Conditions: Spinocerebellar Ataxias Spinocerebellar Ataxia Genotype Type 1 Spinocerebellar Ataxia Genotype Type 2 Spinocerebellar Ataxia Genotype Type 3 Spinocerebellar Ataxia Genotype Type 6 Spinocerebellar Ataxia Genotype Type 7 Spinocerebellar Ataxia Genotype Type 8 Spinocerebellar Ataxia Genotype Type 10
Keywords: Spinocerebellar Ataxia SCA
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 141
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to compare the efficacy of BHV-4157 (Troriluzole) 140 milligrams (mg) once daily versus placebo after 8 weeks of treatment in subjects with spinocerebellar ataxia (SCA).

Detailed description:
The study was conducted in 2 phases: Randomization Phase (8 weeks) followed by an open-label Extension Phase (48 weeks). During the Randomization Phase, participants received either Troriluzole 140 mg or matching placebo up to 8 weeks. Participants who agreed to enter the Extension Phase continued dosing of Troriluzole 140 mg for 48 weeks. The study was subsequently amended to follow participants for a total of 192 weeks in the Extension Phase.

Arms:
arm 1: Troriluzole - Randomization Phase: Participants received Troriluzole 140 mg capsules orally once daily (QD) for 8 weeks.

Troriluzole/Troriluzole - Extension Phase: Participants received Troriluzole 140 mg capsules orally QD for 48 weeks. arm 2: Placebo - Randomization Phase: Participants received matching placebo capsules orally QD for 8 weeks.

Placebo/Troriluzole - Extension Phase: Participants who received placebo during randomization phase, received Troriluzole 140 mg capsules orally QD for 48 weeks.

Interventions: intervention 1: Troriluzole intervention 2: Placebo intervention 3: Troriluzole
Intervention descriptions: intervention 1: Randomization Phase: Neat (i.e., drug substance without excipients); loose filled capsule. intervention 2: Drug: Placebo Randomization Phase: Matching placebo loose filled capsule. intervention 3: Extension phase: Neat capsule or formulated capsule (i.e., drug substance with excipients).

Protocol document:
Prot_000.pdf: 
BHV4157-201; Clinical Protocol 
Confidential 
Troriluzole in Adult Subjects with Spinocerebellar Ataxia 
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DRUG: 
Troriluzole  
STUDY NUMBER(S): 
BHV4157-201 
 
PROTOCOL(S) TITLE: 
A Phase IIb/III, Randomized, Double-blind, 
Placebo-controlled Trial of Troriluzole  in Adult 
Subjects with Spinocerebellar Ataxia 
 
IND NUMBER: 
129397 
SPONSOR: 
Biohaven Pharmaceuticals, Inc. 
ORIGINAL PROTOCOL 
DATE: 
16 June 2016 
 
VERSION NUMBER: 
V08 (Incorporates Amendments 02, 03, 04, and 05, 
06 and 07; Administrative Letters 1, 2, 3, and 4,) 
 
VERSION DATE: 
17April2020 
 
 
 


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CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title: A Phase IIb/III, Randomized, Double-blind, Placebo-controlled Trial of Troriluzole in Adult 
Subjects with Spinocerebellar Ataxia 
 
Study No: BHV4157-201 
 
Original Protocol Date: 16 June 2016 
Protocol Version No: V08 
Protocol Version Date: 17 April 2020 
This study protocol was subject to critical review and has been approved by the appropriate 
protocol review committee of the sponsor.  The information contained in this protocol is 
consistent with: 
- 
The current risk-benefit evaluation of the investigational product. 
- 
The moral, ethical and scientific principles governing clinical research as set out in the 
Declaration of Helsinki, and principles of GCP as described in 21 CFR parts 50, 54, 56 
and 312 and according to applicable local requirements. 
- 
The Investigator will be supplied with details of any significant or new findings, 
including adverse events, relating to treatment with the investigational product. 
 
 
Name and Title 
Signature Approval 
Date 
Other: 
_____________________   _____________ 
[Name] [Title] 
 
 


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SUMMARY OF CHANGES 
 
Version Number 
Brief description summary of changes 
Date 
Version 01 Original 
Protocol 
NA 
16 Jun16 
Version 02 
Amendment 01 
Protocol revisions made based on site feedback. Minor 
administrative corrections made as well. See below for 
a description of changes.  
27 Sept 2016 
Version 03 
Amendment 02 
Protocol revisions incorporate changes based on 
Administrative Letters 1 and 2; Addition of Exclusion 
Criteria (Section 5.3) 1.f;  Updates to Statistical 
Sections; Correction of typographical errors. 
16 May 2017 
Version 04 
Amendment 03 
The Patient Global Impression of Change (PGI-C) was 
promoted from an exploratory endpoint to a secondary 
endpoint. 
 
27 July 2017 
Version 05 
Amendment 04 
An additional 48 weeks is added to the extension 
phase. Language was added to allow a dose increase to 
280mg/d for subjects who experience clinical decline 
as evidenced on the SARA scale.
 
 
 Exclusion criteria were modified to 
accommodate subjects who are re-entering the 
expanded extension phase
 
 
 
 Protocol 
version 05 also incorporates Administrative Letter 3, 
which provided updates to the Investigational Product 
and Study Drug Management sections. Safety 
Reporting section was updated to reflect the addition 
of 
as the Pharmacovigilance vendor. 
19 Jun 18 


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Version 06 
Amendment 05 
Table 4 Schedule of Assessments updated Expanded 
Extension Visit 10 (for continuing subjects) and Expanded 
Extension Visit 8 (for returning subjects) as also being an 
Early Discontinuation Visit.  
 
  
Section 6.5 Early Discontinuation of Study: Clarified that 
Early Discontinuation Visit is required in addition to 2-
Week Post Last Dose Visit unless the last dose occurred 2 
weeks prior to Early Discontinuation Visit.  
Section 7.3 Blinding and Unblinding: Clarified Sponsor 
remains blinded until primary analysis is complete.  
16.1 Appendix 1: Updated Medical Monitor and Medical 
Monitor Back-up information. 
 
 
 
Incorporates changes based on Administrative Letter 4. 
11 Dec 2018 
 
 


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Version 07 
Amendment 06 
BHV-4157 has been replaced with troriluzole 
throughout protocol.  
Time and Events schedule has been modified to 
include and additional 48 weeks of Expanded 
Extension. Some procedures have been removed at EE 
Week 60 for continuing subjects (or Week 108 for 
returning subjects). The length of the expanded 
extension phase has been updated in the time and 
events and throughout the document. 
Sheehan Suicidality Tracking Scale (S-STS): 
Additional language was added to the S-STS 
description specifying that any score above zero 
should be evaluated by Investigator and recorded as 
AE or SAE as determined by investigator and reported 
within 24 hours to Sponsor. 
Section 6.2.2 updated to note any abnormal ECGs 
should be reviewed by a cardiologist or 
 
 
6.2.4 updated to note that any local lab that is out of 
range should be brought to the attention of the 
Biohaven Medical Monitor. 
Declaration of Helsinki Appendix II deleted as this is 
covered in Ethics and Responsibility Section. 
08 July 2019 


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Version 08 
Amendment 07 
Time and Events schedule has been modified to extend 
the Expanded Extension for another 48 weeks. 
Length of Expanded Extension has been revised 
throughout document to 192 weeks (continuing 
subjects) or 144 weeks (returning subjects).  
Section 4.3.3: Language has been added to confirm 
sites may do remote safety visits, if sponsor medical 
monitor approved, due to subjects inability to come to 
the office for regular study visits due to COVID-19. 
Updated Medical Monitor contact information. 
17 April 2020 
 
 
 
 
Changes included in Amendment 04: 
 
STUDY SUMMARY (SYNOPSIS) Objectives 
 
The exploratory objectives: 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
 
  
 
Section 1.1 Background 
 
  
 
 
 
 
 
  
 
• New section added (Section 1.1.6.2) to provide preliminary BHV4157-201 AE profile 
data.  
 
Section 2 Study Objectives  
 
The exploratory objectives: 
 
 
 
 
 
 
 
 
 
Section 3 Study Endpoints 
 
The secondary endpoint: 
 
 
 
Section 4.1 Study Design and Duration 
 
• Updated Section 4.1 to include 48-week Expanded Extension Phase as well as the 
rationale and criteria for dose increase to 280mg. 
• Updated Study Schematic to include dose increase language as well as the addition of 
the 48-week expanded extension phase. 
 
Section 4.3 Schedule of Assessments 
 


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• Section 4.3 Tables 3-5 updated to include 48-week Expanded Extension Phase, 
additional Laboratory Tests required for subjects re-entering study, and requirement 
for additional Laboratory Testing for subjects who’s dose has been increased.  
 
 
 
• Miscellaneous updates to footnotes to support the above referenced changes. 
 
Section 4.3.3 Extension Phase 
• Updated to include Expanded Extension Phase description and requirements.  
 
Section 5.3 Exclusion Criteria 
 
 
 
 
 
 
 
Section 6 Study Conduct and Description of Study Procedures 
 
 
 
 
Section 7.1.1 Investigational Product  
  
Currently written:  
 
In this protocol, the investigational products are: BHV-4157 capsules 140 mg (and matching 
placebo). BHV-4157 will be provided as a loose filled capsule.  
Should read:  
 
In this protocol, the investigational products are: BHV-4157 capsules 140 mg (and matching 
placebo). BHV-4157 will be provided as a loose filled capsule in the Randomization Phase 
and as loose filled or formulated capsules (dependent on lot) in the Extension Phase. 
Formulated capsules have black markings on the capsule which differentiates them from the 
loose filled capsules. Study BHV4157-102 demonstrated bioequivalence of the two 
formulations 
 
 
 


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Section 7.2 Dose and Administration 
 
Currently written: Subjects will receive placebo (QD) or BHV-4157 (140 mg QD) loose filled 
capsule.  
 
Should read: Subjects will receive placebo (QD) or BHV-4157 (140 mg QD) loose filled 
capsules in the Randomization Phase and loose filled or formulated capsules (dependent on 
lot) in the Extension Phase. Formulated capsules have black markings on the capsule which 
differentiates them from the loose filled capsules. 
 
Section 7.2 Study Drug Management 
 
• Section 7.2 was updated to include criteria for dose increase as well as inclusion of the 
48-week Expanded Extension Phase  
• Section 7.2.1 was updated to provide method of assigning IP to subjects re-entering 
the study for the 48-week Expanded Extension Phase 
 
Section 8.1.3 Collection and Reporting Serious Adverse Events 
 
• Section 8.1.3 and 8.1.5 were updated to replace 
 as the 
pharmacovigilance vendor. 
 
Changes included in Amendment 05: 
 
Table 4 Schedule of Assessments updated Expanded Extension Visit 10 (for continuing 
subjects) and Expanded Extension Visit 8 (for returning subjects) as also being an Early 
Discontinuation Visit.  
 
 
  
 
Section 6.5 Early Discontinuation of Study: Clarified that Early Discontinuation Visit is 
required in addition to 2-Week Post Last Dose Visit unless the last dose occurred 2 weeks 
prior to Early Discontinuation Visit.  
 
Section 7.3 Blinding and Unblinding: Clarified Sponsor remains blinded until primary 
analysis is complete.  
 
16.1 Appendix 1: Updated Medical Monitor and Medical Monitor Back-up information. 
 
 
  
 
 
 
 
 


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Changes in Amendment 06 include: 
 
BHV-4157 replaced with troriluzole throughout document 
 
Time and Events schedule has been modified to include and additional 48 weeks of Expanded 
Extension. Some procedures have been removed at EE Week 60 for continuing subjects (or 
Week 108 for returning subjects). The length of the expanded extension phase has been 
updated in the time and events and throughout the document. 
 
Sheehan Suicidality Tracking Scale (S-STS): Additional language was added to the S-STS 
description specifying that any score above zero should be evaluated by Investigator and 
recorded as AE or SAE as determined by investigator and reported within 24 hours to 
Sponsor. 
 
Section 6.2.2 updated to note any abnormal ECGs should be reviewed by a cardiologist or 
 Medical Lead. 
 
6.2.4 updated to note that any local lab that is out of range should be brought to the attention 
of the Biohaven Medical Monitor. 
 
Declaration of Helsinki Appendix II deleted as this is covered in Ethics and Responsibility 
Section. 
 
Changes in Amendment 07 include: 
 
Time and Events schedule has been modified to extend the Expanded Extension for another 
48 weeks. 
 
Length of Expanded Extension has been revised throughout document to 192 weeks 
(continuing subjects) or 144 weeks (returning subjects).  
 
Section 4.3.3: Language has been added to confirm sites may do remote safety visits, if 
sponsor medical monitor approved, due to subjects inability to come to the office for regular 
study visits due to COVID-19. 
 
Updated Medical Monitor contact information.  
 
 


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BHV4157-201 
A Randomized, Phase IIb/III, 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 Pharmaceutical Holding Company 
Limited, and except as may be required by federal, state or local laws or regulation, may not 
be disclosed to others without prior written permission of Biohaven Pharmaceutical Holding 
Company Limited. 
I have read the protocol, including all appendices, and I agree that it contains all of the 
necessary information for me and my staff to conduct this study as described. I will conduct 
this study as outlined herein, in accordance with the regulations stated in the Federal Code of 
Regulations for Good Clinical Practices and International Conference on Harmonization 
guidelines and will make a reasonable effort to complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Biohaven Pharmaceutical Holding 
Company Limited. or specified designees. I will discuss the material with them to ensure that 
they are fully informed about Biohaven and the study. 
 
 
 
Principal Investigator Name (printed) 
Signature 
 
 
 
 
 
Date 
Site Number 
 
 


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STUDY SUMMARY (SYNOPSIS) 
 
 
Title: 
A Phase IIb/III, Randomized, Double-blind, Placebo-controlled Trial of 
Troriluzole in Adult Subjects with Spinocerebellar Ataxia 
Rationale: 
Troriluzole is a glutamate modulating drug that is being developed for 
eventual commercial use in the treatment of spinocerebellar ataxia (SCA). 
There are currently no FDA approved medications indicated for SCA. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Troriluzole was developed to advance upon the limitations of riluzole that 
have restricted its broader clinical application.  
 
