Clinical trial NCT04436510
Conditions: Amyotrophic Lateral Sclerosis
Keywords: ALS Placebo-Controlled Double-Blind Regimen Specific Appendix Lou Gehrig's Disease Verdiperstat Biohaven Pharmaceuticals
Sponsor: Merit E. Cudkowicz, MD
Start date: 2020-07-28; Completion date: 2022-12-06
Enrollment: 167 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The HEALEY ALS Platform Trial is a perpetual multi-center, multi-regimen clinical trial evaluating the safety and efficacy of investigational products for the treatment of ALS.

Regimen B will evaluate the safety and efficacy of a single study drug, verdiperstat, in participants with ALS.

Detailed description:
The HEALEY ALS Platform Trial is a perpetual multi-center, multi-regimen clinical trial evaluating the safety and efficacy of investigational products for the treatment of ALS. This trial is designed as a perpetual platform trial. This means that there is a single Master Protocol dictating the conduct of the trial. The HEALEY ALS Platform Trial Master Protocol is registered as NCT04297683.

Once a participant enrolls into the Master Protocol and meets all eligibility criteria, the participant will be eligible to be randomized into any currently enrolling regimen. All participants will have an equal chance of being randomized to any currently enrolling regimen.

If a participant is randomized to Regimen B - Verdiperstat, the participant will complete a screening visit to assess additional Regimen B eligibility criteria. Once Regimen B eligibility criteria are confirmed, participants will complete a baseline assessment and be randomized in a 3:1 ratio to either active Verdiperstat or matching placebo.

Regimen B will enroll by invitation as participants may not choose to enroll in Regimen B. Participants must first enroll into the Master Protocol and be eligible to participate in the Master Protocol before being able to be randomly assigned to Regimen B.

For a list of enrolling sites, please see the HEALEY ALS Platform Trial Master Protocol under NCT04297683.

Arms: arm 1: Verdiperstat is administered twice daily p.o. for 24 weeks. arm 2: Matching placebo is administered twice daily p.o. for 24 weeks.
Interventions: intervention 1: Matching Placebo intervention 2: Verdiperstat
Intervention descriptions: intervention 1: Drug: Matching Placebo

Administration: Oral

Dose: two tablets twice daily intervention 2: Drug: Verdiperstat

Administration: Oral

Dose: 600mg twice daily

Protocol documents:
Prot_000.pdf: 
HEALEY ALS Platform Trial - Regimen B Verdiperstat 
NCT04436510 
Document Date: 02 Dec 2021 


HEALEY ALS Platform Trial 
Regimen-Specific Appendix B, Verdiperstat 
 
Version 6.0 , 02-December-2021  
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REGIMEN-SPECIFIC APPENDIX [B] 
 
FOR VERDIPERSTAT (BHV-3241) 
 
 
Regimen-Specific Appendix Date: 02 December 2021 
Version Number: 
6.0 
 
 
 


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Regimen-Specific Appendix B, Verdiperstat 
 
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TABLE OF CONTENTS 
 
SIGNATURE PAGE..................................................................................................................... 5 
LIST OF ABBREVIATIONS ...................................................................................................... 6 
REGIMEN-SPECIFIC APPENDIX (RSA) SUMMARY ......................................................... 9 
SCHEDULE OF ACTIVITIES – 24-WEEK PLACEBO-
CONTROLLED PHASE ............................................................................................................ 11 
SCHEDULE OF ACTIVITIES – REGIMEN-SPECIFIC 
OPEN-LABEL EXTENSION PHASE (OPTIONAL) ............................................................. 15 
1 
INTRODUCTION REGIMEN B: VERDIPERSTAT 
(BHV-3241) ................................................................................................................................. 17 
1.1 
Verdiperstat Background Information ................................................................ 17 
1.1.1 
Primary Pharmacodynamics............................................................................. 17 
1.1.2 
Secondary Pharmacodynamics ....................................................................... 18 
1.1.3 
Safety Pharmacology......................................................................................... 18 
1.2 
Verdiperstat Rationale ............................................................................................ 19 
1.2.1 
Dosage Selection and Justification ................................................................. 20 
2 
STUDY OBJECTIVES AND ENDPOINTS .................................................................... 21 
3 
RSA DESIGN ...................................................................................................................... 22 
3.1 
Scientific Rationale for RSA Design ................................................................... 22 
3.3 
End of Regimen Definition ......................................................................................... 23 
4 
RSA ENROLLMENT ......................................................................................................... 24 
4.1 
Number of Study Participants .............................................................................. 24 
4.2 
Additional RSA Inclusion and Exclusion Criteria ........................................... 24 
4.2.1 
RSA Inclusion Criteria ....................................................................................... 24 
4.2.2 
RSA Exclusion Criteria ...................................................................................... 24 
4.3 
Treatment Assignment Procedures .................................................................... 24 
5 
INVESTIGATIONAL PRODUCT ..................................................................................... 25 
5.1 
Investigational Product Manufacturer ................................................................ 25 
5.2 
Labeling, Packaging, and Resupply ................................................................... 25 
5.2.1 
Labeling ............................................................................................................... 25 
5.2.2 
Acquisition and Preparation .............................................................................. 25 


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5.2.3 
Drug Returns and Destruction .......................................................................... 26 
5.3 
Study Medication/Intervention, Administration and Duration, and Titration
 
26 
5.3.1 
Administration and Duration ............................................................................. 26 
5.3.2 
Dosage Modification .......................................................................................... 27 
5.4 
Drug Holiday .............................................................................................................. 28 
5.5 
Participant Compliance .......................................................................................... 28 
5.6 
Justification for Dosage ......................................................................................... 28 
5.7 
Overdose .................................................................................................................... 28 
5.8 
Drug-Drug interactions and Prohibited Medications ..................................... 29 
5.8.1 
Effect of other drugs on verdiperstat metabolism ......................................... 29 
5.8.2 
Effect of verdiperstat on the metabolism of other drugs: ............................. 29 
5.9 
Verdiperstat Known Potential Risks and Benefits .......................................... 30 
5.9.1 
Known Potential Risks ....................................................................................... 30 
5.9.2 
Known Potential Benefits .................................................................................. 33 
6 
REGIMEN SCHEDULE ..................................................................................................... 34 
6.1 
Placebo-Controlled Period .................................................................................... 35 
6.1.1 
Verdiperstat Regimen Specific Screening Visit ............................................. 35 
6.1.2 
Baseline Visit....................................................................................................... 35 
6.1.3 
Week 2 Telephone Visit .................................................................................... 36 
6.1.4 
Week 4 Visit ........................................................................................................ 36 
6.1.5 
Week 8 Visit ........................................................................................................ 36 
6.1.6 
Week 12 Telephone Visit .................................................................................. 37 
6.1.7 
Week 16 Visit ...................................................................................................... 37 
6.1.8 
Week 20 Telephone Visit .................................................................................. 37 
6.1.9 
Week 24 Visit or Early Termination Visit ........................................................ 38 
6.1.10 
Follow-Up Safety Call ........................................................................................ 39 
6.1.11 
Process for Early Terminations ........................................................................ 39 
6.1.12 
Criteria for Participant Termination .................................................................. 39 
6.2 
Open Label Extension (OLE)................................................................................. 40 
6.2.1 
Week 2 Telephone Visit - OLE ......................................................................... 41 
6.2.2 
Week 4 Visit – OLE ............................................................................................ 41 
6.2.3 
Week 8 Visit - OLE ............................................................................................. 41 
6.2.4 
Week 12 Telephone Visit – OLE ...................................................................... 41 
6.2.5 
Week 16 Visit – OLE .......................................................................................... 41 


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6.2.6 
Week 20 Telephone Visit – OLE ...................................................................... 42 
6.2.7 
Week 24 Telephone Visit – OLE ...................................................................... 42 
6.2.8 
Week 28 Visit and Q12 Weeks – OLE ............................................................ 42 
7 
OUTCOME MEASURES AND ASSESSMENTS ......................................................... 43 
7.1 Voice Analysis ................................................................................................................ 43 
7.2 ALSAQ-40 ........................................................................................................................ 43 
7.3 Center for Neurologic Study Bulbar Function Scale ........................................... 43 
8 
BIOFLUID COLLECTION................................................................................................. 44 
8.2 Pharmacokinetic Assessments ................................................................................. 44 
8.3 Pharmacodynamic Biomarker Assessments ........................................................ 44 
9 
SAFETY AND ADVERSE EVENTS ............................................................................... 45 
9.1 
Adverse Events of Special Interest – Thyroid Function ................................ 45 
10 
REGIMEN-SPECIFIC STATISTICAL 
CONSIDERATIONS .................................................................................................................. 46 
10.1 
Deviations from the Default Master Protocol Trial Design ........................... 46 
10.2 
Regimen Specific Operating Characteristics ................................................... 46 
10.3 
Sharing of Controls from Other Regimens ....................................................... 50 
11 
REFERENCES ............................................................................................................... 51 
Appendix I: The Bulbar Function Scale (CNS-BFS) .................................................... 53 
Appendix II: The ALSAQ-40............................................................................................... 56 
 
List of Figures 
Figure 1. 
Regimen Specific Appendix Schematic ........................................................... 22 
 


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SIGNATURE PAGE 
I have read the Regimen-Specific Appendix (RSA) entitled, Verdiperstat (BHV-3241) in 
Participants with Amyotrophic Lateral Sclerosis (ALS) dated July 15, 2021 (Version 5.0.) and 
agree to abide by all described RSA procedures. I agree to comply with the International 
Conference on Harmonisation Tripartite Guideline on Good Clinical Practice, applicable FDA 
regulations and guidelines identified in 21 CFR Parts 11, 50, 54, and 312, central Institutional 
Review Board (IRB) guidelines and policies, and the Health Insurance Portability and 
Accountability Act (HIPAA). 
By signing the RSA, I agree to keep all information provided in strict confidence and to request 
the same from my staff. Study documents will be stored appropriately to ensure their 
confidentiality. I will not disclose such information to others without authorization, except to the 
extent necessary to conduct the study.  
 
 
Site Name: 
 
 
 
 
Site 
Investigator: 
 
 
 
 
Signed: 
 
 
 
 
 
Date: 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALS 
Amyotrophic Lateral Sclerosis 
ALSFRS-R 
ALS Functional Rating Scale-Revised 
ALSAQ-40 
Amyotrophic Lateral Sclerosis Assessment Questionnaire 
Anti-TPO  
Anti-Thyroid Peroxidase 
AUC 
Area Under the Curve 
BHV-3241 
Verdiperstat 
BID 
Twice daily 
°C 
Degrees Celsius 
CBC 
Complete blood count 
Cmax 
Maximum Plasma Concentration 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CSF 
Cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
Cytochrome P450 
DNA 
ECG 
eCRF 
ER 
°F 
FVC 
GRAS 
HDPE 
HHD 
HIPAA 
HR 
Deoxyribonucleic Acid 
Electrocardiogram 
Electronic Case Report Form 
Extended Release 
Degrees Fahrenheit 
Forced Vital Capacity 
Generally recognized as safe 
High-density polyethylene  
Hand Held Dynamometry 
Health Insurance Portability and Accountability Act 
Hazard Ratio 


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IB 
ICF/IC 
ICH 
IP 
IRB 
IWRS 
LPLV 
MAD 
mg 
MPO 
MSA 
NADPH 
NfL 
NOEL 
NOX 
NRF2 
OLE 
PD 
PET 
P-gp 
PK 
PMA 
PP 
QD 
QTcF 
ROS 
RNS 
RSA 
SAD 
SAE 
Investigator Brochure 
Informed Consent Form 
International Council on Harmonization  
Investigational Product 
Institutional Review Board 
Interactive Web-Based Response System 
Last participant last visit 
Modification of Diet in Renal Disease 
Milligram 
Myeloperoxidase 
Multiple System Atrophy 
Nicotinamide adenine dinucleotide phosphate 
Neurofilament Light Chain 
No-Observed-Effect-Level 
NADPH oxidase 
Nuclear factor erythroid 2–related factor 2 
Open-Label Extension 
Pharmacodynamic 
Positron emission tomography 
P-glycoprotein 
Pharmacokinetic 
Phorbol-12-myristate-13-acetate 
Polypropylene 
Once Daily 
Corrected QT Interval by Fridericia 
Reactive oxygen species 
Reactive nitrogen species 
Regimen-specific appendix 
Single Ascending Dose 
Serious Adverse Event 


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SI 
SOA 
SOD 
SVC 
T3 
T4 
TSPO 
TPO 
TSH 
TSPO 
USB 
USP 
VC 
WOCBP 
Site Investigator 
Schedule of Activities 
Superoxide dismutase 
Slow Vital Capacity 
Triiodothyronine 
Thyroxine 
Translocator Protein 
Thyroid Peroxidase 
Thyroid Stimulating Hormone 
Translocator Protein 
Universal Serial Bus 
US Pharmacopoeia 
Vital Capacity 
Women of Childbearing Potential 
 
 
 


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REGIMEN-SPECIFIC APPENDIX (RSA) SUMMARY 
Regimen-Specific Appendix [B] 
For verdiperstat (also known as BHV-3241). 
Rationale and RSA Design 
The proposed study is based on cumulative preclinical and clinical studies that implicate 
myeloperoxidase (MPO) activity in the onset and progression of neurodegenerative diseases and 
suggest treatment with verdiperstat at a dosage of 600 mg twice daily (BID) has the potential to 
slow neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). 
Allocation to Treatment Regimens 
Participants must first be screened under the Master Protocol before they are randomized to an 
RSA. As soon as pre-defined criteria for futility for the RSA are met, or the target number of 
randomized participants for the RSA has been reached, enrollment will stop in the RSA.  
Number of Planned Participants and Treatment Groups 
The number of planned participants for this regimen is approximately 160.   
There are 2 treatment groups for this regimen, active and placebo. Participants will be 
randomized in a 3:1 ratio to active treatment or placebo (i.e., 120 active: 40 placebo).   
Planned Number of Sites 
Research participants will be enrolled from approximately 60 centers in the US.  
Treatment Duration 
The maximum duration of the placebo-controlled portion is 24 weeks.  
Follow-up Duration 
At the conclusion of the 24-week placebo-controlled period of the study, all participants will 
either schedule a 28-day follow up phone call and end their participation in the regimen or have 
the option to receive verdiperstat in the open-label extension (OLE) phase of the study.  
The OLE portion of the study will continue until verdiperstat is approved and available in the 
United States, or Biohaven Pharmaceuticals terminates development of verdiperstat for ALS. At 
the completion of the OLE, a Follow-up Safety Call should be conducted approximately 28 days 
after the last dose of study drug. 
For participants who early terminate from the placebo-controlled phase, an in-person Early 
Termination Visit and a Follow-up Safety Call should be conducted. At the Early Termination 
Visit the same procedures as described for the Week 24 visit should be conducted. At the 
Follow-up Safety Call, information on clinical status should be collected.  


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For participants who early terminate from the OLE, an in-person Early Termination Visit and a 
Follow-up Safety Call should be conducted. At the Early Termination Visit the same procedures 
as described for the Final visit should be conducted. At the Follow-up Safety Call, information 
on clinical status should be collected. 
Total Planned Trial Duration 
For participants completing only the placebo-controlled Treatment Period of the study, the 
planned amount of time for participation in the trial is 34 weeks, or about 8 months. This 
duration assumes a 6-week screening window, a 24-week placebo-controlled treatment period, 
and a 28-day safety follow-up period for those participants who do not enter the OLE. 
Participants will complete approximately 10 study visits during the placebo-controlled period of 
the study.


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SCHEDULE OF ACTIVITIES – 24-WEEK PLACEBO-CONTROLLED PHASE 
As per the Schedule of Activities (SOA) below, visits must occur every 4 weeks and will be alternatively clinic-, phone-, or telemedicine-based, as applicable. 
There is a maximum 24-week duration of placebo-controlled treatment for a Regimen. 
 
Activity  
Master 
Protocol 
or 
Regimen-
Specific 
Master 
Protocol 
Screening1 
Regimen 
Specific 
Screening1 
Baseline 
Week 
22 
Week 
418,19 
Week 
818,19 
Week 
12 
Week 
1618,19 
Week 
20 
Week 
24 or 
Early 
Term. 
Visit3, 
18 
Follow-
up 
Safety 
Call3,4 
Clinic 
Clinic 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
-42 to -1 
Days 
-41 to 0 
Days 
Day 0 
Day 
14 +3 
Day 
28 ±7 
Day 
56 ±7 
Day 
84 ±3 
Day 
112 
±7 
Day 
140 
±3 
Day 
168 
±7 
28±7 
days 
after 
last 
dose 
Written Informed Consent – 
Placebo-controlled Period5 
Master 
X 
X 
 
 
 
 
 
 
 
 
 
Written Informed Consent - 
OLE 
Regimen 
 
 
 
 
 
 
 
X 
 
 
 
Inclusion/Exclusion Review 
Master 
X 
X6 
 
 
 
 
 
 
 
 
 
ALS & Medical History 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Neurological Exam 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs7 
Master 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Slow Vital Capacity 
Master 
X20 
 
X 
 
 
X 
 
X 
 
X 
 
Home Spirometry 
Regimen 
X20 
 
X 
 
 
X 
 
X 
 
X 
 
Muscle Strength Assessment 
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 
ALSFRS-R 
Master 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
ALSAQ-40 
Regimen 
 
 
X 
 
 
 
 
 
 
X 
 
CNS bulbar Function Scale 
Regimen 
 
 
X 
 
 
X 
 
X 
 
X 
 
12-Lead ECG 
Regimen 
X 
 
 
 
 
X 
 
 
 
X 
 


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Activity  
Master 
Protocol 
or 
Regimen-
Specific 
Master 
Protocol 
Screening1 
Regimen 
Specific 
Screening1 
Baseline 
Week 
22 
Week 
418,19 
Week 
818,19 
Week 
12 
Week 
1618,19 
Week 
20 
Week 
24 or 
Early 
Term. 
Visit3, 
18 
Follow-
up 
Safety 
Call3,4 
Clinic 
Clinic 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
-42 to -1 
Days 
-41 to 0 
Days 
Day 0 
Day 
14 +3 
Day 
28 ±7 
Day 
56 ±7 
Day 
84 ±3 
Day 
112 
±7 
Day 
140 
±3 
Day 
168 
±7 
28±7 
days 
after 
last 
dose 
Clinical Safety Labs8 
Master 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Verdiperstat (BHV-
3241specific PD 
biomarkers10 
Regimen 
 
 
X 
 
X 
X 
 
X 
 
X 
 
PK Blood Collection10 
Regimen 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Biomarker Blood Collection 
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 
Biomarker Urine Collection 
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 
DNA Collection11(optional) 
Master 
 
 
X 
 
 
 
 
 
 
 
 
CSF Collection (optional) 
Master 
 
 
X 
 
 
 
 
X17 
 
 
 
Concomitant Medication 
Review 
Master 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Concomitant Medication 
Review 
Regimen 
 
 
 
X 
 
 
 
 
 
 
 
Adverse Event Review9 
Master 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Columbia-Suicide Severity 
Rating Scale 
Master 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Install Smartphone App21 
Regimen 
 
 
X 
 
 
 
 
 
 
 
 
Voice Recording12 
Regimen 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Uninstall Smartphone App 
Master 
 
 
 
 
 
 
 
 
 
X 
 
Assignment to the Regimen  
Master 
X 
 
 
 
 
 
 
 
 
 
 
Randomization within the 
Regimen 
Master 
 
X 
 
 
 
 
 
 
 
 
Administer/Dispense 
Investigational product 
Regimen 
 
 
X13 
 
X 
X 
 
X 
 
X14 
 


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Activity  
Master 
Protocol 
or 
Regimen-
Specific 
Master 
Protocol 
Screening1 
Regimen 
Specific 
Screening1 
Baseline 
Week 
22 
Week 
418,19 
Week 
818,19 
Week 
12 
Week 
1618,19 
Week 
20 
Week 
24 or 
Early 
Term. 
Visit3, 
18 
Follow-
up 
Safety 
Call3,4 
Clinic 
Clinic 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
-42 to -1 
Days 
-41 to 0 
Days 
Day 0 
Day 
14 +3 
Day 
28 ±7 
Day 
56 ±7 
Day 
84 ±3 
Day 
112 
±7 
Day 
140 
±3 
Day 
168 
±7 
28±7 
days 
after 
last 
dose 
Study Drug 
Accountability/Compliance 
Master 
 
 
 
X2,22 
X 
X 
X22 
X 
X22 
X 
 
Dose Escalation 
Regimen 
 
 
X15 
X15 
 
 
 
 
 
 
 
Exit Questionnaire 
Master 
 
 
 
 
 
 
 
 
 
X 
 
Vital Status Determination 
Master 
 
 
 
 
 
 
 
 
 
X16 
 
1 Master Protocol Screening procedures must be completed within 42 days to 1 day prior to the Baseline Visit. The Regimen-Specific Screening Visit and 
Baseline Visit should be combined if possible.  
2 At the end of Week 2, an assessment of compliance and tolerance to this dose titration schedule will be conducted. The assessment will be conducted by phone. 
If tolerability issues are experienced with 300 mg QD or 300 mg BID dosing, the titration schedule may be modified (see Section 5.3.2). 
3  Participants will only have a Follow-Up Safety Call at this time if they do not continue into the OLE or if they discontinue prior to Week 24. Participants who 
continue into OLE will have a Follow-Up Safety Call after their last dose of study drug during the OLE phase.   
4 Participants who continue into the OLE and then early terminate will be asked to complete an Early Termination Visit and Follow-Up Safety Call as described 
in the body of this RSA.  
5 During the Master Protocol Screening Visit, participants will be consented via the Master Protocol informed consent form (ICF). After a participant is 
randomized to a regimen, participants will be consented a second time via the RSA ICF.  
6At the Regimen Specific Screening Visit, participants will have regimen-specific inclusion and exclusion criteria assessed, if applicable.  
7 Vital signs include weight, systolic and diastolic pressure, respiratory rate, heart rate and temperature. Height is measured at Master Protocol Screening Visit 
only. 
 8 Clinical safety labs include hematology (CBC with differential), complete chemistry panel, thyroid function (TSH) and urinalysis. Serum pregnancy testing will 
occur in women of child-bearing potential at the Master Protocol Screening Visit and as necessary during the study. Pregnancy testing is only repeated as 
applicable if there is a concern for pregnancy.  
9 Adverse events that occur after signing the master protocol consent form will be recorded.  
10 Myeloperoxidase protein and activity, and plasma concentrations of verdiperstat will be measured. For each sample, the time of the last verdiperstat or 
matching placebo dose prior to sample collection, time of the last meal prior to sampling and time of the PD/PK sample collection should be reported on the 
CRF. 


