Clinical trial NCT04615923
Conditions: Amyotrophic Lateral Sclerosis
Keywords: ALS Placebo-Controlled Double-Blind Regimen Specific Appendix Lou Gehrig's Disease Pridopidine Prilenia Therapeutics
Sponsor: Merit E. Cudkowicz, MD
Start date: 2020-12-18; Completion date: 2022-07-14
Enrollment: 163 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 D will evaluate the safety and efficacy of a single study drug, pridopidine, 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 D Pridopidine, the participant will complete a screening visit to assess additional Regimen D eligibility criteria. Once Regimen D eligibility criteria are confirmed, participants will complete a baseline assessment and be randomized in a 3:1 ratio to either active pridopidine or matching placebo.

Regimen D will enroll by invitation, as participants may not choose to enroll in Regimen D. 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 D.

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

Arms: arm 1: Pridopidine is administered orally twice daily for 24 weeks. arm 2: Matching placebo is administered orally twice daily for 24 weeks.
Interventions: intervention 1: Pridopidine intervention 2: Matching Placebo
Intervention descriptions: intervention 1: Administration: Oral

Dose: 45mg twice daily intervention 2: Administration: Oral

Dose: one capsule twice daily

Protocol documents:
Prot_000.pdf: 
HEALEY ALS Platform Trial - Regimen D Pridopidine 
NCT04615923 
Document Date: 15 Jul 2021 
 


REGIMEN-SPECIFIC APPENDIX D 
 
FOR PRIDOPIDINE 
 
 
Regimen-Specific Appendix Date: 15 July 2021 
Version Number:  2.0 
 
 
 


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Regimen-Specific Appendix D, Pridopidine 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................. 2 
SIGNATURE PAGE ..................................................................................................................... 5 
LIST OF ABBREVIATIONS ...................................................................................................... 6 
Regimen-Specific Appendix (RSA) SUMMARY ....................................................................... 8 
SCHEDULE OF ACTIVITIES – PLACEBO CONTROLLED PERIOD ............................ 10 
SCHEDULE OF ACTIVITIES – OPEN LABEL EXTENSION (OPTIONAL) .................. 13 
1 
INTRODUCTION Regimen D: Pridopidine .................................................................... 15 
1.1 
Pridopidine Background Information ........................................................................ 15 
1.1.1. 
Overview of the Nonclinical Development Program.............................................. 15 
1.1.2. 
Overview of the Clinical Development Program .................................................... 17 
1.2. 
Pridopidine Therapeutic Rationale ............................................................................ 21 
2 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................... 24 
3 
RSA DESIGN ...................................................................................................................... 26 
3.1 
Scientific Rationale for RSA Design ........................................................................... 26 
3.2      End of Participation Definition................................................................................... 26 
3.3 
End of Regimen Definition .......................................................................................... 27 
4 
RSA Enrollment .................................................................................................................. 28 
4.1 
Number of Study Participants .................................................................................... 28 
4.2 
Inclusion and Exclusion Criteria ................................................................................ 28 
4.3 Treatment Assignment Procedures ................................................................................. 28 
5 
INVESTIGATIONAL PRODUCT.................................................................................... 34 
5.1 
Investigational Product Manufacturer....................................................................... 34 
5.2 
Labeling, Packaging, and Resupply............................................................................ 34 
5.3 
Acquisition, Storage, and Preparation ....................................................................... 34 
5.4 
Drug Returns and Destruction .................................................................................... 34 
5.5      Study Medication/Intervention, Administration, Escalation, and Duration .......... 35 
5.6 
Justification for Dose ................................................................................................... 35 
5.7    Dosage Changes ............................................................................................................ 35 
5.8    Participant Compliance ................................................................................................. 35 
5.9 
Overdose ........................................................................................................................ 36 


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5.10 Prohibited Medications ................................................................................................ 36 
6  
REGIMEN SCHEDULE .................................................................................................... 39 
6.1 Placebo-Controlled Period ............................................................................................... 39 
6.1.1 Regimen Screening/Baseline Visit .................................................................................. 40 
6.1.2 Week 2 Telephone Visit .................................................................................................. 41 
6.1.3 Week 4 Visit .................................................................................................................... 41 
6.1.4 Week 8 Visit .................................................................................................................... 41 
6.1.5 
Week 12 Telephone Visit........................................................................................ 41 
6.1.6 
Week 16 Visit ......................................................................................................... 42 
6.1.7 
Week 20 Telephone Visit........................................................................................ 42 
6.1.8 
Week 24 Visit or Early Termination Visit .............................................................. 42 
6.1.9 
 Follow-Up Safety Call ........................................................................................... 43 
6.1.10 Process for Early Terminations ..................................................................................... 44 
6.2 
Open Label Extension .................................................................................................. 44 
6.2.1 
Week 2 OLE Telephone Visit ................................................................................. 45 
6.2.2 
Week 4 OLE Visit ................................................................................................... 45 
6.2.3 
Week 8 OLE Visit ................................................................................................... 46 
6.2.4 
Week 12 OLE Telephone Visit ............................................................................... 46 
6.2.5 
Week 16 OLE Visit ................................................................................................. 46 
6.2.6  Week 20 OLE Telephone Visit ...................................................................................... 47 
6.2.7 
Week 24 and Q12 Weeks OLE Visit ...................................................................... 47 
7 
OUTCOME MEASURES AND ASSESSMENTS ........................................................... 49 
7.1 Voice Analysis...................................................................................................................... 49 
7.4 CNS-Lability Scale .............................................................................................................. 50 
7.5 Home Spirometry ................................................................................................................ 50 
8 
BIOFLUID COLLECTION ............................................................................................... 51 
8.1 Pharmacokinetic Sample ...................................................................................................... 51 
9 
REGIMEN-SPECIFIC STATISTICAL CONSIDERATIONS ...................................... 52 
9.1 
Deviations from the Default Master Protocol Trial Design...................................... 52 
9.2 
Regimen-Specific Operating Characteristics............................................................. 52 


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9.3  
Sharing of Controls from other Regimens ................................................................. 52 
9.4 
Secondary Efficacy Endpoints .................................................................................... 52 
10  REFERENCES .................................................................................................................... 54 
Appendix I: The ALSAQ-40 ...................................................................................................... 57 
Appendix II: The Bulbar Function Scale (CNS-BFS) ............................................................. 66 
Appendix III: The Lability scale (cns-ls) .................................................................................. 68 
 
List of Figures and Tables  
Figure 1: Pridopidine in vivo S1R Target Engagement in a PET Imaging Study in Humans . 16 
Figure 2: ECG Monitoring Flow for Regimen Specific Screening Visit to Assess for Regimen 
D Eligiblility* (before IP administration): ................................................................................ 31 
Figure 3: ECG Monitoring Flow for Regimen Specific Baseline post-dose and Week 4 post-
dose Visits ................................................................................................................................. 32 
 
 
Table 1: Clinical Events indicating Proarrhythmic Potential across Entire Safety Database .. 21 
Table 2: Clinical Events indicating Proarrhythmic Potential in Placebo-Controlled Period of 
the PRIDE-HD Study ................................................................................................................ 21 
 
 
 


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SIGNATURE PAGE 
I have read the attached Regimen-Specific Appendix (RSA) entitled, “Regimen D: Pridopidine”, 
dated July 15, 2021 (Version 2.0) 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 
ALSAQ-40 
Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 
BID 
 
Twice Daily 
Cmax 
 
Maximum Concentration 
CNS 
 
Central Nervous System 
CNS-BFS  
Center for Neurologic Study Bulbar Function Scale 
CNS-LS  
Center for Neurologic Study Lability Scale 
CYP  
Cytochrome P450 
dHMN  
Distal Hereditary Motor Neuronopathies 
DSMB  
Data and Safety Monitoring Board 
ECG 
 
Electro Cardiogram 
EM 
 
Extensive Metabolizer 
EoS 
 
End of Study 
ERK 
 
Extracellular-signal-regulated kinase 
FVC 
 
Forced Vital Capacity 
GFR 
 
Glomerular Filtration Rate 
HD 
 
Huntington’s Disease 
HDPE 
 
High-density polyethylene 
HHD 
 
Hand Held Dynamometry  
IP 
 
Investigational Product 
iPSC 
 
Induced pluripotent stem cells  
ITT 
 
Intent to Treat 
MAM 
 
Mitochondria-associated membrane 
MATE1  
Multi Drug and Toxin Extrusion Protein 1 
MATE2-K 
Multi Drug and Toxin Extrusion Protein 2-K 
MN 
 
Motor Neuron 
MOP 
 
Manual of Procedures 
mHTT  
Mutant Huntingtin 
NMJ 
 
Neuromuscular Junction 
OLE 
 
Open Label Extension 
OCT1 
 
Organic Cation Transporter 1 
OCT2 
 
Organic Cation Transporter 2 
QD 
 
Once Daily 
PD-LID  
Parkinson’s Disease-Levodopa Induced Dyskinesias 
PET  
 
Positron emission tomography 
PO 
 
By Mouth 
PPK 
 
Population Pharmacokinetic Model 
PM 
 
Poor Metabolizer 


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PY 
 
Participant-Years 
QTcF 
 
Fridericia-corrected QT  
RSA 
 
Regimen-Specific Appendix 
S1R 
 
Sigma-1 Receptor 
SAE 
 
Serious Adverse Event 
SI 
 
Site Investigator 
SOA 
 
Schedule of Activities 
SVC  
 
Slow Vital Capacity 
TDD 
 
Total Daily Dose 
 
 
 


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REGIMEN-SPECIFIC APPENDIX (RSA) SUMMARY 
Regimen-Specific Appendix D 
For pridopidine 45 mg oral capsule administered twice daily (BID) or its matching placebo. 
 
Rationale and RSA Design 
The proposed study is based on cumulative preclinical and clinical studies that demonstrate that 
pridopidine acts primarily as a Sigma-1 Receptor (S1R) agonist and demonstrates 
neuroprotective properties mediated by S1R. The purpose of this study is to evaluate the effect of 
pridopidine 45 mg BID on ALS functional decline, specifically bulbar, upper and lower limb, 
and respiratory function in participants with ALS. 
 
Allocation to Treatment Regimens 
Participants must first be screened under the Master Protocol before they are randomized to a 
regimen.   
 
As soon as pre-defined criteria for futility for the regimen are met, or the target number of 
randomized participants has been reached, enrollment will stop in the regimen.   
 
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 across the US.   
 
Treatment Duration 
The maximum duration of the placebo-controlled treatment period is 24 weeks.  
 
Follow-up Duration 
At the conclusion of the 24-week placebo-controlled treatment 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 pridopidine in the Open Label Extension (OLE) period of 
the study.  
 
In the OLE, pridopidine will be provided by Prilenia Therapeutics, until the primary results of 
the 24 week double-blind portion of the study are available, or they terminate development of 
pridopidine for ALS.   
 
Total Planned Trial Duration 
For participants completing the placebo-controlled treatment period of the study, the planned 
amount of time for a participant in the trial is up to 34 weeks, or about 8 months.  This duration 
assumes a 6-week screening window, a 24-week placebo-controlled treatment period, and a 4-


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week safety follow-up period for those participants who do not enter the OLE period of the 
study. Participants will complete approximately 10 study visits during the placebo-controlled 
period of the study.  
 


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SCHEDULE OF ACTIVITIES – PLACEBO CONTROLLED PERIOD 
As per the Schedule of Activities (SOA) below, visits must occur every 4 weeks and will be 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 
Base-
line 
Week 
2 
Week 
414 
Week 
819  
Week 
12 
Week 
1619 
Week 
20 
Week 
24 or 
Early 
Term. 
Visit14, 
22 
Follow-Up 
Safety 
Call11 
Clinic 
Clinic 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
-42 to -1 
Days 
-41 to 0 
Day 
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 days 
after last 
dose 
Written Informed Consent2 
Master 
X 
X 
 
 
 
 
 
 
 
 
 
Written Informed Consent - 
OLE 
Master 
 
 
 
 
 
 
 
X 
 
 
 
Inclusion/Exclusion Review 
Master 
X 
X3 
 
 
 
 
 
 
 
 
 
ALS & Medical History 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Neurological Exam 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs4 
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 
 
CNS Lability Scale 
Regimen 
 
 
X 
 
 
X 
 
X 
 
X 
 
12-Lead ECG 
Regimen 
X 
X15 
X16 
 
X16 
 
 
 
 
X15, 16, 17 
 
Clinical Safety Labs5, 21 
Master 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Biomarker Blood Collection21 
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 


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Activity 
Master 
Protocol 
or 
Regimen-
Specific 
Master 
Protocol 
Screening1 
Regimen 
Specific 
Screening1 
Base-
line 
Week 
2 
Week 
414 
Week 
819  
Week 
12 
Week 
1619 
Week 
20 
Week 
24 or 
Early 
Term. 
Visit14, 
22 
Follow-Up 
Safety 
Call11 
Clinic 
Clinic 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
-42 to -1 
Days 
-41 to 0 
Day 
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 days 
after last 
dose 
Plasma PK collection21 
Regimen 
 
 
 
 
X 
 
 
 
 
X 
 
Biomarker Urine Collection 
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 
DNA Collection7, 21 (optional) 
Master 
 
 
X 
 
 
 
 
 
 
 
 
CSF Collection (optional) 
Master 
 
 
X 
 
 
 
 
X13 
 
 
 
Concomitant Medication 
Review 
Master 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Event Review6 
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 App23 
Regimen 
 
 
X 
 
 
 
 
 
 
 
 
Voice Recording9 
Regimen 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Uninstall Smartphone App 
Regimen 
 
 
 
 
 
 
 
 
 
X 
 
Randomization to Regimen 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Randomization within Regimen 
Master 
 
X 
 
 
 
 
 
 
 
 
Administer/Dispense  
Investigational Product (IP) 
Master 
 
 
X8 
 
X18 
X 
 
X 
 
X10,18 
 
Drug 
Accountability/Compliance 
Master 
 
 
 
X24 
X 
X 
X24 
X 
X24 
X 
 
Exit Questionnaire 
Master 
 
 
 
 
 
 
 
 
 
X 
 
Vital Status Determination12 
Master 
 
 
 
 
 
 
 
 
 
X 
 
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 During the Master Protocol Screening Visit, participants will be consented via the Platform Trial informed consent form (ICF). After a participant is randomized to a regimen, 
participants will be consented a second time via the regimen-specific ICF.  
3 At the Regimen Specific Screening Visit, participants will have regimen-specific eligibility criteria assessed.   
4 Vital signs include weight, systolic and diastolic pressure, respiratory rate, heart rate and temperature.  Height measured at Master Protocol Screening Visit only. 
5 Clinical safety labs include hematology (CBC with differential), complete chemistry panel, thyroid function 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. 


