokinetic (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 10,11.
1.2.2.2.1
BHV4157 Phase I 
Refer to the Investigators Brochure for detailed and updated information on Phase 1 studies.
1.2.2.2.1.1
Study BHV4157-101
Study BHV4157-101 was a Phase 1 randomized, double-blind, placebo-controlled study to 
evaluate the safety, tolerability, and PK of single and multiple ascending doses of troriluzole in 
normal healthy volunteers. Single doses of troriluzole were assessed (sequential cohorts 1 to 5 
with 17.5, 35, 70, 140 and 200 mg) with cohort 5 (200 mg) undergoing a repeat single-dose 
administration under conditions of a high-fat meal (to determine food effects).  Multiple dose 
cohorts were assessed for 5 days of dosing (sequential cohorts 6 to 10 with total daily doses of 
35, 70, 140, and 200 mg).

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With regards to Pharmacokinetics (PK), a single dose of 140 mg troriluzole yields exposures 
(e.g., AUCinf 1,059 ng*h/mL) that are expected to be similar to those achieved in prior academic 
clinical trials using twice daily riluzole in various indications (e.g., approximately
1254 ng*h/mL, based on Chandu 12, a dose which was previously studied in ataxia7,8.  The 
multiple dose AUC for 200 mg troriluzole yielded AUC exposures of 1804 ng*h/mL riluzole.
Safety / Tolerability: Oral administration of troriluzole (17.5 mg to 200 mg) was well tolerated 
in healthy volunteers in this study at single doses up to 200 mg and multiple doses up to 200 mg 
daily. No evidence of new, clinically significant safety signals or lab abnormalities were evident, 
as compared to the Rilutek package label. There were no SAEs and the vast majority of AEs 
were mild in severity. 
1.2.2.2.1.2
Study BHV4157-102
Study BHV4157-102 was a single-center, open-label, single-dose, randomized, 4-period, 
2-sequence, fully replicated crossover study to compare the rate and extent of absorption of 
2 formulations (i.e., Phase 2 formulation vs commercial-grade capsule formulation) and to 
evaluate the safety, tolerability, and PK of troriluzole in healthy subjects performed under fasting 
conditions. Subjects were randomized equally into 1 of the 4 treatment sequences to receive the 
2 treatments twice (1 x 140 mg troriluzole as formulated capsule or 1 x 140 mg troriluzole as 
Phase 2-formulated capsule – without excipients) under fasting conditions in each period. Each 
period was separated by a washout period of at least 7 days. Subjects at the end of each period 
were crossed over to the next treatment in their sequence. Each subject was scheduled to receive 
a total of 4 treatments (each of the 2 treatments twice) by the end of the study.
Safety / Tolerability:  Oral administration of 140 mg troriluzole formulated capsule 
(Commercial-ready formulation) or Phase 2 capsule was safe and well tolerated in healthy adult 
subjects, with no SAEs or deaths reported in the study.
Pharmacokinetics:  Bioequivalence (BE) was demonstrated between the two formulations in 
accordance with both FDA and EMA guidance. 
1.2.2.2.1.3
Study BHV4157-103
Study BHV4157-103 was a single-center, randomized, multiple-dose, placebo-controlled, 
double-blind,1-period, 1-cohort study to evaluate the safety, tolerability, and PK of troriluzole in 
healthy subjects under fasting conditions. Subjects were randomized to receive multiple doses of 
either troriluzole or placebo based on stratification factor of age group (< 65 years old vs. ≥ 65 
years old). Six subjects were to be 65 to ≤ 85 years old and 4 subjects were to be < 65 years old. 
For subjects receiving matching placebo, 1 subject was to be < 65 years old and 1 subject was 
≥65 years old. Eight (8) subjects were dosed with troriluzole, administered as a dose of 280 mg 
(2 x 140 mg capsules) once daily for 5 consecutive days. 
Safety / Tolerability:  Overall, the 280 mg dose of troriluzole was safe and well tolerated in 
healthy adult subjects. There were no deaths or other SAEs reported in this study. 

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Pharmacokinetics (preliminary data):
After administration of a single dose, 280 mg of troriluzole yielded geometric mean values for 
AUC0-24 of 4.46 ng*hr/mL and Cmax of 5.40 ng/mL  for  BHV4157;  and geometric mean values 
for AUC0-24 of 2797.0 ng*h/mL and Cmax of 510.4 ng/mL, for riluzole. After administration of  
multiple doses (once daily for 5 days), 280 mg of troriluzole yielded geometric mean values for 
AUC 0-inf of 4.94 ng*hr/mL and Cmax of 4.22 ng/mL for BHV4157; and an AUC 0-inf of 3439.6 
ng*h/mL and Cmax of 481.7 ng/mL, for riluzole. 
These findings, taken together, provide reassurance that the riluzole exposure achieved in this 
study with troriluzole was well within the exposure range that has been safely administered 
previously. The 280 mg dose of troriluzole is the molar equivalent of 140 mg of riluzole.
Based on the visual inspection of the Ctrough and repeated-measure analysis for riluzole, the 
steady-state could be considered as achieved after 5 days of oral administration of 280 mg 
troriluzole. The PK variability of riluzole AUC and CMax (CVs of ~30%) was lower than what 
has been previously reported with riluzole tablets.
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). The study consisted of a double-blind 8 week 
randomization phase. Subjects completing the randomization phase were offered open-label 
troriluzole treatment based on investigator discretion. The randomization phase is complete. The 
expanded open-label extension phase through Week 192 is ongoing. 
Overall, at greater than 2 years, the observed changes from randomization baseline in total 
SARA scores of +0.3 points in patients treated with troriluzole suggest an attenuation of disease 
progression versus the expected rate of decline of approximately +1 to +2 points per year in the 
SARA in untreated patients, based on cumulative natural history data. These results strongly 
suggest attenuation of disease progression in troriluzole treated subjects.
1.2.2.4
BHV4157Phase 2: BHV4157-202
BHV4157-202 is a 2b/3, multicenter, randomized, double-blind, 2-arm placebo-controlled 
parallel-group study designed to assess safety, tolerability, and efficacy of troriluzole as 
adjunctive therapy when added to standard of care (SOC) treatment in subjects with OCD who 
failed to respond adequately to SOC pharmacotherapy. Inadequate response on the subjects’ 
current SOC treatment was defined by a Yale–Brown Obsessive Compulsive Scale (Y-BOCS) 
score of 19 or greater despite at least 10 weeks of treatment at Baseline with the maximum 
tolerated dose of a selective serotonin reuptake inhibitor (SSRI), clomipramine, venlafaxine or 
desvenlafaxine medication. The primary objective of the study is to evaluate the efficacy of 
troriluzole as adjunctive therapy in subjects with OCD who have had an inadequate response to a 
selective serotonin reuptake inhibitor (SSRI), clomipramine, venlafaxine or desvenlafaxine 
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Subjects were randomized to additionally receive placebo (QD) or troriuluzole (200 mg QD after 
4 weeks at 140 mg QD). The total duration of the randomization phase was 12 weeks. Subjects 
who completed the randomization phase were to be offered approximately 96 weeks of open-
label troriluzole in an extension phase, as per investigator discretion. The open-label extension 
phase is ongoing. 
Efficacy findings indicate troriluzole 200 mg, administered once daily as adjunctive therapy in 
subjects with OCD who had an inadequate response to SOC treatment resulted in numerically 
greater improvement versus placebo in the total Y-BOCS score at Weeks, 4, 8, and 12 of the 
randomization phase. This difference was statistically significant at Week 8 (p < 0.041). At 
Week 12, the improvement in Y-BOCS score was numerically greater in the troriluzole group
relative to placebo, but the treatment difference did not reach statistical significance (p = 0.220). 
In a post-hoc analysis, treatment with troriluzole resulted in improvement in OCD symptoms that 
was greater both at Week 8 and Week 12 in subjects who had more severe symptoms 
 
 versus less severe symptoms 
 at baseline. The 
treatment difference was statistically significant at Week 8 in the cohort with 
 
1.2.2.5
BHV4157 Phase 2: BHV4157-203
BHV4157-203 is an ongoing Phase 2, multi-center, randomized, double-blind, placebo-
controlled, parallel group study in subjects with mild to moderate AD. Subjects were randomized 
(1:1) to receive either troriluzole or placebo for 48 weeks. There was a 2-week fixed titration 
period with a starting dose of troriluzole 140 mg QD or placebo QD. If there were no issues with 
tolerability of the study drug during the first 2 weeks of the study, the subjects received two 140 
mg capsules (total daily dose of 280 mg) for the remaining duration of the study (46 weeks). 
Subjects who completed the randomization phase were offered approximately 48 weeks of open-
label troriluzole in an extension phase, as per investigator discretion.13 The randomization phase 
is complete. The open-label extension phase is ongoing. Results for the Week 48 co-primary 
endpoints indicated troriluzole 280 mg, administered once daily as adjunctive therapy on a 
background of AchEI and/or memantine medication for up to 48 weeks in participants with mild 
to moderated AD did not statistically differentiate from placebo on the study’s co-primary 
endpoints, the Alzheimer’s Disease Assessment Scale – 11-item cognitive subscale (ADAS-Cog 
11) and the Clinical Dementia Rating Sum of Boxes (CDR-Sob).
1.2.2.6
BHV4157 Phase 2: BHV4157–207
BHV4157-207 was a Phase 3, 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 ≥ 1 year and at least of moderate severity on the Clinical Global 
Impression Scale-Severity of Illness scale at study entry. Subjects were randomized to receive 
either troriluzole 200 mg (administered as 100 mg BID) or matching placebo for 8 weeks. 
Eligible subjects had the opportunity to continue in a 48 week extension phase. A total of 
390 subjects were treated in the randomization phase. 