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11 The DNA sample can be collected after baseline if a baseline sample is not obtained or the sample is not usable. 
12 In addition to study visits outlined in the SOA, participants may be asked to complete twice weekly voice recordings at home. During weeks when a participant 
is doing a voice recording in-clinic, he or she would only do one other voice recording at home that week.  
13 Administer first dose of investigational product (IP) only after Baseline Visit procedures are completed. Participants should take the first dose of IP while in the 
office/clinic on the day of the Baseline visit and stay at the clinic for approximately 30 minutes post-dose for observation. 
14 Investigational product will only be dispensed at this visit if the participant continues in the OLE.  
15 From start to end of Week 1, participants will ingest either 300 mg QD of verdiperstat or matching placebo QD. From start to end of Week 2, participants will 
ingest either 300 mg BID of verdiperstat or matching placebo BID. Starting with Week 3 and continuing to Week 24, participants will ingest either 600 mg BID 
of verdiperstat or matching placebo BID. 
16 Vital status, defined as a determination of date of death or death equivalent or date last known alive, will be determined for each randomized participant at the 
end of the placebo-controlled portion of their follow-up (generally the Week 24 Visit, as indicated). If at that time the participant is alive, his or her vital status 
should be determined again at the time of the last participant’s last visit (LPLV) of the placebo-controlled portion of a given regimen. We may also ascertain vital 
status at later time points by using publicly available data sources as described in section 8.15 of the Master Protocol. 
17  If the CSF collection cannot happen at the Week 16 Visit for logistical reasons such as scheduling, it can happen at the Week 24 Visit. 
18 Participants should be instructed to skip the morning dose of study drug on the day of the study visit. Study drug should not be taken until after study visit 
procedures are complete. 
19 Visit may be conducted via phone or telemedicine with remote services instead of in-person if this is needed to protect the safety of the participant due to a 
pandemic or other reason.  
20 If required due to pandemic-related restrictions, Forced Vital Capacity (FVC) performed by a Pulmonary Function Laboratory evaluator or with a study-
approved home spirometer, or sustained phonation using a study approved method may be used for eligibility (Master Protocol Screening ONLY).    
21 Two smartphone apps should be installed on the participant’s phone, one to collect the voice recordings and one to collect home spirometry. 
22 Drug accountability will not be done at phone visits. A drug compliance check in must be held during phone visits to ensure participant is taking drug per dose regimen and to 
note any report of missed doses.  


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SCHEDULE OF ACTIVITIES – REGIMEN-SPECIFIC OPEN-LABEL EXTENSION PHASE (OPTIONAL) 
Open Label Extension (Optional) 
Activity 
Week 
24 
Visit  
Week 
21 
Week 
411 
Week 
811 
Week 
12 
Week 1610,11 
Week 
20 
Week 
24 
Week 2810,11 
and Q12 
weeks 
Follow-up 
Safety Call3,4 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Phone 
Day 0 
Day 
14 +3 
Day 28 
+7 
Day 
56 
±7 
Day 
84 +3 
112 +7 days 
140+3 
days 
168+3 
days 
Q12 weeks 
+14 days 
28±7 days after 
last dose 
Vital Signs5 
X 
 
X 
X 
 
X 
 
 
X 
 
Slow Vital Capacity 
X 
 
X 
X 
 
X 
 
 
X 
 
Home Spirometry 
 
 
X 
X 
 
X 
 
 
X 
 
Muscle Strength Assessment 
X 
 
 
 
 
 
 
 
 
 
ALSFRS-R 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
ALSAQ-40 
X 
 
 
 
 
 
 
 
X14 
 
CNS bulbar Function Scale 
X 
 
 
X 
 
X 
 
 
X 
 
12-Lead ECG 
X 
 
X 
 
 
 
 
 
X13 
 
Clinical Safety Labs6 
X 
 
X 
X 
 
X 
 
 
X 
 
Biomarker Blood Collection 
X 
 
 
 
 
X 
 
 
X12 
 
Verdiperstat (BHV-3241specific 
PD biomarkers7 
X 
 
 
 
 
X 
 
 
X12 
 
PK Blood Collection7 
X 
 
 
 
 
X 
 
 
X12 
 
Biomarker Blood Collection 
X 
 
 
 
 
X 
 
 
X12 
 
Biomarker Urine Collection 
X 
 
 
 
 
X 
 
 
X12 
 
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Event Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Columbia-Suicide Severity 
Rating Scale 
X 
 
X 
X 
 
X 
 
 
X 
 
Administer/Dispense 
Investigational product 
X8 
 
X 
X 
 
X 
 
 
X15 
 
Drug 
Accountability/Compliance 
X 
X16 
X 
X 
X16 
X 
X16 
X16 
X 
 
Dose Escalation 
 
X9 
 
 
 
 
 
 
 
 


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1 At the end of Week 2, an assessment of compliance and tolerance to this dose titration schedule will be conducted. The assessment will be conducted by phone. 
If tolerability issues are experienced with 300 mg QD or 300 mg BID dosing, the titration schedule may be modified (see Section 5.3.2). 
2 The last visit for the open-label extension will be at Week 52. Participants who withdraw consent or terminate early (prior to Week 52) from the study will be 
asked to be seen for an in-person Early Termination Visit and should have the same procedures as the Week 52 visit.  
3 Participants who continue into the OLE and then early terminate will be asked to complete an Early Termination Visit and Follow-Up Safety Call as described 
in the body of this RSA.  
4  Participants will have a Follow-up Safety Call approximately 28 days after the last dose of study drug. At this call, information on clinical status should be 
collected.  
5 Vital signs include weight, systolic and diastolic pressure, respiratory rate, heart rate and temperature. 
6 Clinical safety labs include hematology (CBC with differential), complete chemistry panel, liver function tests, thyroid function (TSH) and urinalysis. Serum 
pregnancy testing will occur in women of child-bearing potential at the Master Protocol Screening Visit and as necessary during the study. Pregnancy testing is 
only repeated as applicable if there is a concern for pregnancy. 
7 Myeloperoxidase protein and activity, and plasma concentrations of verdiperstat will be measured. For each sample, the time of the last verdiperstat dose prior 
to sample collection, time of the last meal prior to sampling, and time of the PD/PK sample collection should be reported on the CRF. 
8 Administer first dose of investigational product (IP) only after Week 24 procedures are completed. Participants should take the first dose of IP while in the 
office/clinic on the day of the Week 24 visit and stay at the clinic for approximately 30 minutes post-dose for observation. 
9 From start to end of Week 1, participants will ingest 300 mg QD of verdiperstat QD. From start to end of Week 2, participants will ingest 300 mg BID of 
verdiperstat BID. Starting with Week 3 and continuing to Week 52, participants will ingest 600 mg BID of verdiperstat BID.  
10 Participants should be instructed to skip the morning dose of study drug on the day of the study visit – at OLE Weeks 16, 28 and 52. Study drug should not be 
taken until after study visit procedures are complete. 
11 Visit may be conducted via phone or telemedicine with remote services instead of in-person if this is needed to protect the safety of the participant due to a 
pandemic.  
12 Biomarker Blood Collection, Biomaker Urine Collection and all regimen-specific samples will occur at OLE Weeks 16, 28 and 52 only. 
13 12-Lead ECG is performed at OLE Weeks 4 and 52 only 
14 The ALSAQ-40 is performed at OLE Weeks 28 and 52 only 
15 Investigational product is not administered at the participant’s final in-clinic visit at the completion of the OLE. 
16 Drug accountability will not be performed at phone visits.  A drug compliance check-in must be held during phone visits to ensure participant is taking drug 
per dose regimen and to note any report of missed doses. 
 


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Version 4.0 , 09/02/2020 
CONFIDENTIAL 
1 
   INTRODUCTION REGIMEN B: VERDIPERSTAT (BHV-3241)  
1.1 
Verdiperstat Background Information 
Biohaven Pharmaceuticals, Inc [Biohaven] is developing a new drug, verdiperstat (also known as 
BHV-3241), for the treatment of neurodegenerative diseases, including amyotrophic lateral 
sclerosis (ALS). 
Verdiperstat is a first-in-class, potent, selective, brain-permeable, irreversible myeloperoxidase 
(MPO) enzyme. MPO is one of the most abundant enzymes in activated myeloid cells, including 
microglia [1]. It is a lysosomal enzyme that plays essential roles in immune surveillance and host 
defense. In disease, innate immune system activation leads to MPO-induced pathological 
oxidative stress and further inflammation that contribute to cellular injury [1]. Increasing 
evidence suggests MPO is involved several neurodegenerative diseases [1],[2]. 
The proposed study is based on cumulative nonclinical, clinical, and neuroimaging studies that 
implicate MPO activity in the onset and progression of neurodegenerative diseases and suggest 
treatment with verdiperstat has the potential to slow neurodegeneration. The high unmet need for 
an effective treatment, together with the available data, provide a compelling rationale for the 
development of verdiperstat as a treatment for ALS. 
Summaries of relevant findings from nonclinical and clinical studies conducted with verdiperstat 
are provided. Please refer to the Investigator Brochure [3] for additional information.  
1.1.1 Primary Pharmacodynamics  
1.1.1.1 In Vitro Pharmacology  
Verdiperstat inhibitory potency was characterized in biochemical and cellular assays. In the 
biochemical assay, which was based on the physiological enzymatic activity of MPO (using 
chloride and hydrogen peroxide as substrates and hypochlorous acid as product), verdiperstat 
inhibited human MPO with an IC50 of 630 nmol/L. In cellular assays, MPO is not active in 
cellular systems unless the cells expressing the enzyme are activated, which can be accomplished 
by using phorbol-12-myristate-13-acetate (PMA), which promotes both an oxidative burst and 
extracellular release of MPO. Using PMA-activated neutrophils from human donors, verdiperstat 
was measured to have IC50 of 88 nmol/L; and using PMA-activated rat peritoneal leukocytes 
(primarily neutrophils), it had similar potency with an IC50 of 100 nmol/L.  
1.1.1.2 In Vivo Pharmacology  
• Verdiperstat efficiently inhibited MPO activity in vivo during acute rat peritonitis. 
• Verdiperstat shows the ability to reduce neurodegeneration and microglial activation in MSA 
animal models, suggesting a potential therapeutic effect in other neurodegenerative patients.  


 
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1.1.2 Secondary Pharmacodynamics  
• Verdiperstat is 14 times more potent at human MPO than at human thyroid peroxidase 
(TPO).  
• No significant interactions were observed for any other of the over 150 targets tested, 
resulting in a selectivity of more than 15- to 150-fold.  
1.1.3 Safety Pharmacology  
A battery of safety pharmacology studies was performed with verdiperstat to examine potential 
effects on the cardiovascular, nervous, respiratory, renal, and gastrointestinal functions in 
accordance with the International Conference on Harmonization (ICH) S7A and ICH S7B 
guidelines for safety pharmacology studies. Please refer to the Investigator’s Brochure (IB) for 
additional information. 
• Verdiperstat had no significant effects on central nervous system, gastrointestinal, or 
respiratory function in rats.  
• Verdiperstat had no effects on arterial blood pressure or electrocardiograms (ECGs) in 
telemetry studies in rats and dogs. Verdiperstat increased heart rate by 46% compared to 
baseline 15 minutes after administration of 600 μmol/kg (152 mg/kg) in rats.  
• In the dog cardiovascular telemetry study, verdiperstat affected only heart rate, which was 
increased by a maximum of 52% at the mid dose and by a maximum of 84% at the high dose 
at 1-2 hours. The no-observed-effect level (NOEL) for cardiovascular effects was therefore 
90 μmol/kg, giving a Cplasma of 49.8 µmol/L.  
• Hemodynamic effects of verdiperstat were evaluated in telemetered dogs following acute 
administration of 3.5, 8, 18, and 45 mg/kg. At the three lower doses, there were no major 
effects compared to vehicle on mean arterial pressure, heart rate, myo-cardiac contractility, 
cardiac output, or total peripheral resistance. At 178 μmol/kg, with a Cplasma of 100 μmol/L, 
verdiperstat increased heart rate. In addition, aortic blood flow was slightly increased and 
total peripheral resistance and stroke volume were slightly decreased. The cardiovascular 
response evoked by a rapid orthostatic tilt following oral administration of verdiperstat at 5, 
18, and 45 mg/kg was evaluated. Administration of 45 mg/kg verdiperstat caused a 
significant increase in heart rate at pre-tilt for up to 2 hours post-dosing, whereas no relevant 
variations were observed on arterial blood pressure. No incidents of orthostatic hypotension 
were observed following administration of verdiperstat at any of the doses tested. 


 
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1.2 
Verdiperstat Rationale 
Oxidative stress 
Based on extensive supportive evidence from human ALS and animal models, oxidative stress is 
thought to promote neurodegeneration in ALS and other disorders [4]. MPO catalyzes generation 
cytotoxic oxidizing and nitrosylating compounds, e.g., hypochlorous acid and peroxynitrite [5] 
[6] which are strongly implicated in the pathophysiology of ALS. This is because biological 
macromolecules undergo oxidative damage by reactive oxygen and nitrogen species 
(ROS/RNS), which leads to organelle dysfunction and neuronal death. Free radical scavengers 
and other antioxidants are obvious treatment approaches but have had disappointing effects in 
clinical trials. Advances in ROS/RNS biology explain the failure of such antioxidants and 
suggest more mechanistic strategies for reducing oxidative stress. ROS/RNS are not merely toxic 
metabolic waste products. Rather, they are part of complex cellular signaling networks that 
include ROS/RNS producing enzymes (MPO, NADPH oxidase [NOX], xanthine oxidase), ROS 
targets (NF-κB mediated inflammatory pathways, inflammasomes), and ROS-metabolizing 
enzymes (SOD and NRF2-regulated antioxidant pathways). Deregulation of ROS/RNS pathways 
contributes to other known neurodegenerative disease mechanisms, i.e., microglial activation and 
neuroinflammation. Thus, it may be advantageous to inhibit ROS/RNS producing enzymes, such 
as MPO, thereby reducing oxidative stress and inflammation in a physiologic manner. The 
general relevance of this strategy is supported by preliminary data that suggest inhibiting NOX 
reduces microglial activation and may have other benefits in an ALS model [7].  
Neuroinflammation 
Based on extensive supportive evidence from human ALS and animal models, 
neuroinflammation is also thought to be an important mediator of neurodegeneration in ALS and 
other disorders [8], [9]. Microglia, the primary innate immune cells of the brain, are central 
players that drive neuroinflammation. In disease, resting microglia are activated or transformed 
into a pathological “M1” phenotype that is characterized by secretion of pro-inflammatory 
cytokines and ROS/RNS as well as an ameboid morphology and phagocytic properties similar to 
peripheral macrophages. Modulating microglial activation is a promising and common 
therapeutic strategy for neurodegenerative diseases, including ALS. However, it is unclear how 
to determine the optimal molecular target for intervention in this dynamic, in vivo process from 
studies in disease models.  
Positron emission tomography (PET) imaging of translocator protein (TSPO) is a state-of-the-art 
method for assessing pathological neuroinflammation in human disease states Because TSPO is 
highly expressed in activated microglia, signal from TSPO-specific radioligands, such as [11C]-
PBR28, is interpreted as a measure of microglial activation. [11C]-PBR28 PET signal is dynamic, 
responsive to treatment, and potentially predictive of benefit on clinical outcome measures. 
Thus, [11C]-PBR28 PET is a valuable pharmacodynamic biomarker for anti-inflammatory 
therapies that can demonstrate central target engagement and provide proof of mechanism of 
action in human neurodegenerative disorders [10]. Cross-sectional and longitudinal [11C]-PBR28 
PET studies in participants with ALS show that [11C]-PBR28 signal is increased in ALS but 


 
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stable over at least 6 months of disease progression. Corresponding sample size and power 
calculations suggest [11C]-PBR28 PET is a sensitive biomarker allowing for efficient signal 
detection in smaller, early phase studies. Several such studies are ongoing to assess 
investigational treatments in ALS, however none of these treatments has yet demonstrated the 
ability to decrease [11C]-PBR28 uptake. By contrast, MPO inhibition is the only approach that 
has demonstrated the ability to decrease [11C]-PBR28 uptake in human neurodegenerative 
disease, highlighting the therapeutic relevance of this target for ALS. 
Additional 
MPO may also play a role in increasingly recognized disease mechanisms mediated by 
peripheral myeloid cells, including those that migrate into the brain as well as those that remain 
in the periphery [8], suggesting relevance of MPO as a therapeutic target at both sites. For 
example, circulating immune cell numbers (particularly neutrophils) appear to correlate with 
ALS disease progression measured by ALSFRS-R. And, MPO+ neutrophils seem to contribute to 
distal motor axon and muscular pathology in human ALS autopsy tissue and in an ALS animal 
model. 
1.2.1 Dosage Selection and Justification 
The dosage of verdiperstat selected for evaluation in this study is 600 mg BID. This dosage was 
selected based on cumulative experience, including nonclinical toxicology and 
safety/tolerability, pharmacokinetic, pharmacodynamic, and preliminary efficacy data from 
phase 1 and phase 2 studies.  
Nonclinical toxicology: The program for verdiperstat is comprehensive and supports oral 
administration in the clinic for chronic treatment. The following studies were included in the 
toxicology program: single and repeat-dose toxicity in rats and dogs, genotoxicity, reproductive 
toxicity, phototoxicity, and safety pharmacology. The verdiperstat 600 mg BID dosage is 
anticipated to produce pharmacokinetic exposures below limits set based on nonclinical 
toxicology data. 
Clinical studies: As of January 2021, approximately 490subjects have received verdiperstat in 
completed and ongoing studies. In the phase 1 studies (5 completed studies) in healthy subjects, 
treatment with multiple dosages of up to 900 mg BID was generally safe and well tolerated. In 
the completed phase 2 studies in participants with Parkinson’s disease and Multiple System 
Atrophy (MSA), treatment at dosages of up to 600 mg BID for 8-12 weeks was generally safe 
and well tolerated. In the phase 2 studies, the 600 mg BID dosage decreased MPO activity in 
plasma, providing evidence of peripheral target engagement; reduced TSPO binding on brain 
PET imaging, providing evidence of central target engagement and proof of mechanism 
(decreased microglial activation/neuroinflammation); and demonstrated favorable, dose-
dependent trends on clinical efficacy measures at 12 weeks in subjects with MSA. 
A phase 3 study in patients with MSA is ongoing and currently is still blinded.  In this study, 
approximately 336 subjects have received verdiperstat or placebo.  Subjects are randomized 1:1 


 
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to receive verdiperstat or placebo, 600 mg BID, for 48 weeks with the option to continue in the 
study for an additional 48 weeks of open-label treatment with verdiperstat.  Please refer to the 
Investigator’s Brochure [3] for additional information. 
2 
STUDY OBJECTIVES AND ENDPOINTS 
Primary Efficacy Objective: 
To evaluate the efficacy of verdiperstat as compared to placebo on ALS disease progression.  
 
Secondary Efficacy Objective: 
• To test the effect of verdiperstat on selected secondary measures of disease progression, 
including survival.  
 
Safety Objective: 
• To evaluate the safety of verdiperstat for ALS.  
 
Exploratory Efficacy Objective: 
• To test the effect of verdiperstat on selected biomarkers and endpoints. 
• To explore verdiperstat pharmacokinetics (PK) and pharmacodynamic (PD) effects. 
 
Primary Efficacy Endpoint: 
Change in disease severity as measured by the ALS Functional Rating Scale-Revised (ALSFRS-
R) total score using a Bayesian repeated measures model that accounts for loss to follow-up due 
to mortality.  
 
Secondary Efficacy Endpoints: 
• Change in respiratory function as assessed by slow vital capacity (SVC). 
• Change in muscle strength as measured isometrically using hand-held dynamometry 
(HHD) and grip strength. 
• Survival. 
 
Safety Endpoints: 
• Treatment-emergent adverse and serious adverse events. 
• Changes in laboratory values and treatment-emergent and clinically significant laboratory 
abnormalities. 
• Changes in ECG parameters and treatment-emergent and clinically significant ECG 
abnormalities. 
• Treatment-emergent suicidal ideation and suicidal behavior. 
 
Exploratory Efficacy Endpoints: 
• Changes in quantitative voice characteristics. 
• Changes in biofluid biomarkers of neurodegeneration. 


 
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• Changes in patient reported outcomes. 
• 
Changes in verdiperstat PK and PD biomarkers.  
• Change in respiratory function as assessed by home spirometry. 
 
3 
RSA DESIGN 
This study is a multicenter, randomized, double-blind, 2-arm placebo-controlled parallel-group 
study designed to evaluate the efficacy and safety of verdiperstat in a population of participants 
with ALS. The study is planned to consist of a Screening phase lasting a maximum of 
approximately 6 weeks (42 days) and a randomized double-blind treatment phase of 
approximately 24 weeks (see Figure 1). It is anticipated that the Randomization phase will 
include a dose titration period of approximately 2 weeks followed by a full dosage period of 
approximately 22 weeks. Participants completing 24 weeks of treatment with verdiperstat or 
placebo will be eligible to continue to an Open-label Extension Phase (OLE) which will include 
an additional 52 weeks of dosing. Approximately 160 participants in total are planned to be 
randomized in a 3:1 ratio to receive either verdiperstat 600 mg BID, or matching placebo BID. 
The assessments for each visit are outlined in the Schedule of Activities (SoA).  
  
Figure 1. 
Regimen Specific Appendix Schematic 
 
3.1 
Scientific Rationale for RSA Design 
This RSA is designed to correspond with the design of the Master Protocol and the goals of that 
study. 
Verdiperstat (BHV-3241) 
600 mg BID 
Placebo BID 
Master/RSA 
Screening 
Phase 
6 weeks 
(maximum) 
Randomized Double Blind 
Phase 
24 weeks 
R
Open-label 
Extension Phase 
52 weeks  
Verdiperstat 


 
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3.2 End of Partipation Definition  
A participant is considered to have ended his or her participation in the placebo-controlled period 
of the Regimen if they:  
• Complete planned placebo-controlled period visits, as described in the SOA, including 
participants on or off study drug 
• Early terminate from the study and complete the Early Termination Visit and Follow-Up 
Phone call as described in Section 6.1.11 
• Withdraw consent to continue participation in the study, or are lost to follow-up 
If a participant initiates open-label study drug in the OLE period, he or she is considered to have 
completed his or her participation in the OLE period of the Regimen if they choose to 
discontinue participation or if all planned OLE period visits, including the last visit or the last 
scheduled procedure shown in the SOA, have been completed.  
3.3    End of Regimen Definition 
 
The end of the placebo-controlled period in a Regimen occurs when all randomized participants 
have completed their participation in the placebo-controlled period as defined in section 3.2. 
The end of the OLE period in a Regimen occurs when all participants who initiated open-label 
study drug in the OLE period have completed their participation in the OLE period as defined in 
Section 3.2. 
 
 


 
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4 
RSA ENROLLMENT  
4.1 
Number of Study Participants 
Approximately 160 participants will be randomized into this Regimen. 
4.2 
Additional RSA Inclusion and Exclusion Criteria 
To be randomized to an RSA, participants must meet the Master Protocol eligibility criteria. In 
addition, participants meeting all the following inclusion and exclusion criteria will be allowed to 
enroll in this Regimen. 
4.2.1 RSA Inclusion Criteria 
There are no additional RSA Inclusion Criteria from those described in the Master Protocol. 
4.2.2 RSA Exclusion Criteria  
• Participants who are taking strong inhibitors of CYP1A2 (i.e., ciprofloxacin, enoxacin, 
fluvoxamine, zafirlukast) for chronic/long-term use defined as more than two weeks.  
• Participants who are taking strong inhibitors of CYP3A4 (i.e., conivaptan, itraconazole, 
ketoconazole, posaconazole, troleandomycin, voriconazole, clarithromycin, diltiazem, 
idelalisib, nefazodone, and certain antiviral agents [cobicistat, danoprevir, ritonavir, 
elvitegravir, indinavir, lopinavir, paritaprevir, ombitasavir, dasabuvir, saquinavir, tipranavir, 
nelfinavir]) for chronic/long-term use defined as more than two weeks. Note: Topical 
antifungal use is not exclusionary. Participants should not consume large quantities of 
grapefruit juice (more than 8oz per day) on a regular basis.  
There are RSA-specific requirements that apply to Master Protocol exclusion criteria #6. For 
further details of contraceptive requirements for this RSA, please refer to Section 5.8.2. 
Guidance regarding CYP1A2 and CYP3A4 has been updated in Protocol Section 5.8 Drug-Drug 
Interactions and Prohibited Medications, however this exclusion criteria has not been modified 
as all participants have been enrolled. 
4.3 
Treatment Assignment Procedures 
Each participant who meets all eligibility criteria for the RSA will be randomized to receive 
either verdiperstat or matching placebo for approximately 24 weeks of treatment. Participants 
who complete the 24-week blinded Treatment Period will be eligible to continue treatment with 
open-label verdiperstat for an additional 52 weeks. 