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6 Adverse events that occur after signing the master protocol consent form will be recorded.  
7 The DNA sample can be collected after Baseline Visit if a baseline sample is not obtained or the sample is not usable. 
8 Administer first dose of IP only after Baseline Visit procedures are completed, except for the post-dose ECG. 
9 In addition to study visits outlined in the SOA, participants will be asked to complete twice weekly voice recordings at home.  
10 Drug will only be dispensed at this visit if the participant continues in the OLE. 
11 Participants will only have a Follow-Up Safety Call at this time if they do not continue on in the OLE.  Participants who continue into OLE will have a Follow-Up Safety Call 
after their last dose of IP during the OLE period. 
12 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. 
13 If the CSF collection is unable to be performed for logistical reasons, such as scheduling, at the Week 16 Visit, it may be performed at the Week 24 Visit. 
14 If a participant’s visit occurs in the morning, the participant should be instructed that the morning dose of study medication should not be taken, and the morning dose should be 
administered in-clinic 1-2 hours prior to the POST-DOSE ECG. If a participant’s visit occurs in the afternoon, the participant should be instructed to take the morning dose 
immediately upon waking in the morning, and the second dose should be administered in-clinic 1-2 hours prior to the POST-DOSE ECG. 
15 At the regimen-specific Screening visit (and Week 24 for participants enrolling in OLE) , QTcF will be determined by the mean of three, 10-second recordings of a 12-Lead 
ECG (performed at least 1 minute a part) BEFORE IP administration. For participants on Nuedexta, the Nuedexta dose should be taken within 6 hours BEFORE the ECG, refer 
to the MOP for additional guidelines.  
16 At Baseline and Week 4 (and Week 24 for participants enrolling in OLE) QTcF will be determined by a single 10-second 12-lead ECG, 1-2 hours AFTER IP administration. If 
stopping or monitoring rules are met, refer to Section 4.4.  For participants on Nuedexta, the Nuedexta dose should be taken within 6 hours BEFORE the ECG, refer to the MOP 
for additional guidelines. 
17 For participants that will NOT be enrolling into the OLE, QTcF will be determined by a single 10-second 12 lead ECG BEFORE administration of the IP. If stopping or 
monitoring rules are met, refer to Section 4.4. For participants on Nuedexta, the Nuedexta dose should be taken within 6 hours BEFORE the ECG, refer to the MOP for additional 
guidelines.  
18 IP must be administered at Week 4 (and Week 24 for participants enrolling into the OLE) 1-2 hours prior to the POST-DOSE ECG.  
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 
reasons. 
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 All blood draws should occur after the ECG is collected, or at least 1 hour prior to the ECG.  
22 If participant’s visit occurs in the morning, the participant should be instructed not to take the morning dose at home but rather in-clinic after the PRE-DOSE ECG.  
If visit occurs in the afternoon, morning dose should be taken immediately upon waking in the morning and the second dose after the PRE-DOSE ECG. 
23 Two smartphone apps should be installed on the participant’s phone, once to collect the voice recordings and one to collect home spirometry. 
24  Drug accountability will not be done at phone visits. A drug compliance check in should 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 – OPEN LABEL EXTENSION (OPTIONAL) 
Activity 
Master 
Protocol 
or 
Regimen 
Specific 
Open Label Extension (Optional)5 
Week 2 
Week 47 
Week 811 
Week 12 
Week 1611 
Week 20 
Week 24 and 
Q12 Wks 6, 13 
Follow-up Safety 
Call4,6 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
Day 14 
±3 
Day 28 ±7 
Day 56 
±7 
Day 84 ±3 
112 ±7 days 
140 ±3 days 
196 ±14 days 
28 ±3 days after 
last dose 
Vital Signs1 
Master 
 
X 
X 
 
X 
 
X 
 
Slow Vital 
Capacity 
Master 
 
X 
X 
 
X 
 
X 
 
Home 
Spirometry 
Regimen 
 
X 
X 
 
X 
 
X 
 
ALSFRS-R 
Master 
 
X 
X 
X 
X 
X 
X 
 
ALSAQ-40 
Regimen 
 
 
 
 
 
 
X 
 
CNS Bulbar 
Function Scale 
Regimen 
 
 
X 
 
X 
 
X 
 
CNS Lability 
Scale 
Regimen 
 
 
X 
 
X 
 
X 
 
12-Lead ECG 
Regimen 
 
X8 
 
 
 
 
X9,15 
 
Clinical Safety 
Labs2,12 
Master 
 
X 
X 
 
X 
 
X 
 
Biomarker 
Blood 
Collection12 
Master 
 
 
 
 
X 
 
X9 
 
Biomarker 
Urine 
Collection 
Master 
 
 
 
 
X 
 
X9 
 
Concomitant 
Medication 
Review 
Master 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Event 
Review3 
Master 
X 
X 
X 
X 
X 
X 
X 
X 
Columbia-
Suicide 
Severity Rating 
Scale 
Master 
 
X 
X 
 
X 
 
X 
 
Administer/Dis
pense  
Master 
 
X10 
X 
 
X 
 
X14 
 


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1 Vital signs include weight, systolic and diastolic pressure, respiratory rate, heart rate and temperature.  Height in cm measured at Master Protocol Screening Visit only. 
2 Clinical safety labs include hematology (CBC with differential), complete chemistry panel, thyroid function 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. 
3 Adverse events that occur after signing the master protocol consent form will be recorded.  
4 Participants who continue into the OLE will have a Follow-Up Safety Call (as described in the body of this RSA) after their last dose of IP during the OLE period. 
5 The duration of the OLE will be at least 24 weeks.  
6 Participants who continue into the OLE and early terminate will be asked to complete an Early Termination Visit and Follow-Up Safety Call as described in Section 6.1.10..  
7 If a participant’s visit occurs in the morning, the participant should be instructed that the morning dose of study medication should not be taken, and the morning dose should be 
administered in-clinic 1-2 hours prior to the POST-DOSE ECG. If a participant’s visit occurs in the afternoon, the participant should be instructed to take the morning dose 
immediately upon waking in the morning, and the second dose should be administered in-clinic 1-2 hours prior to the POST-DOSE ECG. 
8 QTcF will be determined by a single 10-second 12-lead ECG 1-2 hours AFTER IP administration. If stopping or monitoring rules are met refer to Section 4.4. For participants on 
Nuedexta, the Nuedexta dose should be taken within 6 hours BEFORE the ECG, refer to the MOP for additional guidelines. 
9 Biomarker Blood Collection, Biomaker Urine Collection and all regimen-specific samples will occur at OLE Weeks 24 and 52 only. 
10 IP must be administered at 1-2 hours prior to the POST-DOSE ECG.  
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, or other reason. 
12 All blood draws should occur after the ECG, or at least one hour prior to the ECG. 
13 At Week 24 and Final OLE visit, if participant’s visit occurs in the morning, the participant should be instructed not to take the morning dose at home but rather in-clinic after 
the PRE-DOSE ECG. If visit occurs in the afternoon, morning dose should be taken immediately upon waking in the morning and the second dose after the PRE_DOSE ECG. 
14 IP will not be dispensed at the participant’s final visit.  
15 At Week 24 and Final OLE visit,, QTcF will be determined by a single 10-second 12-lead ECG BEFORE IP administration. If stopping or monitoring rules are met refer to Section 4.4. 
For participants on Nuedexta, the Nuedexta dose should be taken within 6 hours before this ECG.  
16  Drug accountability will not be done at phone visits. A drug compliance check in should be held during phone visits to ensure participant is taking drug per dose regimen and to 
note any report of missed doses.  
 
 
 
 
Investigational 
Product (IP) 
Drug 
Accountability/
Compliance 
Master 
X16 
X 
X 
X16 
X 
X16 
X 
 


 
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1 INTRODUCTION REGIMEN D: PRIDOPIDINE 
Regimen D: Pridopidine 
 
1.1 
Pridopidine Background Information 
 
Pridopidine is an investigational small molecule that acts primarily as a Sigma-1 Receptor (S1R) 
agonist (Johnston, et al. 2019; Sahlholm et al. 2013). The S1R is a highly conserved 
transmembrane protein located at the endoplasmic reticulum (ER) and specifically enriched in 
the sub-regions contacting mitochondria (Mitochondria Associated Membranes, MAM). It acts 
as a ligand-activated chaperone that modulates diverse cellular processes, including calcium 
signaling, ion channel signaling and the ER stress response (Hayashi and Su 2005; Su et al. 
2010). Importantly, S1R activation exerts neuroprotective effects, acting to stimulate brain repair 
and plasticity, by modulating pathways common to many neurodegenerative diseases (Francardo 
et al. 2014; Hyrskyluoto et al. 2013; Luedtke et al. 2012; Vagnerova et al. 2006). Loss of the 
S1R exacerbates disease onset and progression in preclinical models of ALS (Mavlyutov et al, 
2010; Watanabe et al, 2016). Importantly, mutations leading to complete loss-of-function (LOF) in 
the S1R gene are associated with juvenile onset of ALS. However, missense mutations that impair the 
S1R protein, but still retain some normal function, are associated with an adult form of ALS, showing a 
dose response between function of the S1R and age of onset of ALS. (Al-Saif, Al-Mohanna, and Bohlega 
2011; Izumi et al. 2018; Watanabe et al. 2016).  
 
Pridopidine demonstrates neuroprotective properties mediated by the S1R in several in vivo and 
in vitro models of neurodegeneration, including models of ALS. In ALS SOD1G93A motor neurons 
(MNs), pridopidine increases MN survival, improves axonal transport, and restores neuromuscular 
junction (NMJ) synaptic activity. These effects are exquisitely mediated by the S1R, as a genetic 
deletion of the S1R gene abolishes the protective effects of pridopidine. In-vivo, pridopidine 
treatment of SOD1G93A mice reduces toxic protein aggregates, enhances MN innervation, and 
ameliorates muscle fiber wasting (Ionescu et al. 2019).  
 
In Huntington Disease (HD) models, pridopidine demonstrates a robust and dose-dependent 
neuroprotective effect against mutant huntingtin-(mHTT)-induced cell death in human HD 
induced pluripotent stem cells (iPSCs) and mouse HD cortical neurons (Eddings et al. 2019). 
Furthermore, pridopidine restores mitochondrial function, spine density, and aberrant calcium 
signalling (Ryskamp et al. 2017), all known features of neurodegenerative disorders. 
 
1.1.1. 
Overview of the Nonclinical Development Program 
 
Pharmacology 
 
The molecular target of pridopidine was assessed using in-vitro affinity binding assays to many 
central nervous system (CNS) receptor targets. These studies demonstrate that pridopidine has 
the highest affinity for the S1R, with low affinity for other receptors including the adrenergic 
α2C, dopamine-D3 and serotoninergic 5-HT1A receptors (Johnston, et al. 2019; Sahlholm et al. 


 
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2013). Pridopidine has ~ 30-fold higher affinity towards the S1R vs D3Rs, and 100-500-fold 
higher affinity vs D2Rs. Selective binding of pridopidine to the S1R with no dopamine D2/D3R 
binding was confirmed using positron emission tomography (PET) imaging in rats (Sahlholm K, 
et al 2015), and in humans at 90 mg single dose (plasma exposure correlates to 45 mg BID at 
steady state) (Figure 1).  
 
Figure 1: Pridopidine in vivo S1R Target Engagement in a PET Imaging Study in Humans 
 
a) [18F]fluspidine shows ~90% S1R receptor occupancy after 90 mg single dose pridopidine 
 
b) [C11]-fallypride shows ~3% D2R/D3R receptor occupancy after 90 mg single dose 
pridopidine 
 
From: Grachev et al, EJNMMI, 2020 
Representative PET images of a human brain showing complete 18F-Fluspidine (A) and [C11]-fallypride (B) displacement after a single oral dose 
of 90 mg pridopidine (exposure correlates to 45 mg bid at steady state). Before: PET image 90 min after [18F]-fluspidine or [C11]- fallypride IV, 
without prior pridopidine administration (baseline). After: PET image 90 min after [18F]-fluspidine or [C11]-fallypride which was injected IV 2 
hours post pridopidine oral administration. After 90 mg single-dose pridopidine, [18F]-Fluspidine shows ~90% receptor occupancy and [C11]-
fallypride shows ~3% D2R/D3R occupancy. 
 
Pharmacokinetics 
 
The pharmacokinetic properties of pridopidine and its main non-active metabolite, TV-45065 [4-
(3-(methylsulfonyl) phenyl) piperidine, previously named ACR30], have been investigated in 
several single- and repeat-dose studies in mice, rats, and dogs, as well as in single-dose studies in 
non-human primates. Studies using radiolabeled 14C-pridopidine in both rats and dogs examined 
the absorption, distribution, and excretion of 14C-pridopidine-related material, and investigated 
the metabolite profiles in whole blood, plasma and excreta. Plasma protein binding in-vitro was 
determined for pridopidine and its metabolite, TV-45065, as well as in-vitro and in-vivo binding 
of pridopidine to rodent brain tissue. 
 
Pridopidine was shown to have high oral bioavailability in all species evaluated, with fast 
absorption. The pridopidine fraction that is bound to plasma proteins is relatively low in mouse, 
rat, rabbit, dog, monkey, and human, with 12% to 32% binding at 30 to 30000 ng/mL (human 
26% to 32.2%). Pridopidine is primarily metabolized by cytochrome P450 (CYP 2D6) to one 
non-active metabolite, TV-45065, observed as the major metabolite in all species examined, 
validating the animal species used in the non-clinical studies conducted to characterize the safety 


 
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of pridopidine. At steady state, pridopidine is mainly excreted through the urine. In humans, the 
steady state plasma exposure of the metabolite is ~5% of the total drug exposure. 
 
In-vitro, pridopidine shows no induction of CYP isoenzyme expression and does not cause 
inhibition of any tested CYP except for CYP2D6, in which metabolism-dependent inhibition was 
detected (auto-inhibition). Pridopidine is not actively transported by any of the tested 
transporters.  
 
Similar to pridopidine, the metabolite TV-45065 was tested as an inhibitor or inducer of CYP, 
and only metabolism-dependent inhibition of CYP2D6 (at high concentrations) was observed.  
 
Toxicology 
 
The non-clinical safety profile of pridopidine has been evaluated in a battery of non-clinical 
studies, including safety pharmacology, genotoxicity, reproductive toxicity, and repeat-dose 
toxicity studies of up to 52 weeks. A battery of non-clinical abuse liability studies was also 
completed. 
 
Pridopidine was not genotoxic in a standard battery of genotoxicity studies, including an in-vitro 
bacterial reverse mutation assay (Ames test), an in-vitro mouse lymphoma assay, and an in-vivo 
micronucleus assay in mice. 
 