 
 


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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 120 randomized subjects (limit of approximately 
10% of subjects with SCA3) 
Objectives: 
Primary Objectives 
• To compare the efficacy of troriluzole (140 mg once daily) 
versus placebo on ataxia symptoms in subjects with 
spinocerebellar ataxia (SCA) after 8 weeks of treatment as 
measured by the total score on the Scale for the Assessment 
and Rating of Ataxia [SARA] 
Secondary Objectives 
• To assess of the safety and tolerability of troriluzole in 
subjects with SCA 
• To compare efficacy of troriluzole with placebo on patient 
impression of benefit via use of the PGI-C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study 
Design: 
 
BHV4157-201 is a Phase IIb/III, multicenter, randomized, double-blind, 
2- arm placebo-controlled parallel-group study designed to assess safety, 
tolerability, and efficacy signals in a population of patients with 
Spinocerebellar Ataxia (SCA). Subjects will be randomized to receive 
placebo (QD) or troriluzole (140 mg QD), 
 
 
 
Subjects with SCA3 genotype will be limited to comprise up to 
approximately 10% of the total population so that this most common type 
of SCA is not over-represented. 
 
Dosing will continue for 8 weeks. Subjects will return to the clinic two 
weeks after discontinuing study medication for a follow-up safety visit. In 
addition, subjects completing the Randomization Phase will be offered up 
to approximately 192 weeks of open-label treatment as long as the PI 


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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 would have their first Extension 
Visit four weeks after the Week 8 Randomization Phase visit. If there is a 
delay of two weeks or more in dosing between the Randomization Phase 
and the Extension Phase, subjects will be required to complete an 
Extension Baseline Visit. All subjects will undergo a post study drug 
termination visit two weeks after the last dose of study drug in the 
Extension Phase.   
 
Subjects who previously completed the extension phase will be allowed to 
participate in the expanded extension phase for a total of 144 weeks of 
open-label administration of troriluzole, provided the PI deems this 
treatment to present an acceptable risk-benefit profile.  Such subjects who 
have been off of medication for at least 2 weeks, will need additional 
Baseline Visits followed by visits scheduled approximately every 12 
weeks, as well as laboratory assessments at approximately 4 and 8 weeks 
after re-starting medication.  In addition, these subjects will be required to 
have clinical laboratory assessment results that are not deemed clinically 
significant, available prior to the Baseline Visit and drawn within 6 weeks 
prior to that visit. These subjects should have not taken riluzole for at least 
12 hours prior to re-starting troriluzole. 
 
For subjects who experienced decline (as defined below) over at least 9 
months of treatment with 140 mg troriluzole in the first Extension Phase, 
the PI may offer an increased dose of 280 mg daily based on anticipated 
tolerability (e.g., the patient was tolerating the 140 mg dose well). Decline 
will be defined as demonstration of a 2 point or greater decline from 
Randomization Phase baseline on the SARA scale on each of two most 
recent consecutive visits (at least one month apart) accompanied by PI 
impression of clinical worsening.  Patients who do not tolerate 280 mg 
daily or demonstrate clinically significant lab abnormalities may have 
their dose adjusted to 140 mg daily. Subjects who increase to 280 mg 
daily will have lab tests at approximately 4, 8 and 12 weeks after the dose 
increase, then no less often that approximately every 12 weeks.  Subjects 
who are given a trial of 280 mg daily troriluzole will require additional 
clinical lab assessments (LFTs) at approximately 4 and 8 weeks after 
starting the increased dosing. For subjects who were tolerating 140 mg 


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without adverse effects, the dose increase may occur at the usual dosing 
time.  Some subjects may better tolerate dosing at bedtime to minimize 
any impact of sedation.  In addition, the PI may split doses (twice daily) if 
adverse events suggest that this could enhance tolerability.   
 
Primary 
Endpoint: 
The total score on the Scale for the Assessment and Rating of Ataxia 
(SARA) 
Secondary 
Endpoints: 
  PGI-C 
 
Tolerability and safety of troriluzole will be measured by the frequency 
and severity of adverse events and discontinuations secondary to adverse 
events. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Measures of 
Interest: 
Safety and Other assessments: 
o Sheehan Suicidality Tracking Scale (STS) 
o ECG assessments 
o Vital Sign and Physical Measurements 
 
 
 
 
 
 


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STUDY SCHEMATIC 
  
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
CLINICAL PROTOCOL APPROVAL FORM............................................................. 2 
SUMMARY OF CHANGES ............................................................................................ 3 
STUDY SUMMARY (SYNOPSIS) ................................................................................ 12 
STUDY SCHEMATIC .................................................................................................... 19 
TABLE OF CONTENTS ................................................................................................ 20 
LIST OF ABBREVIATIONS ......................................................................................... 24 
1 
INTRODUCTION AND RATIONALE ................................................................. 27 
1.1 
BACKGROUND.................................................................................................. 27 
1.1.1 
SPINOCEREBELLAR ATAXIA (SCA) ..................................................... 27 
 
 
 
 
 
 
 
 
1.1.6 
CLINICAL ADVERSE EVENT PROFILE ............................................... 44 
1.1.7 
POTENTIAL RISK TO FETAL DEVELOPMENT ................................. 48 
1.2 
STUDY RATIONALE ........................................................................................ 49 
 
 
 
 
 
 
1.3 
RESEARCH HYPOTHESIS .............................................................................. 53 
2 
STUDY OBJECTIVES ............................................................................................ 54 
2.1 
PRIMARY ............................................................................................................ 54 
2.2 
SECONDARY...................................................................................................... 54 
 
 
3 
STUDY ENDPOINTS .............................................................................................. 55 
3.1 
PRIMARY ............................................................................................................ 55 
3.2 
SECONDARY...................................................................................................... 55 
 
 
3.4 
MEASURES OF INTEREST ............................................................................. 56 
4 
STUDY PLAN .......................................................................................................... 57 
4.1 
STUDY DESIGN AND DURATION ................................................................. 57 
4.2 
STUDY SCHEMATIC ........................................................................................ 58 
4.3 
SCHEDULE OF ASSESSMENTS ..................................................................... 59 
4.3.1 
SCREENING PHASE ................................................................................... 67 
4.3.2 
RANDOMIZATION PHASE ....................................................................... 67 
4.3.3 
EXTENSION PHASE (IF APPLICABLE) ................................................ 67 
4.4 
POST STUDY ACCESS TO THERAPY (IF APPLICABLE) ....................... 68 
5 
POPULATION ......................................................................................................... 68 
5.1 
NUMBER OF SUBJECTS ................................................................................. 68 
5.2 
INCLUSION CRITERIA ................................................................................... 68 
5.3 
EXCLUSION CRITERIA .................................................................................. 71 
5.4 
PROHIBITED CONCOMITANT MEDICATION ......................................... 74 
5.5 
DEVIATION FROM INCLUSION/EXCLUSION CRITERIA ..................... 77 
6 
STUDY CONDUCT AND DESCRIPTION OF STUDY PROCEDURES ......... 78 
6.1 
STUDY MATERIALS ........................................................................................ 78 
PI


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6.1.1 
MINI MENTAL STATE EXAMINATION (MMSE)................................ 78 
6.1.2 
NEUROLOGICAL EXAM .......................................................................... 78 
6.1.3 
MEDICAL HISTORY .................................................................................. 78 
6.2 
SAFETY ASSESSMENTS ................................................................................. 78 
6.2.1 
VITAL SIGNS AND PHYSICAL MEASUREMENTS (HEIGHT AND 
WEIGHT) ...................................................................................................... 79 
6.2.2 
ELECTROCARDIOGRAM (ECG) ............................................................ 79 
6.2.3 
PHYSICAL EXAM ....................................................................................... 79 
6.2.4 
LABORATORY ASSESSMENTS .............................................................. 80 
6.2.5 
SHEEHAN SUICIDALITY TRACKING SCALE (SHEEHAN STS) ..... 83 
6.3 
CLINICAL OUTCOME ASSESSMENTS ....................................................... 83 
6.3.1 
THE SCALE FOR THE ASSESSMENT AND RATING OF ATAXIA 
(SARA) ........................................................................................................... 83 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.5 
EARLY DISCONTINUATION FROM THE STUDY .................................... 88 
7 
STUDY DRUG MANAGEMENT .......................................................................... 88 
7.1 
DESCRIPTION OF STUDY DRUG ................................................................. 88 
7.1.1 
INVESTIGATIONAL PRODUCT .............................................................. 88 
7.1.2 
PACKAGING, SHIPMENT AND STORAGE .......................................... 88 
7.2 
DOSE AND ADMINISTRATION ..................................................................... 89 
7.2.1 
METHOD OF ASSIGNING PATIENT IDENTIFICATION ................... 89 
7.2.2 
SELECTION AND TIMING OF DOSE AND ADMINISTRATION ...... 90 
7.2.3 
DOSE MODIFICATIONS ........................................................................... 90 
7.3 
BLINDING AND UNBLINDING ...................................................................... 90 
7.4 
TREATMENT COMPLIANCE ........................................................................ 91 
7.5 
DESTRUCTION AND RETURN OF STUDY DRUG .................................... 91 
8 
ADVERSE EVENTS ................................................................................................ 92 
8.1 
SERIOUS ADVERSE EVENTS ........................................................................ 92 
8.1.1 
DEFINITION OF SERIOUS ADVERSE EVENT (SAE) ......................... 92 
8.1.2 
DEFINITION OF TERMS ........................................................................... 93 
8.1.3 
COLLECTION AND REPORTING SERIOUS ADVERSE EVENTS ... 94 
8.1.4 
OVERDOSE .................................................................................................. 95 
8.1.5 
PREGNANCY ............................................................................................... 95 
8.1.6 
POTENTIAL DRUG INDUCED LIVER INJURY (DILI) ....................... 96 


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8.2 
NON-SERIOUS ADVERSE EVENTS .............................................................. 96 
8.2.1 
COLLECTION AND REPORTING OF NON-SERIOUS ADVERSE 
EVENTS ......................................................................................................... 96 
9 
STATISTICS ............................................................................................................ 98 
9.1 
GENERAL PROCEDURES ............................................................................... 98 
9.2 
SAMPLE SIZE .................................................................................................... 98 
9.3 
STATISTICAL METHODS .............................................................................. 98 
9.3.1 
PRIMARY ENDPOINT(S) ........................................................................... 98 
9.3.2 
SECONDARY ENDPOINT(S)..................................................................... 99 
9.3.3 
ANALYSIS OF SAFETY ............................................................................. 99 
9.3.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................... 99 
10 ETHICS AND RESPONSIBILITIES .................................................................. 100 
10.1 
DATA AND SAFETY MONITORING COMMITTEE ................................ 100 
10.2 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE ................................................................................................... 100 
10.3 
INFORMED CONSENT .................................................................................. 101 
10.4 
CASE REPORT FORMS ................................................................................. 101 
10.5 
RECORDS MANAGEMENT AND RETENTION ....................................... 102 
10.6 
SOURCE DOCUMENTATION ...................................................................... 103 
10.7 
STUDY FILES AND RECORD RETENTION .............................................. 103 
11 AMENDMENTS .................................................................................................... 103 
12 STUDY REPORT AND PUBLICATIONS ......................................................... 103 
13 STUDY DISCONTINUATION ............................................................................ 104 
14 CONFIDENTIALITY ........................................................................................... 104 
15 REFERENCES ....................................................................................................... 105 
16 APPENDICES ........................................................................................................ 111 
16.1 
APPENDIX I – NAMES OF STUDY PERSONNEL ..................................... 111 
 
 


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LIST OF TABLES 
 
Table 1.  
Genetic and Clinical Features of Common SCAs ................................ 30 
Table 2.  
Schedule of Assessments and Events - Randomization Phase ............. 59 
Table 3.  
Schedule of Assessments and Events - Extension Phase ...................... 60 
Table 4.  
Schedule of Assessments and Events - 48-Week Expanded Extension Phase 
(continuing subjects) ............................................................................... 61 
Table 5.  
Schedule of Assessments and Events - 48-Week Expanded Extension Phase 
(returning subjects) ................................................................................. 64 
 
 
 
 
LIST OF FIGURES 
 
Figure 1.  
Genetic mechanisms in hereditary ataxias............................................ 29 
Figure 2.  
Mean (±SD) of Riluzole concentrations over Time Following IV or Oral 
Gavage Administration of BHV-4157, Male and Female Cynomolgus 
Monkeys (N=6) ........................................................................................ 51 
Figure 3.  
Schematic representation on the mechanism of action of riluzole ...... 53 
Figure 4.  
Study Schematic ...................................................................................... 58 
 
 
 
 


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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 
 
 


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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 
iv 
Intravenous 
kg 
Kilogram 
L 
Liters 
mg 
Milligram 
min 
Minute 
mmHg 
Millimeters Mercury 
NOEL 
No Observed Effect Level 
 
 


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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 a kindred. Lifespan is 
significantly shortened due to complications related to neurologic deficits. There are currently 
no FDA approved medications for the treatment of SCA. 
Biohaven Pharmaceutical Holding Company Limited [Biohaven] is developing a new drug, 
troriluzole, for treatment of SCA. Troriluzole is a novel pro-drug formulation of the generic 
drug riluzole. 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.1.1 
Spinocerebellar Ataxia (SCA) 
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 
movements); decreased speed of eye movements that affect eye gaze (including nystagmus and 


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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 a 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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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] 
(10, 11) 
 
 
 
 
 
 
 
 
 
 
 
 


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1.1.6.2 
BHV4157-201: Phase 2 Clinical Adverse Event Profile  
During the double-blind randomization phase of the current study (BHV4157-201), 
administration of 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. 
A total of 141 participants were enrolled into the randomization phase of this study. Overall, 
troriluzole 140 mg once daily for 8 weeks was well tolerated in adult participants with SCA. 
The majority of adverse events were mild or moderate in severity. To date, there have been no 
deaths reported in the study and no SAE has been judged by the investigator to be treatment 
related.  During the randomization phase, treatment-emergent SAEs were reported for five 
(3.55%) subjects, including four troriluzole -treated subjects (SAEs by subject: dehydration, 
elevated CPK, and weakness; suicidal ideation; cerebral infarction; and, back pain) and one 
placebo-treated subject (SAE: chest discomfort, high blood pressure).  The frequency of 


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treatment emergent AEs that led to withdrawal from the study drug was 4.2% (3/71 subjects) in 
the troriluzole group and no subjects in the placebo group. AEs that led to withdrawal from 
study drug occurred in one subject each and included asthenia, gait disturbance, anhedonia, 
suicidal ideation, increase in blood creatine phosphokinase, dehydration, dizziness, 
somnolemnce, and hospitalization.  The majority of treatment-emergent AEs were mild or 
moderate in severity, not related to study drug, and resolved spontaneously by the end of 
treatment.  The most frequently reported treatment-emergent AEs were dizziness, fatigue, fall, 
headache, nausea, and muscle spasms.   
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. 
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.  
131 subjects entered this phase. During this phase, there were no deaths SAEs were reported in 
5 subjects (syncope considered as possibly related by the PI; pneumonia in three subjects 
considered as not related in two subjects [one of whom also had inflammation of mesenteric 
tissue] and unlikely related in one subject; and, an additional subject with a pre-study history of 
breathing difficulties and pneumonia was hospitalized for worsened breathing difficulties, with 
the investigator considering this event as possibly related). 
1.1.6.3 
Riluzole 
Clinical information on riluzole, as reflected in the USPI, is predominantly based on experience 
from approximately 4000 patients given riluzole for ALS. Refer to the US Prescribing 
Information (15) where greater details on the adverse event profile of riluzole can be found.  
 