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The study has been completed. Results for the Week 8 primary and secondary endpoints, showed 
no improvement in GAD symptoms in subjects treated with troriluzole relative to placebo.
1.2.3
Potential for Drug-Drug Interactions
Troriluzole is rapidly converted to riluzole by aminopeptidases in plasma.
Preliminary results from a recently completed clinical drug-drug interaction study with 
fluvoxamine (CYP1A2 inhibitor) are available and described below.  
The potential for troriluzole and riluzole to act as a victim and/or a perpetrator for drug-drug 
interactions has been evaluated in a number of in vitro assessments with the following 
conclusions: 
Summary of CYP substrate and perpetrator potential assessment:

Troriluzole is not a CYP substrate, while riluzole is a substrate for CYP1A2 

Neither troriluzole nor riluzole directly inhibits CYPs at >50x therapeutic concentrations (2 
µM); 

Both troriluzole and riluzole have the potential to induce CYP2B6 and do not induce 
CYP3A4/5, whereas riluzole shows potential for inducing CYP1A2 at clinically relevant 
concentrations.
In transporter studies:

 
 
 
 
 
 
 
 
In conclusion, CYP1A2 is the principal isozyme involved in the initial oxidative metabolism of 
riluzole and, therefore, potential interactions may occur when troriluzole is given concurrently 
with agents that affect CYP1A2 activity. Potent inhibitors of CYP1A2 (e.g., ciprofloxacin, 
enoxacin, fluvoxamine, methoxsalen, mexiletine, vemurafenib) could decrease the rate of 

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riluzole elimination, while inducers of CYP1A2 (e.g., cigarette smoke, charcoal-broiled food, 
rifampicin, and omeprazole) could increase the rate of riluzole elimination. 
Results from a drug-drug interaction clinical study of troriluzole with a strong CYP1A2 
inhibitor, fluvoxamine, indicate that riluzole concentrations may be increased up to 3-fold, 
consistent with CYP1A2 inhibition of riluzole metabolism. These findings are consistent with in 
vitro results suggesting that riluzole is a sensitive CYP1A2 substrate. 
Potential interactions may occur when troriluzole is given concurrently with other agents which 
are also metabolized primarily by CYP1A2 (e.g., theophylline, caffeine, and tacrine) and to a 
lesser extent, CYP2B6; these are however, less likely to be of clinical significance. Currently, it 
is not definitively known whether riluzole results in clinically significant CYP1A2 or CYP2B6 
enzyme induction in humans, although lack of evidence of substantial autoinduction of riluzole 
metabolism after multiple dosing suggests only modest effects on CYP1A2. Additionally, 
although the BCRP and OAT3 transporters are inhibited by riluzole in vitro (IC50 > 5 µM for 
both), the magnitude of inhibition at the clinical dose of troriluzole is unlikely to be of clinical 
significance.
1.2.4
Specific Populations
As per the United States Product Insert (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). Dedicated 
studies with troiluzole have not been conducted.
1.2.5
Clinical Adverse Event Profile
Troriluzole readily metabolizes to riluzole. Therefore, the 20 years’ global clinical experience is 
important to summarize herein.
1.2.5.1
Troriluzole
As described in the current IB, clinical experience with troriluzole derives from Phase 1 studies 
in healthy volunteers and a Phase 2b/3 studies in subjects with SCA, OCD, GAD and AD. Single 
doses up to 200 mg and multiple doses up to 280 mg daily have been well tolerated without 
evidence of new, clinically significant safety signals or lab abnormalities compared to the 
Rilutek package label. As described in the current IB, clinical experience with troriluzole during 
the double-blind randomization phase of study BHV4157-201 at 140 mg QD for 8 weeks was 
well tolerated in adult subjects with SCA. The randomization phase is complete and the Week 
192 extension phase is ongoing. Preliminary safety findings indicate that troriluzole up to 280 
mg QD appear to be generally well tolerated.
1.2.5.2
BHV4157-201:  Phase 2 Clinical Adverse Event Profile
Study BHV4157-201 is an ongoing study of adult subjects with spinocerebellar ataxia. In the 
initial part of the study subjects were either given BHV-4157 (140 mg once daily) or placebo.  A 

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total of 141 subjects were enrolled. Of these subjects, 138 continued into a 48-week open label 
phase, where all subjects received troriluzole 140 mg daily. Troriluzole at 140 mg daily was 
well-tolerated without any meaningful events for safety or clinical lab values.
During the double-blind randomization phase, administration of troriluzole at 140 mg QD for 
8 weeks was well tolerated in adult subjects with SCA. The safety profile of troriluzole 140 mg 
QD during long-term treatment (combined randomization and extension phases through the 
07-Sep-2018 data cutoff date) was consistent with the troriluzole safety profile observed during 
the randomization phase.
There have been three deaths reported in this study as of July 28, 2022. The frequency of 
treatment-emergent serious AEs (SAE) was ≥5%. 
During the randomization phase, no single SAE preferred term was reported by more than 
1 subject. Pneumonia was the most frequently reported SAE for subjects who received at least 
1 dose of troriluzole in either phase of the study (3 subjects). All other SAEs were reported for 
single subjects.  As of 17-Sept-2018, in subjects who received at least one dose of troriluzole,  
there were 13 SAEs reported in 8 subjects: these events included syncope, fever, inflammation of 
the mesenteric tissue, pneumonia, dehydration, elevated CPK, weakness, severe back pain, 
suicidal ideation, cerebral infarction, atrial fibrillation, chest tightness and high blood pressure. 
All of these SAEs were considered not related to treatment with troriluzole, with the exception of 
4 SAEs reported in 3 subjects. These treatment-related SAEs included atrial fibrillation and 
cerebral infarction (1 subject), pneumonia (1 subject) and syncope (1 subject). 
Syncope was considered possibly related. Atrial fibrillation, cerebral infarction, and pneumonia
were considered unlikely related to troriluzole.
The frequency of AEs leading to discontinuation was 4.2% in the troriluzole group and 0% in the 
placebo group during the randomization phase and 8.0% overall after at least 1 dose of 
troriluzole in either phase of the study. 
During the randomization phase, no single AE preferred term led to discontinuation of more than 
1 subject.  Dizziness led to discontinuation of treatment for 3 (2.2%) subjects after at least 1 dose 
of troriluzole in either phase of the study. Fatigue, headache, and nausea each led to 
discontinuation of 2 (1.5%) troriluzole-treated subjects.
The majority of treatment-emergent AEs were mild in severity, not related to study therapy, and 
resolved spontaneously by the end of treatment.  The most frequently (≥ 5%) reported treatment-
emergent AEs during the randomization phase were dizziness (8/71 [11.3%] in the troriluzole 
group and 1/70 [1.4% in the placebo group), fatigue (6/71 [8.5%] in the troriluzole group and 
3/70 [4.3% in the placebo group), fall (5/71 [7.0%] in the troriluzole group and 1/70 [1.4% in the 
placebo group), headache (4/71 [5.6%] in the troriluzole group and 4/70 [5.7% in the group 
placebo), nausea (4/71 [5.6%] in the troriluzole group and 4/70 [5.7% in the placebo group), and 
muscle spasm (4/71 [5.6%] in the troriluzole group and 2/70 [2.9% in the placebo group).
The most frequently (≥ 5%) reported treatment-emergent AEs after receiving at least 1 dose of 
troriluzole were similar to those reported during the randomization phase: fall (15.9%), dizziness 

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(12.3%), headache (10.1%), fatigue (9.4%), nausea (9.4%), balance disorder (8.0%), viral upper 
respiratory tract infection (7.3%), arthralgia (6.5%), back pain (6.5%), and muscle spasms 
(6.5%).  The most frequently reported treatment-emergent AEs are presented in Table 2:
Table 2: 
Most Frequently Reported Treatment-emergent AEs in Study 
BHV4157-201
Treatment Emergent AE
Number of Participants (%)
Study Group
Dizziness
8 (11.27%)
1 (1.43%)
Troriluzole
Placebo
Fatigue
6 (8.45%)
3 (4.29%)
Troriluzole
Placebo
Fall
5 (7.04%)
1 (1.43%)
Troriluzole
Placebo
Headache
4 (5.63%)
4 (5.71%)
Troriluzole
Placebo
Nausea
4 (5.63%)
4 (5.71%)
Troriluzole
Placebo
Muscle Spasms
4 (5.63%)
2 (2.86%)
Troriluzole
Placebo
There were no clinically meaningful trends in laboratory values identified during the 
randomization phase and no subjects had AST or ALT laboratory values >3 X ULN. Refer to the 
most current IB for details.
1.2.5.3
Riluzole
The following key information regarding clinical safety of riluzole in ALS is presented from the 
current USPI. The adverse reactions of hepatic injury, neutropenia, and interstitial lung disease 
have been described under “Warnings and Precautions” in the riluzole USPI. See current IB for 
details. 
The adverse reactions that occurred in at least 2% of Rilutek-treated patients (50 mg twice daily) 
in pooled placebo-controlled trials (Study 1 and 2), and at a higher rate than placebo are 
presented in the table below. 
A recent systematic review and meta-analysis of riluzole clinical trial data from other
neurological disease indications showed that treatment with riluzole was well tolerated at doses 
of up to 200 mg daily.14 This study analyzed safety data from 9 studies encompassing 
1528 randomized patients, with Huntington’s disease, Parkinson’s disease, multiple systems atrophy, 
progressive supranuclear palsy, and several forms of ataxia. 