The principal adverse effects of pridopidine, observed at high doses in animals, were clinical 
signs of CNS toxicity including convulsions, tremors, recumbency, and hypo-activity. 
In animal studies, there appears to be a relationship between exposure and convulsions. The 
maximum concentration in plasma (Cmax) exposure causing convulsions started at about 
6000 ng/mL in both rats and dogs, while no convulsions were observed at exposures below these 
levels in all studies. Cmax exposure of 6000 ng/mL is ~9.7-fold higher than the anticipated mean 
peak plasma concentrations at 45 mg BID (618 ng/mL), the proposed dose for the ALS clinical 
trial. 
 
In non-clinical abuse liability studies, including a physical dependence study in rats, drug 
discrimination studies in rats, and a self-administration study in non-human primates, 
pridopidine showed no propensity to produce physical dependence or gross behavioral changes, 
and was found to have a very low potential for abuse. 
 
1.1.2. 
Overview of the Clinical Development Program 
 
To date, 1,334 participants have received at least one dose of pridopidine across numerous 
clinical trials. Of these 1,334 participants, the large majority (74%, 987 participants) were 
exposed to a daily pridopidine dose of 45 mg BID, with the remaining participants exposed to a 
daily dose ranging between 10 mg to 112.5 mg BID. On a cumulative exposure level, 
approximately 1,300 participant-years of exposure to pridopidine have been accumulated. 
The majority of participants exposed to pridopidine to date have been participants with HD. 
 


 
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Clinical Pharmacology 
 
To date, 13 studies have been conducted investigating the pharmacokinetics of pridopidine. 
Seven studies were used for the development of the population pharmacokinetic model (PPK), 
including phase 1 studies: ACR16C012, ACR16C013, ACR16C016, and ACR16C018; phase 2 
studies: ACR16C009 (HART) and TV7820-CNS-20002 (PRIDE-HD); and a phase 3 study 
ACR16C008 (MermaiHD). Pridopidine steady-state pharmacokinetics are described by a 2-
compartment linear model with first-order absorption. Of the covariates studied, only weight and 
participant CYP2D6 metabolizer status influenced apparent clearance. 
 
Pridopidine has a relatively fast and almost complete absorption after oral administration, with 
individual Cmax occurring between 0.5 and 4 hours after dosing (the median time to maximum 
concentration in plasma [Tmax] is 1.25 to 2 hours). Food intake has no impact on the extent of 
absorption of pridopidine.  After absorption, pridopidine is eliminated partly by urinary excretion 
and partly by hepatic metabolism (primarily via the CYP2D6 pathway), with a mean half-life 
(t½) of approximately 10 hours at steady-state. In extensive metabolizers (EMs), pridopidine is 
metabolized by CYP2D6 to 1 main metabolite (TV-45065). Conversely, poor metabolizers 
(PMs) depend on renal excretion as their main elimination pathway. 
 
Prior to reaching steady-state pharmacokinetics, pridopidine is metabolized by CYP2D6 to one 
main inactive metabolite (TV-45065). However, since CYP2D6 undergoes auto-inhibition; the 
fraction of pridopidine that is metabolized by CYP2D6 decreases with multiple doses, renal 
elimination becomes a more important elimination pathway, and the fraction excreted unchanged 
increases. Steady state is reached after approximately 10 days. 
 
Mild renal impairment (defined as glomerular filtration rate (GFR) of 60-89 mL/min/1.73 m2) 
did not affect the steady-state pharmacokinetics of 45 mg of pridopidine once daily (QD). 
Participants with moderate renal impairment (defined as GFR of 30-59 mL/min/1.73 m2) had 
1.68-fold higher AUC and 1.26-fold higher Cmax values than matching healthy participants at 
steady state. 
 
Studies in participants with hepatic impairment have not been performed, but PMs are expected 
to represent a worst-case scenario for hepatic impairment with minimal increase in pridopidine 
exposure (Cmax or AUC). In the PRIDE-HD study, no dose adjustment was implemented for 
PM participants, and this population was administered up to 112.5 mg BID with no difference in 
the safety profile. Therefore, no dose adjustments are proposed for participants with hepatic 
impairment. 
 
The potential for drug-drug interactions with pridopidine is predicted to be very low, with the 
exception of co-administration of pridopidine with CYP2D6 substrates. Pridopidine is a 
CYP2D6 inhibitor, and increased exposures of co-administered CYP2D6 substrates are 
anticipated. Caution should be exercised with medications that are mainly eliminated via a 
CYP2D6-dependent pathway and have a narrow therapeutic index and/or have a concern related 
to QT prolongation. 
 
Clinical Safety 


 
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All AEs across all clinical studies (22 studies) were combined into an integrated safety database. 
Since the majority of participants exposed to pridopidine to date have been on the 45 mg BID 
dosage regimen (74% of participants, 84% of the cumulative participant-years of exposure), AEs 
are presented for the following two groups:  
(1) 
Pridopidine 45 mg BID - all participants who received pridopidine 45 mg BID at 
least one time but did not receive a dose higher than 45 mg BID 
(2) 
Placebo - all participants in pridopidine clinical studies who did not receive a 
single dose of pridopidine  
 
Due to the considerably different number of participant-years (PY) of exposure between the 
groups, an analysis of AE reporting rates corrected for participant-years of exposure was 
performed in addition to AE incidence. 
 
The incidence and rate (events/participant years) of AEs in the pridopidine 45 mg BID group 
(n=981, participant years= 1091) and placebo group (n=338, participant years=148.8) was 
evaluated across the integrated safety analysis of the 22 trials. 
 
The integrated analysis of safety data from the 22 pridopidine clinical studies, primarily 
conducted in Huntington Disease (HD) participants, indicated that the adverse events (AE) 
profile of the 45 mg BID dose is generally comparable with that of placebo. Pooled analysis 
suggests no increased risk of cardiac toxicity, exacerbation of psychiatric complications, or 
suicidality attributed to the 45 mg BID dose. 
 
Over all in the integrated dataset, the rate of participants reporting at least 1 AE was similar 
between the placebo group (rate=2.35 events/participant year) and the pridopidine 45 mg BID 
group (rate =1.81 events/participant year). Most AEs for participants in both the placebo and 
pridopidine 45 mg BID groups were reported as mild or moderate in severity. Severe AEs 
occurred with a similar frequency across treatment groups. 
 
Serious adverse events (SAEs) were observed across both active and placebo groups. There was 
a slight increase in the number of participants with SAEs in the active groups compared with the 
placebo group, but no dose-dependence was observed (detailed in the IB safety section). 
 
AEs indicating Proarrhythmic Potential 
 
Across the integrated safety database (22 trials), the rate (events/participant year) of AEs of QT 
prolongation was higher in the placebo group (rate=0.013 events/participant year) compared to 
the pridopidine 45 mg BID group (rate=0.005 events/participant year) (Table 1).  
 
The 52-week placebo-controlled PRIDE-HD study included 5 treatment arms: placebo, 
pridopidine 45 mg BID, pridopidine 67.5 mg BID, pridopidine 90 mg BID, and pridopidine 
112.5 mg BID. The AE data from this trial provides a more sensitive analysis of dose-
dependency and is thus analyzed separately. The number of participant-years of exposure was 
similar in each of the treatment groups in this study; therefore, only tables of AE incidence were 
generated. 


 
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In the PRIDE-HD trial, there was a higher overall incidence of AE-reports of QT prolongation 
(unrelated to any other proarrhythmic event) in pridopidine-treated participants compared to 
placebo-treated participants:1.5% in pridopidine-treated participants vs 0% in placebo-treated 
participants. However, there was no evidence of dose-response (Table 2).  
 
In accordance with the ICH E14 Guideline, Clinical Evaluation of QT/QTc Interval Prolongation 
and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, the safety database was analyzed for 
rates of clinical events indicating a proarrhythmic potential, and the rates observed in treated and 
control participants were compared. An analysis of the full safety database that includes all 
participants treated with at least one dose of pridopidine found no events of torsade de pointes 
following treatment with pridopidine at doses of up to 112.5 mg BID. One case of mild 
ventricular arrhythmia was reported. 
 
Exposure-response analysis of QT Prolongation 
 
The PRIDE-HD trial incorporated extensive electrocardiogram (ECG) monitoring and a 
pharmacokinetic (PK) sampling schedule that captured peak plasma concentrations over 52 
weeks. 
 
ECGs and PK data from the PRIDE-HD study resulted in a comprehensive exposure-response 
analysis, including data from >400 HD participants, treated with 5 doses of pridopidine 
(including placebo), for up to 1 year.  
 
A concentration-dependent effect of pridopidine on the QTcF interval was observed with a slope 
of 0.012 ms per ng/mL (90% CI: 0.0109 to 0.0127 ms per ng/mL). 
At the proposed dose of 45 mg BID, the predicted QT effect (∆∆QTcF) in participants with HD 
was 6.6 ms (with an upper bound of the 90% confidence interval of 8 ms), which is not clinically 
meaningful.  
 
In summary, in the PRIDE-HD study, QT prolongation was found to be an adverse drug reaction 
associated with the use of pridopidine. At 45 mg BID, the dose to be tested in the ALS trial, there 
is no clinical significance of QT prolongation. 
 
 


 
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Table 1 Clinical Events indicating Proarrhythmic Potential across Entire Safety Database 
 
Placebo 
Pridopidine 45 mg BID 
 
Incidence 
N=338 
Rate 
PY = 148.8 
Incidence 
N=981 
Rate 
PY = 1091 
QT Prolongation 
2 (0.6%) 
Rate = 0.013 5 (0.5%) 
Rate = 0.005 
Torsade de pointes 0 
0 
0 
0 
Sudden death 
0 
0 
0 
0 
Ventricular 
arrhythmias 
0 
0 
1 (0.1%) 
Rate=0.0009 
Ventricular 
tachycardia  
0 
0 
0 
0 
Ventricular 
fibrillation  
0 
0 
0 
0 
Ventricular flutter 0 
0 
0 
0 
Syncope 
1 (0.3%) 
Rate =0.007 
16 (1.6%) 
Rate =0.016 
           PY= participant year; rate is events/participant year 
 
Table 2 Clinical Events indicating Proarrhythmic Potential in Placebo-Controlled Period of 
the PRIDE-HD Study 
 
PRIDE-HD 
 
Placebo 
N=82 
45 mg 
BID 
N=81 
67.5 mg BID 
N=82 
90 mg BID 
N=81 
112.5 mg 
BID 
N=82 
All Pridopidine 
N=327 
QT Prolongation 
0 
2 (2.5%) 
0 
1 (1.2%) 
2 (2.5%) 
5 (1.5%) 
Torsade de 
pointes 
0 
0 
0 
0 
0 
0 
Sudden death 
0 
0 
0 
0 
0 
0 
Ventricular 
arrhythmias 
0 
0 
0 
0 
0 
0 
Ventricular 
tachycardia 
0 
0 
0 
0 
0 
0 
Ventricular 
fibrillation  
0 
0 
0 
0 
0 
0 
Ventricular flutter 
0 
0 
0 
0 
0 
0 
Syncope 
0 
1 (1.2%) 
1 (1.2%) 
1 (1.2%) 
1 (1.2%) 
4 (1.2%) 
 
In the PRIDE-HD study, there were no participants exhibiting QTcF>500 ms. Seven participants 
exhibited QTcF >480 ms (3 subjects in each of the 45 mg BID and 112.5 mg BID groups and 
one subject in the 90 mg BID group) and 4 participants exhibited change-from-baseline QTcF 
(ΔQTcF) >60 ms (1 subject each in the pridopidine 45 mg and pridopidine 90 mg BID groups 
and 2 subjects in the pridopidine 112.5 mg BID group) at any time point during the study. 
 
1.2. 
Pridopidine Therapeutic Rationale 
 


 
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Target engagement in humans and prior evidence of clinical efficacy 
The proposed dose for the HEALEY ALS Platform Trial Regimen D is 45 mg BID. At this dose, 
pridopidine shows near to complete occupancy of the S1R in human brains (>90% S1R 
occupancy) with negligible (~3%) binding to the D2/D3Rs, suggesting its dominant 
pharmacological effect at this dosage is mediated via the S1R.  
 
The S1R regulates cellular signaling pathways that are commonly impaired in various 
neurodegenerative disorders, such as calcium signaling, mitochondrial function, and spine loss. 
Loss of function (LOF) mutations in S1Rs are associated with juvenile ALS and missense 
mutations with adult-onset ALS.  LOF mutations are also associated with distal hereditary motor 
neuronopathies (dHMN). Pridopidine, via activation of the S1R, exerts neuroprotective 
properties in numerous preclinical models including ALS, HD, PD and AD and may, therefore, 
have therapeutic effects in ALS.  
The PRIDE-HD study was a 52-week, double-blind, phase 2 trial to evaluate the efficacy and safety 
of pridopidine in participants with HD. Post-hoc analysis of data from PRIDE-HD demonstrated 
pridopidine 45 mg BID significantly maintained total functional capacity (TFC) in early HD 
participants at 52 weeks. (Reilmann, Olanow, et al. 2019)  
TFC is the most widely accepted and validated tool for assessing disease stage and correlates with 
advancing pathology and disease progression (Shoulson and Fahn 1979; Marder et al. 2000). Decline 
in TFC parallels the decline in other measures, including motor, cognitive, neuropsychiatric, and 
functional assessments (Tabrizi et al. 2013; 2012; Dorsey et al. 2013). It has been used as an endpoint 
in more than ten other clinical trials of drugs seeking to demonstrate impact on HD progression, none 
of which were positive.  
 
Pridopidine 45 mg BID also demonstrates a good safety profile. An integrated analysis of 
adverse events (AEs) was performed using a large safety database (over 1,300 participants) 
generated from 22 clinical studies with pridopidine. This analysis shows that the AE profile of 
pridopidine 45 mg BID is comparable to placebo. These results further suggest that there is no 
increased risk of psychiatric symptoms or cardiac toxicity with pridopidine 45 mg BID.  
Taken together, compelling preclinical data and clinical data demonstrate that pridopidine 45 mg 
BID has:  
(1) Robust and selective human in-vivo S1R target engagement (PET imaging)  
(2) Neuroprotective effects in numerous preclinical models of neurodegeneration, 
including ALS, HD, PD and AD 
(3) Significant effect on maintaining total functional capacity at 52 weeks in early HD 
participants in comparison to placebo in a double-blind study, and  
(4) A favorable safety and tolerability profile   
These, and the genetic link between the S1R and ALS, justify a study to test the clinical benefits of 
pridopidine in ALS. 
 
Dosing Regimen 
 
The proposed dose to be tested in the planned study is 45 mg twice daily (BID), taken in the 
morning and in the early afternoon (approximately 7 to 10 hours after the morning dose). 


 
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There will be a titration period leading up to the proposed dose whereby participants will initiate 
pridopidine at 45mg once daily (QD) and then increase to 45mg BID after 2 weeks. 
 