Overall, riluzole tablets have been well tolerated in populations with ALS and diverse 
neuropsychiatric conditions that include MDD and GAD. In randomized controlled trials 
comparing a 100 mg daily dose of riluzole with placebo, no AEs occurred at rates greater than 
5% and twice that of placebo.
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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1.1.6.3.1 
Elevations in Liver Function Tests 
Troriluzole has not been associated with significant changes in liver function or pathology in 
nonclinical toxicology studies to date, as reflected in the IB.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.1.6.3.2 
Neutropenia 
Troriluzole has not been associated with hematologic findings in nonclinical toxicology studies 
to date. 
 
 
 
 
1.1.6.3.3 
Interstitial Lung Disease 
Troriluzole has not been associated with pulmonary findings in nonclinical toxicology studies 
to date. 
 
 
 
 
 
 
 
1.1.7 
Potential Risk to Fetal Development 
Troriluzole has not yet been assessed in fertility and fetal development studies. 
 
 
 
 


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1.2 
Study Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 3.  
Schematic representation on the mechanism of action of riluzole 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.3 
Research Hypothesis 
Troriluzole  monotherapy for 8 weeks is superior to placebo in the treatment of Spinocerebellar 
Ataxia. 


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2 STUDY OBJECTIVES 
2.1 
Primary 
 
• To compare the efficacy of troriluzole (140 mg once daily) versus placebo on ataxia 
symptoms in subjects with spinocerebellar ataxia (SCA) after 8 weeks of treatment 
as measured by the total score on the Scale for the Assessment and Rating of 
Ataxia [SARA] 
2.2 
Secondary 
 
• To assess the safety and tolerability of troriluzole in subjects with SCA 
 
• To compare efficacy of troriluzole with placebo on patient impression of benefit via 
use of the PGI-C 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3 STUDY ENDPOINTS 
3.1 
Primary 
 
• The total score on the Scale for the Assessment and Rating of Ataxia (SARA). 
3.2 
Secondary 
 
• Tolerability and safety of troriluzole will be measured by the frequency and severity 
of adverse events and discontinuations of adverse events. 
 
• Patient Global Impression of Change (PGI-C); 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.4 
Measures of Interest 
 
• Safety and Other assessments: 
o Sheehan Suicidality Tracking Scale (STS) 
 
o ECG assessments; 
o Vital Sign and Physical Measurements; 
 
 
 
 
 
 
 


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4 STUDY PLAN 
4.1 
Study Design and Duration 
BHV4157-201 is a Phase IIb/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. Subjects will be randomized to receive 
placebo (QD) or troriluzole (140 mg QD), 
 
 
Subjects with SCA3 genotype will be limited to comprise up to approximately 10% so that this 
most common type of SCA is not over-represented. 
Dosing will continue for 8 weeks. Subjects will return to the clinic two weeks after 
discontinuing study medication for a follow-up safety visit. In addition, subjects completing the 
Randomization Phase will be offered approximately 192 weeks of open- label 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 not complete the follow-up safety visit and should 
continue dosing as specified. 
Subjects entering the Extension Phase would have their first Extension Visit four weeks after 
the Week 8 Randomization Phase visit. If there is a delay of two weeks or more in dosing 
between the Randomization Phase and the Extension Phase, subjects would be required to 
complete an Extension Baseline Visit. Thereafter, subjects will undergo visits every fourth 
week through Week 12 of this phase. Then subjects will undergo visits every 12 weeks up to 
Week 192 of this phase. All subjects will undergo a termination visit two weeks after the last 
dose of study drug. 
Subjects who previously completed the  extension phase will be allowed to participate in the 
expanded extension phase for a total of 144 weeks of open-label administration of troriluzole, 
provided the PI deems this treatment to present an acceptable risk-benefit profile.  Such 
subjects who have been off of medication for at least 2 weeks, will need additional Baseline 
Visits followed by visits scheduled approximately every 12 weeks, as well as laboratory 
assessments at approximately 4 and 8 weeks after re-starting medication.  In addition, these 
subjects will be required to have clinical laboratory assessment results that are not deemed 
clinically significant, available prior to the Baseline Visit and drawn within 6 weeks prior to 
that visit. These subjects should not have taken riluzole for at least 12 hours prior to re-starting 
troriluzole. 
For subjects who experienced decline (as defined below) over at least 9 months of treatment 
with 140 mg troriluzole, the PI may offer an increased dose of 280 mg daily based on 
anticipated tolerability (e.g., the patient was tolerating the 140 mg dose well). Decline will be 
defined as demonstration of a 2 point or greater decline from baseline on the SARA scale on 
two most recent consecutive visits (at least one month apart) accompanied by PI opinion 
clinical worsening.  Patients who do not tolerate 280 mg daily or demonstrate clinically 
significant lab abnormalities may have their dose adjusted to 140 mg daily. Subjects who 
increase to 280 mg daily will have lab tests at approximately 4, 8 and 12 weeks after the dose 
increase, then no less often that approximately every 12 weeks. Subjects who are given a trial 


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of 280 mg daily troriluzole will require additional clinical lab assessments (LFTs) at 
approximately 4 and 8 weeks after starting the increased dosing. For subjects who were 
tolerating 140 mg without adverse effects, the dose increase may occur at  the usual dosing 
time.  Some subjects may better tolerate dosing at bedtime to minimize any impact of sedation.  
In addition, the PI may split doses (twice daily) if adverse events suggest that this could 
enhance tolerability.  Dosing regimen should be recorded in the CRF.  
Subjects will be assessed at clinic visits per the Schedule of Assessments/Time & Events. 
4.2 
Study Schematic 
Figure 4.  
Study Schematic 
   
 
 
 
 
 
 


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4.3 
Schedule of Assessments 
Table 2.  
Schedule of Assessments and Events - Randomization Phase 
SCR 
Baseline 
Wk 4 
Wk 8 
2-Wk Post Last Dose 
(ONLY for subjects NOT 
entering extension phase 
or who discontinue early) 
Additional Instruction 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Eligibility Assessments 
Informed Consent 
X 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
Should be re-reviewed at Baseline 
Medical History 
X 
 
 
 
 
Demographic Assessment 
X 
 
 
 
 
Disease History 
X 
 
 
 
 
Neurological Exam 
X 
 
 
X 
 
Mini Mental State Exam (MMSE) 
X 
 
 
 
 
Pregnancy Test for WOCBP (serum) 
X 
X 
 
X 
 
Pregnancy Test for WOCBP (urine) 
 
 
X 
 
X 
 
 
To be done within 72 hours prior to dosing at visit 2 
(Baseline Visit). The site may test a patient at any time 
if they suspect the patient may be pregnant. 
Safety Assessments 
Laboratory Assessments including 
urinalysis 
X 
X 
 
X 
X 
No fasting required 
Serum Chemistry 
 
 
 
X 
 
 
A physician who is not the SARA rater must be 
available to review lab tests and manage any 
potential medical evaluation throughout the 
randomization phase 
Physical Exam 
X 
 
 
X 
 
PE will be done at W4 if warranted by 
emergence of new AE’s 
Physical Measurements 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
 
12-Lead ECG 
X 
 
 
X 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
Adverse Event Assessments 
 
X 
X 
X 
X 
Sheehan Suicidality Tracking Scale 
(STS) 
X 
X 
X 
X 
X 
Clinical Outcome Assessments 
SARA 
X 
X 
X 
X 
X 
This should be the first clinical outcome 
assessment done at each visit. 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
Dispense Study Drug 
 
X 
X 
X 
 
Dispense at Wk 8 only if entering Extension 
Phase 
Drug Accountability 
 
 
X 
X 
 
Visit Window is +/- 2 days during the Randomization Phase 
 
 


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Table 3.  
Schedule of Assessments and Events - Extension Phase 
1Baseline 
Visit  
Ext.  
Wk 4 
Ext.  
Wk 8 
Ext. 
Wk 12 
Ext. 
Wk 24 
Ext.  
Wk 36 
Ext.  
Wk 48 
Visit 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Eligibility Assessments 
 
 
 
 
 
 
 
4Informed Consent 
X 
 
 
 
 
 
 
Neurological Exam 
 
 
 
 
X 
 
X 
Pregnancy Test for WOCBP (serum) 
X 
 
 
 
X 
 
X 
2Pregnancy Test for WOCBP (urine) 
X 
X 
X 
X 
 
X 
 
Safety Assessments 
 
 
 
 
 
 
 
Laboratory Assessments 
including urinalysis 
X 
 
 
 
X 
 
 
X  
3Lab: LFT tests only (ALT, AST, BILI, 
GGT)  
 
X 
X 
X 
 
X 
 
Physical Exam 
X 
 
 
 
X 
 
X 
Physical Measurements 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
 
X 
 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessments 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Sheehan Suicidality Tracking 
Scale (Sheehan STS) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
* Clinical Outcome Assessment 
 
 
 
 
 
 
 
SARA 
X  
 
X 
 
X 
X 
X 
Clinical Drug Supply 
 
 
 
 
 
 
 
Dispense Study Drug 
X  
X 
X 
X 
X 
X 
X 
Drug Accountability 
 
X 
X 
X 
X 
X 
X 
 
1 Baseline visit for the Extension Phase is only required if there is an extended break (≥2 weeks) in dosing between the 
Randomization and Extension Phases. 
2 Subjects will be provided with pregnancy tests to take in between every 3-month office visit. Subjects should be instructed to 
contact 
 if they become pregnant at any time during the study. 
3, Subjects whose dose is increased to 280 mg daily will require LFT tests approximately 4 and 8 weeks after the increase and 
then approximately every 12 weeks thereafter 


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4  Informed Consent for continuing subjects entering the expanded extension phase will be obtained at next scheduled visit. 
Visit window is +/- 7 days during the extension phase.  
 
Table 4.  
Schedule of Assessments and Events - 144-Week Expanded 
Extension Phase (continuing subjects)  
Exp.Ext. Wk 
60 
Exp. Ext. Wk 
72 
Exp. Ext. Wk 84 
Exp. Ext. Wk 96 or early 
discontinuation visit 
(less than or equal 
to EE Wk 96) 
Visit 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Eligibility Assessments 
 
 
 
 
Neurological Exam 
 
X 
 
X 
Pregnancy Test for WOCBP (serum) 
 
X 
 
X 
1Pregnancy Test for WOCBP (urine) 
X 
 
X 
 
Safety Assessments 
 
 
 
 
Laboratory Assessments including 
urinalysis 
 
X 
 
X 
2Lab: LFT tests only (ALT, AST, BILI, GGT)  
X 
 
X 
 
Physical Exam 
 
X 
 
X 
Physical Measurements 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
12-Lead ECG 
 
X 
 
X 
Concomitant Medication Review 
X 
X 
X 
X 
Adverse Event Assessments 
 
X 
 
X 
 
X 
 
X 
Sheehan Suicidality Tracking Scale 
(Sheehan STS) 
 
X 
 
X 
 
X 
 
X 
* Clinical Outcome Assessment 
 
 
 
 
SARA 
X 
X 
X 
X 
Clinical Drug Supply 
 
 
 
 
Dispense Study Drug 
X 
X 
X 
 
Drug Accountability 
X 
X 
X 
X 
 
 
 
 
 


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EE Wk108 
EE Wk 120 
EE Wk 132 
 EE Wk 144  
Visit 
Visit 11 
   Visit 12 
 Visit 13 
Visit 14  
Eligibility 
Assessments 
 
 
 
 
Neurological Exam 
  
X 
  
X 
3Pregnancy Test for 
WOCBP (serum) 
X 
X 
X 
X 
Safety Assessments 
  
  
  
  
2, 3Lab:  LFT tests only 
(ALT, AST, BILI) 
X 
X 
X 
X 
Physical Exam 
  
X 
  
X 
Physical 
Measurements 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
12-Lead ECG 
  
X 
  
X 
Concomitant 
Medication Review 
X 
X 
X 
X 
Adverse Event 
Assessments 
X 
X 
X 
X 
Sheehan Suicidality 
Tracking Scale 
(Sheehan STS)  
X 
X 
X 
X 
Clinical Outcome 
Assessments 
  
  
  
  
SARA 
X 
X 
X 
X 
Clinical Drug Supply 
  
  
  
  
Dispense Study Drug4 
X 
X 
X 
  
Drug Accountability 
X 
X 
X 
X 
 
 
 


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EE Wk 156 
EE Wk 168 
EE Wk 180 
 EE Wk 192 or 
Early 
Discontinuation 
EE 2-Wk 
Post Last 
Dose  
Visit 
Visit 15 
   Visit 16 
 Visit 17 
Visit 18  
Visit 19      
Eligibility Assessments 
 
 
 
 
 
Neurological Exam 
  
X 
  
X 
  
3Pregnancy Test for 
WOCBP (serum) 
X 
X 
X 
X 
  
Safety Assessments 
  
  
  
  
  
2, 3Lab:  LFT tests only 
(ALT, AST, BILI) 
X 
X 
X 
X 
X 
Physical Exam 
  
X 
  
X 
  
Physical Measurements 
X 
X 
X 
X 
  
Vital Signs 
X 
X 
X 
X 
  
12-Lead ECG 
  
X 
  
X 
  
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
Adverse Event 
Assessments 
X 
X 
X 
X 
X 
Sheehan Suicidality 
Tracking Scale (Sheehan 
STS)  
X 
X 
X 
X 
X 
Clinical Outcome 
Assessments 
  
  
  
  
  
SARA 
X 
X 
X 
X 
X 
Clinical Drug Supply 
  
  
  
  
  
Dispense Study Drug4 
X 
X 
X 
  
  
Drug Accountability 
X 
X 
X 
X 
  
 
1 Subjects will be provided with pregnancy tests to take in between every 3-month office visit. Subjects should be instructed to contact 
 if 
they become pregnant at any time during the study. Pregnancy testing in between visits is not required EE Week 108 through EE 2-Week Post 
Dose. 
2 Subjects whose dose is increased to 280 mg daily will require LFT tests approximately 4 and 8 weeks after the increase and then 
approximately every 12 weeks thereafter 
3 Lab will not be done by a Central Lab and must be done at local lab. 
4 If the study site needs to send drug overnight via certified and tracked courier and this is acceptable to the institution because a visit is 
absolutely not possible because of the COVID-19 pandemic, this is permissible per study. The sponsor should be consulted prior to shipping 
drug.  
Visit window is +/- 7 days during the extension phase.  
 