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Riluzole-Adverse Reactions in Pooled Placebo-Controlled Trials in Patients with ALS 
Rilutek 50 mg 
Twice Daily 
(N=313) 
Placebo 
(N=320) 
Asthenia 
19% 
12% 
Nausea 
16% 
11% 
Decreased lung function 
10% 
9% 
Hypertension 
5% 
4% 
Abdominal Pain 
5% 
4% 
Vomiting 
4% 
2% 
Arthralgia 
4% 
3% 
Dizziness 
4% 
3% 
Dry Mouth 
4% 
3% 
Insomnia 
4% 
3% 
Pruritus 
4% 
3% 
Tachycardia 
3% 
1% 
Flatulence 
3% 
2% 
Increased Cough 
3% 
2% 
Peripheral Edema 
3% 
2% 
Urinary Tract Infection 
3% 
2% 
Circumoral Paresthesia 
2% 
0% 
Somnolence 
2% 
1% 
Vertigo 
2% 
1% 
Eczema 
2% 
1% 
Source: COVIS USPI, 2020
1.2.5.4
Elevations in Liver Function Tests
In the Phase I studies BHV4157-101, BHV4157-102, BHV4157-103, BHV4157-104, 
BHV4157-105, BHV4157-106 or BHV4157-107 no clinically significant LFT changes (values 
>3x ULN) were observed in subjects on study drug. 
In the 8 week placebo controlled phase of BHV4157-201 study, there were no subjects who 
received at least one dose of troriluzole either during the randomization phase or the open-label 
extension phase (through 48 weeks) that experienced treatment emergent AST or ALT laboratory 
abnormalities > 3x ULN, or total bilirubin elevations > 2x ULN. 
In the 12 week placebo controlled phase of BHV4157-202 study, most subjects in both treatment 
groups had normal ALT, AST, and total bilirubin both at baseline and on treatment. Assessment 
of maximum observed LFT abnormalities on treatment in the troriluzole group identified 2/118 
(1.7%) subjects with on-treatment ALT > 3x and <5x ULN (both with normal ALT at baseline), 
and 2/118 (1.7%) subjects with AST > 5x ULN (both with normal AST at baseline). No subjects 
in the troriluzole group had on-treatment abnormalities of total bilirubin > 2x ULN during the 
randomization phase; one subject had total bilirubin 1.9x ULN. None of subjects had both ALT 
and total bilirubin elevations that met criteria for Hy’s Law. 

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In the BHV4157-203 study, overall, the liver profile of troriluzole was comparable to that of 
placebo. For most subjects in both treatment groups, the maximum observed LFT measurements
were normal at baseline and on treatment. Assessment of maximum observed abnormalities on 
treatment identified 4 subjects in the troriluzole group with ALT > 3x ULN on treatment (1 with 
ALT > 5x ULN, and all 4 with normal ALT at baseline) and 1 subject with AST > 3x ULN on 
treatment (and normal AST at baseline). None of the placebo-treated subjects had ALT or AST 
> 3x ULN. One subject in the troriluzole group had total bilirubin > 2x ULN on treatment (with 
> ULN to ≤ 1.5x ULN at baseline), and 2 subjects in the placebo group had total bilirubin > 2x 
ULN on treatment, both with elevated total bilirubin at baseline. 
In the BHV4157-206 study which is ongoing in the randomization phase and remains blinded to 
treatment assignment, 216 subjects have been randomized and received at least 1 dose of blinded 
study drug (either troriluzole or placebo, with a 1:1 randomization assignment) as of 28-Jun-
2021. SAEs have been reported in 18 subjects; 1 SAE (liver function test increased) was 
considered related to study drug. 
In the BHV4157-207 study, most subjects in both treatment groups had normal ALT, AST and 
total bilirubin both at baseline and on-treatment during the double-blind randomization phase. 
Assessment of maximum observed LFT abnormalities on treatment in the troriluzole group 
identified 7 (3.6%) on-treatment ALT > 3x ULN, and 2 (1%) on-treatment AST > 3x ULN in the 
troriluzole group. One (0.5%) on-treatment ALT > 3x ULN and 1 (1.1%) on-treatment AST > 3x 
ULN was observed in the placebo group. On-treatment abnormalities of total bilirubin were 
infrequent (none in the troriluzole group and 1 in the placebo group).
Cases of drug-induced liver injury, some of which were fatal, have been reported in patients 
taking Rilutek. Asymptomatic elevations of hepatic transaminases have also been reported, and 
in some patients have recurred upon re-challenge with Rilutek. In clinical studies, the incidence 
of elevations in hepatic transaminases was greater in Rilutek-treated patients than placebo-
treated patients. The incidence of elevations of ALT above 5x ULN was 2% in Rilutek-treated 
patients. Maximum increases in ALT occurred within 3 months after starting Rilutek. About 
50% and 8% of Rilutek-treated patients in pooled Studies 1 and 2, had at least one elevated ALT 
level above ULN and above 3x ULN, respectively. Monitor patients for signs and symptoms of 
hepatic injury, every month for the first 3 months of treatment, and periodically thereafter. The 
use of Rilutek is not recommended if patients develop hepatic transaminases levels greater than 
5x ULN. Discontinue Rilutek if there is evidence of liver dysfunction (e.g., elevated bilirubin).
1.2.5.5
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. Cases of severe neutropenia (absolute neutrophil count less than 500 per mm3 ) within the first 
2 months of Rilutek treatment have been reported. Advise patients to report febrile illnesses.

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1.2.5.6
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.
1.2.6
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.
1.3
Study Rationale
1.3.1
Study Design Rationale
 
 
 
 
 
 
 
 
 

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1.3.3
Preclinical Pharmacology
Troriluzole is a new chemical entity prodrug that upon being cleaved in the plasma releases
riluzole. Troriluzole is stable in saliva and gastric fluids, and was designed to avoid first pass 
metabolism in the liver before being cleaved to riluzole. Preclinical studies in rodents with 
troriluzole show extended riluzole concentrations as compared to oral doses of riluzole itself. 
Both oral gavage and IV administration of troriluzole to cynomolgus monkeys results in 
cleavage to riluzole.  This is consistent with data suggesting that the main route of prodrug 
cleavage is mediated by serum-based enzymes.
Because of its unique glutamate-modulating properties that have been elucidated over the last 
decade, riluzole has gained considerable attention. Riluzole appears to modulate glutamate 
neurotransmission by several pharmacological mechanisms. The drug was originally developed 
as an anticonvulsant, and early studies showed it to oppose several actions of glutamate in vitro 
and in vivo 23,24 . More recent studies demonstrate that the drug may act by several distinct 
mechanisms effecting amino acid neurotransmitter (AANt) function. Riluzole has also been 
shown to inhibit the release of glutamate in vivo 25 and in vitro 26-28. Riluzole interacts with a 
large number of ion channels (voltage-activated sodium channels 29-32, voltage-gated calcium 
channels 33,34, and voltage-gated potassium channels 31,35-38) that may contribute to a reduction in 
glutamate release.
Recently another action of riluzole has been described which may prove to be of substantial 
importance for its clinical actions: enhancement of glial reuptake of glutamate occurring in 
animal models at free concentrations achieved with clinical doses. In rat synaptosomes, acute 
riluzole treatment was shown to increase glutamate uptake 39,40. More recently, the drug was 
found to specifically enhance glutamate uptake by astrocytes in culture 41, and in HEK cells 
expressing excitatory amino acid transporters 42. The same effect has been documented in vivo in 
rat spinal cord, where riluzole reverses the decrease in glutamate transport seen after nerve 
injury43. While the molecular mechanisms underlying this effect remain unclear, it is likely that 
riluzole interacts with and/or upregulates one or more of the excitatory amino acid transporters 
(EAAT).
Recent evidence, supports this mechanism by demonstrating that chronic administration of 
riluzole increases EAAT2 (also called GLT-1) expression and increases both glial and neuron 
amino acid neurotransmitter cycling in rats 44,45. This finding is consistent with the observation in 
humans that riluzole increases glutamate-glutamine cycling 46.