 
 
 


 
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2 STUDY OBJECTIVES AND ENDPOINTS 
 
Primary Efficacy Objective: 
• To evaluate the efficacy of pridopidine as compared to placebo on ALS disease 
progression.  
 
Secondary Efficacy Objective: 
• To evaluate the effect of pridopidine on selected secondary measures of disease 
progression, including survival. 
 
Safety Objective: 
• To evaluate the safety of pridopidine in ALS patients. 
 
Exploratory Efficacy Objective: 
• To evaluate the effect of pridopidine on selected biomarkers and endpoints. 
 
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 bulbar function as measured by the ALSFRS-R bulbar subdomain (Q1-Q3) 
score among participants with bulbar dysfunction at baseline. 
• Change in bulbar function as measured by the ALSFRS-R bulbar subdomain (Q1-Q3) 
score among all randomized participants. 
• Change in speech as measured by the ALSFRS-R speech domain score (Q1) among all 
randomized participants. 
• Change in respiratory function as measured by slow vital capacity (SVC). 
• Change in bulbar function as measured by the ALSFRS-R bulbar subdomain (Q1-Q3) 
score among participants with rapid pre-baseline progression. 
• Time to first evidence of bulbar dysfunction. 
• 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: 


 
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• Changes in quantitative voice characteristics. 
• Changes in biofluid biomarkers of neurodegeneration. 
• Changes in patient reported outcomes (e.g. CNS-BFS, CNS-LS).  
• Change in respiratory function as assessed by home spirometry. 
 
 
 
 
 
 


 
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3 RSA DESIGN 
 
This study is a multi-center, randomized, placebo-controlled trial, testing active dose of 
pridopidine (45mg BID), given orally daily versus placebo. Participants will be randomized 3:1 
active: placebo. 
 
The study will consist of a screening/baseline visit, a 2-week double-blind, placebo-controlled 
up-titration period, a 22-week double-blind, full-dose, placebo-controlled treatment period, and a 
28-day safety follow-up period (after the last dose of IP) for those participants who do not enter 
the Open Label Extension (OLE) period of the study.  
 
After signing informed consent, participants will undergo screening assessments to determine 
eligibility and eligible participants will be randomly assigned in a 3:1 ratio to 1 of 2 study 
intervention groups: 
• Treatment Arm 1 (active): pridopidine 45 mg orally (PO), BID (total daily dose of 90 mg 
after two week up-titration period at 45mg PO, QD) 
• Treatment Arm 2 (control): matching placebo, PO BID 
 
During the 2 week up-titration period (starting on Day 1), all participants will self-administer 
1 capsule of study intervention PO once daily (QD) in the morning. In the full-dose treatment 
period (starting on Day 14) study intervention will be taken BID, in the morning and in the 
afternoon (approximately 7-10 hours apart). Participants who complete all scheduled visits will 
have the option of participating in the OLE period of the study.  
 
Throughout the study, participants will be assessed through on-site clinic visits and telephone 
calls, as specified in the Schedule of Activities (SoA) table. 
 
For participants who complete all scheduled visits, their final visit will be the Follow-Up 
Safety Call (28 days after the Week 24 clinic visit), unless participants continue on in the 
OLE. Participants who discontinue study intervention early will be encouraged to complete 
all other visits as scheduled for the full course of the study per ITT. For participants who 
withdraw early from the placebo-controlled period, 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. 
 
Participants who complete the full study regimen (24 weeks) will have the option to enroll into 
the OLE period of the study and receive pridopidine 45 mg orally BID (total daily dose of 90 
mg), following a 2 week up-titration period at QD.  
 
3.1 
Scientific Rationale for RSA Design 
 
This RSA is designed to correspond with the design of the Master Protocol and the goals of the 
Platform Trial. 
 
3.2      End of Participation Definition 


 
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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 
 
 
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 IP 
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 one hundred-sixty participants will be randomized for this Regimen.   
 
4.2 
Inclusion and Exclusion Criteria 
 
To be randomized to a Regimen, participants must meet the Master Protocol eligibility criteria.  
In addition, participants meeting all of the following inclusion and exclusion criteria at the 
Regimen Screening Visit 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  
 
1. Participants with a confirmed prolonged Fridericia-corrected QT (QTcF) interval 
(defined as a QTcF interval of >450 ms for men and >470 ms for women). 
 
2. Participants with clinically significant heart disease, clinically significant history of 
arrhythmia, symptomatic or uncontrolled atrial fibrillation despite treatment, or 
asymptomatic sustained ventricular tachycardia, or presence of left bundle branch block. 
 
3. Participants with known history of long QT syndrome or a first degree relative with this 
condition. 
 
4. Participants using prohibited medications within the 4 weeks prior to the Regimen 
Specific Screening Visit, as detailed in section 5.9. 
 
5. Participants using the following medications at the time of the Regimen Specific 
Screening Visit: 
a. Nuedexta – at a dosage higher than 20 mg dextromethorphan + 10 mg quinidine 
BID  
b. Citalopram – at a dosage higher than 20 mg/day  
c. Escitalopram – at a dosage higher than 10 mg/day 
6. Participants with a known allergy to any ingredient of the study intervention (pridopidine, 
silicified microcrystalline cellulose, and magnesium stearate). 
 
4.3 Treatment Assignment Procedures 
 
Each participant who meets all eligibility criteria for the Regimen will be randomized to receive 
either pridopidine 45 mg BID or placebo for approximately 24 weeks of placebo-controlled 
treatment. 
 


 
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4.4 ECG Monitoring 
 
In addition to the ECG performed at the Master Protocol Screening visit, additional ECG 
monitoring with stopping and monitoring rules will be completed as described below: 
 
QT Stopping Rules: 
 QTcF > 500 ms or 
 QTcF > 480 ms AND ΔQTcF > 60 ms from regimen baseline value (pre-dose)  
o The regimen baseline QTcF value is the average of triplicate ECGs collected 
pre-dose during the regimen Screening Visit.  
o For all subsequent visits the ΔQTcF is calculated using the regimen baseline 
QTcF value (pre-dose), as described above (average triplicate screening QTcF).  
 For Baseline post dose visit only, ΔQTcF is calculated from the initial 
printout, as the ERT Overread will not be available at the time of the 
Baseline Visit.  
 For all other ECGs (i.e.Week 4 and Week 24), ΔQTcF should be 
calculated using the baseline QTcF pre-dose (average triplicate 
screening QTcF) from the ERT Overread.   
o For participants who transition into the OLE, the new baseline QTcF is the 
average triplicate QTcF collected pre-dose during the Week 24 visit.  
 If a participant meets either of the above stopping rules, IP must be held and the 
participant will be asked to return to the clinic after 3-14 days for a follow up ECG.  
 If the local ECG reading results at the site match either of the above stopping rules, the 
IP will be held until the ERT overread report is received. If the ERT overread does not 
confirm a participant meets the stopping rule above, then the participant can restart the 
study drug.  
 If a participant meets either of the above stopping rules, confirmed by the ERT 
overread, IP must be discontinued and the participant will be asked to return to the 
clinic after 3-14 days for a follow up ECG.    
 
QT Monitoring Rule:  
 QTcF > 480 ms OR ΔQTcF > 60 ms from regimen baseline value (pre-dose)  
o The regimen baseline QTcF value is the average of triplicate ECGs collected 
pre-dose during the regimen Screening Visit.  
o For all subsequent visits the ΔQTcF is calculated using the regimen baseline 
QTcF value (pre-dose), as described above (average triplicate screening QTcF).  
 For Baseline post dose visit only, ΔQTcF is calculated from the initial 
printout, as the ERT Overread will not be available at the time of the 
Baseline Visit.  


 
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 For all other ECGs (i.e.Week 4 and Week 24), ΔQTcF should be 
calculated using the baseline QTcF pre-dose (average triplicate 
screening QTcF) from the ERT Overread.   
o For participants who transition into the OLE, the new baseline QTcF is the 
average triplicate QTcF collected pre-dose during the Week 24 visit.  
 
 The first time a participant meets the Monitoring Rule they will be asked to return to 
the clinic after 3-14 days and repeat a post-dose ECG (1-2 hours AFTER administration 
of IP). 
o If the local ECG reading results at the site meet the Monitoring Rule, the 
participant can continue the IP per protocol until the ERT central ECG report is 
received. If the central read confirms meeting Monitoring Rule, the participant 
will stay on IP (per protocol) and will be asked to return for a follow-up ECG 
after 3-14 days. 
  
 The second time a participant meets the Monitoring Rule, the participant should 
decrease IP to QD dosing.  
o A follow-up post-dose ECG (1-2 hours AFTER administration of IP) should 
occur 3-14 days after decreasing to QD dosing. 
o If the participant meets the monitoring rule again during this follow-up ECG, 
the participant must discontinue IP.   
 
 


 
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Figure 2: ECG Monitoring Flow for Regimen Specific Screening Visit to Assess for 
Regimen D Eligiblility* (before IP administration): 
 
Initial ECG assessment will be done to assess eligibility (Figure 2): 
 QTcF will be measured by a mean of 3 (triplicate) 12-lead ECG assessments 
o Three 10-second ECG recordings should be performed, with at least one minute 
between each recording. QTcF will be automatically calculated by the ECG 
machine, and will be copied onto source documents. Mean QTcF from the three 
ECG recordings will be calculated manually. The SI should review and confirm 
the mean QTcF value.  
 If the mean QTcF is >450 ms for men and >470 ms for women, then participant will 
screen fail and will not be randomized within the regimen.  
 For participants on Nuedexta, the Nuedexta dose should be taken within 6 hours before 
triplicate ECG.  
 
 
 
 
  
 
 
 
 


 
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Figure 3: ECG Monitoring Flow for Regimen Specific Baseline post-dose and Week 4 post-dose 
Visits* 
 
 
 
 
*For participants on Nuedexta, the Nuedexta dose should be taken within 6 hours before the ECG  
 
QTcF value will be automatically calculated by the ECG machine, and will be copied into source 
documents (Figure 3): 
 QTcF will be measured by a single 12-lead ECG, 1-2 hours post-dose administration. 
 If QTcF meets Stopping/Monitoring Rules, then ECG will be repeated twice1 and the 
QTcF will be determined by the average of the 3 ECGs. 
 If the average QTcF meets Stopping Rules, IP will be held, and a follow-up ECG will 
be performed as soon as practicable (but at least 2 days after stopping IP) to ensure 
recovery from QT-prolongation. 
 If the average QTcF meets Monitoring Rule for the 1st time, participant will be 
instructed to continue on IP per-protocol and have a follow up, post-dose ECG after 3 
-14 days  
 If a participant meets the Monitoring Rule for the second time, the participant will be 
instructed to decrease IP to QD dosing for the remainder of the study. 
o A follow-up ECG should occur 3-14 days after decreasing to QD dosing. If the 
participant meets the monitoring rule for the 3rd time, the participant must 
discontinue IP immediately.   
 
 
 
1 Standard ECG procedure for abnormal QTcF readings will be for the ECG to be repeated twice (at least 5 minutes 
after the 1st ECG, and with an interval of at least 1 minute between each of the 2 additional 10-second recordings), 
and the mean of the 3 measurements will be used to determine final QTcF. 


 
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ECG Monitoring Flow at Week 24 for Participants not Enrolling into the OLE 
 
QTcF will be automatically calculated by the ECG machine, and will be copied into source 
documents: 
 QTcF will be measured by a single 12-lead pre-dose ECG. 
o For participants taking Nuedexta, the Nuedexta dose should be taken 
within 6 hours before the ECG  
 If QTcF meets Stopping/Monitoring Rules, then ECG will be repeated twice2 and the 
QTcF will be determined by the average of the 3 ECGs. 
 If the average QTcF meets Stopping Rules, IP will be stopped, and a follow-up ECG 
will be performed as soon as practicable (but at least 2 days after stopping IP) to ensure 
recovery from QT-prolongation. 
 
ECG Monitoring Flow at Week 24 for Participants who choose to Enroll into the OLE 
 
 Baseline QTcF for the purpose of OLE will be measured by a mean of 3 (triplicate) 
12-lead pre-dose ECG assessments 
o Three 10-second ECG recordings should be performed, with at least one minute 
in between each ECG recording. QTcF will be automatically calculated by the 
ECG machine, and will be copied onto source documents. Mean QTcF from the 
three ECG recordings will be calculated manually and used as Baseline pre-
dose QTcF for the OLE. The SI should review and confirm the mean QTcF.  
 For participants taking Nuedexta, the Nuedexta dose should be taken within 6 hours 
before the ECG.  
 If the mean QTcF is >450 ms for men and >470 ms for women at the Week 24 Visit, 
then participant will not be eligible to continue into the OLE.  
 The OLE IP should then be administered to the participant, and a single 10-second 
ECG should be collected 1-2 hours after administration of the OLE IP.  
 If QTcF meets Stopping/Monitoring Rules then ECG will be repeated twice2 and the 
QTcF will be determined by the average of the 3 ECGs. 
 If the mean QTcF meets Stopping Rules, IP will be held , and a follow-up ECG will be 
performed as soon as practicable (but at least 2 days after stopping IP) to ensure 
recovery from QT-prolongation. 
 If the mean QTcF meets Monitoring Rule, participant may continue on IP per-protocol 
and have another ECG after 3 -14 days.  
 If a participant meets the Monitoring Rule for the second time, the participant may 
decrease to QD dosing for the remainder of the study. 
 A follow-up ECG should occur 3-14 days after decreasing to QD dosing. If the 
participant meets the monitoring rule during this follow-up ECG, the participant must 
discontinue IP immediately. 
 
 
2 Standard ECG procedure for abnormal QTcF readings will be for the ECG to be repeated twice (at least 5 minutes 
after the 1st ECG, and with an interval of at least 1 minute between each of the 2 additional 10-second recordings), 
and the mean of the 3 measurements will be used to determine final QTcF. 


 
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5 INVESTIGATIONAL PRODUCT  
 
5.1      Investigational Product Manufacturer 
 
Pridopidine active drug product and matching placebo are manufactured by Teva Pharmaceutical 
Industries, Ltd or by Apotek Production & Laboratories AB (APL) and will be provided 
centrally by the Sponsor or subsidiary, or designee. 
 
The investigational product will be oral capsules containing 45 mg of pridopidine and matching 
placebo capsules (as the control treatment product) identical in appearance. 
Pridopidine capsules contain the active ingredient pridopidine and inactive excipients. The 
excipients are silicified micro crystalline cellulose and magnesium stearate. 
 
The investigational product will be produced and packed in 60 count bottles provided by Apotek 
Produktion & Laboratorier AB, Sweden.  
 