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Table 5.  
Schedule of Assessments and Events – 144 -Week Expanded 
Extension Phase (returning subjects) 
1Baseline 
Visit 1 
2Baseline 
Visit 2 
Exp.Ext.
Wk 
4 
Exp. Ext. 
Wk 
8 
Exp. Ext. 
Wk 
12 
Exp. Ext. 
Wk 
24 
Exp. Ext. 
Wk 
36 
Exp. Ext. Wk 48 or 
early 
discontinuation 
(less than or 
equal to EE Wk 
48) 
Visit 
Visit EE1 
Visit EE2 
Visit EE3 
Visit EE4 
Visit EE5 
Visit 
EE6 
Visit EE7 
Visit EE8 
Eligibility Assessments 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
5Neurological Exam 
X 
 
 
 
 
X 
 
X 
Pregnancy Test for WOCBP 
(serum) 
 
 
 
 
 
X 
 
X 
3Pregnancy Test for WOCBP 
(urine) 
X 
 
 
 
X 
 
X 
 
Safety Assessments 
 
 
 
 
 
 
 
 
6Laboratory 
Assessments including 
rinal sis
X 
X 
 
 
 
X 
 
X 
4Lab: LFT tests only (ALT, AST, 
BILI, GGT)  
 
 
X 
X 
X 
 
X 
 
Physical Exam 
X 
 
 
 
 
X 
 
X 
Physical Measurements 
X 
 
 
 
X 
X 
X 
X 
Vital Signs 
X 
 
 
 
X 
X 
X 
X 
12-Lead ECG 
 
 
 
 
 
X 
 
X 
Concomitant Medication Review 
X 
 
 
 
X 
X 
X 
X 
Adverse Event Assessments 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Sheehan Suicidality 
Tracking Scale (Sheehan 
STS) 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
* Clinical Outcome Assessment 
 
 
 
 
 
 
 
 
SARA 
 
X 
 
 
X 
X 
X 
X 
Clinical Drug Supply 
 
 
 
 
 
 
 
 
Dispense Study Drug 
 
X 
 
 
X 
X 
X 
 
Drug Accountability 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 


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Exp. Ext. 
Wk 60 
 
Exp. Ext.  
Wk 72 
 
Exp. Ext. 
Wk 84 
 
Exp. Ext. Wk 
96  
                     
Exp. Ext.  
2-Wk Post 
Last Dose  
Visit 
Visit EE 9 
Visit EE 10 
Visit EE 11 
Visit EE 12  
Visit EE 13   
Eligibility Assessments 
 
 
 
 
 
Neurological Exam 
  
X 
  
X 
  
7Pregnancy Test for 
WOCBP (serum) 
X 
X 
X 
X 
  
Safety Assessments 
  
  
  
  
  
4,7Lab:  LFT tests only 
(ALT, AST, BILI) 
X 
X 
X 
X 
X 
Physical Exam 
  
X 
  
X 
  
Physical Measurements 
X 
X 
X 
X 
  
Vital Signs 
X 
X 
X 
X 
  
12-Lead ECG 
  
X 
  
X 
  
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
Adverse Event 
Assessments 
X 
X 
X 
X 
X 
Sheehan Suicidality 
Tracking Scale (Sheehan 
STS)  
X 
X 
X 
X 
X 
Clinical Outcome 
Assessments 
  
  
  
  
  
SARA 
X 
X 
X 
X 
X 
Clinical Drug Supply 
  
  
  
  
  
Dispense Study Drug8 
X 
X 
X 
  
  
Drug Accountability 
X 
X 
X 
X 
  
 
 
 
 
 
 
 
 
 


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Exp. Ext. 
Wk 108 
 
Exp. Ext.  
Wk 120 
 
Exp. Ext. 
Wk 132 
 
Exp. Ext. Wk 
144 or Early 
Discontinuation  
                     
Exp. Ext.  
2-Wk Post 
Last Dose  
Visit 
Visit EE 9 
Visit EE 10 
Visit EE 11 
Visit EE 12  
Visit EE 13   
Eligibility Assessments 
 
 
 
 
 
Neurological Exam 
  
X 
  
X 
  
7Pregnancy Test for 
WOCBP (serum) 
X 
X 
X 
X 
  
Safety Assessments 
  
  
  
  
  
4,7Lab:  LFT tests only 
(ALT, AST, BILI) 
X 
X 
X 
X 
X 
Physical Exam 
  
X 
  
X 
  
Physical Measurements 
X 
X 
X 
X 
  
Vital Signs 
X 
X 
X 
X 
  
12-Lead ECG 
  
X 
  
X 
  
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
Adverse Event 
Assessments 
X 
X 
X 
X 
X 
Sheehan Suicidality 
Tracking Scale (Sheehan 
STS)  
X 
X 
X 
X 
X 
Clinical Outcome 
Assessments 
  
  
  
  
  
SARA 
X 
X 
X 
X 
X 
Clinical Drug Supply 
  
  
  
  
  
Dispense Study Drug8 
X 
X 
X 
  
  
Drug Accountability 
X 
X 
X 
X 
  
 
1 Baseline 1 and Baseline 2 visits for the 48-Week Expanded Extension Phase are only required for subjects re-entering the study.  
2Baseline 2 visit for the Extension Phase is only required if results of Baseline 1 visit meet study eligibility criteria.  
3 Subjects will be provided with pregnancy tests to take in between every 3-month office visit. Subjects should be instructed to contact 
 if they 
become pregnant at any time during the study. Pregnancy testing in between visits is not required EE Week 60 through EE 2-Week Post Dose. 
4 Subjects whose dose is increased to 280 mg daily will require LFT tests approximately 4 and 8 weeks after the increase and then approximately every 
12 weeks thereafter. Subjects re-entering the extension phase will require LFT tests approximately 4 and 8 weeks after dosing is re-started. 
5 Neurological exam is required for subjects whose Baseline 2 visit is greater than 7 days after Baseline 1.  
6 Safety Laboratory Assessments are required for subjects whose Baseline 2 visit is greater than 7 days after Baseline 1. Repeat of BL visit 1 labs can be 
done with permission from Sponsor. 
7 Lab will not be done by a Central Lab and must be done by local lab.  
8 If the study site needs to send drug overnight via certified and tracked courier and this is acceptable to the institution because a visit is absolutely not 
possible because of the COVID-19 pandemic, this is permissible per study. The sponsor should be consulted prior to shipping drug.  
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 138 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. 
Subjects will receive placebo (QD) or troriluzole (140 mg QD). Dosing will continue for 8 
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 48 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 in the mornings.  If tolerability issues arise 
please refer to section 7.2.3 
Please refer to the Schedule of Assessments/Time & Events for details on procedures during 
the Randomization Phase. There is a visit window of +/- 2 day visit window during the 
Randomization Phase of the study. It is estimated that approximately 120 subjects will enter 
this phase of the trial. 
4.3.3 
Extension Phase (if applicable) 
The Extension Phase includes a Baseline Visit; however, that visit is only required if there is a 
break in dosing two weeks or greater between the Week 8 Visit in the Randomization Phase 
and the Week 4 visit in the Extension Phase. The Extension Phase also includes a Baseline 
Visit 1 and Baseline Visit 2; however those visits are only required for subjects who have 
previously completed the 2 week post-dose visit in the Extension Phase, and who will be re-
entering the extension phase of open-label treatment beginning at Week 60 through Week 144. 
Subjects re-entering the extension phase will complete the Baseline 1 visit to confirm that they 
meet safety eligibility requirements, then return for the Baseline 2 visit, followed by visits 
scheduled approximately every 12 weeks, as well as laboratory assessments at approximately 4 
and 8 weeks after re-starting medication. Thereafter, subjects will undergo visits every 12 
weeks up to Week 144 of the Extension Phase (or 192 weeks for continuing subjects). All 
subjects will undergo a termination visit two weeks after the last dose of study drug. 
 
 
 
 
 


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Sponsor Medical Monitor 
 
 
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.  
4.4 
Post Study Access to Therapy (if applicable) 
There is an extension phase of this trial for up to 192 weeks (144 weeks for returning subjects) 
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 120 subjects are expected to be randomized in this study. 
5.2 
Inclusion Criteria 
1.
Informed Consent
a.
Subjects (or legally acceptable representative as required by the IRB/IEC) must provide
a written signed informed consent form/forms (IRB/EC specific) prior to the initiation
of any protocol required procedures.
2.
Age and Sex
a.
Male and female outpatient subjects between the ages of 18 - 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;


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b. Ability to ambulate 8 meters without assistance (canes and other devices 
allowed); 
c. Screening total SARA total score ≥8; 
d. Score of ≥ 2 on gait subsection of the SARA; 
e. 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; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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5.3 
Exclusion Criteria 
1.   
Target Disease Exceptions 
a. 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, multisystem atrophy) or that 
can confound assessment of ataxia symptoms (for example, stroke, arthritis); 
b. MMSE score < 24; 
 
 
 
 
 
 
 
d. SARA total score of > 30 points at screening; 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.  
 
 
 
 
 
 
2.  
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]; 
 
 
 
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 Medication 
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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Woman of Childbearing Potential 
Women of childbearing potential (WOCBP) include any female who has experienced 
menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral 
tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Post menopause is defined 
as: 
o Amenorrhea greater than or equal to 12 consecutive months without another cause 
and a documented serum follicle stimulating hormone (FSH) level > 35mIU/mL 
or; 
 
o Woman with irregular menstrual periods and a documented serum follicle 
stimulating hormone (FSH) level > 35mIU/mL or; 
 
o NOTE: FSH level testing is not required for women greater than or equal to 62 
years old with amenorrhea of greater than or equal to one year; 
 
o Woman on hormone replacement therapy (HRT). 
The requisite drug interaction studies to determine the interaction of troriluzole  with oral 
contraceptives have not been performed to date. It is therefore not possible to determine the 
efficacy of oral contraceptives as an effective method of contraception for WOCBP who 
participating this study. Oral estrogen and progestin hormonal contraceptives as a sole method 
of contraception are therefore prohibited. It is required that all WOCBP use two methods of 
contraception for the duration of the study (i.e. beginning at 30 days prior to baseline) through 
30 days after the last dose of study drug. The two methods should include one barrier method 
(e.g. diaphragm with spermicidal gel, condom with spermicidal gel, intrauterine devices, 
cervical cap) and one other method. The other method could include oral contraceptives 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. 
 


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5.5 
Deviation from Inclusion/Exclusion Criteria 
Any significant event that does not comply with the inclusion exclusion criteria, study conduct, 
or study procedures will be documented as a deviation. Deviations will be documented and 
reported through the clinical monitoring of the trial. Deviations will be reported to the IRB/EC 
at the frequency required by your IRB/EC. There will be no protocol exceptions granted by the 
Sponsor for Inclusion/Exclusion criteria. 
 


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6 STUDY CONDUCT AND DESCRIPTION OF STUDY PROCEDURES 
6.1 
Study Materials 
The sponsor will provide investigational product which will include including troriluzole, 140 
MG capsules and matching placebo. 
Sites will also be provided with a Regulatory binder, Rating Scale Binder, IVRS Manual and a 
Source Document Template. Instructions on all specimens collected will be provided by a 
central laboratory. 
All sites will use an Electronic Data Capture (EDC) tool to submit study data. Electronic Case 
Report Forms (eCRFs) will be prepared for all data collections. 
Sites will be provided with a Biohaven approved protocol and any amendments. 
The investigator will be required to have a centrifuge, a secure locked cabinet or similar (for 
drug storage) as well as appropriate containers and dry ice for shipment and storage of blood 
and plasma samples. Enough dry ice, when indicated, should be utilized to allow samples to 
arrive at their designated laboratory in a frozen state. 
Eligibility Assessments 
6.1.1 
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. 
6.1.2 
Neurological 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. 
6.1.3 
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. 
6.2 
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, 
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The SARA rating (primary outcome measure) must NOT  be performed by the staff (including 
principal investigator) who are evaluating test lab results during the 8 week randomization 
phase.  Specifically, these tests include Serum Chemistry, Hematology and Urinalysis acquired 
after baseline (i.e., Week 4 scheduled labs, potentially other unscheduled tests, through Week 8 
scheduled labs).  After completion of the Week 8 visit assessments and sign-off on SARA 
ratings as final, a SARA rater who is the principal investigator may evaluate labs that will be 
acquired within the Extension Phase.  Based on this requirement, a site may potentially need to 
identify a qualified physician or other medical personnel who can be available to review lab 
tests during the randomization phase for each subject.  This is further described in Section 
6.3.1.  
6.2.1 
Vital Signs and Physical Measurements (Height and Weight) 
Sitting vital sign measurements (temperature, blood pressure, and heart rate) will be recorded 
during the scheduled visits as specified in the Schedule of Assessments/Time & Events and as 
medically necessary. 
Body weight and height will be recorded at scheduled visits. The following guidelines will aid 
in the standardization of these measurements. 
 
1) The same scale should be used to weigh a given subject throughout the study. 
 
2) Scales should be calibrated and zeroed just prior to each subject’s weigh-in session.  
 
3) A subject should void just prior to being weighed.    
 
4) Weight should be recorded before a meal (if applicable) and at approximately the 
same time each day.    
 
5) A subject should be minimally clothed (i.e., no shoes or heavy garments). 
 
6.2.2 
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 to determine clinical significance. If a site is unable to identify a 
cardiologist for this task, the Medical Lead at 
 can review the 
ECG to determine clinical significance. 
6.2.3 
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. 