 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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Synaptic and extrasynaptic glutamate can have dramatically different effects on a neuron. 
Synaptic glutamate, and specifically the activation of synaptic NMDA and AMPA receptors 47-50, 
activates trophic downstream effectors, including CREB and BDNF, and preserves neuronal 
viability. Conversely, extrasynaptic glutamate and activation of extrasynaptic NMDA receptors 
reduces CREB activity and BDNF expression, opposes trophic effects on neurons, and can lead 
to atrophy and cell death 51-54. It is therefore postulated that the upregulation of glial glutamate 
reuptake results in decreased extrasynaptic glutamate concentrations and a release from the tonic 
inhibition of the presynaptic neurons by activation of the presynaptic mGluR 2/3 receptors. This 
may provide a mechanism for the finding that riluzole can induce trophic factors, including 
BDNF, and lead to neuroprotection and resiliency 55-57. As an additional potential mechanism of 
neuroplasticity action, riluzole has also been recently shown to enhance the surface expression of 
GluR1 and GluR2 and increase membrane potential depolarization in a time- and dose-dependent 
manner in cultured hippocampal neurons 58.
While the prominence of riluzole effects on glutamatergic neurotransmission has been amply 
documented, riluzole apparently alters signaling of other neurotransmitter systems, as well. 
While these effects occur at higher concentrations, it cannot be excluded that some of the 
biological effects of riluzole are attributable to non-glutamatergic effects.
Figure 2:
Schematic representation on the mechanism of action of riluzole
The putative mechanism of action for riluzole involves facilitation of glutamate update 
at Excitatory Amino Acid Transporters located on glia (60).
In summary, riluzole has been documented to have a wealth of pharmacological actions, 
including interactions with several types of ion channels, cellular signaling mechanisms, and 
facilitation of glutamate reuptake. Several of these actions of riluzole could be viewed as 

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neuroprotective, and potentially confer therapeutic effects in SCA. Specifically, the Sponsor 
considers several mechanisms as relevant to SCA (illustrated in Figure 2):

Activating effects at small-conductance (KCa2.1-2.3) and intermediate-conductance 
(KCa3.1) calcium-activated potassium channels;

Altering GABAergic neurotransmission;

Facilitation of glutamate uptake via EAATs located on glial cells;

Reducing presynaptic glutamate release through actions at the voltage-gated ion channels;

Enhanced transmission through synaptic AMPA receptors;

Effects on neurotrophic agents such as BDNF.
1.4
Research Hypothesis
Troriluzole monotherapy for 48 weeks is superior to placebo in the treatment of Spinocerebellar 
Ataxia.
2
STUDY OBJECTIVES
2.1
Primary

To compare the efficacy of troriluzole (200 mg once daily) versus placebo on ataxia 
symptoms in subjects with spinocerebellar ataxia (SCA) after 48 weeks of treatment as 
measured by the total score on the Modified Functional Scale for the Assessment and Rating 
of Ataxia [f-SARA]
2.2
Secondary

To compare the efficacy of troriluzole versus placebo on patient impression of benefit via use 
of the Patient Impression of Function and Activities of Daily Living Scale (PIFAS), an 
internally developed twelve-item instrument modeled after the FACIT-Fatigue Scale 

To compare the efficacy of troriluzole versus placebo on activities of daily living as 
measured by the Activities of Daily Living Scale from the Friedreich’s Ataxia Rating Scale 
(FARS-ADL)

To compare the efficacy of troriluzole versus placebo on daily functioning as measured by 
the Functional Staging for Ataxia Scale from the Friedreich’s Ataxia Rating Scale (FARS-
FUNC)

To assess of the safety and tolerability of troriluzole in subjects with SCA

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2.3
Exploratory

To compare the efficacy of troriluzole versus placebo on lower extremity mobility and 
activities as measured by the Neuro-QOL Lower extremity mobility scale 

To compare the efficacy of troriluzole versus placebo on upper extremity function and 
activities as measured by the Neuro-QOL Upper Extremity Scale 

To compare the efficacy of troriluzole versus placebo on daily fatigue and activities as 
measured by the Neuro-QOL Fatigue Scale 

To compare efficacy of troriluzole versus placebo on clinician impression of global functioning 
via use of the Clinical Global Impression-Global Improvement Scale (CGI-I)

To compare the efficacy of troriluzole versus placebo on patient impression of global 
functioning as measured by the Patient Global Impression Scale (PGI)

 
3
STUDY ENDPOINTS 
3.1
Primary

The total score on the Modified Functional Scale for the Assessment and Rating of Ataxia (f-
SARA) at Week 48
3.2
Secondary

Patient Impression of Function and Activities of Daily Living Scale (PIFAS)

Activities of Daily Living Scale from the Friedreich’s Ataxia Rating Scale (FARS-
ADL)

Functional Staging for Ataxia (FARS-FUNC)

Safety and tolerability of troriluzole will be measured by the frequency and severity of 
adverse events and discontinuations due to adverse events.

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3.3
Exploratory Outcome Measures

Neuro-QOL Lower Extremity

Neuro-QOL Upper Extremity 

Neuro-QOL Fatigue

Clinical Global Impression-Global Improvement Scale (CGI-I)

Patient Global Impression Scale (PGI)

 
3.4
Clinical Lab Test

Hematology: hemoglobin, hematocrit, platelets, CBC with differential and absolute 
neutrophil count;

Serum Chemistry: sodium, potassium, chloride, calcium, ALT, AST, LDH, alkaline 
phosphatase, GGT, phosphorous, bicarbonate, CPK, total protein, albumin, total bilirubin (if 
2 mg/dl bilirubin will be fractionated for reporting of direct and indirect values), glucose, 
eGFR, creatinine, BUN, uric acid, and pregnancy testing (WOCBP). Additionally, at 
screening, total cholesterol, LDL, HDL, triglycerides, folate, HbA1C, P-Amylase, Lipase, 
TSH, and T4

Urinalysis: pH, specific gravity, protein, ketones, glucose, blood, and microscopic exam 
(completed only if any part of the urinalysis is not negative);

Additional tests:  HIV, HBsAg and HCV antibody at screening
4
STUDY PLAN
4.1
Study Design and Duration
BHV4157-206 is a Phase III, multicenter, randomized, double-blind, 2-arm placebo-controlled 
parallel-group study designed to assess safety, tolerability, and efficacy in a population of 
patients with Spinocerebellar Ataxia (SCA). Subjects will be randomized to receive placebo 
(QD) or troriluzole (200 mg QD) and will be stratified by diagnosis (genotype).  The 200 mg 
dosage was selected for evaluation in the current study based on evidence summarized in 
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Subjects with SCA1, SCA2, and SCA3 genotypes will comprise approximately 80%-90% of the 
randomized subjects.  Patients with SCA6, SCA7, SCA8, and SCA10 genotypes will comprise 
approximately 10% of the randomized subjects in total.  Eligible subjects will be randomized to 
receive once daily dosing of troriluzole or placebo. Randomization will be stratified by 3 SCA 
subgroups: SCA1 & 2; SCA3; and SCA 6, 7, 8, 10. Subjects will receive either troriluzole
(140mg) or matching placebo for the first 4 weeks and then will be increased to 200 mg (or 
matching placebo) for the duration of the study.  Down titration in the Randomization Phase will 
only be temporarily allowed for tolerability purposes.  Prior to down titration, these cases 
should be discussed with the Biohaven Medical Monitor. For patients who experience 
fatigue or dizziness after dosing, dosing should be given every night at bedtime (QHS).
Dosing will continue for approximately 48 weeks.  If absolutely necessary, treatment duration 
may be longer due to the COVID-19 pandemic as detailed in the time and events table. Under 
these circumstances, the sponsor medical monitor should be consulted and must approve the
request to change the treatment duration (may be extended if necessitated by the COVID-19 
pandemic from 48 weeks up to maximum of 60 weeks (12 week extension)). 
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 up to 
192 weeks of open-label treatment provided the Primary Investigator (PI) believes open-label 
treatment offers an acceptable risk-benefit profile. Subjects who agree to enter the Extension 
Phase will not be required to wash-out of drug or complete the follow-up safety visit, but instead 
should continue dosing as specified in the extension phase.  
Subjects entering the Extension Phase will have their first Extension Visit four weeks after the 
Week 48 Randomization Phase visit. Thereafter, subjects will undergo visits every four weeks up 
through week 12 of the Extension Phase as outlined in Table 4 (Schedule of Assessments/Time 
& Events- Extension Phase). Subjects will then undergo visits every 12 weeks up to Week 192 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 on placebo in the Randomization Phase will be switched in a 
blinded manner to troriluzole 140 mg for the first four weeks and then will be increased to 
200 mg for the duration of the study.  Temporary down titration while on the 200 mg dosing will 
only be allowed for tolerability purposes and must be discussed with the medical monitor.  All 
Visits after Extension week 4 will be open-label.  Subjects who enter the Extension Phase on 
140mg due to intolerability issues can be rechallenged to increase to 200mg after Extension 
Week 4 at PI discretion.
Subjects will be assessed at clinic visits per the Schedule of Assessments/Time & Events.
4.2
Study Schematic
Figure 3: 
Study Schematic

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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R, signifies randomization; randomization will be stratified by 3 SCA subgroups: SCA1 & 2; SCA3; and SCA 6, 7, 
8, 10.
* Eligible subjects for the Extension Phase will include those for whom the PI believes extended treatment with 
troriluzole would offer an acceptable risk-benefit profile.
**Subjects will receive 140 mg for the first four (4) weeks and will then be increased to 200 mg for the duration of 
the study.  Down titration to 140 mg will only be temporarily allowed to address tolerability issues.
***Subjects entering the Extension Phase will continue with the same dose taken at the end of 
the Randomization Phase.  Subjects on placebo in the Randomization Phase will be switched in a 
blinded manner to 140 mg QD for the first four weeks and then will be increased to 200 mg QD 
for the duration of the study.  Down titration after the first four weeks of the Extension Phase 
will only be allowed for tolerability purposes.  All visits after Extension Phase Week 4 will be 
open-label.