5.2      Labeling, Packaging, and Resupply 
 
IP will be provided in high-density polyethylene (HDPE) bottles labeled with child resistant caps. 
All packaging and labeling operations for IP will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory requirements. 
Participants will be provided with sufficient IP supplies to cover the period until their next study 
visit when IP will be dispensed. Each bottle will be labelled with the protocol number, storage 
information, warning language (i.e., as required by local legislation for investigational drug 
products), dosing and storage instructions.  
 
5.3      Acquisition, Storage, and Preparation 
 
At each investigational site, the IP will be kept at 15 to 25 ºC in a secure, limited-access, 
controlled storage area. Only authorized personnel will have access to the IP. The study 
personnel at each site will be responsible for the correct storage and handling of the IP.  
Each bottle will be labelled with the protocol number, storage information, warning language 
(i.e., as required by local legislation for IP), dosing and storage instructions.  
The Investigator is responsible for recording the receipt and use of all IP supplied, and for 
ensuring the supervision of the storage and allocation of these supplies. Full accountability will 
be performed for all used and unused IP. 
 
5.4 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 


 
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approval is provided by the study monitoring team. Sites should follow their local drug 
destruction policies. 
 
5.5      Study Medication/Intervention, Administration, Escalation, and Duration 
 
Participants will take 45 mg capsules of active IP/placebo BID (1 capsule in the morning and 1 
capsule in the afternoon, approximately 7 to 10 hours after the morning dose); total daily dose 
(TDD) of 90 mg. Capsules should be swallowed whole with a drink of water (or other liquid) or 
swallowed whole with substances of other consistencies as appropriate (e.g. applesauce), and can 
be taken irrespective of meals. For delivery via gastrostomy tube, the capsule can be opened and 
the contents diluted in 20-30mL of water and mixed. The prepared solution  should be used 
immediately. Flushing with water is recommended to minimize clogging of the gastrostomy 
tubing after administration. 
All participants receiving study intervention are intended to receive the same fixed-dose 
regimen, in terms of dose and daily (BID) frequency, according to the study schedule. There will 
be a titration period leading up to the proposed dose whereby at the baseline visit participants 
will initiate pridopidine/placebo at 45 mg QD and then increase to 45 mg BID after 2 weeks.  
  
5.6     Justification for Dose  
 
The dosage of pridopidine (45 mg BID) was selected on the basis of three large HD clinical 
studies (HART, MermaiHD, and PRIDE-HD) and has been shown to be safe and well-tolerated 
in >1300 participants. Pridopidine 45 mg BID showed potential beneficial clinical effects in the 
PRIDE-HD study, including potential sustainable effects based on the long-term open-label 
study, and is therefore anticipated to provide efficacy with low safety and tolerability risks. In 
vivo target engagement was demonstrated by a positron emission tomography (PET) imaging 
study in humans. At 45 mg BID, pridopidine shows near to complete (~90%) S1R binding 
([18F]fluspidine) (Figure 1). 
 
5.7    Dosage Changes 
 
After the 2-week up-titration period, participants who are unable to tolerate a BID schedule will 
be allowed to stay in the study at the lower dose QD schedule for 1 additional week. After 1 
additional week of study intervention on the QD schedule, the dose will be increased to a BID 
dose schedule. If the participant cannot tolerate the second increase to a BID dose schedule, they 
will be allowed to continue on QD for the remainder of the study.  
 
If a participant meets the ECG Monitoring Rule for a second time, the participant may decrease 
to QD dosing for the remainder of the study, as long as the Monitoring Rule is not met for a third 
time. 
 
5.8    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 
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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 
IP 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.  
  
5.9 
Overdose 
 
Certain safety events that occur in association with IP may require reporting. These safety events 
include, but are not limited to, the following: 
• Overdose of the IP, where ‘overdose’ is defined as a participant ingesting more than 3 times 
the intended dose  
• Suspected abuse/misuse of the IP 
• Inadvertent or accidental exposure to the IP 
• Medication error involving IP (with or without participant exposure to the IP, e.g., name 
confusion) 
 
These safety events should be reported to the Coordination Center whether they result in an 
AE/SAE or not. Safety events associated with an AE/SAE should also be reported in the EDC. 
In the event of overdose, study staff should monitor the participant and provide supportive care 
as needed. The SI should also contact the Medical Monitor within 24 hours of the SI’s 
awareness.  
 
5.10 
Prohibited Medications  
Excluded Medications: 
 
Class 
Drugs 
Antipsychotics 
Clozapine, haloperidol, mesoridazine, thioridazine, pimozide, 
chlorpromazine, perphenazine, risperidone, zuclopenthixol, and 
sulpiride. 
Antiarrhythmic 
Disopyramide, procainamide, flecainide, propafenone, amidiarone, 
dofetilide, ibutilide, and sotalol 
Others 
Astemizole, terfenadine, azithromycin, erythromycin, moxifloxacin, 
pentamidine, sparfloxacin, clarithromycin, chloroquine, halofantrine, 
bepridil, cisapride, domperidone, droperidol, levomethadyl, 
sevoflurane, anagrelide, budipine, fluconazole, levofloxacin, 
lidoflazine, ondansetron, probucol, terodiline, vandetanib, tramadol, 
tamoxifen, atomoxetine, tolterodine 
 


 
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Participants who use the above medications while enrolled in Regimen D of the HEALEY ALS 
Platform Trial increase their risk of QT prolongation and torsades. If participants inadvertently 
use these medications while they are on IP, the Medical Monitor should be notified and a single 
12-lead ECG should be collected within 3-14 days of initiating the new prohibited co-
medication, or higher dose, to test for QTcF prolongation meeting the Monitoring or Stopping 
Rules. 
 
If there is a clinical indication for any medication specifically prohibited during the study, the 
Medical Monitor will be notified and engaged in consultation as to how to address.  
 
5.11 Pridopidine Known Potential Risks and Benefits 
 
5.11.1 Known Potential Risks 
 
QT prolongation: 
In the PRIDE-HD trial of 408 participants, the cardiac effects of pridopidine were evaluated in 
people with HD at doses up to 112.5 mg BID for 52 weeks. Although low, there was a higher 
overall incidence of AE-reports of QT prolongation in pridopidine-treated participants compared 
to placebo-treated participants: 1.5% in pridopidine-treated participants vs 0% in placebo-treated 
participants. However, there was no evidence of a dose response in QT-related AEs (QT 
prolongation AEs: 0 in placebo, 2 in 45 mg BID, 0 in 67.5 mg BID, 1 in 90 mg BID and 2 in 
112.5 mg BID; total 5/327=1.5%). Using the PRIDE-HD data, a cardiac exposure-response 
model was developed utilizing ECG data paired with PK samples collected for up to a year. Only 
ECGs that were paired with PK samples (n=3071) were used to develop the cardiac exposure-
response model, which was based on 2753 ECGs from pridopidine-treated participants and 763 
from placebo-treated participants.   
 
A concentration-dependent effect of pridopidine on the QTcF interval was observed in this study, 
with a slope of 0.012 ms per ng/mL (90% CI: 0.0109 to 0.0127 ms per ng/mL). 
 
At 45 mg BID, the predicted QT effect (∆∆QTcF) in participants with HD was 6.6 ms (with an 
upper bound of the 90% CI 8 ms), which is not clinically meaningful. Pridopidine 45 mg BID is 
the dose to be tested in the HEALEY ALS Platform Trial. Although this was not a clinically 
meaningful QT effect, as there is no prior experience with pridopidine in the ALS patient 
population, we plan to include additional safety monitoring and risk mitigation measures. 
 
5.11.2 Potential Benefits 
 
Loss of function mutations in S1R cause neurodegenerative diseases such as ALS (Al-Saif, Al-
Mohanna, and Bohlega 2011; Watanabe et al., n.d.; Izumi et al. 2018) and distal hereditary motor 
neuropathies (dHMN) (Gregianin et al. 2016; Li et al. 2015), suggesting restoration of S1R function 
could be beneficial in these motor neuron diseases. Denervation at the neuromuscular junction 
(NMJ) is considered one of the earliest events in ALS disease progression (Fischer et al. 2004). 
Using in vitro ALS models, pridopidine was shown to restore NMJ function (percent of 
contracting ALS SOD1G93A myotubes) to wild-type (WT) levels (Ionescu et al. 2019). 
 


 
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Additionally, pridopidine has been shown to exert neuroprotection via activation of the S1R in 
numerous preclinical models including ALS, HD, PD, and AD, where it promotes pro-survival 
pathways, promotes neurite growth and spine density, restores abnormalities in calcium signaling 
(Ryskamp et al. 2017), and restores mitochondrial function (Geva et al. 2016; Ionescu et al. 2019; 
Francardo et al. 2019; Kusko et al. 2018). This body of preclinical data, generated from multiple 
labs using a diverse set of models, in addition to the results of the PRIDE-HD study, and 
combined with the genetics, suggests that pridopidine possesses potential neuroprotective effects 
and may, therefore, have therapeutic effects in ALS. 
 
 


 
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6  REGIMEN SCHEDULE  
 
6.1 Placebo-Controlled Period 
 
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 (CNS-BFS) 
• CNS-Lability Scale (CNS-LS) 
• Additional ECG monitoring 
• PK analysis of pridopidine and metabolite plasma exposure 
o All blood samples should be collected after the ECG, or at least one hour prior to 
the ECG 
• Smartphone installation and removal 
• Voice Recording 
 
Participants may be required to reconsent to the regimen if new procedures or information are/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. 
 
 
Modifications to Regimen Schedule  
 
Designated visits in the Schedule of Activities (i.e. 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 


 
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remote services, only selected procedures will be performed. Instructions on how to document 
missed procedures are included in the Manual of Procedures (MOP). 
 
If a remote visit is scheduled, the ECG must still be conducted in-clinic within the visit window, 
and all other procedures can be collected via telemedicine (or phone if telemedicine is not 
available) as described 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-BFS 
• CNS-LS 
 
Details on collection of the CNS Bulbar Function Scale, CNS Lability Scale, ECG monitoring, 
dispensing IP during remote visits, and documenting participants’ willingness to participate in 
OLE are described in the MOP. 
 
 
 
6.1.1 Regimen Screening/Baseline Visit 
 
This visit will take place on Day 0. The following procedures will be performed for the regimen 
schedule: 
 
• ALSAQ-40 
• CNS-BFS 
• CNS-LS 
• Install Smartphone Apps 
• Home Spirometry 
• Voice Recording 
• Collect blood sample prior to the first dose of IP  
• Dispense IP to participant, and administer first dose after all Baseline procedures have been 
completed, with the exception of the post-dose ECG  
• ECG 
o Screening Visit – administer triplicate ECG to determine eligibility 
o Baseline - administer post-dose single ECG 1-2 hours after the first dose of IP is 
administered 
 Note: if the participant is taking Nuedexta, the Nuedexta dose should be 
taken within 6 hours prior to the pre dose ECG. If participant has taken 
Nuedexta outside of this window, the ECG should still be completed and a 
protocol deviation recorded. Refer to the MOP for additional guidance. 
• Remind participant to bring study drug to the next visit 
 


 
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6.1.2 Week 2 Telephone Visit 
 
This visit will take place 14 ± 3 days after the Baseline Visit via telephone. The following 
procedures will be performed for the regimen schedule: 
 
• Participant will be reminded to up-titrate to 45mg/placebo BID of IP following an assessment 
of tolerability of 45 mg/placebo QD dose 
 
6.1.3 Week 4 Visit 
 
If a participant’s visit occurs in the morning, the participant should be instructed not to take the 
morning dose at home, and the morning dose should be administered in-clinic 1-2 hours prior to 
the post-dose ECG. If a participant’s visit occurs in the afternoon, the participant should be 
instructed to take the morning dose immediately upon waking in the morning, and the second 
dose should be administered in-clinic 1-2 hours prior to the post-dose ECG. 
 
These visits will take place on Day 28 ± 7.  The following procedures will be performed for the 
regimen schedule: 
 
• Administer single ECG 1-2 hours AFTER IP is administered 
o Note: if the participant is taking Nuedexta, the Nuedexta dose should be taken 
within 6 hours prior to the ECG. If participant has taken Nuedexta outside of this 
window, the ECG should still be completed and a protocol deviation recorded. 
Refer to the MOP for additional guidance. 
• Plasma collection AFTER ECG 
o All blood samples should be collected after the ECG is performed. If the blood 
samples cannot be collected after the ECG due to scheduling constraints, blood 
samples should be collected at least one hour prior to the ECG. 
• Voice Recording 
• Remind participant to bring study drug to the next visit   
 
6.1.4 Week 8 Visit 
 
 
These visits will take place on Day 56 ± 7 days.  The following procedures will be performed for 
the regimen schedule: 
 
• Home Spirometry 
• CNS-BFS  
• CNS-LS  
• Voice Recording 
• Dispense IP  
• Remind participant to bring in study drug to the next visit   
 
6.1.5 Week 12 Telephone Visit 
 


 
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This visit will take place 84 ± 3 days after the Baseline Visit via telephone.  
 
6.1.6 Week 16 Visit 
 
 
This visit will take place in-person 112 ± 7 days after the Baseline Visit. The following 
procedures will be performed: 
 
• Home Spirometry 
• CNS-BFS 
• CNS-LS 
• Voice Recording 
• Dispense IP 
• 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. 
• 
Remind participant to bring in study drug to the next visit 
 
6.1.7 Week 20 Telephone Visit 
 
This visit will take place 140 ± 3 days after the Baseline Visit via telephone.  
 
6.1.8 Week 24 Visit or Early Termination Visit 
 
Participants Not Enrolling into the OLE 
 
Only a pre-dose ECG is required at this visit for participant who are not enrolling into the OLE.  
 
If a participant’s visit occurs in the morning, the participant should be instructed not to take the 
morning dose at home, and the morning dose should be administered in-clinic after the pre-dose 
ECG. If a participant’s visit occurs in the afternoon, the participant should be instructed to take 
the morning dose immediately upon waking in the morning, and the second dose should be taken 
after the pre-dose ECG. 
 
Participants Enrolling into the OLE 
 
A pre-dose and post-dose ECG are required for participants who enroll into the OLE. The SI 
should confirm the mean QTcF following the pre-dose triplicate ECG. If the mean QTcF is >450 
ms for men and >470 ms for women, then participant will not be eligible to continue into the 
OLE. 
 
If a participant’s visit occurs in the morning, the participant should be instructed not to take the 
morning dose at home. A pre-dose triplicate ECG should be collected prior to administration of 
the first dose of OLE IP in-clinic. A single post-dose ECG should then be collected 1-2 hours 
after administration of the first dose of OLE IP.  
 


 
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If a participant’s visit occurs in the afternoon, the participant should be instructed to take the 
morning dose immediately upon waking in the morning, and a pre-dose triplicate ECG should be 
collected prior to administration of the first dose of OLE IP in-clinic (which will be the 2nd daily 
dose).  
 