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6.2.4 
Laboratory Assessments 
Laboratory testing will include the following: 
a) Hematology: hemoglobin, hematocrit, platelets, CBC with differential and absolute 
neutrophil count 
b) Serum Chemistry: sodium, potassium, chloride, calcium, ALT, AST, LDH, alkaline 
phosphatase, GGT, phosphorous, bicarbonate, CPK, total protein, albumin, total 
bilirubin (if greater than 2 mg/dl bilirubin will be fractionated), glucose, creatinine, 
BUN, uric acid, and pregnancy testing (WOCBP). Additionally, at screening, total 
cholesterol, LDL, HDL, triglycerides, folate, HbA1C, P-Amylase or Lipase, TSH, and 
T4; 
c) Urinalysis: macroscopic examination, pH, specific gravity, ketones, nitrites, 
urobilinogen, leukocyte esterase, protein, creatinine, glucose, and occult blood will be 
performed during the scheduled visits as specified in the Schedule of 
Assessments/Time & Events and as 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. Any local lab results that are out of range must be brought to the attention of the 
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6.2.4.4 
Pregnancy Testing 
Pregnancy testing should be performed on all women of childbearing potential (WOCBP) 
during both the Randomization Phase and Extension Phase of the study. Refer to the Schedule 
of Assessments/Time & Events for detailed time points in which serum pregnancy tests and 
urine pregnancy tests are required. Urine pregnancy testing may also be done at the discretion 
of the Investigator at any time during the study. Subjects should not continue in the study if the 
pregnancy test is positive at any time. 
6.2.4.5 
Evaluation of Laboratory Assessments 
As described above, the SARA rating (primary outcome measure) must NOT be performed by 
the staff (including principal investigator) who are evaluating test lab results during the 8 week 
randomization phase.  Specifically, these tests include Serum Chemistry, Hematology and 
Urinalysis acquired after baseline (i.e., Week 4, potentially other unscheduled tests, through 
Week 8 scheduled labs).  After completion of the Week 8 visit assessments and sign-off on 
SARA ratings as final, a SARA rater who is the principal investigator may evaluate lab tests 
acquired in the Extension Phase.  Based on this requirement, a site may potentially need to 
identify a qualified Lab Monitor (i.e., physician or other medical personnel) who can be 
available to review labs during the randomization phase for each subject.  This requirement 
does not apply during the Extension Phase.   
The rationale for this process is to assure adequate blinding while maintaining subject safety.  
Riluzole itself is associated with low rates of transient increases in transaminases.  According 
to the US Prescribing information for riluzole (the active metabolite of troriluzole), the rates of 
markedly elevated transaminases (AST or ALT > 5x ULN) are approximately 2%.  The rates of 
less elevated transaminases (i.e., AST or ALT > 3x ULN) are approximately 8%.  While 
troriluzole was designed to diminish risk for LFT changes (e.g., diminished first-pass liver 
metabolism, approximately 30% lower molar burden than the 100 mg dose of riluzole),  the 
study is designed to address the possibility of such increases while maintaining the integrity of 
the primary outcome measure.  Other lab abnormalities, based on known literature of riluzole, 
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abnormalities as medically warranted to assure subject safety.  The SARA Rater (who may be 
the PI) should be shielded from the nature of any additional evaluation triggered by these lab 
tests. 
The management of abnormal LFTs are described herein. Scheduled LFTs (ALT, AST, 
bilirubin, alkaline phosphatase) at the Week 4 and Week 8 visits will be evaluated by the Lab 
Monitor (LM), who will be a physician or other qualified medical personnel designated by the 
PI and who has no involvement in the conduct of the SARA Ratings.  
If AST or ALT values are between 3x ULN and <5x ULN, then the Lab Monitor, potentially 
with administrative assistance from the Study Coordinator, 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 the Week 4 visit shows ALT or AST>5x ULN,  the Lab Monitor will notify the PI and the PI 
will assess this as a potential SAE. The subject will be managed as appropriate, including:  
• Study medication must be discontinued immediately  
• Bring subject in for physical exam and evaluation.  
o Assess for right heart failure, hypotension, and signs/symptoms of alcohol 
abuse 
o assess for exposure to toxic dietary/herbal supplements and/or prescriptions 
drugs that are associated with hepatic effects, such as acetaminophen;  
o assess for potential exposure to environmental toxins 
o Evaluate for abdominal pain, splenomegaly, hepatomegaly 
• Repeat LFTs (AST, ALT, total and direct bilirubin, alkaline phosphatase) as soon as 
possible, with either a local lab or preferably central lab; and, follow to resolution; 
• Order other labs tests to rule-out other causes of lab abnormalities and to assess extent 
of hepatic effects 
o coagulation factors (PT, aPTT, INR) 
o Hepatitis A, B and C serologies 
o Ebstein-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 
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not begin until such labs near normal limits or in the case of elevated transaminases (ALT or 
AST) are within 3x ULN.  If results from the scheduled Week 8 assessment show emergence of 
potentially clinically significant lab abnormalities and the subject has already started open-label 
troriluzole, then labs must be repeated and the 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. 
Other Safety Assessments 
6.2.5 
Sheehan Suicidality Tracking Scale (Sheehan STS) 
The Sheehan 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. 
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. 
6.3 
Clinical Outcome Assessments 
The clinical outcome assessments and other interviews/scales (e.g., Sheehan STS) 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 SARA prior to other 
clinical / safety outcome assessments 
   
6.3.1 
The Scale for the Assessment and Rating of Ataxia (SARA) 
The SARA was developed as a clinician-administered instrument to measure severity of 
symptoms in patients with SCA. While there are multiple scales available, the SARA has been 
tested in the most patients with SCA to date. It has been demonstrated to have excellent inter-
rater reliability [i.e., intraclass correlations of > 0.95 (61, 62)], good test- retest reliability 
[intraclass coefficient of 0.90 (61)], high internal consistency [Cronbach’s alpha of > 0.94 (61, 
62)], sensitivity to change over time in populations with SCA (2, 63, 64) and able to detect 
treatment effects (65). In addition, the SARA scores were highly correlated with measures of 
activities of daily living, such as the Barthel Index (typically used in stroke) and the Unified 
Huntingtons Disease Rating Scale Part IV (typically used in Huntingtons Disease). 
The SARA scores range from 0 (no ataxia) to 40 (severe). The SARA takes approximately 15 
minutes to administer.  Assessed items include: 
 
1. Gait (rated 0 to 8) 
 
2. Stance (0 to 6) 
 
3. Sitting (0 to 4) 
 


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4. Speech disturbance (0 to 6) 
 
5. Finger chase (0 to 4) 
 
6. Nose-finger test (0 to 4) 
 
7. Fast alternating hand movements (0 to 4) 
 
8. Heel-shin slide (0 to 4) 
 
Once each of the 8 categories has been assessed, the total score is calculated to determine the 
severity of ataxia. For motor activities of the four extremities (items 5-8), assessments are 
performed bilaterally and the mean values are used to obtain the total score. 
Raters must be pre-approved by sponsor or sponsor representative (i.e. CRO) to rate 
subjects on the SARA 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.5 
Early Discontinuation from the Study 
All 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 stopped taking study medication 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). 
7 STUDY DRUG MANAGEMENT 
7.1 
Description of Study Drug 
7.1.1 
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 matching 
placebo). Troriluzole will be provided as a loose filled capsule in the Randomization Phase and 
as loose filled or formulated capsules (dependent on lot) in the Extension Phase. Formulated 
capsules have black markings on the capsule which differentiates them from the loose filled 
capsules. Study BHV4157-102 demonstrated bioequivalence of the two formulations. 
7.1.2 
Packaging, Shipment and Storage 
Clinical Trial Materials should be stored at controlled temperature between 200C and 250 C 
(680F -770F) with excursions permitted between 150C and 300 C (590F -860F).  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 manufacturing and/or expiry/retest date. Individual subject doses 
will be dispensed according to the randomization scheme in appropriate envelopes/containers 
indicated with at least the project number, the period number and the subject number/ spare 
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7.2 
Dose and Administration 
Subjects will receive placebo (QD) or troriluzole (140 mg QD) loose filled capsules in the 
Randomization Phase and loose filled or formulated capsules (dependent on lot) in the 
Extension Phase. Formulated capsules have black markings on the capsule which differentiates 
them from the loose filled capsules 
It is recommended that all patients ingest this drug once every day in the morning 
(approximately at the same time each day),  without regard to meals.  
• 
If subjects have difficulty tolerating morning dosing (such as experiencing 
sedation) then the investigator may permit the subject to switch to night time 
dosing (and document this change). 
 
For subjects who experienced decline (as defined below) over at least 9 months of treatment 
with 140 mg troriluzole in the first Extension Phase, the PI may offer an increased dose of 280 
mg daily based on anticipated tolerability (e.g., the patient was tolerating the 140 mg dose 
well). Decline will be defined as demonstration of a 2 point or greater decline from 
Randomization Phase baseline on the SARA scale on two most recent consecutive visits (at 
least one month apart) accompanied by PI opinion clinical worsening.   
Subjects who are dosed with 280 mg troriluzole in the Expanded Extension phase may continue 
dosing at their regular time if they experienced no adverse events.  Otherwise, consideration 
should be given to bedtime dosing so as to mitigate impact of adverse events such as sedation. 
In addition, the PI may consider splitting dosing (twice daily) based upon an adverse event 
profile that may suggest improved tolerability with such a regimen. 
7.2.1 
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 will be assigned. After completion of all screening evaluations, 
all eligible subjects will be randomized, in a 1:1 ratio 
 
 to receive either placebo (QD) or troriluzole (140mg QD). Treatment 
assignments will be obtained by the investigator (or designee) via the IWRS system. 
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 
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Subjects who complete 8 weeks of treatment in the Randomization Phase may be eligible for 
an Extension Phase of the study. The investigator or designee must access the IWRS to enter 
the subject in the Extension Phase. Investigational sites will access the IWRS at each scheduled 
study visit throughout the Extension Phase to track patient enrollment.   
Open Label Extension study medication will be supplied in bulk bottles.   Bottle numbers will 
be assigned via the IWRS system in the Extension Phase. Sites will be responsible for 
recording the bottle numbers dispensed to the subject on the Drug Accountability Form 
provided in the Regulatory Binder, as well as ensure appropriate documentation of dispensation 
in the subject’s medical record.  Once a subject completes the Extension Phase or if a subject is 
discontinued early from the Extension Phase of the study, the investigator or designee must 
access the IWRS to document the discontinuation of the subject from participation in the study.  
For all subjects entering the Expanded Extension Phase, including those who are re-entering 
the study (as described in section 4.3.3) bottle numbers will be assigned manually and sites will 
be responsible for recording the bottle numbers on the Drug Accountability Form provided in 
the Regulatory Binder. Subjects re-entering the study will retain the same subject number as 
assigned at the initial Screening Visit.  
7.2.2 
Selection and Timing of Dose and Administration 
Subjects will receive placebo (QD) or troriluzole (140 mg QD). Study medication should be 
administered in the morning without regard to meals. 
See Section 7.2 for subjects who are dosed with 280 mg troriluzole in the extension phase. 
7.2.3 
Dose Modifications 
For subjects who do not tolerate their study treatment, the investigator may permit them to 
switch to night time dosing if there is reason to believe that may help tolerability.  In addition, 
the investigator may permit up to one week of every other day dosing prior to re-instituting 
daily dosing.  Any such changes must be documented by the investigator.  If these procedures 
do not result in acceptable tolerability then dosing should be discontinued.  
See Section 7.2 for subjects who are dosed with 280 mg troriluzole in the Expanded Extension  
phase. 
7.3 
Blinding and Unblinding 
Blinding is critical to the integrity of this clinical study. However, in the event of a medical 
emergency or pregnancy in an individual patient, in which knowledge of the investigational 
product is critical to the patient’s management, the blind for that patient may be broken by the 
treating physician. 
Before breaking the blind of an individual patient’s treatment, the investigator should have 
determined that the information is necessary, i.e., that it will alter the patient’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 patient is 


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receiving active product without the need for unblinding. Unblinding will be managed via the 
IWRS system.  
The Biostatistician, or designee, will be unblinded to the randomized treatment assignments in 
order to minimize unnecessary analysis of sample from a control group of patients. A 
pharmacokinetics and IWRS randomization manager may all be unblinded before data is more 
generally unblinded. These summaries will not reveal individual patients’ treatment 
assignments. Except as noted above, other members of the BHV research team and CRO will 
remain blinded until after the primary analysis is completed. 
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt to 
preserve the blind is made. 
7.4 
Treatment Compliance 
Responsible study personnel will dispense the study drug. Accountability and compliance 
verification should be documented in the patient’s study records. 
Patients have to 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 patient from the 
trial should be considered. 
 
7.5 
Destruction and Return of Study Drug 
If study drugs (those supplied by the sponsor or sourced by the investigator) are to be destroyed 
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 BHV Study monitor or the sponsor’s designee. 
Study drug will not be returned. All unused and/or partially used study drug may be destroyed 
on site providing the site has an applicable standard operating procedure on file. 
 
 


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8 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 relate 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. 
8.1 
Serious Adverse Events 
There are two types of adverse events, Serious Adverse Events (SAE) and Non-Serious 
Adverse Events (AEs). 
8.1.1 
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 BHV- 
4157; 
 
• Other: Important medical events that may not result in death, be life-threatening, or 
require hospitalization, may be considered an SAE when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such events are (but not limited to): 
 
o Intensive treatment in an emergency room or at home for allergic 
bronchospasm; 
 
o Blood dyscrasias or convulsions that do not result in inpatient 
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o Development of drug dependency or drug abuse; 
 
o Potential drug induced liver injury (see section 8.1.6). 
8.1.2 
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 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). 
 