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2The Extension Week 16 Visit is only for routine labs, which may be done locally.
3 PK samples to be drawn only if there is an AE determined to be related to study drug.
4All subjects who discontinue study treatment early should complete an early discontinuation visit as well as the 2-Week Post Dose Visit.  The 2-Week Post Dose 
Visit would not need to occur if the subject discontinued dosing more than 2 weeks prior to the early discontinuation visit.   
Visit window is +/- 7 days during the extension phase. 

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4All subjects who discontinue study treatment early should complete an early discontinuation visit as well as the 2-Week Post Dose Visit.  The 2-Week Post Dose 
Visit would not need to occur if the subject discontinued dosing more than 2 weeks prior to the early discontinuation visit.   
Visit window is +/- 7 days during the extension phase.

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4.3.1
Screening Phase
The Screening Phase will range from a minimum of 3 days to a maximum of 42. The purpose of 
the Screening Visit is to ensure that the appropriate patients are entered into the trial. The 
investigator will determine that the patient meets eligibility criteria and will collect demographic 
and medical data presenting a full characterization of the patient. It is estimated approximately 
270 subjects will enter this phase of the trial.
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. It is 
estimated that approximately 210 subjects will enter this phase of the trial. Randomization will 
be stratified by 3 SCA subgroups: SCA1 & 2; SCA3; and SCA 6, 7, 8, 10. Subjects will receive 
either troriluzole (140 mg) or matching placebo (in a 1:1 ratio) for the first 4 weeks and then will 
be increased to 200 mg (or matching placebo) for the duration of the study.  
Dosing will continue for approximately 48 weeks. Subjects will return to the clinic two weeks 
after discontinuing study medication for a follow-up safety visit. Subjects completing the 
Randomization Phase will be offered approximately 192 weeks of open-label treatment as long 
as the PI believes open-label treatment offers an acceptable risk-benefit profile.

Subjects should take their medication daily.  If tolerability issues, such as fatigue or dizziness
arise, patients should be instructed to take their medication at bedtime (QHS).

Subjects who continue to experience issues with tolerability after switching to nighttime
dosing may temporarily down titrate to 140mg.  However, prior to down titrating their 
dose, these patients should be discussed with the Biohaven Medical Monitor. 
Please refer to the Schedule of Assessments/Time & Events for details on procedures during the 
Randomization Phase. There is a visit window of +/- 5 days for Week 4, Week 8, Week 12, and 
Week 16 Visits; and +/- 7 days for Week 24 and Week 36 Visits during the Randomization 
Phase of the study.  The Week 48 Visit is +/- 2 weeks to ensure the primary f-SARA rater is 
present at the 48 Week Visit. If absolutely necessary, treatment duration may be longer due to the 
COVID-19 pandemic. Under these circumstances, the sponsor medical monitor should be 
consulted and must approve the request to change the treatment duration (may be extended if 
necessitated by the COVID-19 pandemic from 48 weeks up to maximum of 60 weeks (12 week 
extension)). 
 
 
 
 
 
 

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Sponsor Medical Monitor
4.3.3
Extension Phase
Subjects will have visits in the Extension Phase every four weeks through Week 12 and then 
every 12 weeks thereafter up to Week 192. 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. Subjects receiving placebo in the randomization phase will be 
switched in a blinded manner to 140mg for the first 4 weeks and will then be increased to 
200 mg (at the Week 4 visit). Temporary down titration will only be allowed to address 
tolerability issues and must be discussed with the medical monitor. All visits starting at Week 4 
of the Extension Phase will be open-label.  Subjects who enter the Extension Phase on 140 mg 
due to tolerability issues can be rechallenged to increase to 200 mg beginning at Extension Week 
4 at PI discretion.  
Please refer to the Schedule of Assessments/Time & Events for details on procedures during the 
Extension Phase. There is a visit window of +/- 7 days during the Extension Phase of the study. 
4.3.4
Post Study Access to Therapy (if applicable)
There is an open-label extension phase of this trial for up to 192 weeks as described in 
Section 4.3.3. No other study drug access is available after the extension.
5
POPULATION
5.1
Number of Subjects
Approximately 210 subjects are expected to be randomized into this study.

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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 - 75, inclusive.
3. Target Population
a.
Subjects with a known or suspected diagnosis of the following specific hereditary ataxias: 
SCA1, SCA2, SCA3, SCA6, SCA7, SCA8 and SCA10;
i.
A subject should have a confirmed genotypic diagnosis from a CLIA certified lab 
(can produce test results); or, 
ii. A subject has a family member that has a confirmed genotypic diagnosis from a 
CLIA certified lab (can produce test results) and must be willing to undergo genetic 
testing to confirm underlying SCA diagnosis; or, 
iii. A subject has a confirmed genotypic diagnosis from a lab that is not CLIA certified 
and must be willing to undergo genetic testing to confirm underlying SCA diagnosis; 
or, 
iv. A subject has clinical evidence that supports diagnosis of one of the aforementioned 
SCA genotypes but does not have producible test results from a CLIA certified lab 
from either a family member or for his or herself and the subject must be willing to 
undergo such testing to confirm the SCA diagnosis (in this case, site must wait for 
results of genotypic testing prior to randomization)
4. Ability to ambulate 8 meters without human assistance (canes and other devices allowed);
5. Screening f-SARA total score 3;
6. Score of 1 on gait subsection of the f-SARA;
7. 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;
8.
 

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5.3
Exclusion Criteria
12. Target Disease Exceptions
Subjects will be excluded if they have:
a.
A 2-point difference on the Modified Functional SARA score between screening and 
baseline; 
b. MMSE score 24;
c.
Any medical condition other than one of the hereditary ataxias specified in the inclusion 
criteria that could predominantly explain or contribute significantly to the subjects' 
symptoms of ataxia (for example, alcoholism, vitamin deficiencies, multiple sclerosis, 
vascular disease, tumors, paraneoplastic disease, head injury, idiopathic late onset ataxia, 

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multisystem atrophy) or that can confound assessment of ataxia symptoms (for example, 
stroke, arthritis);
d. A prominent spasticity or dystonia that, in the opinion of the investigator, will 
compromise the ability of the f-SARA instrument to assess underlying ataxia severity
e.
A score of 4 on any individual item (Items 1-4) of the f-SARA;
f.
Subjects may not have started physical or occupational therapy within one month of 
screening and are not expected to start such therapy during the randomization phase. 
Subjects with ongoing occupational or physical therapy may be allowed to continue as 
long as the intensity remains unchanged from two months prior to screening throughout 
the randomization period.
g. Subjects should be excluded at screening or baseline if medical conditions have arisen or 
there is a change in disease status that could confound the ability of the f- SARA to 
accurately reflect changes in ataxia severity.
13. Medical History Exclusions
a.
Clinical history of stroke. Note: Subjects with a history of transient ischemic attack (TIA) 
may be enrolled, if it occurred at least 3 months prior to screening and the subject is 
prescribed appropriate treatment [e.g., platelet aggregation inhibitors];
b.
 
 
c.
Active liver disease or a history of hepatic intolerance to medications that in the 
investigator’s judgment, is medically significant;
 
 
 
 
 

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5.4
Prohibited Concomitant Medications
The Biohaven Medical Monitor should be contacted to discuss any subjects who have been 
previously treated with riluzole. Treatment with riluzole in the 60 days prior to randomization 
and during the study is prohibited. Subjects with prior use of riluzole who discontinued due to 
tolerability or lack of clinical benefit (in the opinion of the Investigator) are not eligible for this 

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study.  Reasons for discontinuation of riluzole should be documented in the subjects’ medical 
chart.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5.5
Women 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:

Amenorrhea greater than or equal to 12 consecutive months without another cause and a 
documented serum follicle stimulating hormone (FSH) level > 35mIU/mL or;

Woman with irregular menstrual periods and a documented serum follicle stimulating 
hormone (FSH) level > 35mIU/mL or;

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;

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) 

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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:

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;

Simultaneous use of male condom, and for the female partner, diaphragm with intravaginally 
applied spermicide.
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.
6
STUDY CONDUCT
6.1
Study Materials
The sponsor will provide investigational product which will include troriluzole (140 mg and 60 
mg) capsules and matching placebo.
Sites will also be provided with a Regulatory binder, IWRS Manual and any unique source 
documents and rating scales. Instructions on 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.