 
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5 
INVESTIGATIONAL PRODUCT 
The Investigational Product (IP) should be stored in a secure area according to local regulations. 
It is the responsibility of the Site Investigator (SI) to ensure that the IP is only dispensed to study 
participants. The IP must be dispensed only from official study sites by authorized personnel 
according to local regulations.  
In this protocol, the IP is verdiperstat 300 mg extended release (ER) tablets and matching 
placebo tablets. 
5.1 
Investigational Product Manufacturer 
Biohaven Pharmaceuticals, Inc. is the manufacturer of verdiperstat. 
5.2 
   Labeling, Packaging, and Resupply 
5.2.1 Labeling 
Container(s) of investigational product will bear a label containing (at a minimum) the name of 
the study drug, lot and/or batch number and appropriate storage conditions (15°-25°C [59°-77°F] 
[see USP controlled room temperature] in a tightly closed container, protected from light).  
The drug product is presented as verdiperstat Extended Release (ER) Tablets that are reddish-
beige, film coated and oval (300 mg strength). The tablets each consist of 300 mg of verdiperstat 
drug substance as free base, and generally recognized as safe (GRAS) excipients for oral dosage 
forms including hydroxypropyl methyl cellulose, microcrystalline cellulose, hydroxypropyl 
cellulose, sodium stearyl fumarate and orange color. Matching placebo tablets contain 
microcrystalline cellulose and sodium stearyl fumarate and are film-coated with OPADRY® 
(mixture of hypromellose, polyethylene glycol and titanium dioxide) and iron oxide to give 
reddish-beige color. The tablets are packed in high-density polyethylene (HDPE) bottles. The 
bottles are induction sealed and closed with child resistant polypropylene (PP) screw caps. 
All investigational products should be kept in a secure area with limited access under appropriate 
storage conditions: 15°-25°C (59°-77°F) (see USP controlled room temperature) in a tightly 
closed container, protected from light.  
Excursions outside this storage temperature range should be reported as per the Pharmacy 
Manual Instructions.  
5.2.2    Acquisition and Preparation 
Initially, after informed consent is obtained at the Screening Visit, the SI or designee will enter 
the participant into the study and obtain a participant number assignment. After completion of 
Screening evaluations, all eligible participants will be randomized, in a 3:1 ratio to receive either 
verdiperstat (600 mg BID) or matching placebo, using an EDC.  


 
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5.2.3 Drug Returns and Destruction 
At each in person visit the steps outlined in Manual of Procedures must be followed for study 
drug accountability and compliance, as well as study drug return and destruction.  
 
Prior to study drug destruction, all used and unused IP requires a second accountability 
verification to be completed by a different study team member, and both verifications should be 
documented on the study destruction logs. No study drug may be destroyed on-site until written 
approval is provided by the study monitoring team. Sites should follow their local drug 
destruction policies. 
 
5.3 
Study Medication/Intervention, Administration and Duration, and Titration 
All participants will be randomized to receive verdiperstat 600 mg BID or matching placebo 
BID. Participants should take the study drug twice a day; dosing in the morning and evening 
approximately 12 hours apart. 
The tablets should be swallowed whole with a drink of water (or other liquid) or swallowed 
with substances of other consistencies as appropriate (e.g., apple sauce). The tablets should 
not be split, chewed, or crushed.  
Study medication can be taken without regard to meals. 
5.3.1 Administration and Duration 
Day 1/first dose: 
Participants should be administered the Day 1/first dose of study medication (300 mg QD or 
matching placebo QD) while in the office/clinic on the day of the Regimen-Specific Baseline 
visit after all visit assessments are complete. Participants should stay at the office/clinic for 
monitoring for approximately 30 minutes post-dose. 
Dose titration period: 
From the beginning to the end of Week 1 participants should ingest either 300 mg QD of 
verdiperstat or matching placebo QD. From the beginning to the end of Week 2, participants 
should ingest either 300 mg BID of verdiperstat or matching placebo BID.  
At the end of Week 2, an assessment of compliance and tolerance to this dose titration schedule 
will be conducted. The assessment will be conducted by phone. If tolerability issues are 
experienced with 300 mg QD or 300 mg BID dosing, the titration schedule may be modified (see 
5.3.2). 


 
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Full dose period: 
Starting with the beginning of Week 3 and throughout the remainder of the study, participants 
should ingest either 600 mg BID of verdiperstat or matching placebo BID. 
At the Weeks 4, 8, 16, and 24 study visits, the morning dose of study medication should be held 
on the day of the study visit and administered in the clinic/office during the study visit, to collect 
one pre-dose (trough) PK and PD blood sample (see Section 8). 
5.3.2 Dosage Modification 
Participants will be instructed on the dosing regimen. If tolerability issues are experienced during 
the dosage titration period with the 300 mg QD and/or 300 mg BID doses (or matching placebo), 
the titration schedule may be extended (e.g., up titration to the next dosage level delayed by an 
additional week). Potential tolerability issues may include sudden, clinically significant changes 
from baseline in symptoms of presyncope, syncope, orthostatic hypotension, or falls that are not 
otherwise explained. The SI must consult with the Medical Monitor if he or she believes that a 
change to the dosage titration schedule is warranted; and, the SI must document any such 
changes to the dosage titration schedule.  
During the full dose period of the study, it is anticipated that all participants will receive either 
verdiperstat 600 mg BID or matching placebo BID. If participants have difficulty tolerating 
verdiperstat 600 mg BID or matching placebo BID dosing, the SI may permit the participants to 
switch to verdiperstat 300 mg BID or matching placebo BID dosing (and document this change 
in the participant’s records). Potential tolerability issues may include those listed above as well 
as clinically significant laboratory abnormalities (i.e., thyroid and renal function) that are not 
otherwise explained. Down titration to verdiperstat 300 mg BID or matching placebo BID will 
only be allowed to address tolerability issues and only with Medical Monitor approval. If a 
participant is down titrated to the 300 mg BID dose, they may be allowed to retry the 600 mg 
BID dose (re-challenge), if deemed appropriate by the SI and Medical Monitor. Only two re-
challenges are allowed. Any such changes must be documented. If a switch to verdiperstat 300 
mg BID or matching placebo BID dosing does not result in acceptable tolerability, then dosing 
should be discontinued.  
Dosage modification should be considered if a participant experiences one of the following:  
a. Clinically significant changes in frequency and/or severity from baseline in symptoms of 
presyncope, syncope, orthostatic hypotension, and/or falls that are not explained by disease 
progression or intercurrent illness and not able to be adequately treated with symptomatic 
pharmacological and non-pharmacological treatments, based on the judgement of the SI. 
b. Development of Grade 3 or Grade 4 hypothyroidism. Re-challenge may be attempted, if 
warranted, when improved to less than or equal to Grade 2 (inclusive of treatment with 
thyroxine replacement therapy, see Section 9.1). 


 
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c. Development of a greater than or equal to Grade 3 toxicity or an intolerable side effect 
attributed to verdiperstat based on the judgement of the SI. Re-challenge may be attempted, if 
warranted, when symptoms improve to less than or equal to Grade 1.  
 
5.4 
Drug Holiday 
Other dosage reductions or holidays may be determined by the SI who should consult with the 
Medical Monitor. If a participant experiences an AE for which the SI believes a dose reduction 
or holiday is warranted, then the SI may temporarily suspend dosing (dose holiday) until such 
time as he/she feels it is safe for the participant to return to the assigned dose. Any such 
modifications to the dosage regimen should be noted in the eCRF. If greater than seven days, 
then a discussion with the Medical Monitor must take place and is required. If a participant is off 
study drug for more than 14 consecutive days, the participant should re-escalate using the 
titration paradigm described in section 5.3.1.  
5.5 
Participant Compliance 
Responsible study personnel will dispense the study drug. Participants will be requested to return 
any unused IP including empty packaging and used bottles at each study visit. Treatment 
compliance will be assessed at in clinic study visits through bottle counts and will be 
documented and summarized by a drug-dispensing log for each participant. During phone visits, 
drug compliance check-in will be held to ensure participant is taking drug per dose regimen and 
to note any report of missed doses. Participants will be counseled on the importance of taking the 
study drug as directed at all study visits. If poor compliance continues, (i.e., multiple missed 
doses resulting in less than 80% overall compliance), discontinuation of the participant from the 
trial should be considered and discussed with the Medical Monitor.  
If the participant loses the ability to swallow while enrolled in Regimen B, the participant will no 
longer be able to take the study drug as directed. If this occurs the participant will discontinue 
study drug and will be asked to complete the 6-month study under ITT.  
 
5.6 
Justification for Dosage 
The dosage of verdiperstat proposed for evaluation in this ALS platform trial regimen is 600 mg 
BID. This dosage selection was based on cumulative clinical and nonclinical experience with 
verdiperstat, including nonclinical toxicology, safety and efficacy data in multiple system 
atrophy and Parkinson’s disease patients. Please refer to the Investigator’s Brochure [3] for 
additional information. 
5.7 
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 as 
defined above (suspected or confirmed and irrespective of whether or not it involved 


 
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verdiperstat) must be communicated to the Healey Center and Biohaven Pharmaceutical or a 
specified designee within 24 hours of the SI becoming aware of the updated information and be 
fully documented as an SAE. An SAE is reported for overdose when the SI feels the overdose 
was excessive and medically important. Details of any signs or symptoms and their management 
should be recorded including details of any antidote(s) administered. 
5.8 
Drug-Drug interactions and Prohibited Medications 
5.8.1 Effect of other drugs on verdiperstat metabolism 
Verdiperstat drug-drug interactions have been evaluated in clinical DDI studies. One recently 
conducted study evaluated the effect of fluvoxamine (a strong CYP1A2 inhibitor) on 
concomitantly administered verdiperstat [11]. Fluvoxamine increased the AUC of verdiperstat 
2.2-fold and the Cmax by 68%, indicating that verdiperstat is a moderately sensitive CYP1A2 
substrate. Therefore, interactions are expected to occur when verdiperstat is given concurrently 
with agents that affect CYP1A2. In order to minimize any potential safety risks:  
: 
• Strong inhibitors of CYP1A2 (i.e., ciprofloxacin, enoxacin, fluvoxamine) could potentially 
increase verdiperstat levels and should be excluded for both chronic/long-term and 
acute/short-term use.  
• Moderate inhibitors of CYP1A2 (i.e., methoxsalen, mexiletine) could potentially increase 
verdiperstat levels and should be used with caution for chronic/long-term (>2 weeks) use, 
based on the clinical judgement of the SI. 
• Moderate inducers of CYP1A2 (i.e., phenytoin, rifampin, ritonavir, and teriflunomide) could 
reduce verdiperstat levels and should be used with caution for chronic/long-term (>2 weeks) 
use, based on the clinical judgement of the SI. 
An additional clinical DDI study, which was recently conducted, tested the effect of itraconazole 
(a strong CYP3A4 inhibitor) on concomitantly administered verdiperstat [12]. Itraconazole did 
not have a clinically significant impact on verdiperstat exposure, indicating that verdiperstat is 
not a sensitive CYP3A4 substrate in vivo. Therefore, there are no recommended DDI-based 
restrictions to concomitant administration of CYP3A4 inhibitors or inducers with verdiperstat. 
5.8.2 Effect of verdiperstat on the metabolism of other drugs:  
A clinical DDI study was recently conducted to evaluate the effect of verdiperstat on 
concomitantly administered midazolam (a sensitive CYP3A4 substrate) [13]. Verdiperstat 
moderately reduced the exposure of midazolam and a ~2.5-fold increase of hydroxy-
Metabolite/Parent ratio confirmed metabolic induction as the mechanism for midazolam 
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inducer. Therefore, interactions are expected to occur when verdiperstat is given concurrently 
with agents that are principally metabolized by CYP3A4. 
Drugs principally metabolized by CYP3A4 (i.e., atorvastatin, buspirone,, ethinylestradiol 
[hormonal contraceptives], quetiapine, telithromycin, quinidine, verapamil, warfarin, zileuton) 
should be used with caution, based on the clinical judgement of the SI. Note: The effectiveness 
of certain estrogen-containing oral hormonal contraceptives may potentially be reduced. Women 
of childbearing potential (WOCBP) who use estrogen-containing oral hormonal contraceptives 
must use alternative and/or additional barrier methods of birth control while participating in this 
RSA. Procedures for documenting alternative and/or additional methods of birth control will be 
detailed in the Manual of Procedures. 
 In vitro, verdiperstat markedly induced human CYP2B6 at 50 μmol/L, but not at 1 mol/L [14]. 
The verdiperstat dosage of 600 mg BID measured in previous studies generated a steady state, 
geometric mean Cmax level of 4.15 μmol/L [CV: 41.6%]). Thus, verdiperstat is unlikely to cause 
significant enhancements in the clearance of coadministered drugs through CYP2B6 inductive 
processes at therapeutic verdiperstat concentrations. 
Nonetheless, interactions may theoretically occur when verdiperstat is given concurrently with 
agents that are principally metabolized by CYP2B6. Verdiperstat induction of CYP2B6 may 
reduce exposures of CYP2B6 substrates, leading to potential loss of efficacy.  Therefore, in order 
to minimize any potential safety risks: 
• Drugs principally metabolized by CYP2B6 (i.e., bupropion, cyclophosphamide, efavirenz, 
ifosfamide, methadone) should be used with caution, based on the clinical judgement of the 
SI.  
5.9 
Verdiperstat Known Potential Risks and Benefits 
ALS is an adult-onset, fatal neurodegenerative disease. No disease modifying treatment currently 
exists, only symptomatic and palliative approaches are available. Verdiperstat is an irreversible 
inhibitor of the MPO enzyme that promotes oxidative stress and neuroinflammation. The high 
unmet need for an effective treatment for ALS, together with the available preclinical and 
clinical data with verdiperstat, provide a compelling and favorable overall benefit-risk 
assessment for the development of verdiperstat at the 600 mg BID dosage as a treatment for 
ALS. The safety monitoring in the planned clinical study will minimize the potential risks to 
study participants. 
5.9.1 Known Potential Risks 
Preclinical and clinical studies have demonstrated an acceptable safety and tolerability profile for 
verdiperstat but do suggest specific potential risks. The present study includes general and 
specific safety procedures anticipated to minimize any potential risks. 
General procedures will include frequent safety assessments by SIs, thorough evaluations and 
review of AEs and SAEs on an ongoing basis to monitor for any safety signals or trends by the 


 
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Sponsor and Medical Monitor, and Data Safety Monitoring Board review of the benefit-risk of 
the study for participants. 
5.9.1.1 Thyroid 
In preclinical studies, reversible histopathological changes in the thyroid gland and reversible 
thyroid hormone changes were observed. In clinical studies, verdiperstat has been associated 
with laboratory changes indicative of decreased thyroid function. Specifically, there have been 
increases over time in mean TSH levels and some decreases over time in mean free T4 and mean 
free T3 levels relative to placebo. Most participants did not have thyroid function test values 
outside the normal range, and the abnormalities that occurred were mild. Changes in thyroid 
function tests associated with verdiperstat returned toward baseline levels during the period of 
observation following discontinuation of verdiperstat. 
In aggregate, clinically significant thyroid function abnormalities were rare or infrequent with 
verdiperstat. The present study will involve monitoring of thyroid function. Thyroid function test 
abnormalities indicating clinically significant thyroid hormone deficiency are readily treatable 
with thyroid hormone replacement (see Section 9.1).  
5.9.1.2 Renal 
Reversible renal findings were observed in the 1-month preclinical studies in female rats at high 
doses, and no renal changes were noted in the 6-month study. In clinical studies, verdiperstat has 
been associated with decreases in mean uric acid levels over time relative to placebo. A variable 
proportion of participants receiving verdiperstat have had plasma uric acid levels below the 
lower limit of normal. Decreases in uric acid levels associated with verdiperstat have tended to 
return toward baseline following the discontinuation of dosing. Indices of renal function have not 
shown any abnormalities associated with verdiperstat. The mechanism of the changes in uric acid 
levels is unclear but could include decreased uric acid production or decreased renal tubular 
reabsorption. Hypouricemia is thought to be a biochemically defined disorder with no known 
clinical significance.  
In aggregate, clinically significant renal events associated with decreases in uric acid levels have 
not been observed with verdiperstat. The present study will continue to monitor for indices of 
renal function. 
5.9.1.3 Cardiovascular 
Increases in heart rate were observed in dogs during the preclinical studies. However, 
verdiperstat had no effect on blood pressure or on ECG parameters at any dose. Two studies 
evaluating cardiovascular response to orthostatic tilt in dogs were also performed; no incidences 
of orthostatic hypotension were observed following administration of verdiperstat. 
The first SAD clinical study [15] was discontinued on the basis of AEs that included syncope 
associated with brief sinus pauses detected on cardiac telemetry. Two of the cases of syncope 
were associated with orthostatic testing. There was not a relationship between these events and 


 
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verdiperstat concentrations. There was no evidence of direct proarrhythmic or other cardiotoxic 
effects. It was considered that events of syncope may have represented an exaggerated 
physiological response to study procedures, involving syncope of neurocardiogenic origin. 
However, an effect of verdiperstat could not be ruled out. A second SAD study [16] was 
conducted with 2 modifications designed to reduce the risk of syncope: (1) the exclusion of 
participants with a history of recurrent presyncope and/or syncope in connection with orthostatic 
challenge, and (2) fractionated dosing. In this second SAD study, there were no episodes of 
presyncope or syncope, and no clinically relevant findings involving vital signs or ECG 
parameters. Subsequent clinical studies have used ER formulations and there have been no cases 
of syncope in participants receiving verdiperstat. There have been some AEs potentially related 
to syncope (e.g., dizziness, orthostatic hypotension). Overall, there have been no clinically 
relevant findings involving vital signs or ECGs, with the exception of some decreases in the 
mean RR interval observed in the verdiperstat 600-mg BID group in the safety/tolerability study 
conducted in participants with Parkinson’s disease [17].  
In the clinically concluded Phase 1 study (BHV3241-101), the effect of verdiperstat on ECG 
parameters was evaluated in 14 healthy volunteers.  Preliminary analyses of continuous ECG 
recordings (Holter monitors) demonstrated that verdiperstat may have had an effect on heart rate, 
but no clinically relevant effects on the QTcF, PR, or QRS intervals.  
In the ongoing, blinded Phase 3 study in subjects with MSA (BHV3241-301) and Phase 2/3 
study in subjects with ALS, cardiovascular events have been reported. Independent Data 
Monitoring Committees are responsible for reviewing unblinded study data from each study on a 
regular basis in order to safeguard the interests of the enrolled study subjects and for monitoring 
the benefit-risk profile of the blinded clinical study. 
 
In aggregate, the clinical data do not show clear evidence of significant cardiovascular 
abnormalities associated with administration of verdiperstat ER formulations. However, an effect 
of verdiperstat cannot be ruled out, and cardiovascular TEAEs and parameters, including vital 
signs and ECGs, will continue to be monitored in this study. 
 
5.9.1.4 Liver 
Minimally non-adverse, increased alanine aminotransferase and slight (adaptive) 
histopathological effects in the liver were observed in rats during the preclinical studies; these 
are likely related to enzyme induction (e.g., CYP2B1 induction). In the MAD study [18], several 
participants, including those receiving verdiperstat and placebo, had increases in hepatic 
transaminases.  
In the ongoing, blinded Phase 3 study in subjects with MSA (BHV3241-301), preliminary data 
indicate that 4 subjects (1.2%) discontinued the study due to elevations in liver enzymes.  Of 
these, 3 subjects had elevations 5x upper limit of normal.  All 4 subjects were asymptomatic, and 
the elevations in liver enzymes were isolated without increased bilirubin levels.  Elevated levels 
returned to normal in a few weeks. 


 
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In aggregate, the clinical data show a possible association of asymptomatic and reversible liver 
enzyme increases with verdiperstat. The present study will involve monitoring of liver function 
tests. 
5.9.2 Known Potential Benefits 
The rationale for the proposed study is based on cumulative preclinical and clinical studies that 
implicate MPO activity in the onset and progression of neurodegenerative diseases and suggest 
treatment with verdiperstat has the potential to reduce oxidative stress and neuroinflammation 
(microglial activation). 
 
 
 
 
 
 


 
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6 
REGIMEN SCHEDULE  
In addition to procedures in the Master Protocol, the following regimen specific procedures will 
be conducted during the study: 
• Home Spirometry 
o Note: Home spirometry should be collected within the visit window but will occur 
while the participant is not in the clinic (at home or other remote location).  
• ALSAQ-40 
• CNS Bulbar Function Scale 
• Blood samples for PK and PD analyses  
• Smartphone installation and removal 
• Voice recording 
 
Modifications to Regimen Schedule  
 
Designated visits in the Schedule of Activities (i.e. Week 4, Week 8, and Week 16) may be 
conducted via telemedicine (or phone if telemedicine is not available) with remote services 
instead of in-person if needed to protect the safety of the participant due to a pandemic or other 
reason. If a planned in-clinic visit is conducted via telemedicine (or phone if telemedicine is not 
available) with remote services, only selected procedures will be performed. Instructions on how 
to document missed procedures are included in the MOP.  
 
In addition to the procedures in the Master Protocol that should be conducted during the phone or 
telemedicine and remote visits, the following regimen-specific procedures should be completed:  
 
• Home Spirometry (Week 8 and 16 only) 
• Voice Recording 
• CNS Bulbar Function Scale (Week 8 and 16 only).  
 
Details on collection of the CNS Bulbar Function Scale, dispensing IP during remote visits, and 
documenting subjects’ willingness to participate in OLE are described in the MOP. 
 
Blood samples for PK and PD analyses and the Week 8 ECG (Week 8 only) are not collected 
during the remote visits by the home health agency and this should be recorded as such in the 
applicable source documentation and EDC.  
 


 
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6.1 
Placebo-Controlled Period 
6.1.1  Verdiperstat Regimen Specific Screening Visit 
This visit will take place in-person after the Master Protocol randomization to a regimen. There 
are no additional procedures specific for the verdiperstat RSA other than what is being done at 
the Master Protocol. 
Participants may be required to reconsent to the regimen if new procedures or information is 
added in the future. Should a participant need to reconsent, this should occur during the 
participant’s next in-person visit. If the participant’s next in-clinic visit is conducted remotely, 
reconsent may also be completed remotely using the following procedures: 
 
1. The site staff sends copy of the informed consent form to the participant.  
2. The participant reads through the consent form but does not sign.  
3. The Site Investigator, or other study staff member approved and delegated to obtain informed 
consent, contacts the participant and reviews the informed consent form with the participant.  
4. The participant signs the informed consent form and returns the original signed consent form 
back to the site. 
5. Once received at the site, the individual who consented the participant signs the informed 
consent form. 
 