A single post-dose ECG should then be collected 1-2 hours after administration of the first dose 
of OLE IP. 
 
This visit will take place on Day 168 ± 7.  The following procedures will be performed at either 
the Week 24 Visit or the Early Termination Visit: 
 
• Home Spirometry 
• ALSAQ-40 
• CNS-BFS 
• CNS-LS 
• Triplicate ECG monitoring BEFORE IP administration 
• Administer single ECG 1-2 hours AFTER IP is administered (only for participants enrolling 
into the OLE) 
o Note: if the participant is taking Nuedexta, the Nuedexta dose should be taken 
within 6 hours prior to the pre-dose ECG. If participant has taken Nuedexta 
outside of this window, the ECG should still be completed and a protocol 
deviation recorded. Refer to the MOP for additional guidance. 
• Plasma PK collection  
o after the pre-dose ECG for participants NOT participating in the OLE 
o after the post-dose ECG for participants participating in the OLE  
o All blood samples should be collected after the ECG is performed. If the blood 
samples cannot be collected after the ECG due to scheduling constraints, blood 
samples should be collected at least one hour prior to the ECG. 
• Voice Recording 
• Uninstall Smartphone App  
• Dispense IP [See note below.] 
• Remind participant to bring investigational product to the next visit (only if continuing in 
OLE) 
 
Note: Drug is only dispensed at this visit if the participant is continuing in the OLE. 
 
6.1.9  Follow-Up Safety Call 
 
Participants will have a Follow-Up Safety Call 28±3 days after their last dose of IP.  Only those 
participants NOT continuing on in the Open Label Extension will have the Follow-Up Safety 
Call at 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) 
 


 
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6.1.10 Process for Early Terminations 
 
A research participant may choose to discontinue their participation at any time for any reason. 
The SI or designee will encourage the participant to follow the study protocol under intent-to-
treat principle and follow the study visits, off treatment, up to the week 24 visit.  If a participant 
decides to discontinue IP, but will complete the protocol, an in-person Early Termination Visit 
and Follow-Up Safety Call is not necessary. 
 
Participants who early terminate from the study and do not complete the protocol 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. If 
the participant early terminates 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 days after the last dose of IP.   
 
If the Early Termination Visit occurs approximately 28±3 days after the last dose of IP, the 
information for 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±3 days of the last dose of IP, the Follow-Up Safety 
Call should occur approximately 28±3 days after the last dose of IP and the Early Termination 
Visit will be completed after the Follow-Up Safety Call.      
 
 
6.2 
Open Label Extension  
 
Participants who completed the placebo-controlled portion of the trial on drug, will be eligible to 
continue in the OLE as outlined in the SOA.  Participants will first be asked about their desire to 
continue in the OLE at the Regimen-Specific Screening Visit.  They will also be asked to re-
confirm whether they want to continue in the OLE at the Week 16 Visit of the placebo-controlled 
period. In the OLE, pridopidine will be provided by Prilenia Therapeutics, until the primary 
results of the 24 week double-blind portion of the study are available, or they terminate 
development of pridopidine for ALS.  
 
To preserve the blind, all participants in the OLE, regardless of whether they were in the active 
or placebo arm of the study initially will need to initiate the OLE at a QD dose and then up-
titrate to BID after 2 weeks. 
 
Modifications to OLE Schedule  
Designated visits in the Schedule of Activities for the OLE (i.e. Week 8, Week 16) may be 
conducted via telemedicine (or phone if telemedicine is not available) with remote services 


 
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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 
• CNS-BFS 
• CNS-LS 
• ALSAQ-40  
 
 
6.2.1 Week 2 OLE Telephone Visit 
 
This visit will take place via telephone 14 ± 3 days after the Week 24 Visit of 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) 
• 
Drug Compliance Check-In (Participant should increase dose from QD to BID) 
• 
Remind participant to bring investigational product to the next visit 
 
6.2.2 Week 4 OLE Visit 
 
If a participant’s visit occurs in the morning, the participant should be instructed not to take the 
morning dose at home, and the morning dose should be administered in-clinic 1-2 hours prior to 
the post-dose ECG. If a participant’s visit occurs in the afternoon, the participant should be 
instructed to take the morning dose immediately upon waking in the morning, and the second 
dose should be administered in-clinic 1-2 hours prior to the post-dose ECG. 
 
This visit will take place in-person 28 ± 7 days after the Week 24 Visit of the placebo-controlled 
portion of the trial. The following procedures will be performed: 
 
• 
Collect vital signs including weight 
• 
Perform SVC 
• 
Collect Home Spirometry 
• 
Administer ALSFRS-R questionnaire 
• Administer single ECG 1-2 hours AFTER IP is administered 
o Note: if the participant is taking Nuedexta, the Nuedexta dose should be taken 
within 6 hours prior to the post-dose ECG. If participant has taken Nuedexta 
outside of this window, the ECG should still be completed and a protocol 
deviation recorded. Refer to the MOP for additional guidance. 
• Collect blood samples for Clinical Safety Labs and, for WOCBP, for pregnancy test if 
applicable 


 
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• 
All blood samples should be collected after the ECG is performed. If the blood samples 
cannot be collected after the ECG due to scheduling constraints, blood samples should be 
collected at least one hour prior to the ECG. 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Administer the C-SSRS Since Last Visit questionnaire  
• 
Perform investigational product compliance 
• 
Remind participant to bring investigational product to the next visit 
 
6.2.3 Week 8 OLE Visit 
 
This visit will take place in person at 56 ± 7 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Collect vital signs including weight 
• 
Perform SVC 
• 
Collect Home Spirometry 
• 
Administer ALSFRS-R questionnaire 
• 
CNS Bulbar Function Scale 
• 
CNS Lability Scale 
• 
Collect blood samples for Clinical Safety Labs and, for WOCBP, for pregnancy test if 
applicable and biomarker samples 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Administer the C-SSRS Since Last Visit questionnaire  
• 
Dispense investigational product to participant  
• 
Perform investigational product compliance 
• 
Remind participant to bring investigational product to the next visit 
 
6.2.4 Week 12 OLE Telephone Visit 
 
This visit will take place via telephone at 84 ± 3 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Administer ALSFRS-R questionnaire 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Drug Compliance Check-In 
• 
Remind participant to bring investigational product to the next visit 
 
6.2.5 Week 16 OLE Visit 
 
 
This visit will take place in-person at 112 ± 7 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Collect vital signs including weight 


 
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• 
Perform SVC 
• 
Collect Home Spirometry 
• 
Administer ALSFRS-R questionnaire 
• 
CNS Bulbar Function Scale 
• 
CNS Lability Scale 
• 
Collect blood samples for Clinical Safety Labs and, for WOCBP, for pregnancy test if 
applicable 
• 
Collect urine sample biomarker analyses 
• 
Collect blood sample for biomarker analyses 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Administer the C-SSRS Since Last Visit questionnaire  
• Dispense investigational product to participant  
• 
Perform investigational product compliance 
• 
Remind participant to bring investigational product to the next visit 
 
 
6.2.6  Week 20 OLE Telephone Visit 
 
This visit will take place via telephone at 140 ± 3 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Administer ALSFRS-R questionnaire 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Drug Compliance Check-In 
• 
Remind participant to bring investigational product to the next visit 
 
 
6.2.7 Week 24 and Q12 Weeks OLE Visit 
 
If a participant’s visit occurs in the morning, the participant should be instructed not to take the 
morning dose at home, and the morning dose should be administered in-clinic after the pre-dose 
ECG. If a participant’s visit occurs in the afternoon, the participant should be instructed to take 
the morning dose immediately upon waking in the morning, and the second dose should be taken 
after the pre-dose ECG. 
 
The Week 24 OLE Visit will take place in-person 196 ± 14 days after the Week 24 Visit of the 
placebo-controlled portion of the trial. Following the Week 24 OLE Visit, visits will occur every 
12 weeks ± 14 days as applicable. The following procedures will be performed: 
 
• 
Collect vital signs including weight 
• 
Perform SVC 
• 
Collect Home Spirometry 
• 
Administer ALSFRS-R questionnaire 
• 
ALSAQ-40 
• 
CNS Bulbar Function Scale 


 
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• 
CNS Lability Scale 
• 
Administer ECG BEFORE IP is administered (at Week 24 and Final OLE Visit only) 
o Note: if the participant is taking Nuedexta, the Nuedexta dose should be taken 
within 6 hours prior to the post-dose ECG. If participant has taken Nuedexta 
outside of this window, the ECG should still be completed and a protocol 
deviation recorded. Refer to the MOP for additional guidance. 
• 
Collect blood samples for Clinical Safety Labs and, for WOCBP, for pregnancy test if 
applicable 
• 
All blood samples should be collected after the ECG is performed. If the blood samples 
cannot be collected after the ECG due to scheduling constraints, blood samples should be 
collected at least one hour prior to the ECG. 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Administer the C-SSRS Since Last Visit questionnaire  
• 
Collect urine sample for biomarker analyses 
• 
Collect blood sample for biomarker analyses 
• Dispense investigational product to participant 
• 
Perform investigational product compliance 
• 
Remind participant to bring investigational product to the next visit 
 
 


 
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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 
 
In addition to the scheduled in clinic voice recordings, voice samples will be collected twice per 
week and at each in person visit, 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 participant 
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 participants with ALS and 
motor neuron disease. Higher scores indicate a decrease in quality of life. 
 
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 participant 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 (Smith et al, 2018). The CNS-BFS consists of three 
domains (swallowing, speech, and salivation), which are assessed with a 21-question, self-report 
questionnaire. Higher scores indicate greater bulbar dysfunction. 
 
Participants will be handed the questionnaire and asked to write their answers themselves.  
Caregivers can also help, if needed. 
 
Instructions on administering the questionnaire during a phone or telemedicine visit will be 
included in the MOP. 
 


 
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7.4 
CNS-Lability Scale 
 
The Center for Neurologic Study Lability Scale (CNS-LS) is a participant self-report scale that 
has been developed for use as an endpoint in clinical trials and as a clinical measure for 
evaluating emotional lability. The CNS-LS is a short (seven-question), self-report questionnaire, 
designed to be completed by the participant, that provides a quantitative measure of the 
perceived frequency of PBA episodes. Higher scores indicate greater emotional lability. A CNS-
LS score of 13 or higher may suggest PBA. 
 
For all in person visits, participants will be handed the questionnaire and asked to write their 
answers themselves.  Caregivers can also help, if needed.  During telephone visits, site staff will 
administer and record data for this scale. 
 
7.5 
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 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.   
 
 
 


 
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8 
BIOFLUID COLLECTION 
 
8.1 Pharmacokinetic Sample 
 
PK Collection  
• Collect 4mL of blood in a 4mL K3EDTA tube at the allocated time-points. 
• Invert the collection tube 8-10x  
• Centrifuge the collected sample at 2000 x g for 15 min at 4˚C  
• Aliquot 1mL of obtained plasma in the Primary and Back-up 3.6mL Cryo Vial  
o Note: The plasma should be transferred into the aliquot vials within 60 minutes 
(preferable immediately) of collection  
 
 


 
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9 
REGIMEN-SPECIFIC STATISTICAL CONSIDERATIONS 
 
9.1 
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, except that early success will not be permitted.  
Hence, as with the first 3 regimens, interim analyses for Regimen D will only allow stopping for 
early futility and not for early success.   
 
9.2 
Regimen-Specific Operating Characteristics  
 
Clinical trial simulation is used to quantify operating characteristics for this regimen. Given that 
the statistical design for the regimen does not have any deviations from the design of the first 
three regimens, the simulation of virtual participants, simulation scenarios and operating 
characteristics are available in Appendix I to the master protocol.  
 
 9.3  
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.   
 
 9.4 
Secondary Efficacy Endpoints  
 
If the primary analysis demonstrates significant slowing of decline in ALSFRS-R among 
participants randomized to pridopidine, then the following secondary hypotheses will be tested in 
the specified sequence with overall type I error rate controlled using a sequential closed-testing 
procedure: 
1. Rate of change in ALSFRS-R bulbar subdomain (Q1-Q3) score among participants with 
bulbar dysfunction at baseline, 
2. Rate of change in ALSFRS-R bulbar subdomain (Q1-Q3) score among all randomized 
participants, 
3. Rate of change in the speech sub-score of the ALSFRS-R (Q1) among all randomized 
participants 
4. Rate of change in SVC maximum percent of predicted among all randomized 
participants, 
5. Rate of change in ALSFRS-R bulbar subdomain (Q1-Q3) score among participants with 
pre-baseline slope ≥0.75 points/month, 
6. Time to onset of bulbar symptoms among participants free of bulbar dysfunction at 
baseline, 
7. Rate of change in HHD percent change from baseline among all randomized participants, 
8. Time to death or death equivalent 
 
Analyses for each secondary hypothesis will use an ITT analysis sample that includes placebo 
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CNS-BFS, HHD, and SVC will use shared-baseline linear mixed models that adjust for time 
since onset of weakness, pre-baseline slope, baseline riluzole use, baseline edaravone use, 
baseline Nuedexta use, and site of onset and their interactions with time since baseline, and 
include random intercepts and slopes by regimen and by participant with unstructured covariance 
at each level. Given low expected event rates, time to bulbar onset and time to death or death 
equivalent will use log-rank tests. Per protocol analyses will also be performed to evaluate the 
effects of pridopidine on participants complying with study regimen. Details of endpoint 
measures, analysis samples, statistical models, and the closed-testing procedure will be described 
in the regimen-specific statistical analysis plan. 
 
 


 
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10  
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Ryskamp, Daniel, Jun Wu, Michal Geva, Rebecca Kusko, Iris Grossman, Michael Hayden, and 
Ilya Bezprozvanny. 2017. “The Sigma-1 Receptor Mediates the Beneficial Effects of 
Pridopidine in a Mouse Model of Huntington Disease.” Neurobiology of Disease 97 (Pt A): 
46–59. https://doi.org/10.1016/j.nbd.2016.10.006. 
Sahlholm K, Sijbesma JW, Maas B, Kwizera C, Marcellino D, Ramakrishnan NK, Dierckx RA, 
Elsinga PH, van Waarde A. 2015. “Pridopidine Selectively Occupies Sigma-1 Rather than 
Dopamine D2 Receptors at Behaviorally Active Doses.” Psychopharmacology 232 (18): 
3443–53. https://doi.org/10.1007/s00213-015-3997-8. 
Sahlholm, K., P. Århem, K. Fuxe, and D. Marcellino. 2013. “The Dopamine Stabilizers ACR16 
and ()-OSU6162 Display Nanomolar Affinities at the σ-1 Receptor.” Molecular Psychiatry 
18 (1): 12–14. https://doi.org/10.1038/mp.2012.3. 
Shoulson, Ira, and Stanley Fahn. 1979. “Huntington Disease: Clinical Care and Evaluation.” 
Neurology. https://doi.org/10.1212/wnl.29.1.1. 