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Additionally, sites will be provided with the necessary equipment for videotaping administration 
of the f-SARA.  This will include a high-definition video recording device, aluminum tripod, a 
countdown timer, and gaffers tape.
7
ELIGIBILITY ASSESSMENTS
7.1
Mini Mental State Examination (MMSE)
The MMSE is a 30-point (11-question) measure commonly used to measure cognitive 
impairment. It tests five areas of cognitive function including orientation, registration, attention 
and calculation, recall and language.
7.2
Neurologic Exam
A neurological examination will be performed by a trained examining neurologist, which will 
involve mental status/cognition, cranial nerves, motor system, sensory system, reflexes and 
coordination/gait. The examination should be carefully documented in the subject’s medical 
and/or study chart.
7.3
Medical 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, and family history of ataxia, if available.
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.

The same scale should be used to weigh a given subject throughout the study.

Scales should be calibrated and zeroed just prior to each subject’s weigh-in session. 

A subject should void just prior to being weighed.

Weight should be recorded before a meal (if applicable) and at approximately the sametime
eachday. 

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
A subject should be minimally clothed (i.e., no shoes or heavy garments).
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. Any abnormal ECGs should be reviewed 
by a cardiologist if the PI is unsure of the clinical significance. If a site is unable to identify a 
cardiologist for this task, the Medical Lead at Cognitive Research Corporation can review the ECG 
to determine clinical significance.
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, chest (breast) and lungs, cardiovascular, abdomen, 
skin, and musculoskeletal evaluation by the Principal Investigator or a medically qualified 
delegate.
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, eGFR, creatinine, BUN, 
uric acid, and pregnancy testing (WOCBP). Additionally, at screening, total cholesterol, 
LDL, HDL, triglycerides, folate, HbA1C, P-Amylase, Lipase, TSH, and T4;
c.
Urinalysis: macroscopic examination, pH, specific gravity, ketones, nitrites, urobilinogen, 
leukocyte esterase, protein, glucose, and occult blood will be performed during the 
scheduled visits as specified in the Schedule of Assessments/Time & Events and as 
medically necessary. If blood, protein, or leukocytes, are positive microscopic 
examination will be performed on abnormal findings;
d. Urine pregnancy tests will be performed 72 hours prior to dosing at Baseline, at study 
visits where lab assessments are not performed, or at the discretion of the Investigator;
e.
HBsAg, HCV and HIV antibody detection will be performed at screening.
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 addition, if warranted repeat labs can be drawn.

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If a participant is unable to come in to the study site and needs to have safety labs conducted 
locally this is acceptable. The study site should provide the participant or local laboratory with a 
requisition and should collect the results. All local labs should be sent to the medical monitor for 
review.  Any clinically significant local lab abnormalities should be brought to the Biohaven 
Medical Monitor’s attention immediately. 
7.4.5
Pharmacogenetic Blood Sample Collection
A pharmacogenetic sample will be collected at screening in all subjects, who consent to 
collection of banked sample, for possible exploratory genotype. A pharmacogenetic sample will 
also be collected at screening for diagnostic genotyping in subjects if testing has not been 
previously done on the study subject and a copy of results is not available for verification.
 
7.4.6
Pharmacokinetics
 
 Subjects should take their dose at their routine time 
on the days of these visits. Subjects should record the time of their last dose and time of last meal 
prior to PK assessment to provide to the study staff for entry into the eDC system.
Additionally, PK samples should be drawn if there are any SAEs that could possibly be drug 
related or severe AEs that could be drug related.
 
7.4.7
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. 
WOCBP will be provided with an at home pregnancy test to take in between the every 3 month
visits. 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.
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.

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7.4.8
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 an SAE. The subject 
will be managed as appropriate, including: 

Study medication must be discontinued immediately 

Bring subject in for physical exam and evaluation. 
○
Assess for right heart failure, hypotension, and signs/symptoms of alcohol abuse
○
assess for exposure to toxic dietary/herbal supplements and/or prescriptions drugs that are 
associated with hepatic effects, such as acetaminophen; 
○
assess for potential exposure to environmental toxins
○
Evaluate for abdominal pain, splenomegaly, hepatomegaly

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
○
coagulation factors (PT, aPTT, INR)
○
Hepatitis A, B and C serologies

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○
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 48 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 LM, 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.
7.4.9
Sheehan Suicidality Tracking Scale (Sheehan-STS)
The Sheehan-STS (S-STS) is a prospective, patient self-reported or clinician administered rating 
scale that contains 16 questions to track both treatment-emergent suicidal ideation and behaviors. 
The S-STS will be completed on a paper form by the clinician, or Sponsor approved designee, at 
the site. At the screening visit, the recall period for completing the S-STS is 12 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 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 Outcomes Assessments
The clinical outcome assessments and other interviews/scales should be performed at a similar 
time of day at each visit. 

If subjects are traveling a significant distance consideration should be given to minimizing 
the effects of travel fatigue.  

The order of the tests should include the administration of the f-SARA prior to other clinical / 
safety outcome assessments  
7.5.1
The Modified Functional Scale for the Assessment and Rating of Ataxia 
(f-SARA) 
The Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) is a modified 
version of the standard SARA, designed to create new response categories that reflect clinically 
meaningful changes in patient function.  Additionally, the f-SARA includes only the axial items 

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of the SARA, or items 1 though 4.  The appendicular items (items 5-8) are not included in the f-
SARA, as they are not sensitive to change over a period of time during which there is a clear 
decline on other measures.  This was assessed in a population of SCA patients administered the 
SARA approximately every six months for up to two years.  This analysis was done on the 
population described by Ashizawa in 2013.59
The f-SARA is administered in the same way the SARA is administered, but the response 
categories have been modified.  Response categories for teach item of the f-SARA range from 
“0” to “4.”  In general, these response categories are modified to reflect the following:
0.
Normal (no impairment)
1. Mildly impaired function, but no assistance required
2. Moderately impaired function, but needs assistance for certain parts of the task
3. Severely impaired function to the degree that assistance is needed for all parts of the 
task
4. Unable to perform function
Raters must be pre-approved by sponsor or sponsor representative (i.e. CRO) to rate subjects on 
the f-SARA.  The primary f-SARA rater at each site MUST be present to rate the f-SARA at all 
visits.  A secondary, pre-approved rater may rate visits, with the exception of screening, baseline, 
and Week 48 in the event the primary rater is unavailable. A secondary rater should only be used 
for extenuating circumstances.
All f-SARA raters will participate in training on both administration of the f-SARA and rating of 
the f-SARA.  Additionally, raters will be required to be certified in both administration and 
rating prior to beginning the study, at 3 months, and every 6 months thereafter until completion 
of the study. Recertification will not be required after all subjects complete the Open Label 
Extension Visit Week 48.
Video recording: Each administration of the f-SARA should be video recorded and up-loaded to 
a central repository.  Approved video-recording equipment will be provided to each site and 
standardized instructions for videotaping will be provided.  Each video recording will be 
identified by subject number and date (with no personal identifying information allowed).  These 
recordings may be shown for educational purposes, in which case any identifying features (e.g., 
face) will be blurred so as to protect the identity of any participant. Subjects who do not wish to 
be video recorded will be allowed to participate in the study. Video-recording is not 
required after Open Label Extension Visit Week 48. 

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7.5.2
The Patient Impression of Function and Activities of Daily Living Scale 
(PIFAS)
The Patient Impression of Function and Activities of Daily Living Scale (PIFAS) is a multi-item 
instrument designed to assess level of functional disability.  The scale is rater administered and 
the items were selected to encompass domains of relevance to SCA (ie mobility, 
speech/swallowing, fatigue), and to capture primarily function and activities of daily living 
within these domains. Statements are rated on a 5-point Likert scale ranging from “0” reflecting 
“not at all” to “4” reflecting “very much.”
7.5.3
The Activities of Daily Living Scale from the Friedreich’s Ataxia 
Rating Scale (FARS-ADL)
The FARS is a multicomponent scale designed to assess neurological domains affected in 
Friedreich’s Ataxia, another hereditary cerebellar ataxia disorder.  The FARS-Activities of daily 
Living Sub-scale has been validated in Friedreich’s Ataxia, is a measure of functional disability, 
and correlates with SARA total scores 60. It assesses 9 areas of activities of daily living with 
response categories rated on a 5-point scale with “0” reflecting “normal” and “4” reflecting and 
inability to perform the specific function.
7.5.4
The Functional Staging for Ataxia Scale from the Friedreich’s 
Ataxia Rating Scale (FARS-FUNC)
The FARS-FUNC is a subscale of the FARS designed to provide functional staging for ataxia in 
which clinicians are asked to assess function on a 6-stage staging system, with “0” reflecting 
“normal” and “6” reflecting a stage in which the patient is “total disabled.” Severity of 
neurologic disabilities as expressed by both the FARS-ADL and FARS-FUNC have been shown 
to correlate with disease progression and duration in Friedreich’s Ataxia 61.
7.5.5
The Neurology Quality of Life (Neuro-QOL) Lower Extremity Scale 
(long form)
The Neuro-QOL-Lower Extremity Scale is designed to assess fine motor skills of the lower 
extremities by asking specific questions about activities of daily living62. This is a 19-item scale 
with questions rated on a 5-point Likert Scale, with “5” reflecting “no difficulty” and “1” 
reflecting “unable to do” said activity.
7.5.6
The Neurology Quality of Life (Neuro-QOL) Upper Extremity Scale 
(long form)
The Neuro-QOL-Upper Extremity Scale is designed to assess fine motor skills of the upper 
extremities by asking specific questions about activities of daily living62. This is a 20-item scale 
with questions rated on a 5-point Likert Scale, with “5” reflecting “no difficulty” and “1” 
reflecting “unable to do” said activity.