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Disability/incapacitating: An AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the subject's ability to carry out normal life 
functions. 
Classification of Adverse Events 
The severity of all AEs must be recorded in the eCRF and on the SAE Form, if applicable. The 
severity or intensity of an AE refers to the extent to which it affects the subject’s daily 
activities. The severity of events should be graded as mild, moderate or severe. Refer to the 
BHV4157-201 SAE Reporting and Management Plan for definitions of each grading criteria.  
The Investigator’s assessment of an AEs relationship to study drug is part of the documentation 
process but is not a factor in determining what is or is not reported in the study. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported. The 
relationship or association of the study drug in causing or contributing to the AE will be 
characterized as either not related, unlikely related, possibly related, or related. Refer to the 
BHV4157-201 SAE Reporting and Management Plan for definitions of each criteria. 
8.1.3 
Collection and Reporting Serious Adverse Events 
Following the patient’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specific procedures. All SAEs must be collected that occur during the screening 
period and within 30 days of discontinuation of dosing. The investigator should report any SAE 
occurring after these time periods that is believed to be related to study drug or protocol-
specific procedures. 
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness. 
If the investigator believes that an SAE is not related to the study drug, but is potentially related 
to the conditions of the study (such as a withdrawal of previous therapy or a complication 
related to study procedure), the relationship should be specified in the narrative section of the 
SAE Report Form. 
SAEs, whether related or not related to study drug, overdose (see section 8.1.4), potential drug 
induced liver injury (see section 8.1.6) and pregnancies (see section 8.1.5) must be reported 
within 24 hours of the Investigator becoming aware of the event. For this study we will be 
capturing SAEs through electronic data capture (EDC) and on the SAE form. 
The Investigator is responsible for reporting all SAEs and all Other Important Medical Events 
to 
 immediately via telephone, upon observing or learning of the event. 
 will then 
immediately notify the Biohaven Medical Monitor of the event.  The SAE form must then be 
submitted to 
 within one working day. The Investigator is responsible for submitting all 
applicable events to the Independent Review Board (IRB) as per the IRB’s reporting 
requirements. Additionally, the Investigator, or designated staff, is responsible for entering in 
the SAE information in the Electronic Data Capture (eDC) system (i.e.: event term, start stop 
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Additionally, any serious adverse experience must be reported immediately or no later than 
24 hours after awareness of the event 
  
The Serious Adverse Event Report Form (SAERF) should be submitted 
 by 
facsimile (FAX). 
North America: 
 
Reports can be made by telephone via the Safety Hotline Number below if a SAERF cannot be 
immediately submitted. 
North America: 
 
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. 
8.1.4 
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. 
8.1.5 
Pregnancy 
If following initiation of the investigational product, it is subsequently discovered that a study 
patient is pregnant or may have been pregnant at the time of the investigational product 
exposure, including during at least 6 half-lives after the product administration, the 
investigational product will be permanently discontinued in an appropriate manner (i.e., dose 
tapering if necessary for patient safety). Protocol-required procedures for the study will be 
discontinued and the follow up must be performed on the patient unless contraindicated by the 
pregnancy (i.e., x-ray studies). Other appropriate pregnancy follow-up procedures should be 
considered if indicated. 
Sites should instruct patients to contact the investigator if they become pregnant during the 
course of the study. The investigator must immediately notify 
of the event within 24 hours 
of the Investigator becoming aware of the information. The site must complete a Pregnancy 


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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 
  
8.1.6 
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 8.1.2. 
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. 
8.2 
Non-serious Adverse Events 
A non-serious adverse event is an AE not classified as serious. 
8.2.1 
Collection and Reporting of Non-Serious Adverse Events 
The collection of non-serious AE information should begin at the initiation of study drug. 
Non-serious adverse events should be followed until conclusion or stabilization, or reported as 
SAEs if they become serious. Follow-up is also required for non-serious AEs that cause 
interruption or discontinuation of study drug or those that are present at the end of study 
treatment. 
The following laboratory test abnormalities should be captured on the non-serious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate: 
 


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• Any laboratory test result that is clinically significant or meets the definition of an 
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. 
 
 
 


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9 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. 
9.1 
General Procedures 
Analysis populations: Efficacy data will be assessed using the Full Analysis Set (FAS) 
consisting of all patients with at least one dose of test treatment and at least one efficacy 
observation. No missing data will be imputed as missing data are assumed to be missing at 
random. Safety data will be assessed using the Safety Analysis Set (SAF), which includes all 
patients exposed to at least 1 dose of study treatment. 
Statistical analyses: Descriptive statistics are planned for all outcome measures collected in 
this study.  The randomization phase and the extension phase will be analyzed separately. For 
patients receiving troriluzole during both phases, summary statistics will be provided for data 
from both phases combined. 
9.2 
Sample Size 
The sample size for this study will be approximately 120 randomized subjects to accommodate 
for dropouts and based on the rationale that follows. 
 
For this trial, conservatively 
assuming a TRUE underlying difference between treatments of 1.24 units and pooled SD=2.01, 
N=112 (56/group) has ~90% power to yield a statistically significant (alpha=0.050, 2-sided) 
difference between treatments in change from baseline to week 8 in SARA score. This 
calculation is via 2-sample t-test, which is likely conservative compared to the planned 
repeated measures analysis planned for this trial to leverage the likely correlation of response 
between weeks 4 and 8. 
 
 
9.3 
Statistical Methods 
9.3.1 
Primary Endpoint(s) 
The primary endpoint is change from baseline to week 8 in SARA score; the primary objective 
is the comparison of troriluzole versus placebo. The primary analysis will be carried out via a 
Mixed Model for Repeated Measures (MMRM) analysis model using the FAS population.
 
 
 
 
 


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9.3.2 
Secondary Endpoint(s) 
Continuous secondary, change-from-baseline, endpoints will be analyzed via analysis of 
covariance model
 
 Binary endpoints will be summarized by counts and 
percents by treatment; p-values for comparisons between weeks will be provided by exact 
binomial test. 
9.3.3 
Analysis of Safety 
Safety outcome measures (adverse events, laboratory variables, ECG and vital signs) will be 
descriptively summarized by treatment group for the SAF population. For adverse events, 
treatment-emergent adverse events (TEAEs) are defined as those that developed, worsened, or 
became serious after first dose of test treatment. They will be summarized by counts and 
percents. Observed values and change from baseline in lab variables and vital signs will be 
summarized by count, mean, median, SD, minimum, and maximum. The primary endpoint will 
be assessed when all subjects complete the 8 week randomization phase. In addition, during the 
extension phase, data may be locked, analyses conducted, and reports produced as required to 
support safety monitoring, administrative concerns, and regulatory requirements. 
9.3.4 
Demographic and Baseline Characteristics 
Demographic information will be summarized (n, mean, SD, minimum, maximum for 
continuous endpoints; n and % for categorical endpoints) by treatment group and for treatment 
groups combined. This will be for the Safety Analysis Set; however, if substantial difference 
exists between the numbers of patients in the SAF and the FAS, then a separate similar 
summary will be provided for the FAS. 
 
 


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10 ETHICS AND RESPONSIBILITIES 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
Good Laboratory Practice (GLP) and all applicable regulations, including the Federal Food, 
Drug and Cosmetic Act, U.S. applicable Code of Federal Regulations (title 21), any IEC 
requirements relative to clinical studies. The study will also be conducted in compliance with 
the recommendations laid down in the most recent version of the Declaration of Helsinki, with 
the exception that registration of such Phase 1 trials in a publicly accessible database is not 
mandatory. 
This study will be conducted in compliance with the protocol. The protocol and any 
amendments and the patient informed consent will receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion prior to initiation 
of the study. 
All serious breaches must be reported to Biohaven (or designee) immediately. A Serious breach 
is a breach of the conditions and principles of GCP in connection with the study or protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
patients of the study or the scientific value of the study. 
Study personnel involved in conducting this study will be qualified by education, training, and 
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). 
10.1 Data and Safety Monitoring Committee 
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 cases of emergency will be followed. 
10.2 Institutional Review Board/Independent Ethics Committee 
The Investigators agree to provide the IEC with all appropriate documents, including a copy of 
the protocol/amendments, ICFs, advertising text (if any), Investigator’s brochure (if any) and 
any other written information provided to study subjects. The trial will not begin until the 
Investigators have obtained the IEC favorable written approvals for the above-mentioned study 
documents. A properly executed written ICF shall be read, signed, and dated by each subject 
prior to entering the trial or prior to performing any study procedure. The original signed and 
dated ICF will be kept at the Investigator site and a copy will be given to the subject. 
In the event that the protocol is amended, the revised protocol must be approved by the IEC 
prior to its implementation, unless the changes involve only logistical or administrative aspects 
of the trial. If a revised ICF is introduced during the study, each subject’s further consent must 
be obtained. The new version of the ICF must be approved by the IEC, prior to subsequently 
obtaining each subject’s consent. 


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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. 
10.3 Informed Consent 
Investigators must ensure that patients, or, in those situations where consent cannot be given by 
patients, their legally acceptable representatives, are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they 
volunteer to participate. 
Biohaven (or designee) will provide the investigator with an appropriate (i.e., Global or Local) 
sample informed consent form which will include all elements required by 
ICH, GCP and applicable regulatory requirements. The sample informed consent form will 
adhere to the ethical principles that have their origin in the Declaration of Helsinki. 
Before the potential subject has undergone any study-related screening procedures, the nature 
of the study and the potential risks associated with it will be explained to the subject, and the 
subject will be given an opportunity to ask questions to his or her satisfaction. After the 
questions are answered, but before proceeding further, the subject must read and sign a written 
informed consent form. This signed informed consent form will be reviewed and approved by 
an IRB/IEC, revisions to the protocol and informed consent form will be reviewed and 
approved by the IRB/IEC, a copy retained in the Study Master File, and the date and time the 
subject signed the form will be entered in his or her CRF. The subject will be provided with a 
copy of his or her signed and dated informed consent form. 
If informed consent is initially given by a patient’s legal guardian or legally acceptable 
representative, and the patient subsequently becomes capable of making and communicating 
their informed consent during the study, then the consent must additionally be obtained from 
the patient. 
The informed consent form must also include a statement that Biohaven and its representatives 
and regulatory authorities may have direct access to patient records. 
The rights, safety, and well-being of study patients are the most important considerations and 
should prevail over interests of science and society. 
10.4 Case Report Forms 
An investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation of each study 
patient. Data reported on the CRF that are derived from source documents must be consistent 
with the source documents or the discrepancies must be explained. 
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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. 
10.5 Records Management and Retention 
In accordance with the principles of GCP and GLP, the study may be inspected by regulatory 
authorities, the Sponsor and CRO. The Sponsor is entitled to access information about the 
status of the study and to review the original documents of the study. 
The investigator must retain all study records and source documents for the maximum required 
by the applicable regulations and guidelines, or institution procedures or for the period of time 
specified by the sponsor, whichever is longer. The investigator must contact the Sponsor prior 
to destroying any records associated with this study. 
Biohaven will notify the investigators when the study files for this study are no longer needed. 
If the investigator withdraws from the study (i.e., retirement, relocation), the records shall be 
transferred to a mutually agreed upon designee.  Notice of such transfer will be given in writing 
to Biohaven. 
It is the responsibility of the investigator to ensure that the current disposition record of 
investigational product (those supplied by the sponsor) is maintained at each study site where 
the study drug is inventoried and dispensed. Records or logs must comply with applicable 
regulations and guidelines and should include: 
 
o Amount of study drug received and placed in storage area; 
o Label ID number or batch number or Kit number as specified for the protocol; 
o Amount dispensed to and returned from each patient; 
 
o Amount transferred to another area or site for dispensing or storage if 
applicable; 
 
o Amount of drug lost or wasted; 
o Amount destroyed at the site if applicable; 
o Amount returned to sponsor, if applicable; 
o Retained samples for bioavailability/bioequivalence, if applicable; 
o Record of dates and initials of personnel responsible for IM dispensing and 
accountability. 
 


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10.6 Source Documentation 
An investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent for all subjects on study. 
If source documents are created to support the collection of study information, this must be 
retained with the other pertinent medical record for each patient for verification of data points, 
unless otherwise instructed by the Sponsor or designee to enter data directly on the CRF. 
10.7 Study Files and Record Retention 
The CRO will utilize the Sponsor’s Electronic Trial Master File (eTMF) for the purposes of 
this study. The Sponsor does not require original documents that have already been scanned 
and entered into the eTMF system be forwarded to the Sponsor. Any original documents (i.e. 
1572, signed financial disclosure, signed ICF, etc.) will be retained in the regulatory binder at 
the study site. The CRO will do a final TMF reconciliation to ensure all study files and 
regulatory documents have been correctly uploaded to the TMF prior to the close or 
termination of the study. Any materials or documents to support the clinical trial outside of the 
eTMF (i.e. rater training tapes) should be maintained by the CRO. The Sponsor will be 
contacted to determine whether the study documents/materials that are retained outside of the 
TMF will be forwarded to the Sponsor, destroyed or kept at CRO or at another facility for a 
longer period of time at the Sponsor's expense. 
11 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. 
12 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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13 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. 
14 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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M, Xia G, Subramony SH, Ashizawa T, Kuo SH. Coenzyme Q10 and spinocerebellar 
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15377747. 
 
 
 
 
 


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16 APPENDICES 
16.1 APPENDIX I – Names of Study Personnel 
Sponsor: 
Medical Monitor and 
Medical Monitor 
Back-up: 
Clinical 
Research 
Organizations: 

SAP_001.pdf: 
DocuSign EnvelopeiD: BD8AB61B-7989-408F-A5B1-B84E58727CD3 
Biohaven Pharmaceuticals 
Protocol BHV4157-201 
A Phase lib/III, Randomized, Double-blind, Placebo-
controlled Trial ofBHV4157 in Adult Subjects with Spinocerebellar 
Ataxia 
Statistical Analysis Plan 
Version 4.0 Addendum 
Date: March 27,2020 
This document is confidential and proprietary property of Biohaven Phannaceuticals and to be used only as 
authorized by Biohaven Phannaceuticals. No part is to be reproduced, disclosed to others, or quoted without prior 
written authorization from Biohaven Phannaceuticals. 