 
6.1.2 Baseline Visit 
This visit will take place in-person after the Regimen-Specific Screening Visit. The following 
procedures will be performed for the regimen schedule: 
 
• ALSAQ-40 
• CNS Bulbar Function Scale  
• Collection of plasma samples for verdiperstat PD biomarkers (MPO protein and activity) and 
a plasma PK sample 
• Install Smartphone App 
• Home Spirometry 
• Voice Recording 
• Dispense IP 
• Remind participant to bring IP to the next visit 
 
After all Baseline procedures are completed, administer a single 300 mg tablet of verdiperstat or 
placebo. Participants should stay at the clinic for approximately 30 minutes for observation. 


 
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Participants should be instructed: 
• To ingest either 300 mg QD of BHV-3241 or matching placebo QD for the rest of Week 1. 
• To ingest either 300 mg BID of BHV-3241 or matching placebo BID starting at the 
beginning of Week 2.  
• Participants should take the study drug twice a day; dosing in the morning and evening 
approximately 12 hours apart.  
6.1.3 Week 2 Telephone Visit  
This visit (via telephone) will take place 14 ± 3 days after the baseline Visit. The following 
procedures will be performed for the regimen schedule: 
• Collection of concomitant medication information. 
• An assessment of compliance (i.e. whether participant has stopped taking study drug) and 
tolerance to this dose titration schedule. 
• If tolerability issues are experienced with 300 mg QD or 300 mg BID dosing, the titration 
schedule may be modified (see Section 5.3.2). 
• Participants should be instructed: 
• Starting at the beginning of Week 3, to ingest either 600 mg BID of verdiperstat or 
matching placebo BID and continue taking this dosage through the remainder of the 24-
week Treatment Period. 
 
6.1.4 Week 4 Visit 
Participants should be instructed to skip the morning dose of study drug on the day of the study 
visit. Study drug should not be taken until after study visit procedures are complete. 
 
This visit will take place in-person 28 ± 7 days after the Baseline Visit. The following 
procedures will be performed for the regimen schedule: 
• Collection of plasma samples for verdiperstat PD biomarkers (MPO protein and activity) and 
a plasma PK sample 
• Voice Recording 
• Dispense IP 
• Remind participant to bring study drug to the next visit 
 
6.1.5 Week 8 Visit  
Participants should be instructed to skip the morning dose of study drug on the day of the study 
visit. Study drug should not be taken until after study visit procedures are complete. 
 


 
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This visit will take place in-person 56 ± 7 days after the Baseline Visit.  The following 
procedures will be performed for the regimen schedule: 
• Home Spirometry 
• CNS Bulbar Function Scale  
• 12-Lead ECG 
• Collection of plasma samples for verdiperstat PD biomarkers (MPO protein and activity) and 
a plasma PK sample 
• Voice recording  
• Dispense IP 
• Remind participant to bring IP to the next visit 
 
6.1.6 Week 12 Telephone Visit 
This visit will take place 84 ± 3 days after the Baseline Visit via telephone.  
6.1.7 Week 16 Visit  
Participants should be instructed to skip the morning dose of study drug on the day of the study 
visit. Study drug should not be taken until after study visit procedures are complete. 
 
This visit will take place in-person 112 ± 7 days after the Baseline Visit. The following 
procedures will be performed: 
 
• Document participant’s willingness to participate in the OLE 
o If OLE consent is not obtained at Week 16, it may be obtained at Week 24. 
• Home Spirometry  
• CNS Bulbar Function Scale 
• Collection of plasma samples for verdiperstat PD biomarkers (MPO protein and activity) and 
a plasma PK sample 
• Voice Recording 
• Dispense IP 
• Remind participant to bring IP to the next visit 
 
6.1.8 Week 20 Telephone Visit 
This visit will take place 140 ± 3 days after the Baseline Visit via telephone. 


 
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6.1.9 Week 24 Visit or Early Termination Visit 
Participants should be instructed to skip the morning dose of study drug on the day of the study 
visit. Study drug should not be taken until after study visit procedures are complete. 
 
The Week 24 Visit will take place in-person 168 ± 7 days after the Baseline Visit.  The following 
procedures will be performed at either the Week 24 Visit or the Early Termination Visit for the 
regimen schedule: 
 
• Home Spirometry 
• ALSAQ-40 
• CNS Bulbar Function Scale  
• Collection of plasma samples for verdiperstat PD biomarkers (MPO protein and activity) and 
a plasma PK sample 
• Voice Recording 
• Uninstall Smartphone App 
• Dispense IP (only if continuing in OLE) 
• Remind participant to bring IP to the next visit  
 
For participants rolling into the OLE, all participants should be instructed to follow the dose 
escalation scheme. 
• After all Week 24 procedures are completed, administer a single 300 mg tablet of 
verdiperstat. Participants should stay at the clinic for approximately 30 minutes for 
observation. 
• Dispense study drug to last for the next 4 weeks. 
• Participants should be instructed: 
• To ingest 300 mg QD of BHV-3241 for the rest of Week 1. 
• To ingest 300 mg BID of BHV-3241 starting at the beginning of Week 2. Participants 
should take the study drug twice a day; dosing in the morning and evening approximately 
12 hours apart. 
• If tolerability issues are experienced with 300 mg QD or 300 mg BID dosing, the 
titration schedule may be modified (see Section 5.3.2). 
• To ingest 600 mg BID of BHV-3241 starting at the beginning of Week 3 and through the 
remainder of the 52-week OLE. Participants should take the study drug twice a day; 
dosing in the morning and evening approximately 12 hours apart. 
 
For participants NOT rolling into the OLE: 
A Follow-up Safety Call should be scheduled approximately 28 days after last dose of study drug 
to collect clinical status information. 


 
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6.1.10 Follow-Up Safety Call 
Participants will have a Follow-Up Safety Call 28+7 days after their last dose of study drug.  
Only those participants NOT continuing on in the Open Label Extension will have the Follow-
Up Safety Call following the end of their participation in the placebo-controlled portion of the 
trial.  The following procedures will be performed: 
 
• Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
 
6.1.11 Process for Early Terminations  
Participants who early terminate from the study and do not complete the protocol per ITT will be 
asked to be seen for an in-person Early Termination Visit and complete a Follow-Up Safety Call. 
If a participant is not able to be seen in-person, safety assessments and others that can be 
conducted remotely should be performed. 
 
The in-person Early Termination Visit should be scheduled as soon as possible after a participant 
early terminates. If the participant early terminates during the placebo-controlled portion of the 
Regimen, all assessments that are collected at the Week 24 in-clinic visit should be conducted. 
The Follow-Up Safety Call should be completed approximately 28±7 days after the last dose of 
study drug.  If the participant terminates early during the OLE period, all assessments that are 
intended for collection at the OLE Week 24 in-clinic visit should be conducted. The Follow-Up 
Safety Call should be completed approximately 28±7 days after the last dose of IP. 
 
If the Early Termination Visit occurs approximately 28±7 days after the last dose of study drug, 
the information from the Follow-Up Safety Call can be collected during the Early Termination 
Visit, and a separate Follow-Up Safety Call does not need to be completed. If the in-person Early 
Termination Visit does not occur within 28±7 days of the last dose of study drug, the Follow-Up 
Safety Call should occur approximately 28±7 days after the last dose of study drug and the Early 
Termination Visit will be completed after the Follow-Up Safety Call.   
6.1.12 Criteria for Participant Termination 
Participants MUST discontinue the IP (and non-investigational product at the discretion of the 
SI) for any of the following reasons: 
•  Withdrawal of informed consent (participant’s decision to withdraw for any reason) 
• Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the SI or sponsor, indicates that continued participation in the study is not in the 
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• Disease progression, which, in the opinion of the SI or sponsor, indicates that continued 
participation in the study is not in the best interest of the participant 
• Pregnancy 
• Termination of the study by the Sponsor 
• Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness 
All participants who discontinue study treatment earlier than Week 24 should comply with 
protocol specified Early Termination procedures as appropriate, outlined in the Schedule of 
Activities.  
An exception to the requirement for End of Treatment procedures is when a participant 
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).  
6.2 
Open Label Extension (OLE) 
Participants who have completed the placebo-controlled portion of the trial on drug, will be 
eligible to continue in the Open Label Extension.  The OLE of the study will continue until 
verdiperstat is approved and available in the United States, or Biohaven Pharmaceuticals 
terminates development of verdiperstat for ALS. 
 
Modifications to OLE Schedule  
Designated visits in the Schedule of Activities for the OLE (i.e. Week 4, Week 8, Week 16, 
Week 28, and Week 40) may be conducted via telemedicine (or phone if telemedicine is not 
available) with remote services instead of in-person if needed to protect the safety of the 
participant due to a pandemic or other reason. If a planned in-clinic visit is conducted via 
telemedicine (or phone if telemedicine is not available) with remote services, only selected 
procedures will be performed. Instructions on how to document missed procedures are included 
in the Manaul of Procedures.  
 
In addition to the procedures in the Master Protocol that should be conducted during the phone or 
telemedicine and remote visits, the following regimen-specific procedures should be completed:  
 
• Home Spirometry 
• CNS Bulbar Function Scale (Week 8 and 16 only).  
 


 
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Blood samples for Week 16  PK and PD analysis and the Week 4 and 28 ECGs are not collected 
during the remote visits by the home health agency and this should be recorded as such in the 
applicable source documentation and EDC.  
 
 
 
6.2.1 Week 2 Telephone Visit - OLE 
This visit (via telephone) will take place 14 ± 3 days after the Week 24 visit. The procedures 
listed in the SoA should be performed including: 
• Assess and document AEs and concomitant medications, including Key Study Events 
(see section 10.3 of Master Protocol) 
• Assess compliance and tolerance to this dose titration schedule  
• If tolerability issues are experienced with 300 mg QD or 300 mg BID dosing, the 
titration schedule may be modified (see Section 5.3.2). 
• Instruct participants on appropriate dosing  
• Starting at the beginning of Week 3, to ingest 600 mg BID of verdiperstat and 
continue taking this dose through the remainder of the 52-week OLE 
• Remind participant to bring in IP to the next visit  
6.2.2 Week 4 Visit – OLE 
This visit will take place in-person 28 ± 10 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The procedures listed in the SoA should be performed and 
participants should be provided with 4 weeks of drug and instructions for dosing.  
6.2.3 Week 8 Visit - OLE 
This visit will take place in-person 56 ± 7 days after the Week 24 Visit of the placebo-controlled 
portion of the trial. The procedures listed in the SoA should be performed and participants should 
be provided with 8 weeks of drug and instructions for dosing.  
6.2.4 Week 12 Telephone Visit – OLE 
This visit will take place 84 ± 3 days after the Week 24 Visit of the placebo-controlled portion of 
the trial via telephone. The procedures listed in the SoA should be performed. 
 
6.2.5 Week 16 Visit – OLE 
Participants should be instructed to skip the morning dose of study drug on the day of the study 
visit. Study drug should not be taken until after study visit procedures are complete. 
 


 
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This visit will take place in-person 112 ± 7 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The procedures listed in the SoA should be performed and 
participants should be provided with 12 weeks of drug and instructions for dosing.  
 
6.2.6 Week 20 Telephone Visit – OLE 
This visit will take place in-person 140 ± 3 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The procedures listed in the SoA should be performed. 
 
6.2.7 Week 24 Telephone Visit – OLE 
This visit will take place 196 ± 3 days after the Week 24 Visit of the placebo-controlled portion 
of the trial via telephone. The procedures listed in the SoA should be performed. 
 
6.2.8 Week 28 Visit and Q12 Weeks – OLE 
Participants should be instructed to skip the morning dose of study drug on the day of the study 
visit. Study drug should not be taken until after study visit procedures are complete. 
 
This visit will take place in-person 196 ± 14 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The procedures listed in the SoA should be performed and 
participants should be provided with 8 weeks of drug and instructions for dosing. Following the 
Week 28 OLE Visit, visit will occur every 12 weeks ± 14 days. 
 
 
 


 
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7 
OUTCOME MEASURES AND ASSESSMENTS 
For all assessments listed below, please refer to the Manual of Procedures for detailed 
instructions. 
7.1 Voice Analysis 
Voice samples will be collected twice per week, using an app installed on either an android or 
iOS based smartphone.  The app characterizes ambient noise, then asks participants to perform a 
set of speaking tasks: reading sentences -- 5 fixed and 5 chosen at random from a large sentence 
bank-- repeating a consonant-vowel sequence, producing a sustained phonation, and counting on 
a single breath. Voice signals are uploaded to a HIPAA-compliant web server, where an AI-
based analysis identifies relevant vocal attributes. Quality control (QC) of individual samples 
will occur by evaluation of voice records by trained personnel. 
 
The voice analysis app is only available in English, therefore participants who do not speak 
English should not complete the voice recording. Caregivers cannot provide language assistance 
when the participant is completing the voice recording. 
 
 
7.2 ALSAQ-40 
The Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 (ALSAQ-40) is a patient self-
report health status patient-reported outcome. The ALSAQ-40 consists of forty questions that are 
specifically used to measure the subjective well-being of patients with ALS and motor neuron 
disease. 
 
Participants will be handed the questionnaire and asked to write their answers themselves.  
Caregivers can also help, if needed. 
 
7.3 Center for Neurologic Study Bulbar Function Scale 
The Center for Neurologic Study Bulbar Function Scale (CNS-BFS) is a patient self-report scale 
that has been developed for use as an endpoint in clinical trials and as a clinical measure for 
evaluating and following ALS patients. The CNS-BFS consists of three domains (swallowing, 
speech, and salivation), which are assessed with a 21-question, self-report questionnaire. 
 
Participants will be handed the questionnaire and asked to write their answers themselves.  
Caregivers can also help, if needed. 
 


 
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Instructions on administering the questionnaire during a phone or telemedicine visit will be 
included in the MOP. 
 
7.4 Home Spirometry 
Remote/home-based forced vital capacity will be measured with the MIR Spirobank Smart 
spirometer. Instructions for use will be provided to the participant.  The participant will perform 
the vital capacity maneuver at home with real time video coaching (or phone coaching, if video 
is not available) by the evaluator.  Three to five vital capacity maneuvers will be performed, 
consistent with the manner vital capacity is obtained in clinic.   
 
8 
BIOFLUID COLLECTION 
8.2 Pharmacokinetic Assessments  
Blood samples for PK analysis should be collected at Baseline and Weeks 4, 8, 16, and 24 in the 
Treatment Phase, and at Weeks 16, 28, and 52 for participants who are in the OLE. Participants 
who discontinue early from study medication are not required to have PK samples collected at 
the early discontinuation visit. 
A PK sample should be collected pre-dose at the Baseline visit. 
At Weeks 4, 8, 16, and 24 in the Treatment Phase, and at Weeks 4, 16, 28, 40, and 52 in the 
OLE, the morning dose of study drug should be held and administered in the clinic/office during 
the study visit, so that one pre-dose (trough) PK sample can be collected. For each sample, the 
time of the last dose of study drug prior to sample collection, time of the last meal, and time of 
collection of the PK samples should be reported on the CRF.  
8.3 Pharmacodynamic Biomarker Assessments   
Blood samples for PD biomarker analysis and verdiperstat-specific PD analysis should be 
collected at Baseline and Weeks 4, 8, 16, and 24 in the Treatment Phase, and at Weeks 16, 28 
and 52 for participants who are in the OLE. Participants who discontinue early from study 
medication are not required to have PD samples collected at the early discontinuation visit.  
PD biomarkers should be collected along with the PK samples, so that one pre-dose PD sample 
is collected at each specified visit. For each sample, the time of the last dose of study drug prior 
to sample collection and time of the PD sample collection should be reported on the CRF. The 
verdiperstat-specific PD biomarkers that will be analyzed are MPO protein and MPO activity. 
Uric Acid will be collected and results remain blinded throughout the duration of the trial 
 
 


 
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9 
SAFETY AND ADVERSE EVENTS 
9.1 
Adverse Events of Special Interest – Thyroid Function 
Reversible changes in thyroid function tests were observed during the preclinical studies and 
clinical studies with verdiperstat. Based on prior trials, a small percentage of participants may be 
expected to develop mild (subclinical) hypothyroidism generally with serum TSH < 10 mIU/L. 
Laboratory monitoring of thyroid function will be performed and documented throughout this 
study. Site Investigators should review TSH levels and note the trend over time. The Central 
Laboratory will flag any TSH > ULN, and T3 and free T4 analysis should be performed.  
Any significant abnormal findings should be discussed with the study Medical Monitor and may 
be followed up as per local practice (e.g., investigations and consultation with endocrinologist). 
In cases of suspected hypothyroidism, repeat thyroid function tests should be measured and 
levothyroxine replacement therapy should be considered. Initiation of treatment is at the 
discretion of the SI.  
Potential initiation of levothyroxine (T4) replacement therapy may be considered according to 
the following guidelines: 
• For a serum TSH between 5 and 10, levothyroxine 0.05 mg daily (50 mcg) is a 
reasonable dose to prescribe. 
• For a serum TSH between 10 and 20, levothyroxine 0.075 mg daily (75 mcg) is a 
reasonable dose to prescribe. 
• For a serum TSH greater than 20, many physicians would feel more comfortable having 
an endocrinologist treat such participants.  
 
If signs/symptoms of hypothyroidism (i.e. adverse event, initiation of levothyroxine) and/or 
significant changes in thyroid function develop, collection of follow up clinical chemistry 
samples and/or unscheduled study visits may be warranted. It is recommended to wait for 5 or 6 
half-lives (5 – 6 weeks) to retest thyroid function. Serum T3, free T4 and TSH should be 
monitored in such participants, and the serum TSH assesses whether therapy is adequate. 
If there are clinically significant issues with tolerability that are not able to be treated adequately 
with levothyroxine replacement therapy, the SI may consider modifications to the dosage 
regimen. Consultation with the Medical Monitor is required. Modifications may include reducing 
the dose of verdiperstat /matching placebo to 300 mg BID or taking a dose holiday. Any such 
modifications to the dosage regimen should be noted in the CRF. 


 
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10 REGIMEN-SPECIFIC STATISTICAL CONSIDERATIONS 
10.1 Deviations from the Default Master Protocol Trial Design 
The statistical design for this regimen will be in accordance with the default statistical design 
described in Appendix I of the master protocol with only one deviation. This regimen will not 
include interim analyses for early success. As such, unless this regimen is stopped early for 
futility, it will enroll to the maximum sample size. At the final analysis, the treatment will be 
considered success relative to the shared control group if the posterior probability of superiority 
is greater than 98.0%. This value was selected by simulation to control the overall one-sided 
Type I error rate across the null scenarios to less than 2.5%. Results are based on 5000 
simulations per scenario. 
10.2 Regimen Specific Operating Characteristics 
Clinical trial simulation is used to quantify operating characteristics for this regimen given the 
difference from the default design. The simulation of virtual participants and the simulation 
scenarios are as described in Appendix I to the master protocol. We present here the operating 
characteristics for the regimen, according to the default design but with no opportunity to stop 
early for success. Futility is considered non-binding and as such, Table 10.2.1 shows null 
hypothesis scenarios and resulting Type I error with no futility stopping. We show null and 
alternative hypothesis scenarios inclusive of futility stopping in Tables 10.2.2 and 10.2.3. Table 
10.2.2 shows operating characteristics under the base case assumptions and Table 10.2.3 shows 
operating characteristics for the various sensitivity scenarios.  
This regimen will be one of the first three regimens to be enrolled in the platform and so there 
are no participants in the shared control from regimens already complete. The comparison to 
control will rely entirely upon concurrently randomized controls.  Concurrently randomized 
controls will be defined according to Appendix I to the master protocol. 
Table 10.2.1: Null Hypothesis Scenarios with No Early Futility Stopping 
Sensitivity 
Scenario 
Mean 
Duration 
(Months) 
Mean 
N 
  
Prob.  
Early 
Success 
Prob. Total 
Success 
Prob. 
Early 
Futility 
Mean DRR 
Null Treatment Effect (0% Slowing; Mort HR = 1.0) 
Base 
15 
160 
0.000 
0.020 
0.000 
1.007 
Slower Accrual 
27 
160 
0.000 
0.023 
0.000 
1.007 
Faster Accrual 
11 
160 
0.000 
0.023 
0.000 
1.008 
Less Dropout 
15 
160 
0.000 
0.021 
0.000 
1.006 
More Dropout 
15 
160 
0.000 
0.023 
0.000 
1.007 
Reg. Start Same 
Time 
18 
160 
0.000 
0.025 
0.000 
1.005 


 
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Table 10.2.1: Null Hypothesis Scenarios with No Early Futility Stopping 
Sensitivity 
Scenario 
Mean 
Duration 
(Months) 
Mean 
N 
  
Prob.  
Early 
Success 
Prob. Total 
Success 
Prob. 
Early 
Futility 
Mean DRR 
Reg. Start 3 
Months Apart 
11 
160 
0.000 
0.025 
0.000 
1.017 
ALSFRS-R 
Slower Less 
Var. Progress 
15 
160 
0.000 
0.022 
0.000 
1.006 
ALSFRS-R 
Faster More Var. 
Progress 
15 
160 
0.000 
0.022 
0.000 
1.007 
ALSFRS-R 
Lower Resid. 
Error 
15 
160 
0.000 
0.024 
0.000 
1.006 
ALSFRS-R 
Higher Resid. 
Error 
15 
160 
0.000 
0.022 
0.000 
1.007 
10% Mortality 
Rate 
15 
160 
0.000 
0.025 
0.000 
1.005 
20% Mortality 
Rate 
15 
160 
0.000 
0.023 
0.000 
1.006 
  
Table 10.2.2: Base Scenarios Operating Characteristics. Null and Alternative Hypotheses 
With Futility Stopping 
Scenario 
(% Slowing 
ALSFRS-R) 
HR 
Mort. 
Mean 
Duration 
(Months
) 
Mean 
N 
  
Prob.  
Early 
Success 
Prob. 
Total 
Success 
Prob. 
Early 
Futility 
Mean 
DRR 
0% 
1 
14 
155 
0.000 
0.020 
0.290 
1.049 
25% 
.75 
15 
160 
0.000 
0.615 
0.008 
0.747 
30% 
.7 
15 
160 
0.000 
0.776 
0.002 
0.694 
35% 
.65 
15 
160 
0.000 
0.888 
0.001 
0.642 
30% 
1 
15 
160 
0.000 
0.731 
0.003 
0.708 
30% 
1.3 
15 
160 
0.000 
0.683 
0.004 
0.722 
 
 


 
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Table 10.2.3: Base and Sensitivity Scenarios with Early Futility Stopping.  
Sensitivity 
Scenario 
Mean 
Duration 
(Months
) 
Mean 
N 
  