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7.5.7
The Neurology Quality of Life (Neuro-QOL) Fatigue Scale (long form)
The Neuro-QOL Fatigue Scale is designed to assess level of fatigue in patients with neurologic 
disorders 62.  This is a 19-item, patient-rated scale designed to rate a patient’s fatigue over the 
past 7 days.  Patients are asked to rate answers to these items on a 5-point Likert scale, with “1” 
reflecting “never” and “5” reflecting “always.”
7.5.8
The Clinical Global Impression-Global Improvement Scale (CGI-I)
The CGI-I is a 7-point scale that requires the clinician to assess how much the subject’s illness 
has improved or worsened relative to the baseline visit and it is rated on a 7 point scale, with “1” 
reflecting “very much improved” and “7” reflecting “very much worse.”
7.5.9
The Patient Global Impression Scale (PGI)
The PGI is a patient self-reported, Likert-based scale used to assess the response of a condition 
to a therapy.  The response categories of the scale range from “no change” to “a great deal 
better.”  
8
EARLY DISCONTINUATION OF STUDY
All subjects who discontinue the study early should complete an early discontinuation visit as 
well as the 2-Week Post Dose Visit.  The 2-Week Post Dose Visit would not need to occur if the 
subject discontinued dosing more than 2 weeks prior to the early discontinuation 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
LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study. 

Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, with 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 

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
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. The reason for withdrawal should be noted as lost to follow-up.
10 STUDY DRUG MANAGEMENT
10.1
Description
10.1.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined as followed:
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 140 mg and 60 mg (and 
matching placebo). Troriluzole will be provided as formulated capsules. Troriluzole 140mg 
active and placebo capsules may be white capsules or the capsule may have two black lines 
printed on them. The different capsules will be used equally across the active and placebo 
capsule strengths to maintain the integrity of the blind.
10.2
Packaging and Shipment
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). Clinical Trial Material 
should 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. 
10.3
Dose and Administration
10.3.1
Randomization Phase
During the randomization phase, all subjects will be randomized to receive 140 mg or placebo, 
QD, for the first four (4) weeks of the Randomization Phase.  Subjects will then be increased to 
200 mg (provided as one bottle of 140 mg and one bottle of 60 mg) or matching placebo for the 
duration of the Randomization Phase.

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It is recommended that all patients ingest study drug once every day (approximately at the same 
time each day), without regard to meals. 

If subjects have difficulty tolerating the medication (such as experiencing sedation or 
dizziness) then the investigator should advise the subject to switch to night time dosing (and 
document this change in the subject’s records).

Subjects who continue to experience issues with tolerability after switching to night time 
dosing may temporarily down titrate to 140mg.  However, prior to down titrating their 
dose, these patients should be discussed with the Biohaven Medical Monitor. 
10.3.2
Extension Phase
Subjects completing the Randomization Phase will be offered approximately 192 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 troriluzole. 
In order to maintain the blind of the Randomization Phase and to safely increase all subjects to 
200mg after Extension Phase Week 4, the first 4 weeks of the Extension Phase will remain 
blinded. If a subject has to delay the Randomization Phase Week 48 visit due to concerns about 
COVID-19, the site should contact the Sponsor immediately upon learning about the cancelation 
so that the Sponsor can provide instruction on providing study drug. Subjects will not be allowed 
to transition to the Extension Phase until they have an in-person Week 48 visit.
If a subject was on active treatment in the Randomization Phase, they will start the Extension 
Phase on the same dose that they were taking at Week 48 of the Randomization Phase.
If a subject received placebo in the Randomization Phase, they will be switched in a blinded 
manner to 140mg for the first 4 weeks of the Extension Phase. 
After Extension Phase Week 4 all subjects will be on open label troriluzole 200 mg. Down 
titration to 140mg will only be allowed to address tolerability issues.  Subjects who enter the 
Extension Phase on 140mg due to tolerability issues can be rechallenged to increase to 200 mg 
beginning at Extension Week 4 at PI discretion.
Due to the change of dose throughout the study it is imperative that subjects are educated and 
reminded to take one capsule from each bottle for each dose.
10.3.3
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 via the IWRS. After completion of all screening evaluations, all 
eligible subjects will be randomized, in a 1:1 ratio to receive either placebo (QD) or troriluzole. 
Treatment assignments will be obtained by the investigator (or designee) via the IWRS system.

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Investigational sites will access the IWRS at each scheduled study visit throughout the 
Randomization Phase. 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.
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.
Subjects who complete 48 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 scheduled 
study visit throughout the Extension Phase. If a subject has to delay the Randomization Phase 
Week 48 visit due to concerns about COVID-19, the subject should remain on current blinded 
drug until the subject is in the office. Subjects will not transition to extension phase until 
completing the Week 48 visit in person. If study site needs to send drug via certified and tracked 
courier (and this is acceptable to the institution) because an in person visit is not possible due to
COVID-19 concerns, this is permissible per study. Site should contact Sponsor for IWRS 
instructions to dispense blinded drug that may be needed for subjects who are unable to come 
into the office for Week 48 visit and require drug to be shipped.
Study medication will be assigned via the IWRS system in the Extension Phase. The first 4 
weeks of treatment in the Extension Phase will be blinded in order to maintain the blind in the 
randomization phase.  From Extension Phase Week 4 on, the study will be open-label. 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.
10.3.4
Selection and Timing of Dose Administration
During the randomization phase of the study, subjects will be randomized to receive placebo 
(QD) or troriluzole (QD). 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 in 
the morning without regard to meals. Open label BHV-4157 will be provided during the 
extension phase at Week 4.  
10.3.5
Dose Modifications
Randomization Phase: Subjects will receive 140 mg or Placebo for the first four (4) weeks and 
will then be increased to 200 mg or placebo for the duration of the study.

If subjects have difficulty tolerating the medication (such as experiencing sedation or 
dizziness) then the investigator should advise the subject to switch to night time dosing (and 
document this change in the subject’s records).

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
Subjects who continue to experience issues with tolerability after switching to night time 
dosing may temporarily down titrate to 140mg.  However, prior to down titrating their 
dose, these patients should be discussed with the Biohaven Medical Monitor. 
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 140 mg for the first 4 weeks and will then be 
increased to 200 mg (at the Week 4 visits).  Down titration to 140 mg will only be temporarily 
allowed to address tolerability issues. Subjects who enter the Extension Phase on 140 mg due to 
tolerability issues can be rechallenged to increase to 200 mg beginning at Extension Week 4 at PI 
discretion.
For subjects who do not tolerate their study treatment (200 mg), the investigator may permit 
them to switch to night time dosing if there is reason to believe that may help tolerability. Any 
such changes must be documented by the investigator.  Every other day dosing is NOT 
permitted. 
10.4
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, bioanalytical scientists, IWRS randomization manager, and 
pharmacovigilance role may be unblinded during the course of the study in order to perform 
specific study related activities (i.e. PK assessment, randomization coordination, and unblinded 
safety assessments) before data are unblinded for the primary end point and all subjects complete 
the study. In order to minimize unnecessary analysis of placebo blood PK samples, the 
bioanalytical scientist will be unblinded to treatment prior to unblinding for the primary end 
point. Results of the blood concentration assay will be kept secure until database lock unblinding 
for the primary endpoint. Additionally, an independent statistician will review the unblinded 
randomization assignments when 5% and 10% of the subjects have been randomized to ensure 
the IWRS system is assigning as specified. If enrollment is evenly distributed across the SCA 
strata, 10% will show approximately 2 blocks filled per strata.  If at least 1 block per strata is not 
filled, then a review will occur when 15% of the subjects are randomized. Except as noted above, 
other members of the sponsor and CRO research team will remain blinded until the database is 
locked for the primary analysis.

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In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt to 
preserve the blind is made.
10.5
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 Phase), discontinuation of the subject from the 
trial should be considered.
10.6
Destruction and Return of Study Drug
All unused and/or partially used study drug can be destroyed, per site Standard Operating 
Procedure (SOP), only after being inspected and reconciled by the responsible Biohaven Study 
Monitor or the sponsor’s designee. If a site does not have drug destruction SOPs in place, they 
should contact Biohaven to arrange for study drug to be sent back to the drug depot for 
destruction.
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 
destroyed after being inspected and reconciled by the responsible Biohaven Study Monitor or the 
sponsor’s designee.
11 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.
11.1
Serious Adverse Events
There are two types of adverse events, Serious Adverse Events (SAE) and Non-Serious Adverse 
Events (AEs).