DocuSign Envelope ID: BD8AB61B-7989-408F-A5B1-B84E58727CD3 
Biohaven Pharmaceuticals 
Protocol BHV4157-201 SAP ver 04.0 Addendum 
Table of Contents 
STATISTICAL AN'AL YSIS PLAN' ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• I 
TABLE OF CONTENTS .••.••.••.••.•.••.••.••.••.•..••••.••.••.••.••.••.••••.••.••.••.••.••.••••.••.••.••.••.••.••••.••. 2 
TABLE 0 F TABLES ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 2 
SIGNA TU'RE PAGE •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 3 
1 
IN'TRODUCTION ..••.••.••.••.••••.••.••.••.••.•..••••.••.••.••.••.••.••••.••.••.••.••.••.•.••.••.••.••.••.••.••••.••. 4 
 
 •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 4 
3 
COMPUTIN'G ENVIR.ONMENT ••.••.•..••••.••.••.••.••.••.••••.••.••.••.••.••.•.••.••.••.••.••.••.••••.••. 4 
4 
AN'AL YSIS SETS ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 4 
5 
'VISIT WINDOWS •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 5 
6 
MODIFIED SCALE FOR THE ASSESSMENT AND RATING OF ATAXIA ••. 5 
7 
NATURAL IDS TORY AN'AL YSIS •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• S 
8 
SUWECTS IDENTIFIED FOR NARRATIVES .••.••••.••.••.••.••.••.•.••.••.••.••.••.••.••••.••. 7 
9 
AD HOC AN'AL YSES •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 8 
9.1 
Randomization Phase •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 8 
9.2 
Extension Phase - Week 24 .••.••.••.••.•..••••.••.••.••.••.••.••••.••.••.••.••.••.•.••.••.••.••.••.••.••••.••. 8 
9.3 
Extension Phase - Week 48 ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 9 
9.4 
Extension Phase -Week 72 •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 9 
9.5 
Extension Phase - Week 96 .••.••.••.••.•..••••.••.••.••.••.••.••••.••.••.••.••.••.•.••.••.••.••.••.••.••••.• 1 0 
10 UPDATES TO AN'ALYSES SPECIFIED IN' THE SAP ••••••••••••••••••••••••••••••••••••••• 12 
11 AD VERSE EVENTS .••.••.••.••.•.••.••.••.••.•..••••.••.••.••.••.••.••••.••.••.••.••.••.•.••.••.••.••.••.••.••••.• 13 
12 LABORATORY DATA ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 13 
13 REFERENCES ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 14 
APPENDIX .•••••.••.••.••.•.•..••.••.••.••.••.•.••.••.••.••.•..••••.••.••.••.••.••.••••.••.••.••.••.••.•.••.••.••.••.••.••.••••.• 15 
Table 1a: 
Table 1b: 
Table 2: 
Table3: 
Table 4: 
Table 5: 
Table 6: 
Table 7: 
Table 8: 
Table of Tables 
Evaluation Intervals for ITT Analysis of SARA/MSARA ••••••••••••••••••• 15 
Evaluation Intervals for FAS Analysis ofSARA/MSARA ••.••.••.••.••••.• 16 
Evaluation Intervals for Analysis of PIFAS •••••••••••••••••••••••••••••••••••••••••• 16 
Evaluation Intervals for Analysis of UHDRS-IV, PGI-C, and 
CGI-1 •.•.••.••.••.••.••.••.•.••.••.••.••.••.••••.••.••.••.••.••.••••.••.••.••.••.••.••••.••.••.••.••.••.••••.• 17 
Evaluation Intervals for Analysis of All Other Efficacy Endpoints •••• 17 
Evaluation Intervals for Analysis of Laboratory Assessments, 
S-STS, Physical Measurements, and Vital Signs ••••••••••••••••••••••••••••••••••• 18 
Evaluation Intervals for Analysis of BDNF and proBDNF Blood 
Sampling ....••....••....•....••....••....•.....•....••....••....•....••....••....•....••....••....••....•.. 18 
Evaluation Intervals for Analysis of Physical Examinations ••••••••••••••• 19 
Evaluation Intervals for Analysis of ECG ••••••••••••••••••••••••••••••••••••••••••••• 19 
CONFIDENTIAL 
2 
27Mar2020 






































Confidentiality 
This document is confidential and proprietary property of Biohaven Pharmaceuticals and to be used only as 
authorized by Biohaven Pharmaceuticals.  No part is to be reproduced, disclosed to others, or quoted without prior 
written authorization from Biohaven Pharmaceuticals. 
 
Biohaven Pharmaceuticals 
 
Protocol BHV4157-201 
 
A Phase IIb/III, Randomized, Double-blind, Placebo-controlled Trial of 
BHV-4157 in Adult Subjects with Spinocerebellar Ataxia 
 
Statistical Analysis Plan 
Final Version 2.0 
Date: September 6, 2017 
 




Biohaven Pharmaceuticals                                
Protocol BHV4157-201 
Confidential   
06Sep2017 
 
 
 
3 
TABLE OF CONTENTS 
SIGNATURE PAGE ....................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................ 3 
ABBREVIATIONS ......................................................................................................... 6 
 INTRODUCTION AND OBJECTIVES OF ANALYSIS ............................................. 8 
1.
 
Introduction ............................................................................................ 8 
1.1.
 
Objectives of Statistical Analysis ......................................................... 8 
1.2.
 STUDY DESIGN ..................................................................................................... 10 
2.
 
Synopsis of Study Design ................................................................... 10 
2.1.
 
Randomization Methodology .............................................................. 10 
2.2.
 
Unblinding ............................................................................................. 10 
2.3.
 
Efficacy,
Safety, and 
2.4.
Other Variables ..................................................................................... 11 
2.4.1. Efficacy Variables ................................................................................. 11 
 
 
2.4.4. Safety and Other Variables .................................................................. 12 
 SUBJECT POPULATIONS .................................................................................... 13 
3.
 
Population Definitions ......................................................................... 13 
3.1.
 
Protocol Deviations .............................................................................. 13 
3.2.
 STATISTICAL METHODS ..................................................................................... 14 
4.
 
Sample Size Justification .................................................................... 14 
4.1.
 
General Statistical Methods and Data Handling ................................ 14 
4.2.
4.2.1. General Methods .................................................................................. 14 
4.2.2. Computing Environment ...................................................................... 14 
4.2.3. Methods of Pooling Data ..................................................................... 14 
4.2.4. Adjustments for Covariates
.................................. 15 
4.2.5. Multiple Comparisons/Multiplicity ...................................................... 15 
4.2.6. Subpopulations .................................................................................... 15 
4.2.7. Withdrawals, Dropouts, and Loss to Follow-up ................................. 15 
4.2.8. Missing, Unused, and Spurious Data ................................................. 16 
4.2.9. Visit Windows ....................................................................................... 16 


Biohaven Pharmaceuticals                                
Protocol BHV4157-201 
Confidential   
06Sep2017 
 
 
 
4 
 
Planned Analyses ................................................................................. 17 
4.3.
 
Subject Disposition .............................................................................. 17 
4.4.
 
Demographic and Baseline Characteristics ....................................... 18 
4.5.
 
Efficacy Evaluation ............................................................................... 18 
4.6.
 
 
 
4.6.2. Secondary Efficacy Endpoint .............................................................. 20 
4.6.2.1. 
Patient Global Impression of Change (PGI-C) .............................. 20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety and Other Analyses .................................................................. 28 
4.8.
4.8.1. Extent of Exposure and Compliance to Study Treatment ................. 28 
4.8.2. Adverse Events..................................................................................... 29 
4.8.3. Laboratory Data .................................................................................... 29 
4.8.4. Physical Examinations ......................................................................... 31 
4.8.5. Vital Signs and Physical Measurements ............................................ 31 
4.8.6. Electrocardiogram ................................................................................ 31 
4.8.7. Neurological Assessment .................................................................... 31 
4.8.8. Concomitant Medications .................................................................... 31 
4.8.9. Sheehan-Suicidality Tracking Scale (S-STS) ..................................... 31 


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 REFERENCES ....................................................................................................... 33 
5.
 
 
  
 
 


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ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase  
ALT 
Alanine aminotransferase  
ANOVA 
Analysis of variance 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase  
ATC 
Anatomic therapeutic class 
BCVA 
Best-corrected visual acuity 
 
 
BQL 
Below limit of quantification 
BUN 
Blood urine nitrogen  
 
 
 
  
 
 
CPK 
Creatine phosphokinase  
CSR 
Clinical study report 
ECG 
Electrocardiogram 
 
 
 
  
ERG 
Electroretinography  
FAS 
Full analysis set 
HbA1C 
Hemoglobin A1c  
HBsAg 
Hepatitis B surface antigen  
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein  
HIV 
Human immunodeficiency virus 
IOP 
Intraocular pressure 
GGT 
Gamma-glutamyl transferase  
ICH 
International Conference on Harmonisation 
 
 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase  
LDL 
Low-density lipoprotein  
LogMAR 
Logarithm of the minimum angle of resolution  
LSMeans 
Least square means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model for repeated measures 


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Abbreviation 
Definition 
MMSE 
Mini Mental State Exam 
PGI-C 
Patient Global Impression of Change 
PK 
Pharmacokinetic 
PP 
Per protocol set 
PT 
Preferred term 
QD 
Quaque die (once daily) 
S-STS 
Sheehan-Suicidality Tracking Scale 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARA 
Scale for the Assessment and Rating of Ataxia 
SCA 
Spinocerebellar ataxia 
SD 
Standard deviation 
 
 
SMQ 
Standardized MedDRA query 
SOC 
System organ class 
TSH 
Thyroid-stimulation hormone  
 
 
ULN 
Upper limit of normal  
 
 
WHO-DD 
World Health Organization-Drug Dictionary 
 
 
 


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INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.
 
Introduction 
1.1.
This document presents the statistical analysis plan (SAP) for Biohaven Pharmaceuticals, 
Protocol BHV4157-201: A Phase IIb/III, Randomized, Double-blind, Placebo-controlled Trial 
of BHV-4157 in Adult Subjects with Spinocerebellar Ataxia. 
This SAP is based on Amendment 4 to the final protocol dated July 27, 2017. It contains the 
analysis details and methodology to answer the study objectives, including planned summary 
tables, by-subject listings, and figures, which will provide the basis for the results section of the 
clinical study report (CSR). Operational aspects related to collection and timing of planned 
clinical assessments are not repeated in this SAP unless relevant to the planned analyses.  
 
Objectives of Statistical Analysis 
1.2.
Primary Objective 
• 
To compare the efficacy of BHV-4157 (140 mg once daily) versus placebo on ataxia 
symptoms in subjects with spinocerebellar ataxia (SCA) after 8 weeks of treatment 
as measured by the total score on the Scale for the Assessment and Rating of Ataxia 
(SARA) 
Secondary Objectives 
• 
To assess of the safety and tolerability of BHV-4157 in subjects with SCA 
• 
To compare efficacy of BHV-4157 with placebo on patient impression of benefit via 
use of the Patient Global Impression of Change (PGI-C) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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STUDY DESIGN 
2.
 
Synopsis of Study Design 
2.1.
BHV4157-201 is a Phase IIb/III, multicenter, randomized, double-blind, 2-arm placebo-
controlled parallel-group study designed to assess safety, tolerability, and efficacy signals in a 
population of subjects with SCA.  
Subjects who are determined to be eligible for the study will enter the Randomization Phase. 
Dosing will continue for 8 weeks. Subjects will return to the clinic 2 weeks after discontinuing 
study medication for a follow-up safety visit (see Figure 1). In addition, subjects completing the 
Randomization Phase will be offered 48 weeks of open-label treatment given the principle 
investigator 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 4 weeks after the 
Week 8 Randomization Phase visit. If there is a delay of two weeks or more in dosing between 
the Randomization Phase and the Extension Phase, then subjects will be required to complete an 
Extension baseline visit. Thereafter, subjects will undergo visits every fourth week through 
Week 12 of this phase. Then subjects will undergo visits every 12 weeks up to Week 48 of this 
phase. All subjects will undergo a post study drug termination visit two weeks after the last dose 
of study drug in the Extension Phase. 
 
Randomization Methodology 
2.2.
Subjects will be randomized to receive placebo once daily (QD) or BHV-4157 (140 mg QD),
 
 
 
Unblinding 
2.3.
Blinding is critical to the integrity of this clinical study. However, in the event of a medical 
emergency or pregnancy, in which knowledge of the investigational product is critical to the 
subject’s management, the blind for that subject may be broken by the treating physician. The 
unblinded biostatistician, or designee, will be unblinded to the randomized treatment 
assignments. A PK and interactive web response system (IWRS) randomization manager may 
also be unblinded. Except as noted above, members of the Biohaven research team will remain 
blinded. 


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Figure 1:   Study Schematic 
R=Randomization 
 
 
Efficacy, 
 Safety, and Other 
2.4.
Variables 
2.4.1. 
Efficacy Variables 
Primary Endpoint 
• Change from baseline to Week 8 in SARA total score  
Secondary Endpoints 
• Frequency and severity of adverse events (AEs) and discontinuation due to AEs 
• Patient impression of benefit via use of PGI-C at Week 8 
 
 
 
 
  
 
  
 
 
 
 


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2.4.4. 
Safety and Other Variables 
Safety assessments performed during the study include AEs, laboratory evaluations, physical 
examinations, vital signs and physical measurements, 12-lead electrocardiograms (ECGs), 
concomitant medications, and the Sheehan-Suicidality Tracking Scale (S-STS).
 
 
. 
 


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SUBJECT POPULATIONS 
3.
 
Population Definitions 
3.1.
The following subject populations will be evaluated and used for presentation and analysis of 
the data: 
Full Analysis Set (FAS): All randomized subjects with at least 1 dose of study treatment and a 
baseline and post-baseline total SARA score during the Randomization Phase.  
Per Protocol (PP) Set: All FAS subjects without any major protocol deviations. 
Safety Analysis Set: All subjects who received at least 1 dose of study treatment. 
 
Protocol Deviations 
3.2.
Any significant event that does not comply with the inclusion/exclusion criteria, study conduct 
(e.g., inadequate informed consent, unreported SAEs), or study procedures (e.g., use of 
prohibited medications as defined by the protocol; improper breaking of the blind; overall non-
compliance with study medication <80% for either the Randomization Phase or both phases, 
calculated prior to database lock) will be documented as a major deviation.  
 
 
 
All protocol deviations will be presented in the data listings. 


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STATISTICAL METHODS 
4.
 
Sample Size Justification 
4.1.
The sample size for this study will be 120 randomized subjects to accommodate for dropouts 
and based on the rationale that follows. 
 
For this trial, conservatively assuming a TRUE underlying difference between 
treatments of 1.24 units and pooled SD=2.01, N=112 (56/group) has ~90% power to yield a 
statistically significant (alpha=0.05, 2-sided) difference between treatments in change from 
baseline to Week 8 in the total SARA score. This calculation is via 2-sample t-test, which is 
likely conservative compared to the planned repeated measures analysis planned for this trial to 
leverage the likely correlation of response between Weeks 4 and 8. 
 
 
 
 
General Statistical Methods and Data Handling 
4.2.
4.2.1. 
General Methods 
All output will be incorporated into Microsoft Excel or Word files, sorted and labeled according 
to the International Conference on Harmonization (ICH) recommendations, and formatted to the 
appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, 
 safety, and other parameters.  For categorical variables, summary 
tabulations of the number and percentage within each category of the parameter will be 
presented. If applicable, a category for missing data will also be presented. For continuous 
variables, n, mean, median, SD, minimum and maximum values will be presented.  The median, 
minimum, and maximum values will be presented with the same precision as the data.  The 
mean will be presented with the precision of the data + 1 decimal place.  The SD will be 
presented with the precision of the data + 2 decimal places. 
Formal statistical hypothesis testing and summary statistics will be presented, as well as 
confidence intervals on selected parameters, as described in the sections below. 
4.2.2. 
Computing Environment 
All statistical analyses will be performed using SAS statistical software (Version 9.2 or higher).  
Medical history and AEs will be coding using the Medical Dictionary for Regulatory Activities 
(MedDRA, Version 19.1).  Concomitant medications will be coded using World Health 
Organization Drug Dictionary (WHO-DD, Sep2016).  
 