 
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Su, Tsung-Ping, Teruo Hayashi, Tangui Maurice, Shilpa Buch, and Arnold E. Ruoho. 2010. 
“The Sigma-1 Receptor Chaperone as an Inter-Organelle Signaling Modulator.” Trends in 
Pharmacological Sciences 31 (12): 557–66. https://doi.org/10.1016/j.tips.2010.08.007. 
Tabrizi, Sarah J., Rachael I. Scahill, Gail Owen, Alexandra Durr, Blair R. Leavitt, Raymund A. 
Roos, Beth Borowsky, et al. 2013. “Predictors of Phenotypic Progression and Disease Onset 
in Premanifest and Early-Stage Huntington’s Disease in the TRACK-HD Study: Analysis of 
36-Month Observational Data.” The Lancet Neurology 12 (7): 637–49. 
https://doi.org/10.1016/S1474-4422(13)70088-7. 
Tabrizi, Sarah J, Ralf Reilmann, Raymund AC Roos, Alexandra Durr, Blair Leavitt, Gail Owen, 
Rebecca Jones, et al. 2012. “Potential Endpoints for Clinical Trials in Premanifest and Early 
Huntington’s Disease in the TRACK-HD Study: Analysis of 24 Month Observational 
Data.” The Lancet Neurology 11 (1): 42–53. https://doi.org/10.1016/S1474-4422(11)70263-
0. 
Vagnerova, Kamila, Patricia D. Hurn, Anish Bhardwaj, and Jeffrey R. Kirsch. 2006. “Sigma 1 
Receptor Agonist Act as Neuroprotective Drugs through Inhibition of Inducible Nitric 
Oxide Synthase.” Anesthesia and Analgesia 103 (2): 430–34. 
https://doi.org/10.1213/01.ane.0000226133.85114.91. 
Watanabe, S, H Ilieva, H Tamada, H Nomura, O Komine, F Endo, S Jin, P Mancias, H Kiyama, 
and K Yamanaka. n.d. “Mitochondria-Associated Membrane Collapse Is a Common 
Pathomechanism in SIG.” EMBO Mol.Med. 
  
 
 
 


 
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APPENDIX I: THE ALSAQ-40 
 
 


 
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APPENDIX II: THE BULBAR FUNCTION SCALE (CNS-BFS)  
The following statements all refer to certain difficulties that you may have had during the 
last 2 weeks. Please indicate, by checking the appropriate box, how often the following 
statements have been true for you. 
 
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. 
 
 
 
 
 
 
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. 
 
 
 
 
 
 


 
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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. 
 
 
 
 
 
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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APPENDIX III: THE LABILITY SCALE (CNS-LS)  
 
TOTAL: 
Please select the number that describes the degree to which each item has applied to you DURING THE PAST WEEK. 
 
Does not 
Apply 
1 
Rarely 
Applies 
2 
Occasionally   
Applies 
3 
Frequently  
Applies 
4 
Applies Most  
of the Time 
5 
1. There are times when I feel fine 1 minute, and 
then I’ll become tearful the next over something 
small or for no reason at all. 
 
 
 
 
 
2. Others have told me that I seem to become 
amused very easily or that I seem to become 
amused about things that aren’t funny. 
 
 
 
 
 
3. I find myself crying very easily. 
 
 
 
 
 
4. I find that even when I try to control my 
laughter, I am often unable to do so.  
 
 
 
 
 
5. There are times when I won’t be thinking of 
anything happy or funny at all, but then I’ll 
suddenly be overcome by funny or happy 
thoughts.  
 
 
 
 
 
6. I find that even when I try to control my 
crying, I am often unable to do so. 
 
 
 
 
 
7. I find that I am easily overcome by laughter. 
 
 
 
 
 

SAP_001.pdf: 
HEALEY ALS Platform Trial - Regimen D Pridopidine 
NCT04615923 
Document Date: 06 Oct 2022 


Cudkowicz (PI) HEALEY ALS Platform Trial: RGD Statistical Analysis Plan 
Version 3.0, 06 Oct 2022 
 
Page 1 of 38 
 
 
RGD 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 
RGD: Pridopidine 
Regimen Partner 
Prilenia Neurotherapeutics Ltd. 
Regulatory Sponsor 
Merit E. Cudkowicz, MD 
Master Protocol Version 
4.0, 31 Aug 2020 
RSA Version 
2.0, 15 Jul 2021 
Master SAP Version 
2.0, 01 Aug 2020 
R-SAP Version 
3.0, 06 Oct 2022 
 
SAP APPROVAL SIGNATURES 
 
 
Merit E. Cudkowicz, MD, MSc 
Principal Investigator and Regulatory Sponsor 
Date 
 
 
Sabrina Paganoni, MD, PhD 
Co-Principal Investigator 
Date 
 
 
Y Paul Goldberg, MB ChB, PhD, FRCPC 
CSO & Head of Early Clinical Development 
Prilenia Neurotherapeutics Ltd. 
Date 
10/06/2022
10/06/2022
10/06/2022


Cudkowicz (PI) HEALEY ALS Platform Trial: RGD Statistical Analysis Plan 
Version 3.0, 06 Oct 2022 
 
Page 2 of 38 
 
 
 
Ben Saville, PhD 
Senior Statistical Scientist, Berry Consultants 
Date 
 
 
Eric A. Macklin, PhD 
Study Biostatistician 
Date 
 
 
Munish Mehra, MSc, PhD 
Senior Principal Statistician, Tigermed 
Date 
 
 
Suzanne Hendrix, PhD 
President & CEO, Pentara Corporation 
Date 
10/07/2022
10/06/2022
10/06/2022
10/06/2022


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Page 3 of 38 
 
SAP REVISION HISTORY 
Version 
Date 
Description of Changes 
1.0 
19 May 2022 Initial version 
2.0 
08 Aug 2022 Revision of Section 3.6 Missing Data to clarify that mean 
imputation of any missing baseline covariates will impute after 
transformation for any transformed covariates. 
Revision of Section 4.1 Efficacy Endpoints to clarify reference to 
CNS-BFS total score and serum NfL level. 
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 5.2 SVC to specify details of the calculation 
of age. 
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. 
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 5.10 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  


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Page 4 of 38 
 
Version 
Date 
Description of Changes 
2.0 
(continued) 
08 Aug 2022 
(continued) 
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 and clarify reference to CNS-
BFS total score and serum NfL level. 
Revision of Section 6.3 Primary Efficacy Analysis and 
Supportive Analyses to include the ECM analysis set. 
Revision of Section 6.5.1 Hierarchical Testing to correct 
reference to Section 6.5.6 for survival analyses. 
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 Time to First Evidence of Bulbar 
Dysfunction to reference the FAS and mITT analysis sets and to 
specify a separate supportive analysis that includes baseline serum 
NfL level as an additional covariate. 
Revision of Section 6.5.5 Responder Analysis to specify a separate 
supportive analysis that includes baseline serum NfL level as an 
additional covariate. 
Revision of Section 6.5.6 Survival and Time to Clinical Events to 
include the mITT and ECM analysis sets, 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 adjusted models, and to 
specify an additional adjusted analysis that includes baseline serum 
NfL level as a covariate. 
Revision of Section 6.5.7 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  


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Page 5 of 38 
 
 
2.0 
(continued) 
08 Aug 2022 
(continued) 
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 6.5.8 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 6.5.9 Quantitative Voice Measures to remove 
reference to the shared-baseline assumption of the random-slopes 
mixed model of Section 6.5.3, 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 6.5.10 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 6.5.13 Comparison of Controls across 
Regimens to specify separate analyses that add baseline serum 
NfL level and relevant interaction terms as additional covariates. 
3.0 
06 Oct 2022 
Revision of Section 5.10 Survival to clarify calculation of 
censoring time for the composite endpoint of death or death-
equivalent. 
Revision of Section 7.2 [Validation of] Secondary, Exploratory, 
and Safety Analyses to identify three levels of validation and 
their application and to specify that analyses that fail due to small 
sample size or lack of convergence will be omitted. 
 


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Page 6 of 38 
 
ABBREVIATIONS 
ALD 
After Last Dose 
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 Aminotransferase 
AST 
Aspartate Aminotransferase 
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 
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 38 
 
ABBREVIATIONS (continued) 
FVC 
Forced Vital Capacity 
GLI 
Global Lung Initiative 
HHD 
Hand-held Dynamometry 
HLT 
MedDRA High Level Term 
ICF 
Informed Consent Form 
ITT 
Intention-to-treat Principle 
M-SAP 
Master Statistical Analysis Plan 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention-to-treat 
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 
PEG 
Polyethylene Glycol 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
MedDRA Preferred Term 
RBC 
Red Blood Cell 
RGD 
Regimen D (pridopidine) 
RSA 
Regimen-specific Appendix 
R-SAP 
Regimen-specific Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SI 
Symptom Index 
SoA 
Schedule of Activities 
SOC 
MedDRA System Organ Class 
 


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Page 8 of 38 
 
ABBREVIATIONS (continued) 
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 
ULN 
Upper Limit of Normal 
WHODrug 
World Health Organization Drug Dictionary Enhanced 
 


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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 
RGD Schedule of Activities (SoA) ............................................................................................................... 13 
3. 
General Considerations for Data Analysis ..................................................................................... 16 
3.1 
Statistical Software ........................................................................................................................................ 16 
3.2 
Summary Statistics ........................................................................................................................................ 16 
3.3 
Precision ........................................................................................................................................................ 16 
3.4 
Transformations ............................................................................................................................................ 16 
3.5 
Multiplicity Adjustments ............................................................................................................................... 16 
3.6 
Missing Data ................................................................................................................................................. 17 
4. 
Study Endpoints ............................................................................................................................... 17 
4.1 
Efficacy Endpoints ........................................................................................................................................ 17 
4.2 
Exploratory Endpoints ................................................................................................................................... 19 
5. 
Measurement Definitions ................................................................................................................. 21 
5.1 
ALSFRS-R .................................................................................................................................................... 21 
5.2 
SVC ............................................................................................................................................................... 21 
5.3 
Home Spirometry .......................................................................................................................................... 21 
5.4 
HHD and Grip Strength ................................................................................................................................. 21 
5.5 
Quantitative Voice Characteristics ................................................................................................................ 22 
5.6 
Biofluid Biomarkers of Neurodegeneration .................................................................................................. 22 
5.7 
ALSAQ-40 .................................................................................................................................................... 22 
5.8 
CNS-BFS ....................................................................................................................................................... 22 
5.9 
CNS-LS ......................................................................................................................................................... 22 
5.10 
Survival .................................................................................................................................................... 23 
5.11 
King's ALS Clinical Staging System ........................................................................................................ 23 
5.12 
Hospitalization and Other Clinical Events................................................................................................ 23 
5.13 
Pharmacokinetics of Pridopidine .............................................................................................................. 24 
6. 
Statistical Methodology .................................................................................................................... 24 
6.1 
Analysis Sets ................................................................................................................................................. 24 
6.2 
Baseline Characterization .............................................................................................................................. 25 
6.3 
Primary Efficacy Analysis and Supportive Analyses .................................................................................... 25 
6.4 
Interim Analysis ............................................................................................................................................ 26 
6.5 
Secondary Efficacy Analyses ........................................................................................................................ 26 
6.5.1 
Hierarchical Testing ............................................................................................................................. 26 
6.5.2 
Repeated-measures Model ................................................................................................................... 27 
6.5.3 
Random-slopes Model ......................................................................................................................... 29 
6.5.4 
Time to First Evidence of Bulbar Dysfunction .................................................................................... 31 
6.5.5 
Responder Analysis ............................................................................................................................. 31 
6.5.6 
Survival and Time to Clinical Events .................................................................................................. 31 
6.5.7 
CAFS ................................................................................................................................................... 31 
6.5.8 
HHD0 and HHD02 ............................................................................................................................... 32 
6.5.9 
Quantitative Voice Measures ............................................................................................................... 32 
6.5.10 
Placebo Multiple Imputation................................................................................................................ 33 
6.5.11 
Additional Sensitivity Analyses of Primary and Key Secondary Outcomes ....................................... 33 
6.5.12 
Subgroup Analyses .............................................................................................................................. 33 
6.5.13 
Comparison of Controls across Regimens ........................................................................................... 34 


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6.5.14 
Pharmacokinetic Analyses of Pridopidine ........................................................................................... 34 
6.6 
Safety Analyses ............................................................................................................................................. 35 
6.6.1 
Treatment-emergent Adverse Events ................................................................................................... 35 
6.6.2 
Safety Labs .......................................................................................................................................... 35 
6.6.3 
ECG Results......................................................................................................................................... 36 
6.6.4 
Vital Signs and Weight ........................................................................................................................ 36 
6.6.5 
Suicidality ............................................................................................................................................ 36 
6.7 
Other Analyses .............................................................................................................................................. 36 
6.7.1 
Participant Disposition ......................................................................................................................... 36 
6.7.2 
Study Drug Compliance and Tolerance ............................................................................................... 36 
6.7.3 
Concomitant Medication Use .............................................................................................................. 37 
6.7.4 
Medical History ................................................................................................................................... 37 
6.7.5 
Blindedness .......................................................................................................................................... 37 
6.7.6 
Impact of COVID-19 Pandemic .......................................................................................................... 37 
7. 
Validation .......................................................................................................................................... 37 
7.1 
Primary Efficacy Analysis ............................................................................................................................. 37 
7.2 
Secondary, Exploratory, and Safety Analyses ............................................................................................... 37 
8. 
References ......................................................................................................................................... 38 