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11.1.1
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):
○
Intensive treatment in an emergency room or at home for allergic bronchospasm;
○
Blood dyscrasias or convulsions that do not result in inpatient hospitalization;
○
Development of drug dependency or drug abuse;
○
Potential drug induced liver injury.
11.1.2
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 AE (e.g., elective surgery 
for a pre-existing condition that has not worsened) need not be considered AEs or SAEs. If 

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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 
circumstances).
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.
11.2
Collection and Reporting of 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 (see section 11.2.1 Overdose),
potential drug induced liver injury (see section 11.2.3 Potential Drug Induced Liver Injury 
(DILI)) and pregnancies (see section 11.2.2 Pregnancy) must be reported within 24 hours of the 

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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 
PPD immediately via telephone, upon observing or learning of the event. PPD will then 
immediately notify the Biohaven Medical Monitor of the event.  The SAE form must then be 
submitted to PPD 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 in the 
SAE information in the Electronic Data Capture (eDC) system (i.e.: event term, start stop dates, 
causality, severity).  
Additionally, any serious adverse experience must be reported immediately or no later than 
24 hours after awareness of the event to the PPD Pharmacovigilance (PVG) department. 
The Serious Adverse Event Report Form (SAERF) should be submitted to PPD PVG by 
facsimile (FAX).
North America:  1-888-488-9697
Reports can be made by telephone via the Safety Hotline Number below if a SAERF cannot be 
immediately submitted.
North America:  1-800-201-8725
For any questions relating to SAEs, please contact the Medical Monitor via telephone:
SAE Telephone Contact:   
If only limited information is initially, 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.
11.2.1
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 BHV- 4157) 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.

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11.2.2
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 PPD of the event within 24 hours 
of the Investigator becoming aware of the information. The site must complete a Pregnancy 
Report 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 
PPD. 
11.2.3
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 11.2 Collection and 
Reporting of Serious Adverse Events.
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.

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11.3
Non-Serious Adverse Events
A non-serious adverse event is an AE not classified as serious.
11.3.1
Collecting 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 deemed clinically significant by the PI or meets the 
definition ofan SAE;

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.
12 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.
12.1
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 extension phase will be analyzed 
separately.

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12.2
Sample Size
The sample size for this study will be approximately 210 randomized subjects to accommodate 
for dropouts and based on the rationale that follows.
As the f-SARA is a new scale with no data to estimate changes and variance in this patient 
population a modified SARA from study BHV4157-201 is used as a proxy. Both scales
essentially have the same structure, consisting of 4 items with 5 points/item. The mean changes 
from randomized baseline using a modified SARA were -0.3 (SD=1.35) and 0.0 (SD=1.44) at 
Open-Label Weeks 24 and 48, respectively, for all genotypes. Because this study expects an 
increase on the f-SARA for the non-treated patients, the Week 48 difference in the change from 
baseline in f-SARA between treatment groups (troriluzole – placebo) is estimated to be -0.75. 
For the primary endpoint, 210 mITT subjects will provide 90% power, based on a two-sample 
t—test, assuming a two-sided alpha of 0.05, a SD of 1.44, a delta of 0.75 and 25% dropout.
12.3
Populations for Analysis
The following analysis sets are defined for this protocol:

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 
Interactive Web Response System (IWRS) (troriluzole or placebo).

Treated subjects/Safety: Enrolled subjects who received at least one dose of study therapy 
(blinded or open-label troriluzole, or blinded placebo). 

Troriluzole Safety: Enrolled subjects who received at least one dose of blinded or open-label 
troriluzole.

Modified Intent to Treat (mITT) subjects: Randomized subjects who received at least one 
dose of blinded study therapy and provided at least one post-baseline efficacy assessment
12.4
Statistical Methods
12.4.1
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 (n, mean, SD, minimum, maximum for 
continuous endpoints; n and % for categorical endpoints) by treatment group and for all 
treatment groups combined for select analysis populations in Section 11.3.

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12.4.2
Primary Endpoint(s)
As the primary objective of this study is based on the symptoms of ataxia in subjects with SCA, 
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 f-SARA total score, 
troriluzole relative to placebo at Week 48 in the randomization phase. The treatment effects will 
be summarized as the difference in change from baseline between placebo and troriluzole-treated 
subjects.
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 treatment comparison of troriluzole versus placebo will use a two-sided alpha level of 0.05 
and a Mixed Model for Repeated Measures (MMRM) that will include fixed effect factors for 
treatment group, SCA randomization strata, visit week, treatment group-by-visit week interation, 
country, and baseline f-SARA score as a covariate. MMRM-based estimates (i.e., least-squares 
mean [LSM] with corresponding SE and 95% CI) of values and changes from baseline will be 
presented by treatment group and visit week. In addition, the LSM difference in change from 
baseline between treatment groups (troriluzole – placebo) at Week 48 with corresponding SE, 
95% CI, and p-value from MMRM will also be presented.
Observed values and changes from baseline in f-SARA total score will also be summarized using 
descriptive statistics over time by treatment group during the Randomization and Extension 
Phases.
12.4.3
Secondary Endpoint(s)
Continuous secondary, change-from-baseline endpoints (i.e., PIFAS, FARS-ADL, FARS-
FUNC) will be analyzed for mITT subjects using the same methodology described in 
Section 11.4.2.
12.4.4
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 (i.e., p-value < 0.05), 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 these results. 

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No attempt will be made to adjust for multiplicity when testing the exploratory endpoints. Any 
exploratory endpoint subjected to significance testing will be evaluated at an unadjusted two-
sided alpha level of 0.05.
12.4.5
Missing Data
As a sensitivity analysis to assess missing data assumptions of the MMRM model, the missing 
data will be multiply imputed for the primary endpoint using “jump to reference”, “copy  
reference” and "tipping point" methods. Further details on the handling of missing data are 
provided in the statistical analysis plan.
12.4.6
Analysis of Safety
The investigators will determine the severity of AEs and the relationship of AEs to study 
therapy. The investigators’ terms will be coded and grouped by system organ class using the 
latest version of the Medical Dictionary for Regulatory Activities (MedDRA) available to the 
analyst. AEs will be presented by system organ class and preferred term for each treatment 
group. If a subject had an AE with different severities over time in a study phase, then only the 
worst severity will be reported for that phase. 
The frequency (i.e., number and percentage) of the following safety events are summarized by 
treatment group and overall for treated subjects: AEs (by severity, by relationship to study drug, 
and overall); deaths; SAEs; AEs leading to treatment discontinuation; and clinically relevant 
laboratory abnormalities. Observed values and changes from baseline in continuous safety 
parameters (laboratory tests, ECGs, vital signs) over time will also be presented.
Safety endpoints will be assessed by treatment group separately for the following phases and 
populations:

Double-blind treatment (i.e., Randomization Phase) for the safety set;

Troriluzole treatment (i.e., double-blind or open-label troriluzole during the Randomization 
and Extension Phases combined) for the troriluzole safety set.
13 ETHICS AND RESPONSIBILITIES
13.1
Good Clinical Practice
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.

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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 
experience to perform their respective task(s).
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).
13.2
Data and Safety Monitoring Board
This study will not make use of a Data Safety Monitoring Committee (DMC). The study 
medication troriluzole has been tested and found to be well-tolerated. Safety will be closely 
monitored via the sites and procedures for unblinding in case of emergency will be followed. 
13.3
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 to regulatory authorities when necessary.
13.4
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 

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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.
13.5
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.

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14 RECORDS MANAGEMENT
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:

Amount of study drug received and placed in storage area;

Label ID number or batch number or Kit number as specified for the protocol;

Amount dispensed to and returned from each patient;

Amount transferred to another area or site for dispensing or storage if applicable;

Amount of drug lost or wasted;

Amount destroyed at the site if applicable;

Amount returned to sponsor, if applicable;

Retained samples for bioavailability/bioequivalence, if applicable;

Record of dates and initials of personnel responsible for IM dispensing and accountability.

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14.1
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.
14.2
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.
15 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.
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.
16 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.

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17 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.

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18 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 
ataxia researchers for the purpose of advancing the understanding of SCA, 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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20 APPENDICES
20.1
APPENDIX I – Names of Study Personnel
Sponsor:
Biohaven Pharmaceutical Holding Company Limited
c/o Biohaven Pharmaceuticals, Inc.
215 Church Street
New Haven, CT  06510
Medical 
Monitor:
Biohaven Pharmaceuticals, Inc
215 Church Street
New Haven, CT   06510
Biohaven Pharmaceuticals, Inc
215 Church Street
New Haven, CT   06510
Clinical 
Research 
Organizations:
Cognitive Research Corporation
200 Central Ave., Suite 1230
Saint Petersburg, FL   33701
Central 
Laboratory:
LabConnect, LLC
2304 Silverdale Dr.
Johnson City, TN.  37601

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20.2
APPENDIX II – Potent and Moderate Inhibitors and Inducers of the CYP1A2 
Enzyme System
CYP1A2 Potent and Moderate Inhibitors
Amiodarone
Ciprofloxacin
Efavirenz
Enoxacin
Furafylline
Fluvoxamine
Genistein
Idrocilamide
Interferon
Methoxsalen
Mexiletine
Osilodrostat
Phenylpropanolamine
Pipemidic Acid
Propranolol
Rofecoxib
Rucaparib
Ticlopidine
Troleandomycin
Vemurafenib
Zafirlukast

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CYP1A2 Potent and Moderate Inducers
Beta-napththoflavone
Carbamazepine
Insulin
Methylcholanthrene
Modafinil
Nafcillin
Phenytoin
Primidone
Rifampin
Ritonavir
Teriflunomide
*This list is not exhaustive.