Prob.  
Early 
Success 
Prob. Total 
Success 
Prob. 
Early 
Futility 
Mean DRR 
Null Treatment Effect (0% Slowing; Mort HR = 1.0) 
Base 
14 
155 
0.000 
0.020 
0.290 
1.049 
Slower 
Accrual 
23 
143 
0.000 
0.023 
0.347 
1.063 
Faster Accrual 
11 
160 
0.000 
0.023 
0.257 
1.034 
Less Dropout 
14 
155 
0.000 
0.021 
0.280 
1.047 
More Dropout 
14 
155 
0.000 
0.023 
0.271 
1.047 
Reg. Start 
Same Time 
16 
154 
0.000 
0.025 
0.281 
1.035 
Reg. Start 3 
Months Apart 
10 
160 
0.000 
0.025 
0.219 
1.043 
ALSFRS-R 
Slower Less 
Var. Progress 
14 
155 
0.000 
0.022 
0.283 
1.049 
ALSFRS-R 
Faster More 
Var. Progress 
14 
155 
0.000 
0.022 
0.300 
1.047 
ALSFRS-R 
Lower Resid. 
Error 
14 
155 
0.000 
0.024 
0.295 
1.046 
ALSFRS-R 
Higher Resid. 
Error 
14 
155 
0.000 
0.022 
0.284 
1.050 
10% Mortality 
Rate 
14 
155 
0.000 
0.025 
0.286 
1.046 
20% Mortality 
Rate 
14 
155 
0.000 
0.023 
0.294 
1.046 
Alternative Common Treatment Effect (30% Slowing; Mort HR = .70) 
Base 
15 
160 
0.000 
0.776 
0.002 
0.694 
Slower 
Accrual 
27 
160 
0.000 
0.771 
0.005 
0.695 
Faster Accrual 
11 
160 
0.000 
0.762 
0.002 
0.694 
Less Dropout 
15 
160 
0.000 
0.745 
0.003 
0.694 
More Dropout 
15 
160 
0.000 
0.722 
0.003 
0.694 
Reg. Start 
Same Time 
18 
160 
0.000 
0.782 
0.002 
0.691 


 
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Table 10.2.3: Base and Sensitivity Scenarios with Early Futility Stopping.  
Sensitivity 
Scenario 
Mean 
Duration 
(Months
) 
Mean 
N 
  
Prob.  
Early 
Success 
Prob. Total 
Success 
Prob. 
Early 
Futility 
Mean DRR 
Reg. Start 3 
Months Apart 
11 
160 
0.000 
0.681 
0.003 
0.700 
ALSFRS-R 
Slower 
Progress 
15 
160 
0.000 
0.754 
0.003 
0.693 
ALSFRS-R 
Faster 
Progress 
15 
160 
0.000 
0.791 
0.002 
0.694 
ALSFRS-R 
Lower Resid. 
Error 
15 
160 
0.000 
0.793 
0.003 
0.692 
ALSFRS-R 
Higher Resid. 
Error 
15 
160 
0.000 
0.758 
0.003 
0.694 
10% Mortality 
Rate 
15 
160 
0.000 
0.782 
0.003 
0.693 
20% Mortality 
Rate 
15 
160 
0.000 
0.799 
0.003 
0.695 
Alternative Treatment Effect No Mort. Benefit (30% Slowing; Mort HR = 1.0) 
Base (5% 
Mort. Rate) 
15 
160 
0.000 
0.731 
0.003 
0.708 
10% Mort. 
Rate 
15 
160 
0.000 
0.695 
0.004 
0.721 
20% Mort. 
Rate 
15 
160 
0.000 
0.602 
0.007 
0.749 
Alternative Treatment Effect Worse Mort. (30% Slowing; Mort HR = 1.3) 
Base (5% 
Mort. Rate) 
15 
160 
0.000 
0.683 
0.004 
0.722 
10% Mort. 
Rate 
15 
160 
0.000 
0.592 
0.008 
0.750 
20% Mort. 
Rate 
15 
160 
0.000 
0.411 
0.015 
0.803 
  


 
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10.3  Sharing of Controls from Other Regimens 
The primary analysis of this regimen will include sharing of all controls from the other regimens.  
This is justified by the minor differences in inclusion/exclusion criteria of the RSA, such that 
there are no expected systematic differences in the primary endpoint between the controls across 
regimens.   
 


 
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11 REFERENCES 
1. Lefkowitz, D.L., and Lefkowitz, S.S. (2008). Microglia and myeloperoxidase: a deadly 
partnership in neurodegenerative disease. Free Radic Biol Med 45, 726-731. 
2. Pravalika, K., Sarmah, D., Kaur, H., Wanve, M., Saraf, J., Kalia, K., Borah, A., Yavagal, 
D.R., Dave, K.R., and Bhattacharya, P. (2018). Myeloperoxidase and Neurological Disorder: 
A Crosstalk. ACS Chem Neurosci 9, 421-430. 
3. Biohaven Pharmaeuticals Inc. Investigator Brochure Verdiperstat, Edition 3.0, March 2021. 
4. Singh, A., Kukreti, R., Saso, L., and Kukreti, S. (2019). Oxidative Stress: A Key Modulator 
in Neurodegenerative Diseases. Molecules 24. 
5. Casas, A.I., Dao, V.T., Daiber, A., Maghzal, G.J., Di Lisa, F., Kaludercic, N., Leach, S., 
Cuadrado, A., Jaquet, V., Seredenina, T., et al. (2015). Reactive Oxygen-Related Diseases: 
Therapeutic Targets and Emerging Clinical Indications. Antioxidants & redox signaling 23, 
1171-1185. 
6. van der Vliet, A., Eiserich, J.P., Halliwell, B., and Cross, C.E. (1997). Formation of reactive 
nitrogen species during peroxidase-catalyzed oxidation of nitrite. A potential additional 
mechanism of nitric oxide-dependent toxicity. The Journal of biological chemistry 272, 
7617-7625. 
7. Seredenina, T., Nayernia, Z., Sorce, S., Maghzal, G.J., Filippova, A., Ling, S.C., Basset, O., 
Plastre, O., Daali, Y., Rushing, E.J., et al. (2016). Evaluation of NADPH oxidases as drug 
targets in a mouse model of familial amyotrophic lateral sclerosis. Free Radic Biol Med 97, 
95-108. 
8. Beers, D.R., and Appel, S.H. (2019). Immune dysregulation in amyotrophic lateral sclerosis: 
mechanisms and emerging therapies. Lancet Neurol 18, 211-220. 
9. Hammond, T.R., Marsh, S.E., and Stevens, B. (2019). Immune Signaling in 
Neurodegeneration. Immunity 50, 955-9. 
10. Chew, S., and Atassi, N. (2019). Positron Emission Tomography Molecular Imaging 
Biomarkers for Amyotrophic Lateral Sclerosis. Front Neurol 10, 135. 
11. BHV3241-103. BHV3500-103. A Phase1, Open-Label, Drug Interaction Study to Evaluate 
the Effect of Fluvoxamine on the Pharmacokineticsof Single-Dose 
VerdiperstatAdministeredas anExtended Release Tablet in Healthy Adult Subjects: Biohaven 
Pharmaceuticals, Inc.; in reporting. 
12. BHV3241-107. A Phase1, Open-Label,Drug Interaction Study to Evaluate the Effect of 
Itraconazoleon the Pharmacokineticsof Single-Dose Verdiperstat Administered as an 
Extended Release Tablet in Healthy Adult Subjects: Biohaven Pharmaceuticals, Inc.; in 
reporting. 
13. BHV3241-106. A Phase 1, Open-Label, Drug Interaction Study to Evaluate the Effect of 
Multiple-Dose Verdiperstat Administeredas an Extended Release Tablet on the 
Pharmacokinetics of Midazolam, a Sensitive CYP3A4 Substrate, in Healthy Adult Subjects: 
Biohaven Pharmaceuticals, Inc.; in reporting. 
14. Study 3210-1088-1800. AZD3241: In Vitro Assessment of the Induction Potential of 
AZD3241 in Primary Human Hepatocyte Cultures: AstraZeneca; 2009. 
15. D0490C00001. A First Time in Man, Single-Centre, Placebo Controlled, Randomized, 
Double-blind (within dose panel) Study in Healthy Volunteers to Evaluate Safety, 


 
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Tolerability and Pharmacokinetics after Oral Single Ascending Doses of AZD3241: 
AstraZeneca; 2007. 
16. D0490C00012. A Single-Centre, Placebo-Controlled, Randomised, Double-Blind Study to 
Evaluate the Safety, Tolerability and Pharmacokinetics of AZD3241 following 
Administration of Single Ascending (Part A) and Fractionated Ascending (Part B) Oral 
Doses to Young Healthy Volunteers: AstraZeneca; 2009. 
17. D0490C00005. A Phase IIa, 12 Week, Multicentre, Double-Blind, Randomized, Placebo 
Controlled, Parallel-Group Study to Assess the Safety and Tolerability of Oral AZD3241 in 
Patients with Parkinson’s Disease: AstraZeneca; 2014. 
18. D0490C00002. A Phase I, Single Centre, Double-blind, Randomised, Placebo-controlled, 
Parallel-group Study to Assess the Safety, Tolerability and Pharmacokinetics of Extended 
Release Tablets of AZD3241 after Administration of Multiple Ascending Doses in Healthy 
Male and Female Volunteers including the Effect of Food: AstraZeneca; 2010. 
 
 
 


 
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Appendix I: The Bulbar Function Scale (CNS-BFS)  
BULBAR FUNCTION SCALE (CNS-BFS) 
SIALORRHEA 
Does 
Not 
Apply 
(1) 
Applies 
Rarely 
(2) 
   Applies 
Occasionally 
(3) 
Applies 
Frequently  
(4) 
Applies 
Most 
of the 
Time 
(5) 
 
1. Excessive 
saliva is a concern 
to me. 
 
 
 
 
 
2. I take 
medication to 
control drooling. 
 
 
 
 
 
3. Saliva causes 
me to gag or 
choke. 
 
 
 
 
 
4. Drooling 
causes me to be 
frustrated or 
embarrassed. 
 
 
 
 
 
5. In the morning 
I notice saliva on 
my pillow. 
 
 
 
 
 
6. My mouth 
needs to be 
dabbed to prevent 
drooling. 
 
 
 
 
 
7. My secretions 
are not 
manageable. 
 
 
 
 
 
  
TOTAL Sialorrhea Score: _____ 
SPEECH 
Does 
Not 
Apply 
(1) 
Applies 
Rarely 
(2) 
   Applies 
Occasionally 
(3) 
Applies 
Frequently  
(4) 
Applies 
Most 
of the 
Time 
(5) 
Unable to 
Communicate 
by Speaking 
(6) 
1. My speech is 
difficult to 
understand. 
 
 
 
 
 
 


 
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2. To be 
understood I 
repeat myself. 
 
 
 
 
 
 
3. People who 
understand me tell 
other people what 
I said.  
 
 
 
 
 
 
4. To 
communicate I 
write things down 
or use devices 
such as a 
computer. 
 
 
 
 
 
 
5. I am talking 
less because it 
takes so much 
effort to speak. 
 
 
 
 
 
 
6. My speech is 
slower than usual. 
 
 
 
 
 
 
7. It is hard for 
people to hear me. 
 
 
 
 
 
 
  
TOTAL Speech Score: _____ 
SWALLOWING 
Does 
Not 
Apply 
(1) 
Applies 
Rarely 
(2) 
   Applies 
Occasionally 
(3) 
Applies 
Frequently  
(4) 
Applies 
Most 
of the 
Time 
(5) 
  
    Feeding tube is in place 
1. Swallowing is a 
problem. 
 
 
 
 
 
2. Cutting my 
food makes it 
easier to chew and 
swallow. 
 
 
 
 
 
3. To get food 
down I have 
switched to a soft 
diet. 
 
 
 
 
 
4. After 
swallowing I gag 
or choke. 
 
 
 
 
 


 
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5. It takes longer 
to eat. 
 
 
 
 
 
6. My weight is 
dropping because 
I can't eat 
normally. 
 
 
 
 
 
7. Food gets stuck 
in my throat. 
 
 
 
 
 
  
TOTAL Swallowing Score: _____ 
OVERALL SCORE: _____ 
 
 
 
 
 
 
 


 
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Regimen-Specific Appendix B, Verdiperstat 
 
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SAP_001.pdf: 
HEALEY ALS Platform Trial - Regimen B Verdiperstat 
NCT04436510 
Document Date: 22 Jul 2022 


Cudkowicz (PI) HEALEY ALS Platform Trial: RGB Statistical Analysis Plan 
Version 3.0, 22 Jul 2022 
 
Page 1 of 2 
 
 
RGB REGIMEN-SPECIFIC STATISTICAL ANALYSIS PLAN (R-SAP) 
Master Protocol 
Platform Trial for the Treatment of Amyotrophic Lateral 
Sclerosis (ALS):  A perpetual multi-center, multi-regimen, 
clinical trial evaluating the safety and efficacy of 
investigational products for the treatment of ALS 
Regimen 
RGB: Verdiperstat 
Regimen Partner 
Biohaven Pharmaceuticals, Inc 
Regulatory Sponsor 
Merit E. Cudkowicz, MD 
Master Protocol Version 
4.0, 31 Aug 2020 
RSA Version 
6.0, 02 Dec 2021 
Master SAP Version 
1.0, 24 Jun 2020 
R-SAP Version 
3.0, 22 Jul 2022 
 
SAP APPROVAL SIGNATURES 
 
 
Merit E. Cudkowicz, MD, MSc 
Principal Investigator and Regulatory Sponsor 
Date 
 
 
Sabrina Paganoni, MD, PhD 
Co-Principal Investigator 
Date 
 
 
Daniel Campbell, PhD 
Director, Biostatistics, Biohaven Pharmaceuticals, Inc 
Date 
07/24/2022
07/22/2022
07/22/2022


Cudkowicz (PI) HEALEY ALS Platform Trial: RGB Statistical Analysis Plan 
Version 3.0, 22 Jul 2022 
 
Page 2 of 3 
 
 
 
Ben Saville, PhD 
Senior Statistical Scientist, Berry Consultants 
Date 
 
 
Eric A. Macklin, PhD 
Study Biostatistician 
Date 
07/22/2022
07/22/2022


Cudkowicz (PI) HEALEY ALS Platform Trial: RGB Statistical Analysis Plan 
Version 3.0, 22 Jul 2022 
 
Page 3 of 4 
 
SAP REVISION HISTORY 
Version 
Date 
Description of Changes 
1.0 
17 Mar 2022 Initial version 
2.0 
06 May 2022 Revision of Section 5.9 Survival to specify that both PAV-free 
survival and overall survival will be evaluated at both the Week 
24 Visit time point and the last-participant-last-visit time point 
and to specify that PAV-free survival to the Week 24 Visit time 
point is the primary analysis of survival in this analysis plan. 
Revision of Section 6.5.5 CAFS to specify the following: 
1. CAFS will be used as a supportive analysis for the secondary 
efficacy endpoints of HHD upper and lower extremity 
percentage and SVC,  
2. Additional CAFS analyses will use multiple imputation to 
extend follow-up for participants who early terminate, 
withdraw consent, or are lost to follow-up,  
3. Additional CAFS analyses will use time to death alone 
independent of any death equivalent, and  
4. Primary inference from CAFS analyses will compare survival 
by time to death or death equivalent and will compare change 
in function to the last jointly observed time point. 
3.0 
22 Jul 2022 
Revision of Section 4.2 Exploratory Endpoints to identify serum 
creatinine and serum and CSF neurofilament light chain (NfL) as 
exploratory biomarkers of neurodegeneration and neuromuscular 
degeneration and to include ALSAQ-40 domain scores and 
symptom index (SI) as exploratory endpoints. 
Revision of Section 5.1 ALSFRS-R to specify details of the 
calculation of pre-baseline slope. 
Revision of Section 5.5 Quantitative Voice Characteristics to 
include predicted vital capacity as an additional metric at the 
Baseline Visit. 
Revision of Section 5.6 Biofluid Biomarkers of 
Neurodegeneration to specify the assay techniques used to 
quantify serum creatinine and serum and CSF NfL and to specify 
that levels of serum and CSF NfL will be log-transformed in all 
analyses. 
 


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Version 
Date 
Description of Changes 
3.0 
(continued) 
22 Jul 2022 
(continued) 
Revision of Section 5.7 ALSAQ-40 to specify calculation of 
domain scores and to revise calculation of overall ALSAQ-40 SI. 
Revision of Section 5.8 CNS-BFS to specify that the total score is 
referenced.Revision of Section 5.9 Survival to specify that time 
at risk begins at each participant's Baseline Visit and to specify 
that the date of PAV initiation, where applicable, will be imputed 
as the fifteenth day of a month if not specified more precisely. 
Revision of Section 6.1 Analysis Sets to add the Efficacy 
Common Mode of Administration (ECM) analysis set, to remove 
the restriction on protocol deviations that could be considered for 
exclusion from the Efficacy Per-protocol (EPP) analysis set must 
be classified as major protocol deviations, to specify the time 
point at which data is excluded from the EPP analysis set in the 
case of time-dependent exclusions, and to specify that data from 
placebo participants from other regimens would not be excluded 
from the EPP analysis set due to non-adherence to protocol-
specified dosing. 
Revision of Section 6.2 Baseline Characterization to include 
ALSAQ-40 domain scores and SI. 
Revision of Section 6.5.2 Repeated-measures Model to add a 
fixed term for treatment group (removing the shared-baseline 
assumption at the recommendation of the FDA) and to specify a 
separate supportive analysis that includes fixed terms for centered 
baseline serum NfL level and centered baseline serum NfL level 
× visit interaction. 
Revision of Section 6.5.3 Random-slopes Model to add a fixed 
term for treatment group (removing the shared-baseline 
assumption) and to specify a separate supportive analysis that 
includes fixed terms for centered baseline serum NfL level and 
centered baseline serum NfL level × study month interaction. 
Revision of Section 6.5.4 Survival and Time to Clinical Events to 
clarify that survival analyses that include follow-up beyond the 
placebo-controlled period will be analyzed in the ERO analysis 
set, to include baseline age as an additional covariate in all 
adjusted models, and to specify an additional adjusted analysis 
that includes baseline serum NfL level as a covariate. 
 
 


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Version 
Date 
Description of Changes 
3.0 
(continued) 
22 Jul 2022 
(continued) 
Revision of Section 6.5.5 CAFS to clarify that the primary CAFS 
analysis is specified in the ALS Master Protocol Recommended 
Statistical Analysis, Design and Simulation Report and to add 
two additional sets of CAFS analyses that adjust rank scores in 
linear models, one set that adjusts for time from ALS symptom 
onset, delta-FRS, baseline use of riluzole, and baseline use of 
edaravone, and one set that adjusts for the same set of covariates 
plus baseline serum NfL level. 
Revision of Section 6.5.6 HHD0 and HHD02 to remove reference 
to the shared-baseline assumption of the repeated-measures 
mixed model of Section 6.5.2 and to specify a separate analysis 
that adds baseline serum NfL level as an additional covariate. 
Revision of Section 6.5.7 Quantitative Voice Measures to remove 
reference to the shared-baseline assumption of the random-slopes 
mixed model of Section 6.5.3 and to add a fixed term for 
treatment group (removing the shared-baseline assumption) and 
to specify a separate analysis that includes fixed terms for 
centered baseline serum NfL level and centered baseline serum 
NfL level × B-spline interaction. 
Revision of Section 6.5.8 Placebo Multiple Imputation to specify 
regression over sequential visits by the fully conditional 
specification method, to remove reference to the shared-baseline 
assumption of the repeated-measures mixed model of Section 
6.5.2, and to specify a separate analysis that adds baseline serum 
NfL level as an additional covariate. 
Revision of Section 6.5.11 Comparison of Controls across 
Regimens to specify separate analyses that add baseline serum 
NfL level as an additional covariate. 
 


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Page 6 of 7 
 
ABBREVIATIONS 
ALP 
Alkaline Phosphatase 
ALS 
Amyotrophic Lateral Sclerosis 
ALSAQ-40 
Amyotrophic Lateral Sclerosis Assessment Questionnaire, 40-item version 
ALSFRS-R 
Amyotrophic Lateral Sclerosis Functional Rating Scale, Revised 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
ATC 
WHODrug Anatomical, Therapeutic, and Chemical class 
ATS 
American Thoracic Society 
BLQ 
Below the Limit of Quantitation 
BMI 
Body Mass Index 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CAFS 
Combined Assessment of Function and Survival 
CBC 
Complete Blood Count 
CKD 
Chronic Kidney Disease 
COVID-19 
Coronavirus Disease 2019 
CNS-BFS 
Center for Neurologic Study Bulbar Function Scale 
CSF 
Cerebrospinal Fluid 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events  
delta-FRS 
Pre-baseline Slope in ALSFRS-R  
DAP 
Data Analysis Plan 
DILI 
Drug-induced Liver Injury 
DNA 
Deoxyribonucleic Acid 
DRR 
Disease Rate Ratio 
ECC 
Efficacy Concurrent Control 
ECG 
Electrocardiography or Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
EPP 
Efficacy Per-protocol 
ERO 
Efficacy Regimen-only 
ELISA 
Enzyme-linked Immunosorbent Assay 
FAS 
Full Analysis Set 


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Page 7 of 8 
 
ABBREVIATIONS (continued) 
FVC 
Forced Vital Capacity 
GLI 
Global Lung Initiative 
hCG 
Human Chorionic Gonadotropin 
HHD 
Hand-held Dynamometry 
HLT 
MedDRA High Level Term 
ICF 
Informed Consent Form 
ITT 
Intention-to-treat Principle 
M-SAP 
Master Statistical Analysis Plan 
MDRD 
Modification of Diet in Renal Disease  
MedDRA 
Medical Dictionary for Regulatory Activities 
MP 
Master Protocol 
MPRDR 
ALS Master Protocol Recommended Statistical Analysis, Design and 
Simulation Report 
NCI 
National Cancer Institute 
NEALS 
Northeast ALS 
NfL 
Neurofilament Light Chain 
NIV 
Noninvasive Ventilation 
OLE 
Open-label Extension 
PAV 
Permanent Assisted Ventilation 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
MedDRA Preferred Term 
RBC 
Red Blood Cell 
RDW 
RBC Distribution Width 
RGB 
Regimen B (verdiperstat) 
RSA 
Regimen-specific Appendix 
R-SAP 
Regimen-specific Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
 


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ABBREVIATIONS (continued) 
SI 
Symptom Index 
SoA 
Schedule of Activities 
SOC 
MedDRA System Organ Class 
SRO 
Safety Regimen-only 
STF 
Safety and Tolerability Full 
STN 
Safety and Tolerability Narrow 
SVC 
Slow Vital Capacity 
TBL 
Total Bilirubin 
TEAE 
Treatment-emergent Adverse Event 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHODrug 
World Health Organization Drug Dictionary Enhanced 
 