 
  


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4.2.4. 
Adjustments for Covariates 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
4.2.5. 
Multiple Comparisons/Multiplicity 
Type 1 error will be controlled for the primary and secondary efficacy endpoints by testing them 
with a fixed sequence procedure.  The primary endpoint, change from baseline in the total 
SARA score, will be tested at a two-sided alpha level of 0.05.  If this test is significant, then a 
single secondary endpoint, PGI-C, will also be tested at a two-sided alpha level of 0.05.  If the 
test of the primary endpoint is not significant, then the p-value for the secondary endpoint will 
be presented only for descriptive purposes, and no conclusions may be drawn from this result. 
The multiplicity corrections discussed above apply only to analyses done on the FAS 
population. Any parallel analyses performed on the PP population are considered to be 
sensitivity analyses, and are not corrected for multiplicity. 
 
 
 
 
 
 
   
 
  
4.2.7. 
Withdrawals, Dropouts, and Loss to Follow-up 
Subjects who withdrew from the study were not replaced.  


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4.2.8. 
Missing, Unused, and Spurious Data 
Unless otherwise noted, efficacy analyses will be based on observed data only. No missing data 
will be imputed. We expect the amount of data that will be lost in the 8-week double blind phase 
of this study to be small; most likely less than 10%.
 
  
For efficacy analyses, partial or missing dates will not be imputed. The relative study days, 
where determined, will be calculated for full dates only.  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
4.2.9. 
Visit Windows 
The protocol-specified visit window is ± 2 days during the Randomization Phase and ± 7 days 
during the Extension Phase of the study. Observations collected within ± 1 week visit window 
during the Randomization Phase and ± 2 weeks visit window during the Extension Phase will be 
included in the analyses
 
 
 
 


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Actual dates and times will be used for PK analysis rather than nominal days and times. 
 
Planned Analyses  
4.3.
Data from the double-blind portion of the trial will be unblinded and analyzed after the last 
subject completes 8 weeks of treatment or discontinues from the Randomization Phase. Subjects 
who complete the Randomization Phase may be eligible for an open-label Extension Phase of 
the study. Data from the Extension Phase will be summarized after the last subject completes 
the last visit or discontinues from the Extension Phase.  
 
Subject Disposition 
4.4.
A summary of subject disposition will be tabulated for all subjects by treatment group and 
overall for the Randomization and Extension Phases, separately, including: 
• Number of subjects screened 
• Number of screened subjects excluded from the study and reason for exclusion 
• Number of subjects in each analysis population 
• Number of subjects who entered the Randomization Phase 
• Number of subjects who completed the Randomization Phase 
• Number of subjects who prematurely withdrew from the Randomization Phase and 
reasons for withdrawal 


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• Number of subjects who entered the Extension Phase 
• Number of subjects who completed the Extension Phase 
• Number of subjects who withdrew from the Extension Phase and reasons for withdrawal 
A by-subject listing of study completion information for both the Randomization and 
Extensions Phases, including the reason for withdrawal, if applicable, will be presented. 
 
Demographic and Baseline Characteristics 
4.5.
Demographic information, medical and disease history, and Mini Mental State Exam (MMSE) 
results will be summarized by treatment group and overall, based on the Safety population. 
However, if a substantial difference exists between the number of subjects in the Safety and the 
FAS populations, then a separate similar summary will be provided for the FAS population. 
Demographic and other baseline data will also be provided in by-subject data listings. 
 
Efficacy Evaluation 
4.6.
Unless otherwise noted, all efficacy analyses will be conducted using the FAS and PP 
populations as outlined below. All efficacy data will be included in listings by subject, study 
medication, and visit (as applicable) for the Randomization and Extension phase, separately.  
For the Randomization Phase, baseline is considered as the last visit prior to dosing (Visit 2 
assessment); and for the Extension Phase, baseline is considered as the visit prior to Extension 
Visit 1:  
• If less than 14 days elapsed between the Randomization and Extension Phases, then use 
the Visit 4 (Week 8) assessment during the Randomization Phase, or  
• If 14 or more days elapsed between the Randomization and Extension Phases, then use 
the Repeat Baseline assessment at the beginning of the Extension Phase. 
4.6.1. 
Primary Efficacy Endpoint 
4.6.1.1. Scale for the Assessment and Rating of Ataxia (SARA) 
The severity of ataxia is assessed with the SARA, an 8-item clinical rating scale from 0 (no 
ataxia) to 40 (most severe ataxia). The total score is derived as the sum of the individual items, 
which include gait (0-8), stance (0-6), sitting (0-4), speech disturbance (0-6), finger chase (0-4), 
nose-finger test (0-4), fast alternating hand movements (0-4), and heel-shin slide (0-4). Since the 
finger chase, nose-finger test, fast alternating hand movements, and heel-shin slide are repeated 
on both the right and left side, the average of the right and left side assessments are used to 
derive the total score. 
The primary endpoint is the difference between the BHV-4157 and placebo groups in the 
change from baseline to Week 8 in the total SARA score. The principal analysis will be carried 
out via a Mixed Model for Repeated Measures (MMRM). 
 
 
 
 
 


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4.6.2. 
Secondary Efficacy Endpoint 
4.6.2.1. Patient Global Impression of Change (PGI-C) 
The patient’s impression of benefit via the PGI-C will be summarized descriptively by post-
baseline visit for the Randomization and Extension Phases, separately, including the number 
and percentage of subjects in each category: 
• No change (or condition has gotten worse) 
• Almost the same, hardly any change at all 
• A little better, but no noticeable change  
• Somewhat better, but the change has not made any real difference 
• Moderately better, and a slight but noticeable change  
• Better and a definitive improvement that has made a real and worthwhile difference 
• A great deal better and a considerable improvement that has made all the difference at 
each post-baseline study visit 
The significance of the difference between treatment groups in the PGI-C scores will be 
assessed via an exact Wilcoxon rank-sum test and p-values reported for the Randomization 
Phase only.  
 
 
 


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Safety and Other Analyses 
4.8.
Safety and other exploratory analyses will be conducted on the Safety Population.  All safety 
and other data will be listed for the Randomization and Extension phase, separately.  
Safety outcome measures include: extent of exposure, compliance to study treatment, adverse 
events, laboratory assessments, physical examinations, vital signs, ECGs, concomitant 
medications, and the S-STS questionnaire.  
 
 
Baseline is considered as the last visit prior to dosing, either the Visit 1 or Visit 2 assessment, 
for the Randomization Phase. For the Extension Phase, baseline is considered as the visit prior 
to Extension Visit 1:  
• If less than 14 days elapsed between the Randomization and Extension Phases, then use 
the Visit 4 (Week 8) assessment during the Randomization Phase, or  
• If 14 or more days elapsed between the Randomization and Extension Phases, then use 
the Repeat Baseline assessment at the beginning of the Extension Phase. 
4.8.1. 
Extent of Exposure and Compliance to Study Treatment 
Subjects will receive placebo (QD) or BHV-4157 (140 mg QD) during the Randomization 
phase. Subjects who complete 8 weeks of treatment in the Randomization phase may be eligible 
for an open-label Extension phase of the study. 
For the Randomization phase, the extent of subject exposure to study treatment will be 
quantified as the number of days on study drug (placebo or BHV-4157) and measured from the 
time the subject received the first dose until the time the subject received the last dose, either at 
the end of 8 weeks of treatment or withdrawal from the Randomization phase. 
For the Extension phase, the extent of subject exposure to study treatment will be quantified as 
the number of days on study drug (BHV-4157) and measured from the time the subject received 
the first dose of BHV-4157 until the time the subject received the last dose, either at the end of 
the study or withdrawal from the Extension phase. 
The number of tablets taken will be summarized for both the Randomization and Extension 
phases, separately. Additionally, percent (%) compliance will be calculated and summarized as 
follows: 
Randomization phase % compliance = number of tablets taken during the Randomization phase 
/ (last dose date – first dose date + 1)  × 100. 
Extension phase % compliance = number of tablets taken during the Extension phase / (last dose 
date – first dose date + 1)  × 100. 


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Overall % compliance = number of tablets taken during the study / [(last dose date – first dose 
date + 1) – (number of days with a dosing break in dosing between the Randomization and 
Extension phases)]. 
Study drug administration and compliance will be listed in subject data listings for the 
Randomization and Extension Phases, separately.  
4.8.2. 
Adverse Events 
Adverse eventss will be coded using MedDRA and displayed in tables and listings by system 
organ class (SOC) and preferred term (PT). 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined as any AE that developed, worsened, or became serious 
after first dose of test treatment.   
Adverse events are summarized by subject incidence rates; therefore, in any tabulation, a subject 
contributes only once to the count for a given AE (SOC or PT). 
The number and percentage of subjects with the following on-treatment AEs will be 
summarized by treatment group and overall for the Randomization and Extension Phases, 
separately.   
• Treatment-emergent AEs,  
• AEs related to treatment (definitely, probably, or possibly),  
• SAEs,  
• AEs with Grade 2 or greater severity,  
• AEs leading to discontinuation, and 
• Standardized MedDRA query (SMQ) of interstitial lung disease, including eosinophilic 
pneumonia  
On-treatment AEs are AEs with a start date prior to 30 days after the last dose of study drug. For 
the Randomization Phase, treatment-emergent AEs will be assessed from the date of 
randomization until: 1) the first day of the Extension Phase or 2) if the subject did not continue 
into the Extension Phase, 30 days after the last dose of study drug. For the Extension Phase, 
treatment-emergent AEs will be assessed from the first day of the Extension Phase until 30 days 
after the last dose of study drug. 
In the above tabulations, each subject will contribute only once (i.e., the most related occurrence 
or the most severe occurrence) to each of the incidence rates in the descriptive analysis, 
regardless of the number of episodes. No formal hypothesis-testing analysis of AEs incidence 
rates will be performed.   
All AEs occurring pre-treatment, during the Randomization phase, during the Extension phase, 
and throughout the entire study will be listed. Additional listings will be provided for the 
Randomization and Extension Phases, including deaths, SAEs, and AEs leading to withdrawal 
of study drug. 
4.8.3. 
Laboratory Data 
Clinical laboratory evaluations include: 


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• Hematology: hemoglobin, hematocrit, platelets, complete blood count with differential 
and absolute neutrophil count 
• Serum Chemistry: sodium, potassium, chloride, calcium, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alkaline 
phosphatase (ALP), gamma-glutamyl transferase (GGT), phosphorous, bicarbonate, 
creatine phosphokinase (CPK), total protein, albumin, total bilirubin (if greater than 
2 mg/dl bilirubin will be fractionated), glucose, creatinine, blood urine nitrogen (BUN), 
uric acid, and pregnancy testing (for women of child-bearing potential). Additionally at 
screening, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein 
(HDL), triglycerides, folate, hemoglobin A1c (HbA1C), P-Amylase, Lipase, thyroid-
stimulation hormone (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: human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), and hepatitis C virus (HCV) antibody at screening 
Clinical laboratory values will be expressed using conventional units. In the event of repeat 
values within the same analysis visit, the measurement closest to the target day for the analysis 
visit interval will be used.  
On-treatment laboratory abnormalities are those with an assessment date after the date/time of 
first dose of study drug and within 30 days after the last dose of study drug. For the 
Randomization Phase, treatment-emergent laboratory abnormalities will be assessed from the 
date of randomization until: 1) the first day of the Extension Phase or 2) if the subject did not 
continue into the Extension Phase, 30 days after the last dose of study drug. For the Extension 
Phase, treatment-emergent lab abnormalities will be assessed from the first day of the Extension 
Phase until 30 days after the last dose of study drug.  
The observed value and change from baseline will be summarized for each continuous 
laboratory parameter for the Randomization and Extension Phases, separately. In addition, the 
shift from baseline for laboratory abnormalities (low, normal, high) will be tabulated for the 
Randomization and Extension Phases, separately.  
For the liver function tests, AST and ALT, the shift from baseline will be presented by visit and 
to the maximum observed abnormality for the Randomization and Extension Phases, separately. 
Additionally for ALT, the shift from baseline to the maximum observed treatment-emergent 
abnormality, regardless of phase, will be presented for subjects treated with BHV4157 only. The 
following categories will be used to summarize the shift from baseline based on the upper limit 
of normal (ULN) range:  
• Normal  
• >ULN to ≤ 3x ULN 
• >3x ULN to ≤ 5x ULN 
• >5x ULN 
All laboratory data will be presented in data listings. Additional listings will be presented for all 
abnormal laboratory values for the Randomization and Extension Phases, separately. Subjects 
with a maximum value of ALT or AST >3x ULN and a maximum total bilirubin value >2x 


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ULN observed at any point during the entire study will also be presented in a listing. Note that 
these abnormalities do not need to occur on concurrent visits. 
4.8.4. 
Physical Examinations 
For each body system, the shift from baseline will be summarized as the number and percentage 
of subjects with each result (normal, abnormal, or physical examination not done) by visit for 
the Randomization and Extension Phases, separately. 
4.8.5. 
Vital Signs and Physical Measurements 
The observed value and change from baseline in vital signs will be summarized at each visit for 
the Randomization and Extension Phases, separately.  
4.8.6. 
Electrocardiogram 
The shift from baseline in ECG parameters will be summarized as the number and percentage of 
subjects with normal, abnormal, and clinically significant abnormal results by visit for the 
Randomization and Extension Phases, separately. Descriptive statistics for ECG interval data 
(e.g., QRS, PR, QT, QTcF), and ventricular heart rate will also be reported by visit for the 
Randomization and Extension Phases, separately. 
4.8.7. 
Neurological Assessment 
For each neurological site, the shift from baseline will be summarized as the number and 
percentage of subjects with each result (normal, abnormal, or neurological assessment not done) 
by visit for the Randomization and Extension Phases, separately.                                                                       
4.8.8. 
Concomitant Medications 
Concomitant medications will be coded using the WHO-DD. Results will be tabulated by 
Anatomic Therapeutic Class (ATC) and PT during the Randomization and Extension Phases, 
separately. 
4.8.9. 
Sheehan-Suicidality Tracking Scale (S-STS) 
The S-STS is a prospective, self-reported rating scale that contains 16 questions to track both 
treatment-emergent suicidal ideation and behaviors. In the event the subject is unavailable, the 
S-STS clinician-administered rating scale will be completed that contains 6 yes/no questions. 
Self-reported S-STS scores are calculated as follows: 
• Ideation subscale score: Sum of scores (0 – 4) for Questions 2 – 11 
• Behavior subscale score: Sum of scores (0 – 4) for Questions 1a, (highest of 12 or any 
row of 16), (highest of 14 or any row of 15), 17, and 20 
• Total score: Sum of the ideation and behavior subscale scores 
The self-reported S-STS ideation subscale, behavior subscale, and total score will be 
summarized as the change from baseline (i.e., <-1, -1, no change, 1, >1) at each visit in the 
Randomization and Extension phases, presented separately.  


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REFERENCES 
5.