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Page 9 of 10 
 
Table of Contents 
1. 
Governing Documents ...................................................................................................................... 11 
2. 
Study Design ..................................................................................................................................... 11 
2.1 
Overview ....................................................................................................................................................... 11 
2.2 
Study Objectives ........................................................................................................................................... 12 
2.3 
Study Population ........................................................................................................................................... 12 
2.4 
Participant Flow ............................................................................................................................................ 12 
2.5 
Regimen Allocation ....................................................................................................................................... 12 
2.6 
Treatment Allocation ..................................................................................................................................... 12 
2.7 
Treatment Administration ............................................................................................................................. 13 
2.8 
Allocation Concealment ................................................................................................................................ 13 
2.9 
RGB Schedule of Activities (SoA) ................................................................................................................ 13 
3. 
General Considerations for Data Analysis ..................................................................................... 15 
3.1 
Statistical Software ........................................................................................................................................ 15 
3.2 
Summary Statistics ........................................................................................................................................ 15 
3.3 
Precision ........................................................................................................................................................ 15 
3.4 
Transformations ............................................................................................................................................ 15 
3.5 
Multiplicity Adjustments ............................................................................................................................... 15 
3.6 
Missing Data ................................................................................................................................................. 16 
4. 
Study Endpoints ............................................................................................................................... 16 
4.1 
Efficacy Endpoints ........................................................................................................................................ 16 
4.2 
Exploratory Endpoints ................................................................................................................................... 16 
4.3 
Safety Endpoints ........................................................................................................................................... 16 
5. 
Measurement Definitions ................................................................................................................. 17 
5.1 
ALSFRS-R .................................................................................................................................................... 17 
5.2 
SVC ............................................................................................................................................................... 17 
5.3 
Home Spirometry .......................................................................................................................................... 17 
5.4 
HHD and Grip Strength ................................................................................................................................. 17 
5.5 
Quantitative Voice Characteristics ................................................................................................................ 18 
5.6 
Biofluid Biomarkers of Neurodegeneration .................................................................................................. 18 
5.7 
ALSAQ-40 .................................................................................................................................................... 18 
5.8 
CNS-BFS ....................................................................................................................................................... 18 
5.9 
Survival ......................................................................................................................................................... 18 
5.10 
King's ALS Clinical Staging System ........................................................................................................ 19 
5.11 
Hospitalization and Other Clinical Events................................................................................................ 19 
5.12 
Pharmacodynamic Biomarkers ................................................................................................................. 20 
5.13 
Clinical Safety Laboratory Tests .............................................................................................................. 20 
6. 
Statistical Methodology .................................................................................................................... 21 
6.1 
Analysis Sets ................................................................................................................................................. 21 
6.2 
Baseline Characterization .............................................................................................................................. 22 
6.3 
Primary Efficacy Analysis and Supportive Analyses .................................................................................... 22 
6.4 
Interim Analysis ............................................................................................................................................ 22 
6.5 
Secondary Efficacy Analyses ........................................................................................................................ 23 
6.5.1 
Hierarchical Testing ............................................................................................................................. 23 
6.5.2 
Repeated-measures Model ................................................................................................................... 23 
6.5.3 
Random-slopes Model ......................................................................................................................... 25 
6.5.4 
Survival and Time to Clinical Events .................................................................................................. 26 
6.5.5 
CAFS ................................................................................................................................................... 27 
6.5.6 
HHD0 and HHD02 ............................................................................................................................... 27 
6.5.7 
Quantitative Voice Measures ............................................................................................................... 27 
6.5.8 
Placebo Multiple Imputation................................................................................................................ 28 
6.5.9 
Additional Sensitivity Analyses of Primary and Key Secondary Outcomes ....................................... 29 
6.5.10 
Subgroup Analyses .............................................................................................................................. 29 
6.5.11 
Comparison of Controls across Regimens ........................................................................................... 29 
6.5.12 
Pharmacokinetic Analyses ................................................................................................................... 30 


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6.5.13 
Pharmacodynamic Biomarker Analyses .............................................................................................. 30 
6.6 
Safety Analyses ............................................................................................................................................. 30 
6.6.1 
Treatment-emergent Adverse Events ................................................................................................... 30 
6.6.2 
Safety Labs .......................................................................................................................................... 31 
6.6.3 
ECG Results......................................................................................................................................... 31 
6.6.4 
Vital Signs and Weight ........................................................................................................................ 31 
6.6.5 
Suicidality ............................................................................................................................................ 31 
6.7 
Other Analyses .............................................................................................................................................. 32 
6.7.1 
Participant Disposition ......................................................................................................................... 32 
6.7.2 
Study Drug Compliance and Tolerance ............................................................................................... 32 
6.7.3 
Concomitant Medication Use .............................................................................................................. 33 
6.7.4 
Medical History ................................................................................................................................... 33 
6.7.5 
Blindedness .......................................................................................................................................... 33 
6.7.6 
Protocol Deviations.............................................................................................................................. 33 
6.7.7 
Impact of COVID-19 Pandemic .......................................................................................................... 33 
7. 
Validation .......................................................................................................................................... 33 
7.1 
Primary Efficacy Analysis ............................................................................................................................. 33 
7.2 
Secondary, Exploratory, and Safety Analyses ............................................................................................... 33 
8. 
References ......................................................................................................................................... 34 


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1. Governing Documents 
This Regimen-specific Statistical Analysis Plan (R-SAP) for the verdiperstat regimen (RGB) 
specifies any modification from the default outcome measures, analysis samples, and planned 
analyses for the placebo-controlled period of the HEALEY ALS Platform Trial as specified in 
the Master SAP (M-SAP). The M-SAP and this R-SAP supplement the Master Protocol, the 
"ALS Master Protocol Recommended Statistical Analysis, Design and Simulation Report" 
(Appendix 1 to the Master Protocol), and the RGB Regimen-specific Appendix (RSA). Please 
refer to the Master Protocol and the RGB RSA for details on the rationale for the study design, 
eligibility criteria, conduct of the trial, clinical assessments and schedule of assessments, 
definitions and reporting of adverse events, data management conventions, and regulatory 
oversight and compliance procedures. The "ALS Master Protocol Recommended Statistical 
Analysis, Design and Simulation Report" (MPRDR) and any regimen-specific deviations 
described in the RGB RSA and this R-SAP are authoritative in defining the primary and interim 
analyses. In case of discrepancies between the RGB RSA and this R-SAP concerning use of 
shared placebos, this R-SAP is authoritative. In case of discrepancies between either SAP and the 
Master Protocol and the RGB RSA concerning matters of analysis other than the primary and 
interim analyses and use of shared placebos, the M-SAP and this R-SAP are authoritative. In 
case of discrepancies between the M-SAP and this R-SAP, this R-SAP is authoritative. On all 
matters not related to analysis, the Master Protocol and the RGB RSA are authoritative. The 
following table describes relationships among the relevant documents in adjudicating possible 
discrepancies with higher numbers indicating greater authority. 
Issues potentially requiring adjudication 
Master 
Protocol 
RGB 
RSA 
MPRDR 
M-SAP 
RGB  
R-SAP 
Use of shared placebos 
1 
4 
2 
3 
5 
Primary and interim analysis specifications not 
related to use of shared placebo 
1 
5 
4 
2 
3 
Statistical analysis specifications not related to use 
of shared placebo or primary and interim analyses 
1 
3 
2 
4 
5 
All matters not related to statistical analysis 
4 
5 
1 
2 
3 
2. Study Design 
2.1 
Overview 
The HEALEY ALS Platform Trial is a perpetual multi-center, multi-regimen clinical trial 
evaluating the safety and efficacy of investigational products for the treatment of ALS. RGB 
evaluates the safety and efficacy of verdiperstat administered orally at a dosage of 600 mg BID 
vs. placebo. The RGB RSA describes the nature of the intervention and its mechanism of action, 
the mode and frequency of administration, additional eligibility criteria beyond those specified in 
the Master Protocol, additional enrollment procedures, and additions and modifications of safety 
and efficacy assessments relative to those outlined in the Master Protocol. 


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2.2 
Study Objectives 
Primary Efficacy Objective: 
• To evaluate the efficacy of verdiperstat as compared to placebo on ALS disease 
progression. 
Secondary Efficacy Objectives: 
• To evaluate the effect of verdiperstat on selected secondary measures of disease 
progression, including survival. 
Safety Objectives: 
• To evaluate the safety of verdiperstat for ALS patients. 
Exploratory Efficacy Objectives: 
• To evaluate the effect of verdiperstat on selected biomarkers and endpoints. 
• To explore verdiperstat pharmacokinetics (PK) and pharmacodynamic (PD) effects. 
2.3 
Study Population 
In addition to eligibility criteria specified in the Master Protocol, participants in RGB must not 
be taking strong inhibitors of CYP1A2 (i.e., ciprofloxacin, enoxacin, fluvoxamine, zafirlukast) or 
CYP3A4 (i.e., conivaptan, itraconazole, ketoconazole, posaconazole, troleandomycin, 
voriconazole, clarithromycin, diltiazem, idelalisib, nefazodone, and certain antiviral agents 
[cobicistat, danoprevir, ritonavir, elvitegravir, indinavir, lopinavir, paritaprevir, ombitasavir, 
dasabuvir, saquinavir, tipranavir, nelfinavir]) for chronic/long-term use, defined as more than 
two weeks. 
Participants will be recruited from approximately 60 centers located throughout the US that are 
part of the Northeast ALS (NEALS) Consortium. 
2.4 
Participant Flow 
Participants in RGB follow the consenting, Master screening, regimen assignment, regimen-
specific screening, randomization to active or placebo treatment, and follow-up procedures and 
timing described in the M-SAP. Detailed descriptions of study procedures and timing are 
specified in the Master Protocol and the RGB RSA. 
2.5 
Regimen Allocation 
Participants in RGB are those determined eligible for Master Protocol-level inclusion and 
exclusion criteria and randomly assigned to RGB, stratified by use of riluzole, edaravone, both, 
or neither at the time of screening for the Master Protocol. Details of regimen assignment are 
described in the Platform Trial Regimen Assignment Plan.  
2.6 
Treatment Allocation 
Participants in RGB are randomly allocated in a 3:1 ratio to active or placebo treatment based on 
a pre-specified permuted-block randomization schedule, stratified by use of riluzole, edaravone, 
both, or neither at the time of screening for the Master Protocol. 


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2.7 
Treatment Administration 
Verdiperstat and placebo are supplied as matching reddish-beige, film coated, oval tablets. Each 
tablet of active study drug contains 300 mg of verdiperstat as the free base plus excipients 
generally recognized as safe for oral administration in an extended-release formulation. 
The first dose of study drug should be administered while in the office/clinic on the day of the 
Baseline Visit after all visit assessments are complete. Participants should stay at the office/clinic 
for monitoring for approximately 30 minutes post-dose. From the Baseline Visit to the end of 
Week 1, participants should take one tablet of study drug per day. During Week 2, participants 
should take one tablet of study drug twice per day. Starting at the beginning of Week 3 and 
throughout the remainder of the study, participants should take two tablets of study drug twice 
per day. If tolerability issues are experienced, the titration schedule may be modified. If a 
participant is off study drug for more than 14 consecutive days, the participant should re-escalate 
using the titration paradigm described above. 
Additional details of treatment administration are described in the RGB RSA. 
2.8 
Allocation Concealment 
Allocation concealment is the same as described in the M-SAP. 
2.9 
RGB Schedule of Activities (SoA) 
Activity 
MP 
Scrn1 
RGB 
Scrn1 
Base-
line 
Week 
22 
Week 
418,19 
Week 
818,19 
Week 
12 
Week 
1618,19 
Week 
20 
Week 
243,18 
Final 
Call3,4 
Cln 
Cln 
Cln 
Phn 
Cln5 
Cln5 
Phn 
Cln5 
Phn 
Cln 
Phn 
-42d  
to -1d 
-41d  
to 0d 
Day  
0 
Day 
14±3 
Day 
28±7 
Day 
56±7 
Day 
84±3 
Day 
112±7 
Day 
140±3 
Day 
168±7 
28d ±3 
ALD 
Written Informed Consent5 
X 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Review 
X 
X6 
 
 
 
 
 
 
 
 
 
ALS & Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
Neurological Exam 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs7 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Slow Vital Capacity 
X20 
 
X 
 
 
C 
 
C 
 
X 
 
Home Spirometry 
X20 
 
X 
 
 
X 
 
X 
 
X 
 
Muscle Strength Assessment 
 
 
X 
 
 
C 
 
C 
 
X 
 
ALSFRS-R 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
ALSAQ-40 
 
 
X 
 
 
 
 
 
 
X 
 
CNS-BFS  
 
 
X 
 
 
X 
 
X 
 
X 
 
12-Lead ECG 
X 
 
 
 
 
C 
 
 
 
X 
 
Clinical Safety Labs8 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Verdiperstat PK Samples10 
 
 
X 
 
C 
C 
 
C 
 
X 
 
Verdiperstat PD Samples10 
 
 
X 
 
C 
C 
 
C 
 
X 
 
Biomarker Blood Collection 
 
 
X 
 
 
C 
 
C 
 
X 
 
Biomarker Urine Collection 
 
 
X 
 
 
C 
 
C 
 
X 
 
DNA Collection11 (optional) 
 
 
X 
 
 
 
 
 
 
 
 
CSF Collection (optional) 
 
 
X 
 
 
 
 
C17 
 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Event Review9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Suicidality C-SSRS 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Install Smartphone Apps21 
 
 
X 
 
 
 
 
 
 
 
 


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Activity 
MP 
Scrn1 
RGB 
Scrn1 
Base-
line 
Week 
22 
Week 
418,19 
Week 
818,19 
Week 
12 
Week 
1618,19 
Week 
20 
Week 
243,18 
Final 
Call3,4 
Cln 
Cln 
Cln 
Phn 
Cln5 
Cln5 
Phn 
Cln5 
Phn 
Cln 
Phn 
-42d  
to -1d 
-41d  
to 0d 
Day  
0 
Day 
14±3 
Day 
28±7 
Day 
56±7 
Day 
84±3 
Day 
112±7 
Day 
140±3 
Day 
168±7 
28d ±3 
ALD 
Smartphone Voice Recording12 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Uninstall Smartphone App 
 
 
 
 
 
 
 
 
 
X 
 
Regimen Assignment 
X 
 
 
 
 
 
 
 
 
 
 
Randomization within RGB 
 
 
X 
 
 
 
 
 
 
 
 
Administer/Dispense Study Drug 
 
 
X13 
 
X 
X 
 
X 
 
 
 
Drug Accountability/Compliance 
 
 
 
X2,22 
X 
X 
X22 
X 
X22 
X 
 
Dose Escalation 
 
 
X15 
X15 
 
 
 
 
 
 
 
Exit Questionnaire 
 
 
 
 
 
 
 
 
 
X 
 
Vital Status 
 
 
 
 
 
 
 
 
 
X16 
 
Abbreviations: ALD = after last dose, ALS = amyotrophic lateral sclerosis, ALSAQ-40 = ALS Assessment 
Questionnaire, ALSFRS-R = ALS Functional Rating Scale Revised, BP = blood pressure, C = completed only if the 
visit is conducted in-clinic, CBC = complete blood count, Cln = Clinic visit, CNS-BFS = Center for Neurologic 
Study Bulbar Function Scale, CSF = cerebrospinal fluid, C-SSRS = Columbia-Suicide Severity Rating Scale, d = 
day, DNA = deoxyribonucleic acid, ECG = electrocardiogram, LFTs = liver function tests, MP = Master Protocol, 
PD = pharmacodynamic, Phn = Phone visit, RGB = the verdiperstat regimen, Scrn = Screening Visit. 
1 Master Protocol Screening procedures must be completed within 42 days to 1 day prior to the Baseline Visit. The 
Regimen-Specific Screening Visit and Baseline Visit should be combined if possible. 
2 At the end of Week 2, an assessment of compliance and tolerance to this dose titration schedule will be conducted. 
The assessment will be conducted by phone. If tolerability issues are experienced with 300 mg QD or 300 mg BID 
dosing, the titration schedule may be modified (see RSA Section 5.3.2). 
3 Participants will only have a Follow-Up Safety Call at this time if they do not continue into the OLE or if they 
discontinue prior to Week 24. Participants who continue into OLE will have a Follow-Up Safety Call after their last 
dose of study drug during the OLE phase. 
4 Participants who continue into the OLE and then early terminate will be asked to complete an Early Termination 
Visit and Follow-Up Safety Call as described in the body of this RSA. 
5 During the Master Protocol Screening Visit, participants will be consented via the Master Protocol informed 
consent form (ICF). After a participant is randomized to a regimen, participants will be consented a second time via 
the RSA ICF. 
6 At the Regimen Specific Screening Visit, participants will have regimen-specific inclusion and exclusion criteria 
assessed, if applicable. 
7 Vital signs include weight, systolic and diastolic pressure, respiratory rate, heart rate and temperature. Height is 
measured at Master Protocol Screening Visit only. 
8 Clinical safety labs include hematology (CBC with differential), complete chemistry panel, thyroid function (TSH) 
and urinalysis. Serum pregnancy testing will occur in women of child-bearing potential at the Master Protocol 
Screening Visit and as necessary during the study. Pregnancy testing is only repeated as applicable if there is a 
concern for pregnancy. 
9 Adverse events that occur after signing the master protocol consent form will be recorded. 
10 Myeloperoxidase protein and activity, and plasma concentrations of verdiperstat will be measured. For each 
sample, the time of the last verdiperstat or matching placebo dose prior to sample collection, time of the last meal 
prior to sampling and time of the PD/PK sample collection should be reported on the CRF. 
11 The DNA sample can be collected after baseline if a baseline sample is not obtained or the sample is not usable. 
12 In addition to study visits outlined in the SOA, participants may be asked to complete twice weekly voice 
recordings at home. During weeks when a participant is doing a voice recording in-clinic, he or she would only do 
one other voice recording at home that week. 


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13 Administer first dose of investigational product (IP) only after Baseline Visit procedures are completed. 
Participants should take the first dose of IP while in the office/clinic on the day of the Baseline visit and stay at the 
clinic for approximately 30 minutes post-dose for observation. 
14 Investigational product will only be dispensed at this visit if the participant continues in the OLE. 
15 From start to end of Week 1, participants will ingest either 300 mg QD of verdiperstat or matching placebo QD. 
From start to end of Week 2, participants will ingest either 300 mg BID of verdiperstat or matching placebo BID. 
Starting with Week 3 and continuing to Week 24, participants will ingest either 600 mg BID of verdiperstat or 
matching placebo BID. 
16 Vital status, defined as a determination of date of death or death equivalent or date last known alive, will be 
determined for each randomized participant at the end of the placebo-controlled portion of their follow-up (generally 
the Week 24 Visit, as indicated). If at that time the participant is alive, his or her vital status should be determined 
again at the time of the last participant’s last visit of the placebo-controlled portion of a given regimen. We may also 
ascertain vital status at later time points by using publicly available data sources as described in section 8.15 of the 
Master Protocol. 
17 If the CSF collection cannot happen at the Week 16 Visit for logistical reasons such as scheduling, it can happen 
at the Week 24 Visit. 
18 Participants should be instructed to skip the morning dose of study drug on the day of the study visit. Study drug 
should not be taken until after study visit procedures are complete. 
19 Visit may be conducted via phone or telemedicine with remote services instead of in-person if this is needed to 
protect the safety of the participant due to a pandemic or other reason. 
20 If required due to pandemic-related restrictions, Forced Vital Capacity (FVC) performed by a Pulmonary Function 
Laboratory evaluator or with a study-approved home spirometer, or sustained phonation using a study approved 
method may be used for eligibility (Master Protocol Screening ONLY). 
21 Two smartphone apps should be installed on the participant’s phone, one to collect the voice recordings and one 
to collect home spirometry. 
22 Drug accountability will not be done at phone visits. A drug compliance check in must be held during phone visits 
to ensure participant is taking drug per dose regimen and to note any report of missed doses. 
3. General Considerations for Data Analysis 
3.1 
Statistical Software 
Statistical software use for analyses is the same as described in the M-SAP. 
3.2 
Summary Statistics 
Data summaries are the same as described in the M-SAP. 
3.3 
Precision 
Precision of reported results is the same as described in the M-SAP. 
3.4 
Transformations 
Data transformations are the same as described in the M-SAP. 
3.5 
Multiplicity Adjustments 
Handling of multiplicity adjustments is the same as described in the M-SAP. 


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3.6 
Missing Data 
Handling of missing data is the same as described in the M-SAP. Clinic-based assessments that 
are missing due to COVID-19 restrictions or disruptions are considered missing at random. 
4. Study Endpoints 
4.1 
Efficacy Endpoints 
The primary and secondary efficacy endpoints are the same as described in the M-SAP. 
ALSFRS-R total score is considered the primary efficacy endpoint and hand-held dynamometry 
(HHD) upper and lower extremity percentages, slow vital capacity (SVC), and survival are 
considered key secondary efficacy endpoints in RGB. 
4.2 
Exploratory Endpoints 
The following categories of exploratory endpoints will be evaluated: 
• Change in ALSFRS-R domain scores 
• Change in strength: HHD global percentage, HHD0, and HHD02,  
• Change in quantitative voice characteristics as measured by Aural Analytics: maximum 
phonation time, pause rate, breathy vocal quality, pitch instability, regulation of voicing, 
articulatory precision, speaking rate, articulation rate, and monotonicity,  
• Change in biofluid biomarkers of neurodegeneration and neuromuscular degeneration: serum 
creatinine and serum and cerebrospinal fluid (CSF) neurofilament light chain (NfL),  
• Change in patient-reported outcomes: ALSAQ-40 physical mobility, independence in 
activities of daily living, eating and drinking, communications, and emotional reactions 
domain scores and ALSAQ-40 symptom index, CNS-BFS total score,  
• Change in plasma concentrations of verdiperstat,  
• Change in verdiperstat PD biomarkers: myeloperoxidase protein, total activity, and 
concentration-specific activity,  
• Change in respiratory function as assessed by home spirometry, and  
• Time to clinical events: first hospitalization due to a serious adverse event (SAE), first 
hospitalization due to an ALS-related SAE, first use of assisted ventilation, first placement of 
a feeding tube, first time reaching King's stage 4a or 4b, and first instance of any of the 
following events: hospitalization for an SAE, feeding tube placement, tracheostomy, 
initiation of permanent assisted ventilation (PAV), or death. 
4.3 
Safety Endpoints 
In addition to the safety endpoints described in the M-SAP, the following RGB regimen-specific 
safety endpoint will be evaluated: 
• Thyroid function: Proportion of participants with TSH ≥10 mIU/L, proportion of participants 
with signs or symptoms of hypothyroidism, and levels of free T3, free T4, and TSH.  


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5. Measurement Definitions 
5.1 
ALSFRS-R 
The definitions of ALSFRS-R scores are the same as described in the M-SAP. Pre-baseline slope 
in ALSFRS-R (delta-FRS) is defined as 48 minus the baseline ALSFRS-R total score then 
divided by the number of months from onset of symptomatic weakness to the Baseline Visit. The 
number of months will be calculated as the difference in days from onset of symptomatic 
weakness to the Baseline Visit multiplied by 12 / 365.25. The date of onset of symptomatic 
weakness will be imputed as the fifteenth day of a month if not specified more precisely. 
ALSFRS-R domain scores are exploratory measures of the primary efficacy endpoint ALSFRS-
R total score. 
5.2 
SVC 
The derivation of SVC percent-predicted of normal is the same as described in the M-SAP with 
age calculated as number of days from date of birth to the date of a given SVC assessment 
divided by 365.25 and with the following correspondence between self-identified race and race 
defined by Global Lung Initiative (GLI) classification: 
Self-identified Race 
GLI-defined Race 
American Indian or Alaska Native 
Mixed/Other 
Asian 
South East Asian 
Black or African American 
African American 
Native Hawaiian or Other Pacific Islander 
Mixed/Other 
White 
Caucasian 
Unknown 
Caucasian 
Not reported 
Caucasian 
More than one race indicated 
Mixed/Other 
5.3 
Home Spirometry 
Home spirometry assesses FVC remotely using a smartphone app (ZEPHYRx, Albany, NY) and 
a handheld spirometer (Spirobank Smart, Medical International Research, Rome, Italy). 
Coordinators guide participants through 3 to 8 maneuvers with live-video coaching using the 
ZEPHYRx platform. Flow loops are classified for acceptability and repeatability using American 
Thoracic Society (ATS) criteria and are manually reviewed by the NEALS Outcomes Center 
(Barrow Neurological Institute, Phoenix, AZ). The maximum FVC accepted by the NEALS 
Outcomes Center is converted to percent of predicted normal using GLI norms based on sex, age 
at time of assessment, height at time of screening, and race. Age is calculated as number of days 
from date of birth to the date of a given home spirometry assessment divided by 365.25. Higher 
values indicate greater respiratory function. 
5.4 
HHD and Grip Strength 
The derivation of HHD upper and lower extremity scores and HHD0 are the same as described in 
the M-SAP with the revision that HHD0 is a composite endpoint with death or death equivalent, 
whichever occurs first. 


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A second HHD time-to-event endpoint is defined as the time from the Baseline Visit to the 
second post-baseline occurrence of a muscle with a strength recording of 0 among those muscles 
that were non-zero at baseline or time to death or death equivalent, whichever occurs first 
(HHD02).  
Time at risk for HHD0 and HHD02 will be censored at the last date at an HHD assessment was 
performed up to the end of the Week 24 Visit window. 
HHD global average percentage, HHD0, and HHD02 are exploratory measures of the secondary 
endpoint HHD and grip strength. 
5.5 
Quantitative Voice Characteristics 
Voice samples will be collected using the Aural Analytics app installed on either an Android or 
iOS-based smartphone. At each assessment, participants perform a set of speaking tasks: reading 
5 prespecified sentences, reading 5 sentences chosen at random from a large sentence bank, 
repeating a consonant-vowel sequence, producing a sustained phonation, and counting on a 
single breath. Speech analysis will be performed by Aural Analytics to derive the following 
quantitative voice characteristics: maximum phonation time, pause rate, breathy vocal quality, 
pitch instability, regulation of voicing, articulatory precision, speaking rate, articulation rate, and 
monotonicity. Aural Analytics will use data on quantitative voice characteristics and participant 
age, sex, race, height, and weight to derive a prediction of vital capacity at the Baseline Visit. 
5.6 
Biofluid Biomarkers of Neurodegeneration 
Blood biomarkers of neurodegeneration, including biomarkers of neuromuscular dysfunction, 
will be assayed. These will include serum creatinine and serum and CSF neurofilament light 
chain (NfL). Serum creatinine will be assayed by the kinetic Jaffe method (test 001370, Labcorp, 
Burlington, NC). NfL will be assayed by single-molecule array (Simoa; Quanterix, Billerica, 
MA). Levels of serum and CSF NfL that are reported to be below the limit of quantitation will be 
imputed at the limit of quantitation. Levels of serum and CSF NfL will be log-transformed in all 
analyses. 
5.7 
ALSAQ-40 
The description of the ALSAQ-40 instrument and item-level scores are the same as described in 
the M-SAP. Each of the five domains will be scored as the mean of all domain-specific items 
multiplied by 25 (range 0 to 100). An overall symptom index (SI) will be scored as the mean of 
the five domain scores. A domain score will be missing if more than 20% of the items are 
missing; otherwise, item non-response will be mean-imputed from other completed items from 
the same assessment. The ALSAQ-40 SI will be missing if any domain scores are missing. 
Higher scores indicate worse quality of life. 
5.8 
CNS-BFS 
The definition of CNS-BFS total score is the same as described in the M-SAP. 
5.9 
Survival 
The primary definition of survival time is the same as described in the M-SAP with the 
clarification that PAV is defined as more than 22 hours per day of noninvasive or invasive 


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mechanical ventilation for more than seven consecutive days. The date of PAV initiation, where 
applicable, will be imputed as the fifteenth day of a month if not specified more precisely. A 
secondary survival endpoint of death alone, independent of any death equivalent, is also defined. 
Time at risk for the composite endpoint of death or death equivalent and time at risk for the 
endpoint of death alone will be measured from each participant's Baseline Visit. Time at risk will 
be censored at two time points: (1) at the Week 24 Visit as defined in the M-SAP, and (2) at a 
subsequent assessment of death or death equivalent scheduled approximately at the end of 
placebo-controlled follow-up of the last RGB participant. The primary analysis of survival will 
evaluate PAV-free survival to the Week 24 Visit time point. 
5.10 King's ALS Clinical Staging System 
The King's ALS Clinical Staging System (Roche et al. 2012) is a 4-level ordinal scale with the 
first three levels indicating the number (1, 2, or 3) of distinct central nervous system regions 
(bulbar, upper limb, and lower limb) with neuromuscular dysfunction and levels 4a and 4b 
indicating nutritional or respiratory failure secondary to ALS, respectively. 
Participants will be classified to King's stage 1, 2, 3, 4a, or 4b based on scores from ALSFRS-R 
assessments according to a published derivation (Balendra et al. 2014). Bulbar involvement is 
defined as a score less than 4 on any of the ALSFRS-R questions in the bulbar domain (questions 
1, 2, and 3). Upper limb involvement is defined as a score less than 4 on either of the ALSFRS-R 
questions related to hand function (questions 4 and 5A). Lower limb involvement is defined as a 
score less than 4 on the ALSFRS-R question about walking (question 8). Nutritional failure is 
defined as responding that the participant uses gastrostomy for greater than 50% of their 
nutrition. Respiratory failure is defined as a score of 0 on the ALSFRS-R question addressing 
dyspnea (question 10 or R-1) or a score less than 4 on the ALSFRS-R question about use of 
mechanical ventilation (question 12 or R-3). Participants without evidence by ALSFRS-R scores 
of involvement of any of the three central nervous system regions will be scored as King's stage 
1 due to their confirmed diagnosis with ALS. Participant may meet criteria for both King's stage 
4a and 4b. 
5.11 Hospitalization and Other Clinical Events 
Times to the following clinically relevant events are defined: 
• Time to first hospitalization due to a serious adverse event (SAE),  
• Time to first hospitalization due to an ALS-related SAE,  
• Time to first use of assisted ventilation,  
• Time to first placement of a feeding tube,  
• Time to King's stage 4a or 4b, and  
• Time to first instance of hospitalization for an SAE, feeding tube placement, tracheostomy, 
initiation of PAV, or death. 
Time at risk for each event will be measured from each participant's Baseline Visit. Time to first 
hospitalization excludes hospitalizations for elective procedures. ALS-related SAEs are those 
indicated as related to ALS disease progression by the site investigator. Participants who are 
already using assisted ventilation or have a feeding tube at the time of the Baseline Visit will be 


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excluded from analysis of those endpoints. Death or death equivalent will be considered an 
outcome for each of the events listed, forming a composite endpoint. 
Time at risk for these events will be censored at the Week 24 Visit, if completed, the date of 
consent withdrawal, if withdrawn, or the last date at which the status of each endpoint is known 
prior to the end of the Week 24 Visit window for participants lost to follow-up. Time to King's 
stage 4a or 4b is interval censored between ALSFRS-R assessments. 
5.12 Pharmacodynamic Biomarkers 
Myeloperoxidase protein and activity levels in plasma samples collected at Baseline and Weeks 
4, 8, 16, and 24 will be assayed among participants randomized to active treatment. Details of the 
assay techniques will be specified when known. 
5.13 Clinical Safety Laboratory Tests 
Clinical safety labs include hematology, blood chemistry panel, liver function tests, thyroid 
function, urinalysis, and pregnancy testing in women of childbearing potential as specified in 
Section 9.1.2 Clinical Safety Laboratory Tests of the Master Protocol: 
• Hematology: hematocrit, hemoglobin, platelet count, red blood cell (RBC) count, mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, RBC distribution width (RDW), RBC morphology, white blood cell (WBC) 
count, and counts and percentages of basophils, eosinophils, lymphocytes, monocytes, and 
neutrophils; 
• Blood chemistry panel: bicarbonate, chloride, potassium, sodium, calcium, magnesium, 
phosphate, blood urea nitrogen, creatinine, estimated glomerular filtration rate (eGFR) 
calculated using the Modification of Diet in Renal Disease (MDRD) four-variable equation, 
creatinine clearance calculated using the Cockcroft-Gault equation, and glucose; 
• Liver function tests: alanine aminotransferase (ALT [SGPT]), aspartate aminotransferase 
(AST [SGOT]), alkaline phosphatase (ALP), albumin, total protein, total bilirubin (TBL); 
• Thyroid function tests: thyroid-stimulating hormone (TSH), reflex T3 and T4 when TSH 
levels are abnormal; 
• Urinalysis: clarity, color, specific gravity, pH, microalbumin, protein, glucose, ketones, 
bilirubin, urobilinogen, nitrite, leukocyte esterase, and blood; and  
• Pregnancy: qualitative and quantitative serum human chorionic gonadotropin (hCG). 
Clinical safety labs will also include derived measures of potential drug-induced liver injury 
(DILI), including those that potentially meet the Hy’s law criteria, as distinct safety lab 
outcomes. 
Three potential DILI criteria will be defined: 
• ALT or AST >3x ULN with TBL >1.5x ULN 
• AST or ALT >3x ULN with TBL >2x ULN 
• AST or ALT >3x ULN with TBL >2x ULN and ALP <2x ULN (potential Hy’s Law cases) 
where ULN is upper level of normal and all levels are measured on the same day. 


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6. Statistical Methodology 
6.1 
Analysis Sets 
The ITT analysis set is henceforth referred to as the Full Analysis Set (FAS) and defined as 
follows: 
• 
Full Analysis Set (FAS): Participants who were randomized within RGB plus placebo 
participants from specified regimens, classified according to their randomized treatment 
assignment. Observations made after premature permanent discontinuation of study drug are 
included in this sample, should such participants remain on study. Observations completed 
after regimen data lock are excluded. Participants determined to not meet ALS diagnostic 
criteria are excluded. 
The definition of the STF analysis set is revised as follows: 
• 
Safety Full (STF) Set: Participants who initiated treatment within RGB plus placebo 
participants from specified regimens who are not known to be ineligible for RGB and who 
initiated treatment in their respective regimen, classified according to the treatment they 
actually received. Observations made after premature permanent discontinuation of study 
drug are included in this sample, should such participants remain on study. Observations 
completed after regimen data lock are excluded. 
An analysis set restricting shared placebo participants to those regimens in which study drug is 
administered by the same route as RGB is defined as follows: 
• Efficacy Common Mode of Administration (ECM) Set: The subset of participants in the FAS 
analysis set who are in regimens in which study drug is administered by the same route as 
RGB. 
The definitions of the ECC, ERO, STN, and SRO analysis sets are the same as described in the 
M-SAP with reference to the ITT analysis set now referencing the FAS analysis set. The 
following analysis set is specific to RGB: 
Efficacy Per-protocol (EPP) Set: The subset of participants in the FAS analysis set who initiated 
study treatment and who were not involved in protocol deviations that affected the scientific 
integrity of the trial as documented prior to data lock, classified according to the treatment they 
actually received. Inclusion or exclusion from the EPP analysis set of any participant for whom 
treatment assignment was unblinded prior to data lock will be governed by the prespecified 
criteria above. If a participant's data is truncated for inclusion in the EPP analysis set due to non-
adherence to protocol-specified dosing, clinical events observed up to 28 days after the censoring 
event will be included in the EPP analysis set. For all other events leading to truncation of a 
participant's data, no events beyond that date will be included. Data from placebo participants 
shared from other regimens will not be truncated due to non-adherence to protocol-specified 
dosing.  
• 
 
Applicable analysis sets (FAS, ECM, EPP, STF, and STN) will include shared placebo 
participants from regimens A and C only. Data from shared placebo participants will include 
visits and events that occurred on or before the date of the final placebo-controlled period 
follow-up of a regimen A, B, or C participant. As only concurrently enrolling regimens are 


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contributing to efficacy analyses, the FAS and ECC analysis sets are synonymous and only the 
FAS analysis set will be referenced. As regimen A is administered by subcutaneous injection and 
regimen C is administered orally, only regimen C will contribute shared placebo participants for 
the ECM and STN analysis sets. 
6.2 
Baseline Characterization 
The baseline characteristics summarized for participants randomized within RGB are the same as 
specified in the M-SAP with the addition of ALSAQ-40 domain scores and SI, CNS-BFS total 
score, King's stage, weight, body mass index (BMI), serum urate concentration, serum creatinine 
concentration, and serum NfL concentration. 
6.3 
Primary Efficacy Analysis and Supportive Analyses 
The primary analysis for RGB is a Bayesian shared-parameter, repeated-measures model of 
ALSFRS-R that accounts for loss of follow-up due to mortality. Details of the model, including 
documentation of operating characteristics under a range of scenarios, are provided in the "ALS 
Master Protocol Recommended Statistical Analysis, Design and Simulation Report" (Appendix 1 
to the Master Protocol). The Bayesian shared-parameter, repeated-measures model will be 
applied to the FAS analysis set as the primary analysis, to the ECM and ERO analysis sets as 
sensitivity analyses, and to the EPP analysis sets as a supportive analysis. 
The estimand of the primary analysis is the relative rate of disease progression (the "disease rate 
ratio" or DRR) of active treatment relative to placebo in the FAS population under an assumption 
that active treatment slows mean time to death or death equivalent by the same proportion as 
treatment slows the mean rate of functional progression as measured by change in ALSFRS-R 
total score over time. The estimand is defined by the following attributes: 
• Treatment: verdiperstat administered orally at a dosage of 600 mg BID vs. placebo. 
• Population: FAS population as defined in Section 6.1. 
• Variables: time to death or death equivalent and rate of change in ALSFRS-R total score 
from baseline to the Week 24 Visit. 
• Intercurrent event 1: treatment discontinuation due to death: no ALSFRS-R data from 
participants who reach the death or death equivalent endpoint are included in the analysis, 
handled via mortality component in model, composite variable strategy approach. 
• Intercurrent event 2: treatment discontinuation not due to death: handled via treatment policy 
approach, all data will be used including data collected during the placebo-controlled period 
after treatment discontinuation regardless of concomitant medication, for those participants 
who have not been censored due to mortality. Missing data post-treatment will not be 
imputed, handled via missing at random assumption. 
• Population-level summary: mean ratio of hazard or progression rate of active treatment 
relative to placebo. 
6.4 
Interim Analysis 
RGB will be considered for early stopping for futility according to the interim analysis schedule 
and definition specified in the "ALS Master Protocol Recommended Statistical Analysis, Design 


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and Simulation Report" (Appendix 1 to the Master Protocol). RGB will not be stopped early for 
success. 
6.5 
Secondary Efficacy Analyses 
6.5.1 Hierarchical Testing 
Primary inference for secondary efficacy endpoints will be based on analysis of the FAS analysis 
set using a repeated-measures linear mixed model for functional endpoints (see Section 6.5.2 
below) and by Kaplan-Meier product-limit estimates and log-rank test for the primary survival 
endpoint (see Section 6.5.4 below). The sequence for testing secondary efficacy endpoints is the 
following: 
1. HHD upper extremity percentage,  
2. SVC,  
3. HHD lower extremity percentage, and  
4. Survival. 
If the primary analysis indicates a significant slowing in disease progression from the Bayesian 
shared-parameter, repeated-measures model of ALSFRS-R and mortality, then each secondary 
efficacy endpoint in succession would be declared significant in the specified sequence using a 
comparison-wise criterion of two-tailed p < 0.05. After the first failure to declare significance, no 
endpoints lower in the hierarchy can be significant. This sequential closed-testing procedure 
controls the overall type 1 error rate at 5%. Nominal comparison-wise p-values for secondary 
efficacy endpoints will also be reported. 
6.5.2 Repeated-measures Model 
The specification of the repeated-measures linear mixed model and the primary linear contrast 
for estimating differences in 24-week change from baseline in a given continuous efficacy 
endpoint (ALSFRS-R total and domain scores, HHD upper extremity, lower extremity, and 
global average percentages, SVC, FVC by home spirometry, serum creatinine, serum NfL, 
ALSAQ-40 domain scores and SI, and CNS-BFS total score) are revised from those specified in 
the M-SAP to include a main effect of treatment. 
The model will include fixed terms for discrete visit, treatment group, treatment group × visit 
interaction, centered time since symptom onset and centered time since symptom onset × visit 
interaction, centered delta-FRS and centered delta-FRS × visit interaction, centered baseline 
riluzole use and centered baseline riluzole × visit interaction, and centered baseline edaravone 
use and centered baseline edaravone × visit interaction. The following equations describe the 
model with regimen random effects: 
𝑌𝑌𝑖𝑖𝑖𝑖= 𝑎𝑎𝑘𝑘(𝑖𝑖) + 𝛾𝛾1𝑡𝑡𝑖𝑖+ 𝛾𝛾2,𝑗𝑗𝑣𝑣𝑗𝑗+ 𝜸𝜸𝟑𝟑
′ 𝒛𝒛𝒊𝒊+ 𝛾𝛾4,𝑗𝑗 𝑡𝑡𝑖𝑖𝑣𝑣𝑗𝑗+ 𝜸𝜸𝟓𝟓,𝒋𝒋
′ 𝒛𝒛𝑖𝑖 𝑣𝑣𝑗𝑗+ 𝜖𝜖𝑖𝑖𝑖𝑖 
𝑎𝑎𝑘𝑘 ~ 𝑁𝑁(0, 𝜎𝜎𝑟𝑟
2), 𝝐𝝐𝒊𝒊∙ ~ 𝑁𝑁(𝟎𝟎, 𝑹𝑹), Cov൫𝑏𝑏𝑘𝑘(𝑖𝑖), 𝜖𝜖𝑖𝑖𝑖𝑖൯= 0 
(eqn. 1)
where Yij is a given efficacy endpoint measured in participant i at visit j, ak(i) is a random 
intercept for regimen k to which participant i was assigned, vj is an indicator variable for visit j, zi 
is the vector of covariates (centered time since onset, centered delta-FRS, centered baseline 
riluzole use, and centered baseline edaravone use) for participant i, ti is an indicator variable for 
treatment t to which participant i was assigned, γ1, γ2,j, γ3, γ4,j, and γ5,j are estimated parameters 


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and vectors of parameters for the fixed effects, and ϵij is the residual for participant i at visit j. 
The regimen-specific random effects are normally distributed with mean 0 and variance σ2r. The 
vector of residuals for a given participant are normally distributed with mean 0 and an 
unstructured covariance matrix R. The regimen-specific random effect for a given participant 
and residuals for that participant are uncorrelated. 
The following SAS code specifies the model: 
proc mixed data=xxx method=reml; 
  class regimen id trtrnd visit; 
  model Value = trtrnd|visit  
                sx2bl|visit dFRS|visit rlz|visit edv|visit / solution cl; 
  random intercept / subject=regimen type=vc; 
  repeated visit / subject=id type=un; 
where id is a participant study identifier, trtrnd is the randomly assigned treatment group, 
visit is the visit identifier, Value is value of the efficacy endpoint being tested for a given 
participant at a given visit, sx2bl is years since ALS symptom onset centered at the sample 
median, dFRS is pre-baseline slope centered at the sample median, rlz is an indicator of riluzole 
use at baseline, and edv is an indicator of edaravone use at baseline. The primary estimate will 
be the treatment-dependent difference in change from baseline to the Week 24 Visit. The 
estimate and its 95% Wald confidence bounds will be obtained by a linear contrast of adjusted 
means. The following SAS code specifies the linear contrast for a regimen with one active 
treatment assuming an endpoint measured every 8 weeks and that the sort order for treatment 
group has the active group last and visits are sorted chronologically: 
  estimate "3|Act vs Plb|dWk 24" trtrnd*visit 1 0 0 -1  -1 0 0 1 / cl; 
A significant difference in 24-week change from baseline in the direction of greater 
improvement or less worsening among participants randomized to active treatment would 
support inference of benefit from active treatment for the efficacy endpoint being tested. 
The estimand estimated by the primary linear contrast of the repeated-measures linear mixed 
model is the mean difference in 24-week change from baseline of a given continuous efficacy 
endpoint in the active treatment group relative to the placebo group in the FAS population. The 
estimand is defined by the following attributes: 
• Treatment: verdiperstat administered orally at a dosage of 600 mg BID vs. placebo. 
• Population: FAS population as defined in Section 6.1. 
• Variables: absolute change in endpoint from baseline to the Week 24 Visit. 
• Intercurrent event: treatment discontinuation: handled via treatment policy approach, all data 
will be used including data collected during the placebo-controlled period after treatment 
discontinuation. Missing data post-treatment, including data missing due to death, will not be 
imputed, handled via missing at random assumption. 
• Population-level summary: difference in conditional means of active treatment relative to 
placebo. 
Inference from this analysis is supportive of inference from the Bayesian shared-parameter, 
repeated-measures model for the primary endpoint and is the primary analysis for secondary 


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endpoints. A separate supportive analysis will include centered baseline serum NfL level and the 
interaction of centered baseline serum NfL level and visit as additional covariates. 
6.5.3 Random-slopes Model 
The specification of the random-slopes linear mixed model and the primary linear contrast for 
estimating differences in mean rate of progression in a given continuous efficacy endpoint 
(ALSFRS-R total and domain scores, HHD upper extremity, lower extremity, and global average 
percentages, SVC, FVC by home spirometry, quantitative voice characteristics, serum creatinine, 
serum NfL, ALSAQ-40 domain scores and SI, and CNS-BFS total score) are revised from those 
specified in the M-SAP to include a main effect of treatment and to specify that study months are 
calculated as the difference in days from the Baseline Visit to the date of assessment of a given 
endpoint multiplied by 12 / 365.25. 
The model will include fixed terms for month since the Baseline Visit, treatment group, 
treatment group × month interaction, centered years since ALS symptom onset and centered 
years since ALS symptom onset × month interaction, centered delta-FRS and centered delta-FRS 
× month interaction, centered baseline riluzole use and centered baseline riluzole use × month 
interaction, and centered baseline edaravone use and centered baseline edaravone use × month 
interaction. The following equations describe the model with regimen random effects: 
𝑌𝑌𝑖𝑖𝑖𝑖= 𝛾𝛾1 + 𝑎𝑎𝑘𝑘(𝑖𝑖)
0
+ 𝑏𝑏𝑖𝑖
0 + 𝛾𝛾2𝑡𝑡𝑖𝑖+ 𝜸𝜸𝟑𝟑
′ 𝒛𝒛𝒊𝒊
+ ൫𝛾𝛾4 + 𝑎𝑎𝑘𝑘(𝑖𝑖)
1
+ 𝑏𝑏𝑖𝑖
1 + 𝛾𝛾5𝑡𝑡𝑖𝑖+ 𝜸𝜸𝟔𝟔
′ 𝒛𝒛𝒊𝒊൯ 𝑚𝑚𝑖𝑖𝑖𝑖+ 𝜖𝜖𝑖𝑖𝑖𝑖 
{𝑎𝑎𝑘𝑘
0, 𝑎𝑎𝑘𝑘
1} ~ 𝑁𝑁(𝟎𝟎, 𝚺𝚺𝒓𝒓), {𝑏𝑏𝑘𝑘
0, 𝑏𝑏𝑘𝑘
1} ~ 𝑁𝑁൫𝟎𝟎, 𝚺𝚺𝒑𝒑൯, 𝜖𝜖𝑖𝑖𝑖𝑖 ~ 𝑁𝑁(0, 𝜎𝜎𝜖𝜖
2) 
Cov(𝒂𝒂𝑘𝑘, 𝒃𝒃𝑘𝑘) = 𝟎𝟎, Cov(𝒂𝒂𝑘𝑘, 𝝐𝝐𝑖𝑖∙) = 𝟎𝟎, and Cov(𝒃𝒃𝑘𝑘, 𝝐𝝐𝑖𝑖∙) = 𝟎𝟎 
(eqn. 2)
where Yij is a given efficacy endpoint measured in participant i at visit j, a0k(i) and a1k(i) are 
random intercept and slope for regimen k to which participant i was assigned, b0i and b1i are 
random intercept and slope for participant i, zi is the vector of covariates (centered time since 
onset, centered delta-FRS, centered baseline riluzole use, and centered baseline edaravone use) 
for participant i, mij is the time from baseline to observation j for participant i in months 
calculated as days x 12 / 365.25, ti is an indicator variable for treatment t to which participant i 
was assigned, γ1, γ2, γ3, γ4, γ5, and γ6 are estimated parameters and vectors of parameters for the 
fixed effects, and ϵij is the residual for observation j for participant i. The regimen-specific 
random effects are normally distributed with mean 0 and unstructured covariance matrix Σr. The 
participant-specific random effects are normally distributed with mean 0 and unstructured 
covariance matrix Σp. The residuals for a given participant are normally distributed with mean 0 
and variance σ2ϵ. The regimen-specific random effects, participant-specific random effects, and 
residuals are uncorrelated. 
The following SAS code specifies the model: 
proc mixed data=xxx method=reml; 
  class regimen id trtrnd; 
  model Value = trtrnd|month  
                sx2bl|month dFRS|month rlz|month edv|month / solution cl; 
  random intercept month / subject=regimen type=un; 
  random intercept month / subject=id type=un; 


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where month is time in months from the Baseline Visit (assuming 12 months in an average of 
365.25 days per year) and other fields are the same as identified above in Section 6.5.2. The 
primary estimand will be the treatment-dependent difference in slopes. The estimate and its 95% 
Wald confidence bounds will be obtained by a linear contrast of adjusted means. The following 
SAS code specifies the linear contrast for a regimen with one active treatment assuming that the 
sort order for treatment group has the active group last: 
  estimate "3|Act vs Plb|Slope (/mn)" month 0 trtrnd*month -1 1 / cl; 
A significant difference in slopes in the direction of greater improvement or less worsening 
among participants randomized to active treatment would support inference of benefit from 
active treatment for the efficacy endpoint being tested. 
The estimand estimated by the primary linear contrast of the random-slopes linear mixed model 
is the difference in mean rate of progression of a given continuous efficacy endpoint in the active 
treatment group relative to the placebo group in the FAS population. The estimand is defined by 
the following attributes: 
Treatment: verdiperstat administered orally at a dosage of 600 mg BID vs. placebo. 
Population: FAS population as defined in Section 6.1. 
Variables: mean rate of change in endpoint from baseline to the Week 24 Visit. 
Intercurrent event: treatment discontinuation: handled via treatment policy approach, all data 
will be used including data collected during the placebo-controlled period after treatment 
discontinuation. Missing data post-treatment will not be imputed, handled via missing at 
random assumption. 
Population-level summary: difference in conditional mean slopes of active treatment relative 
to placebo. 
Inference from these analyses is supportive of inference from the Bayesian shared-parameter, 
repeated-measures model for the primary endpoint and inference from the repeated-measures 
linear mixed model for secondary endpoints. A separate supportive analysis will include centered 
baseline serum NfL level and the interaction of centered baseline serum NfL level and study 
month as additional covariates. 
6.5.4 Survival and Time to Clinical Events 
Survival and time to hospitalizations and clinical events will be analyzed in the FAS, ECM, 
ERO, EPP, STF, SFN, and SRO analysis sets. Survival analyses that include follow-up beyond 
the placebo-controlled period will be analyzed in the ERO analysis set. The summaries and 
analyses of time to death or death equivalent are the same as specified in the M-SAP with the 
revision to include baseline age as an additional covariate in adjusted models, with the addition 
that the endpoints of time to death independent of occurrence of death equivalents and time to 
each of the hospitalization and clinical events will be separately analyzed using the same models, 
and with an additional adjusted analysis that includes baseline serum NfL level as a covariate. 
Analysis of time to King's stage 4a or 4b will accommodate interval censoring between 
ALSFRS-R assessments and will be stratified by baseline King's stage. 


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6.5.5 CAFS 
The primary CAFS analysis is as specified in the MPRDR. Additional, unadjusted CAFS 
analyses are the same as specified in the M-SAP, including specification that pair-wise 
comparison of change in ALSFRS-R total score for participants who cannot be ranked by time to 
death or death equivalent is to the maximum follow-up time at which both participants have an 
observation, and with the following additions: 
1. HHD upper and lower extremity percentage and SVC will be analyzed by CAFS by 
substituting change from baseline for those secondary efficacy endpoints in place of 
ALSFRS-R total score,  
2. An additional set of CAFS analyses will use multiple imputation to extend follow-up of 
ALSFRS-R total score, HHD upper and lower extremity percentage and SVC for 
participants who early terminate, withdraw consent, or are lost to follow-up,  
3. An additional set of CAFS analyses for ALSFRS-R total score, HHD upper and lower 
extremity percentage and SVC will use time to death alone independent of any death 
equivalent,  
4. An additional set of CAFS analyses for ALSFRS-R total score, HHD upper and lower 
extremity percentage, and SVC will adjust rank scores in a linear model with the 
following covariates: time from ALS symptom onset, delta-FRS, baseline use of riluzole, 
and baseline use of edaravone, and  
5. An additional set of CAFS analyses for ALSFRS-R total score, HHD upper and lower 
extremity percentage, and SVC will adjust rank scores in a linear model with the 
following covariates: time from ALS symptom onset, delta-FRS, baseline use of riluzole, 
baseline use of edaravone, and baseline serum NfL level. 
The multiple imputation model used to extend follow-up of functional scores for participants 
who early terminate, withdraw consent, or are lost to follow-up will use linear regression with 
covariates of time since symptom onset, delta-FRS, baseline riluzole use, baseline edaravone use, 
and each observed functional score prior to a missing assessment. 
Inference from CAFS analyses is supportive of inference from the Bayesian shared-parameter, 
repeated-measures model for the primary outcome and supportive of inference from the 
repeated-measures model for the secondary outcomes of HHD upper extremity score, SVC, and 
HHD lower extremity score. Primary inference from CAFS analyses will compare survival by 
time to death or death equivalent, will compare change in function to the last jointly observed 
time point, and will adjust for the specified covariates. 
6.5.6 HHD0 and HHD02 
Analyses of HHD0 are the same as specified in the M-SAP with the addition of parallel analyses 
of HHD02, with a separate analysis that includes baseline serum NfL level as an additional 
covariate, and with the clarification that time to zero strength for both analyses is interval 
censored between HHD assessments. 
Inference from these analyses is supportive of inference from the repeated-measures linear mixed 
model for HHD upper and lower extremity scores. 
6.5.7 Quantitative Voice Measures 
Given the high frequency of voice recordings, a repeated-measures analysis with unstructured 
covariance is overly flexible but the assumption of linear change required by the random-slopes 


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model may be overly rigid. To complement estimates from the random-slopes linear mixed 
model, quantitative voice characteristics will be analyzed in a linear mixed model in which the 
temporal profile for both fixed and random terms is modeled using cubic B-splines with knots at 
8 and 16 weeks. The model will include fixed terms for B-splines (4 terms), treatment group (2 
levels), treatment group × B-spline interaction, centered time since symptom onset and centered 
time since symptom onset × B-spline interaction, centered delta-FRS and centered delta-FRS × 
B-spline interaction, centered baseline riluzole use and centered baseline riluzole × B-spline 
interaction, and centered baseline edaravone use and centered baseline edaravone × B-spline 
interaction The model will include random regimen-specific intercepts and slopes with 
unstructured covariance, random participant-specific B-splines (5 terms) with unstructured 
covariance, and a first-order autoregressive structure for residuals. A simplified covariance 
structure assuming no regimen-level covariance, heterogeneous compound symmetric covariance 
among the random B-splines, conditional independence of residuals, or a combination of the 
three simplifying assumptions will be used if the full model fails to converge. The primary 
estimand will be the treatment-dependent difference in 24-week change from baseline. The 
estimate and its 95% Wald confidence bounds will be obtained by a linear contrast of adjusted 
means. A separate analysis will include centered baseline serum NfL level and the interaction of 
centered baseline serum NfL level and B-splines as additional covariates. 
6.5.8 Placebo Multiple Imputation 
Placebo multiple imputation analyses are the same as specified in the M-SAP and will be applied 
to ALSFRS-R total score, HHD upper and lower extremity percentages, and SVC. 
The following SAS code specifies the imputation for an endpoint measured every 8 weeks: 
proc mi data=work.outcomes seed=xxx nimpute=50 out=work.out_mi01  
        minimum=. . . . . x x x x maximum=. . . . . y y y y minmaxiter=1000; 
  class rlz edv trtrnd; 
  fcs reg(Wk08 = sx2bl dFRS rlz edv Wk00); 
  fcs reg(Wk16 = sx2bl dFRS rlz edv Wk00 Wk08); 
  fcs reg(Wk24 = sx2bl dFRS rlz edv Wk00 Wk08 Wk16); 
  mnar model( Wk08 Wk16 Wk24 / modelobs=(trtrnd="0")); 
  var sx2bl dFRS rlz edv Wk00 Wk08 Wk16 Wk24; 
run; 
where Wk00, Wk08, Wk16, and Wk24 are the values of a given efficacy endpoint at the Baseline, 
Week 8, Week 16, and Week 24 Visits, respectively, trtrnd has a value of zero (0) for 
participants randomized to placebo, and x and y take appropriate values to specify the range of a 
given outcome measure (i.e., 0 and 48 for ALSFRS-R total score; 0 and . for HHD upper and 
lower extremity percentages and SVC). 
Inference from these analyses is supportive of inference from the Bayesian shared-parameter, 
repeated-measures model for the primary endpoint and assess sensitivity to the missing data 
assumption of the repeated-measures linear mixed model for secondary endpoints in the FAS 
analysis set. A separate analysis will include centered baseline serum NfL level as an additional 
covariate in both imputation stages. 


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6.5.9 Additional Sensitivity Analyses of Primary and Key Secondary Outcomes 
Sensitivity analyses of primary and key secondary efficacy outcomes are the same as specified in 
the M-SAP. 
6.5.10 Subgroup Analyses 
In addition to the subgroups specified in the M-SAP, the following additional subgroups will be 
analyzed in the random-slope model (see Section 6.5.3) for primary and secondary efficacy 
endpoints in the FAS analysis set: 
• Baseline use of riluzole and edaravone (neither, riluzole only, edaravone only, both),  
• Age (less than 65 years vs. 65 years or older),  
• Sex (female vs. male),  
• Race (white vs. any minority race with greater than 5% prevalence in the sample),  
• Ethnicity (Hispanic or Latino vs. non-Hispanic or Latino),  
• Weight (less than 70 kg, 70 to less than 85 kg, 85 kg or more),  
• BMI (less than 18.5 kg/m2, 18.5 to less than 25 kg/m2, 25 kg/m2 or more),  
• Chronic kidney disease (CKD) stage (stage 1 or better [eGFR 90 mL/min/1.73m2 or more], 
stage 2 [eGFR 60 to 89 mL/min/1.73m2], stage 3 or worse [eGFR less than 60 
mL/min/1.73m2]),  
• Time since onset of weakness (less than 18 months vs. 18 months or longer),  
• Baseline serum NfL concentration (by median split), and  
• Site (individual sites with at least 5 participants per treatment group and all participants from 
sites with fewer than 5 participants per treatment group pooled). 
For each classification, unknown, not reported, and missing will be considered one group. All 
individuals not included in a specified subgroup will be combined into a mixed, "other" group. 
The "other" group will be included in analyses if its prevalence is greater than 5%; otherwise, the 
"other" group will be excluded. 
In cases where a model for a given subgroup and endpoint fails to converge, the covariance 
terms for the regimen-specific random effects will be simplified from unstructured covariance of 
intercepts and slopes to separate, uncorrelated variance components for intercepts and slopes. If 
convergence still fails, regimen-specific intercepts and slopes will be modeled as fixed effects. If 
convergence still fails, the participant-specific random effects will be simplified from 
unstructured covariance of intercepts and slopes to separate, uncorrelated variance components 
for intercepts and slopes. 
6.5.11 Comparison of Controls across Regimens 
Comparisons of placebo participants across regimens are the same as specified in the M-SAP 
with separate analyses that include baseline serum NfL level as an additional covariate in 
adjusted analyses plus applicable interaction terms as relevant to a given model. 


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6.5.12 Pharmacokinetic Analyses 
Pre-dose concentrations of verdiperstat in plasma will be summarized by treatment group and 
visit in the ERO sample. Concentrations below the limit of quantitation (BLQ) will be replaced 
with one half of the lower limit of quantitation. Summaries will include number of observations, 
number and percentage with concentrations BLQ, arithmetic mean, median, standard deviation, 
minimum, maximum, geometric mean, geometric coefficient of variation (calculated as 
sqrt(exp(variance of log-transformed concentrations) – 1)), and 95% confidence bounds for the 
geometric mean assuming log-normally distributed data. 
Plasma concentration data of verdiperstat may be subjected to population pharmacokinetic 
analysis to derive population estimates of pharmacokinetic parameters and test the effect of 
various covariates such as age, weight, and sex. Details of the analysis will be described in a 
separate data analysis plan (DAP). This analysis may be performed by combining data from the 
current study with data from other studies of verdiperstat, if deemed appropriate. The population 
pharmacokinetic analysis will be performed by Biohaven and reported in a separate modelling 
report. 
6.5.13 Pharmacodynamic Biomarker Analyses 
Change in myeloperoxidase protein and activity levels in plasma will be summarized by 
treatment group and visit in the ERO sample. Summary statistics will be provided for the values, 
change from baseline, and percent change from baseline at each scheduled assessment time 
point. Myeloperoxidase protein and activity levels in plasma will be analyzed in a repeated-
measures linear mixed model that includes fixed terms for visit, time from last dose of 
verdiperstat, and time from last meal. 
6.6 
Safety Analyses 
6.6.1 Treatment-emergent Adverse Events 
Summaries and analyses of treatment-emergent adverse events (TEAE) are the same as specified 
in the M-SAP with the following revisions. 
TEAEs are defined as those adverse events with onset dates in the interval from double-blind 
treatment initiation to the earliest of the Final Safety Visit, the date the participant dies, early 
terminates, or is lost to follow-up, 28 days after last dose of study drug, or the date of first dose 
of study drug during participation in the OLE, if so exposed. Adverse events with onset on the 
day of double-blind treatment initiation and adverse events with incompletely specified onset 
date where the ambiguous date spans the day of double-blind treatment initiation or the earliest 
of the events above that define the end of the treatment-emergence interval will be assumed to be 
treatment emergent except for those known to precede first exposure to study drug. 
In addition to summaries specified in the M-SAP, the following categories of adverse events will 
be summarized by Medical Dictionary for Regulatory Activities (MedDRA) system organ class 
and preferred term: (a) all adverse events, including those not classified as TEAEs, (b) fatal 
TEAEs, and (c) TEAEs that occurred during a participant's COVID-19 infection (defined as 5 
days prior to symptom onset to end of COVID-19 symptoms or end of double-blind follow-up, if 
ongoing). 
TEAEs indicating COVID-19 infection are the following: Asymptomatic COVID-19, COVID-
19, COVID-19 pneumonia, COVID-19 treatment, Post-acute COVID-19 syndrome, SARS-CoV-


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2 antibody test positive, SARS-CoV-2 RNA increased, SARS-CoV-2 sepsis, SARS-CoV-2 test 
false negative, SARS-CoV-2 test positive, SARS-CoV-2 viraemia, Suspected COVID-19. 
Treatment-dependent differences in the proportion of participants experiencing a given type of 
TEAE will not be tested. Treatment-dependent differences in TEAE incidence rates in units of 
number per 100 participant years will be estimated as differences rather than ratios, will include 
comparison-wise 95% confidence intervals with variance estimates obtained by the delta method, 
and will be provided for overall classes of TEAEs not further classified by MedDRA term (all 
TEAEs, serious TEAEs, severe TEAEs, TEAEs leading to discontinuation of study drug, TEAEs 
resulting in death, and TEAEs of special interest) and TEAEs with at least 5% prevalence in the 
active arm. 
Listings will document all adverse events (including those not classified as treatment emergent), 
TEAEs, serious TEAEs, severe TEAEs, related TEAEs, TEAEs leading to discontinuation of 
study drug, TEAEs resulting in death, and TEAEs of special interest. 
6.6.2 Safety Labs 
Summaries and analyses of clinical safety labs are the same as specified in the M-SAP with the 
revision that lab results collected more than 28 days after last dose of study drug will not be 
tabulated, that abnormal levels will be classified to a toxicity grade based on quantitative grading 
using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0, and with the addition that maximum toxicity over all post-baseline visits 
that occur within 28 days or fewer after last dose of study drug will be included in shift tables 
along with visit-specific shifts. 
The proportion of participants with TSH ≥10 mIU/L and the proportion with signs or symptoms 
of hypothyroidism will be presented as shift tables vs. the status of each participant at baseline 
for each visit and over all post-baseline visits that occur within 28 days or fewer after last dose of 
study drug by treatment group in all safety samples. The absolute level and the absolute change 
from baseline for free T3, free T4, and TSH will be summarized as means, standard deviations, 
medians, and ranges at each visit by treatment group in all safety samples. 
6.6.3 ECG Results 
Summaries of ECG parameters and findings are the same as specified in the M-SAP with the 
revision that ECG parameters and findings collected more than 28 days after last dose of study 
drug will not be tabulated. 
6.6.4 Vital Signs and Weight 
Summaries and analyses of vital signs and weight are the same as specified in the M-SAP with 
the revision that vital signs and weight collected more than 28 days after last dose of study drug 
will not be tabulated. 
6.6.5 Suicidality 
Summaries of suicidality are the same as specified in the M-SAP with the revision that 
suicidality noted more than 28 days after last dose of study drug will not be tabulated. 


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6.7 
Other Analyses 
6.7.1 Participant Disposition 
All participants consented to the Master Protocol between the time of the first and last consent of 
a participant assigned to a regimen included in the FAS analysis set will be summarized as a 
single set for the following events: consented to the Master Protocol, failed screening for the 
Master Protocol, other reasons not assigned to a regimen (including timing out of the screening 
window, death, withdrawal of consent, early termination, and administrative termination), and 
assigned to a regimen. Reasons for Master Protocol screen failure will be summarized. 
All participants in the above sample assigned to a regimen will be summarized as two sets (final 
screening for RGB vs. final screening for a non-RGB regimen) for the following events: 
consented to a regimen, failed screening for a regimen, other reasons not randomized within a 
regimen (including timing out of the screening window, death, withdrawal of consent, early 
termination, and administrative termination), and randomized within a regimen. If a given 
individual is screened multiple times prior to randomization within a regimen, then the final 
screening experience of that individual will be summarized. Reasons for RGB screen failure will 
be summarized separately for all participants screened for RGB whether that was their final 
screening experience or not. 
All participants in the FAS analysis set will be summarized as two sets (randomization to active 
study drug vs. randomization to placebo) for the following events: initiated regimen-specific 
study drug, prematurely terminated study participation due to death, withdrawal of consent, early 
termination, loss to follow-up, or administrative termination, completed 24-week follow up, and 
completed a safety follow-up visit vs. continued into the OLE. Reasons for withdrawal of 
consent or early termination after randomization will be summarized. 
Any randomized participants excluded from the FAS and EPP analysis sets or included in the 
FAS analysis set but not contributing to the primary analysis will be identified in a listing 
together with the reason for their exclusion. 
6.7.2 Study Drug Compliance and Tolerance 
Summaries of study drug compliance and tolerance are the same as specified in the M-SAP with 
the clarification that summaries will be reported for the ERO and SRO analysis sets and that date 
of permanent discontinuation of study drug is the date of last use of double-blind study drug 
among all participants in a given analysis set. 
The number of days of exposure to study drug will be calculated in three ways: 
• as the number of days from dose initiation to the final safety assessment during the placebo-
controlled period, inclusive,  
• as the number of days from dose initiation to drug withdrawal, inclusive, less any interval 
during which use of study drug was interrupted (individual missed doses will not be 
subtracted unless noted in the dosage management log), and  
• as the number of days from dose initiation to the earlier of final contact during the placebo-
controlled period or 28 days after last dose of study drug, inclusive. 


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The proportion of participants who interrupted study drug or reduced study drug dosage and the 
time to first study drug interruption or dosage reduction will be summarized. The number of days 
of exposure to a reduced dosage of study drug will be summarized. 
6.7.3 Concomitant Medication Use 
Summaries of concomitant medication use are the same as specified in the M-SAP with the 
clarification that medications taken at baseline and those initiated after first dose of study drug 
will be separately summarized and will be classified by ATC Therapeutic class and WHODrug 
Preferred base name. 
6.7.4 Medical History 
Medical histories will be summarized by MedDRA system organ class, high level term, and 
preferred term in the STF and SRO analysis sets. 
6.7.5 Blindedness 
The proportions of participants and site investigators who report on the Exit Questionnaire a 
guess of active vs. placebo treatment assignment, each level of surety of that guess, and each of 
five pre-specified reasons for making a treatment assignment will be summarized by treatment 
group in the FAS and ERO analysis sets. Treatment-dependent differences in the proportion 
guessing active treatment assignment will be tested among all respondents and among those 
stating they are at least somewhat sure of their guess by Fisher's exact test and the difference in 
proportion guessing active treatment assignment will be estimated with confidence bounds. 
6.7.6 Protocol Deviations 
The number of major and minor protocol deviations will be summarized by type of deviation and 
treatment group in all analysis sets. Listings of all protocol deviations will be produced. 
6.7.7 Impact of COVID-19 Pandemic 
The proportions of planned assessments missed due to COVID-19 restrictions or disruptions will 
be summarized by treatment group, visit, and type of assessment in the FAS and ERO analysis 
sets. Protocol deviations that resulted from COVID-19 restrictions or disruptions will be 
summarized by treatment group and type of deviation in the FAS and ERO analysis sets. 
A listing will document participants with assessments missed due to COVID-19 restrictions or 
disruptions and those experiencing protocol deviations that resulted from COVID-19 restrictions 
or disruptions and will describe the manner affected by COVID-19. 
7. Validation 
7.1 
Primary Efficacy Analysis 
Validation of the primary efficacy analysis is the same as specified in the M-SAP. 
7.2 
Secondary, Exploratory, and Safety Analyses 
Validation of secondary, exploratory, and safety analyses are the same as specified in the M-
SAP. 


Cudkowicz (PI) HEALEY ALS Platform Trial: RGB Statistical Analysis Plan 
Version 3.0, 22 Jul 2022 
 
Page 34 of 34 
 
8. References 
The following references are cited in addition to those specified in the M-SAP: 
Balendra R, Jones A, Jivraj N, Knights C, Ellis CM, Burman R, Turner MR, Leigh PN, Shaw 
CE, Al-Chalabi A. Estimating clinical stage of amyotrophic lateral sclerosis from the ALS 
Functional Rating Scale. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Jun;15(3-
4):279-84. 
Roche JC, Rojas-Garcia R, Scott KM, Scotton W, Ellis CE, Burman R, Wijesekera L, Turner 
MR, Leigh PN, Shaw CE, Al-Chalabi A. A proposed staging system for amyotrophic lateral 
sclerosis. Brain. 2012 Mar;135(Pt 3):847-52. 


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