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1. Governing Documents 
This Regimen-specific Statistical Analysis Plan (R-SAP) for the pridopidine regimen (RGD) 
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 RGD Regimen-specific Appendix (RSA). Please 
refer to the Master Protocol and the RGD 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 RGD RSA and this R-SAP are authoritative in defining the primary and interim 
analyses. In case of discrepancies between the RGD 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 RGD 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 RGD 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 
RGD  
RSA 
MPRDR 
M-SAP 
RGD  
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. RGD 
evaluates the safety and efficacy of pridopidine administered orally at a dosage of 45 mg twice 
daily (BID) vs. placebo. The RGD 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 pridopidine as compared to placebo on ALS disease 
progression. 
Secondary Efficacy Objectives: 
• To evaluate the effect of pridopidine on selected secondary measures of disease 
progression, including survival 
Safety Objectives: 
• To evaluate the safety of pridopidine in ALS patients. 
Exploratory Efficacy Objectives: 
• To evaluate the effect of pridopidine on selected biomarkers and endpoints. 
• To explore plasma pharmacokinetics (PK) of pridopidine and its metabolites. 
• To explore relationship between PK of pridopidine and pharmacodynamic endpoints. 
2.3 
Study Population 
In addition to eligibility criteria specified in the Master Protocol, participants in RGD must not 
have a confirmed prolonged Fridericia-corrected QT (QTcF) interval or clinically significant 
heart disease or selected cardiac abnormalities, must not have used selected prohibited 
medications within 4 weeks prior to the Regimen-specific Screening Visit, must not currently use 
selected medications above specified dosage thresholds at the time of the Regimen-specific 
Screening Visit, and must not have a history of allergy to any ingredient of study drug. Detailed 
criteria are specified in the Master Protocol and the RGD RSA. 
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 RGD 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 RGD RSA. 
2.5 
Regimen Allocation 
Participants in RGD are those determined eligible for Master Protocol-level inclusion and 
exclusion criteria and randomly assigned to RGD, 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 RGD are randomly allocated in a 3:1 ratio to pridopidine 45 mg BID 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 
Pridopidine and placebo are supplied as capsules for oral administration. Each capsule of active 
study drug contains 45 mg of pridopidine plus silicified microcrystalline cellulose and 
magnesium stearate as inactive excipients. 
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 except for post-dose ECG recordings. 
From the Baseline Visit to the end of Week 2, participants should take one capsule of study drug 
orally once daily in the morning (the QD dose schedule). Starting at the beginning of Week 3 and 
throughout the remainder of the study, participants should take one capsule of study drug twice 
daily, once in the morning and once in the afternoon (approximately 7 to 10 hours after the 
morning dose; the BID dose schedule). 
After the 2-week up-titration period, participants who are unable to tolerate the BID dose 
schedule should reduce their dosage to the QD dose schedule for one week. If a participant is 
tolerant of the QD dose schedule, then they should resume the BID dose schedule. If the 
participant cannot tolerate the second increase to the BID dose schedule, then they should 
continue on the QD dose schedule for the remainder of the study. 
Additional details of treatment administration are described in the RGD RSA. 
2.8 
Allocation Concealment 
Allocation concealment is the same as described in the M-SAP. Both active and placebo 
formations of study drug are identical in appearance. 
2.9 
RGD Schedule of Activities (SoA) 
Activity 
MP 
Scrn1 
RGD 
Scrn1 
Base-
line 
Week 
2 
Week 
414 
Week 
819  
Week 
12 
Week 
1619 
Week 
20 
Week 
24/E
T14, 22 
Final 
Call11 
Clinic Clinic Clinic Phone Clinic Clinic Phone Clinic Phone Clinic Phone 
-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 Consent2 
X 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Review 
X 
X3 
 
 
 
 
 
 
 
 
 
ALS & Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
Neurological Exam 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs4 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Slow Vital Capacity 
X20 
 
X 
 
 
X 
 
X 
 
X 
 
Home Spirometry 
X20 
 
X 
 
 
X 
 
X 
 
X 
 
Muscle Strength Assessment  
 
 
X 
 
 
X 
 
X 
 
X 
 
ALSFRS-R 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
ALSAQ-40 
 
 
X 
 
 
 
 
 
 
X 
 
CNS Bulbar Function Scale 
 
 
X 
 
 
X 
 
X 
 
X 
 
CNS Lability Scale 
 
 
X 
 
 
X 
 
X 
 
X 
 
12-Lead ECG 
X 
X15 
X16 
 
X16 
 
 
 
 
X15, 16, 
17 
 


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Activity 
MP 
Scrn1 
RGD 
Scrn1 
Base-
line 
Week 
2 
Week 
414 
Week 
819  
Week 
12 
Week 
1619 
Week 
20 
Week 
24/E
T14, 22 
Final 
Call11 
Clinic Clinic Clinic Phone Clinic Clinic Phone Clinic Phone Clinic Phone 
-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 
Clinical Safety Labs5, 21 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Biomarker Blood Collection21 
 
 
X 
 
 
X 
 
X 
 
X 
 
Plasma PK collection21 
 
 
 
 
X 
 
 
 
 
X 
 
Biomarker Urine Collection 
 
 
X 
 
 
X 
 
X 
 
X 
 
DNA Collection7, 21 (optional) 
 
 
X 
 
 
 
 
 
 
 
 
CSF Collection (optional) 
 
 
X 
 
 
 
 
X13 
 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Event Review6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Suicidality C-SSRS 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Install Smartphone App23 
 
 
X 
 
 
 
 
 
 
 
 
Voice Recording9 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Uninstall Smartphone App 
 
 
 
 
 
 
 
 
 
X 
 
Randomization to Regimen 
X 
 
 
 
 
 
 
 
 
 
 
Randomization within Regimen 
 
X 
 
 
 
 
 
 
 
 
Administer/Dispense Study Drug 
 
 
X8 
 
X18 
X 
 
X 
 
X10,18 
 
Drug Accountability/Compliance 
 
 
 
X24 
X 
X 
X24 
X 
X24 
X 
 
Exit Questionnaire 
 
 
 
 
 
 
 
 
 
X 
 
Vital Status Determination12 
 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: ALD = after last dose, ALS = amyotrophic lateral sclerosis, ALSAQ-40 = ALS 
Assessment Questionnaire, ALSFRS-R = ALS Functional Rating Scale Revised, CSF = 
cerebrospinal fluid, C-SSRS = Columbia-Suicide Severity Rating Scale, d = day, DNA = 
deoxyribonucleic acid, ECG = electrocardiogram, MP = Master Protocol, RGD = the pridopidine 
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 During the Master Protocol Screening Visit, participants will be consented via the Platform 
Trial informed consent form (ICF). After a participant is randomized to a regimen, participants 
will be consented a second time via the regimen-specific ICF. 
3 At the Regimen Specific Screening Visit, participants will have regimen-specific eligibility 
criteria assessed. 
4 Vital signs include weight, systolic and diastolic pressure, respiratory rate, heart rate and 
temperature. Height measured at Master Protocol Screening Visit only. 
5 Clinical safety labs include hematology (CBC with differential), complete chemistry panel, 
thyroid function 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. 
6 Adverse events that occur after signing the master protocol consent form will be recorded. 


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7 The DNA sample can be collected after Baseline Visit if a baseline sample is not obtained or 
the sample is not usable. 
8 Administer first dose of IP only after Baseline Visit procedures are completed, except for the 
post-dose ECG. 
9 In addition to study visits outlined in the SOA, participants will be asked to complete twice 
weekly voice recordings at home. 
10 Drug will only be dispensed at this visit if the participant continues in the OLE. 
11 Participants will only have a Follow-Up Safety Call at this time if they do not continue on in 
the OLE. Participants who continue into OLE will have a Follow-Up Safety Call after their last 
dose of IP during the OLE period. 
12 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. 
13 If the CSF collection is unable to be performed for logistical reasons, such as scheduling, at 
the Week 16 Visit, it may be performed at the Week 24 Visit. 
14 If a participant’s visit occurs in the morning, the participant should be instructed that the 
morning dose of study medication should not be taken, and the morning dose should be 
administered in-clinic 1-2 hours prior to the POST-DOSE ECG. If a participant’s visit occurs in 
the afternoon, the participant should be instructed to take the morning dose immediately upon 
waking in the morning, and the second dose should be administered in-clinic 1-2 hours prior to 
the POST-DOSE ECG. 
15 At the regimen-specific Screening visit (and Week 24 for participants enrolling in OLE), 
QTcF will be determined by the mean of three, 10-second recordings of a 12-Lead ECG 
(performed at least 1 minute a part) BEFORE IP administration. For participants on Nuedexta, 
the Nuedexta dose should be taken within 6 hours BEFORE the ECG, refer to the MOP for 
additional guidelines. 
16 At Baseline and Week 4 (and Week 24 for participants enrolling in OLE) QTcF will be 
determined by a single 10-second 12-lead ECG, 1-2 hours AFTER IP administration. If stopping 
or monitoring rules are met, refer to Section 4.4. For participants on Nuedexta, the Nuedexta 
dose should be taken within 6 hours BEFORE the ECG, refer to the MOP for additional 
guidelines. 
17 For participants that will NOT be enrolling into the OLE, QTcF will be determined by a single 
10-second 12 lead ECG BEFORE administration of the IP. If stopping or monitoring rules are 
met, refer to Section 4.4. For participants on Nuedexta, the Nuedexta dose should be taken 
within 6 hours BEFORE the ECG, refer to the MOP for additional guidelines. 
18 IP must be administered at Week 4 (and Week 24 for participants enrolling into the OLE) 1-2 
hours prior to the POST-DOSE ECG. 


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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 reasons. 
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 All blood draws should occur after the ECG is collected, or at least 1 hour prior to the ECG. 
22 If participant’s visit occurs in the morning, the participant should be instructed not to take the 
morning dose at home but rather in-clinic after the PRE-DOSE ECG. 
If visit occurs in the afternoon, morning dose should be taken immediately upon waking in the 
morning and the second dose after the PRE-DOSE ECG. 
23 Two smartphone apps should be installed on the participant’s phone, one to collect the voice 
recordings and one to collect home spirometry. 
24 Drug accountability will not be done at phone visits. A drug compliance check-in should 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. 
Summary statistics for time-to-event endpoints will include the percentage of subjects having the 
event and relevant percentiles of the survival curve depending on frequency of a given event. 
Summary statistics for responder endpoints will include the percentage of responders. 
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 
The primary endpoint will be tested first, and key secondary endpoints will be tested next in a 
fixed sequence with overall family-wise error rate controlled by a closed-testing procedure as 
indicated in Section 6.5.1 Hierarchical Testing below. 


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3.6 
Missing Data 
Handling of missing data is the same as described in the M-SAP except as indicated below. 
Mean imputation of any missing baseline covariates will impute after transformation for any 
transformed covariates. Clinic-based assessments that are missing due to COVID-19 restrictions 
or disruptions are considered missing at random. 
Handling of missing data depends upon the type and pattern of missing data (monotone, non-
monotone, deaths), the endpoint analyzed (ALSFRS-R, SVC, HHD, etc.), the method of analysis 
(continuous, time to event, responder), and the reason for missing data (related to lack of 
efficacy, related to tolerability, administrative reasons unrelated to lack of efficacy or 
tolerability, and unknown reasons). 
Deaths are considered a special type of missing data. 
For continuous analysis of all endpoints, the method described in the M-SAP for handling 
missing data will be followed. 
For time-to-event analyses that depend on scheduled assessments, participants lacking any post-
baseline assessment not due to death or disease progression will be censored at baseline and 
functionally omitted from the analysis. If data are missing not due to death, no imputation will be 
made for the primary analysis. As a sensitivity analysis, multiple imputations as described in 
Section 6.5.10 Placebo Multiple Imputation below will be used. All subjects who die, reach a 
death equivalent, or early terminate due to disease progression before reaching the pre-specified 
time-to-event will be considered as having the unfavorable event being analyzed (e.g., worsening 
by 1 or more points in bulbar subscale score) at the time of death, death equivalent or early 
termination, respectively. 
For responder analysis, participants experiencing the unfavorable event (e.g., worsening in 
bulbar subscale score) are considered non-responders. All participants who die, reach a death 
equivalent, or early terminate due to disease progression will be considered non-responders. Data 
missing not due to death, death equivalent, or early terminate due to disease progression will be 
imputed under an assumption that data are conditionally missing at random (MAR). Under 
MAR, monotone missing data for participants will be imputed using available data from 
participants within the treatment group to which the participant was randomized. Sensitivity 
analyses based on multiple imputation under an assumption that data are missing not at random 
(MNAR) will be performed as described in the M-SAP. 
4. Study Endpoints 
4.1 
Efficacy Endpoints 
The primary efficacy endpoint is the same as described in the M-SAP. 
The following secondary efficacy endpoints are adjusted for multiplicity and will be evaluated 
hierarchically: 
• Time to first decline of 2 points or greater post baseline in the ALSFRS-R total score among 
participants in the FAS with bulbar dysfunction at baseline defined as an ALSFRS-R bulbar 
domain (Q1-Q3) score of less than 12,  


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• Proportion of participants experiencing no worsening in the ALSFRS-R bulbar domain (Q1-
Q3) score from baseline through Week 24 among all participants in FAS,  
• Rate of change in respiratory function as measured by slow vital capacity (SVC) maximum 
percent predicted from baseline through Week 24 among participants in FAS with bulbar 
dysfunction at baseline defined as an ALSFRS-R bulbar domain (Q1-Q3) score of less than 
12,  
• Time to first decline of 1-point or greater post baseline in the ALSFRS-R bulbar domain 
(Q1-Q3) score among all participants in FAS,  
• Time to death or death equivalent through Week 24 among all participants in FAS. 
 
Other Secondary Efficacy Endpoints (pre-specified non multiplicity adjusted non-hierarchical) 
• Time to first decline of 2 points or greater post baseline in the ALSFRS-R total score among 
participants in FAS,  
• Proportion of participants experiencing 5 points or less decline in the ALSFRS-R total score 
from baseline through Week 24 among all participants in FAS,  
• Proportion of participants experiencing 5 points or less decline in the ALSFRS-R total score 
from baseline through Week 24 among all participants in FAS with baseline ALSFRS-R 
greater than or equal to 36 (Early in disease),  
• Proportion of participants experiencing 5 points or less decline in the ALSFRS-R total score 
from baseline through Week 24 among all participants in FAS with bulbar dysfunction at 
baseline defined as an ALSFRS-R bulbar domain (Q1-Q3) score of less than 12,  
• Rate of change in ALSFRS-R Total Score from baseline through Week 24 among 
participants in FAS with bulbar dysfunction at baseline defined as an ALSFRS-R bulbar 
domain (Q1-Q3) score of less than 12,  
• Proportion of participants experiencing no or only a 1-point decline in the ALSFRS-R bulbar 
domain (Q1-Q3) score from baseline through Week 24 among participants in FAS with 
bulbar dysfunction at baseline defined as an ALSFRS-R bulbar domain (Q1-Q3) score of less 
than 12,  
• Time to first decline of 1 or more points post baseline in the ALSFRS-R bulbar domain (Q1-
Q3) score among participants in FAS with bulbar dysfunction at baseline defined as an 
ALSFRS-R bulbar domain (Q1-Q3) score of less than 12,  
• Proportion of participants experiencing no worsening in the ALSFRS-R bulbar domain (Q1-
Q3) score from baseline through Week 24 among all participants in FAS with delta-FRS 
slower than -0.75 points/month (slow progressors),  
• Proportion of participants with ALSFRS-R bulbar domain (Q1-Q3) score greater than or 
equal to 9 (out of 12) at Week 24 among all participants in FAS with bulbar dysfunction at 
baseline defined as an ALSFRS-R bulbar domain (Q1-Q3) score of less than 12,  


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• Proportion of participants experiencing no worsening in the ALSFRS-R bulbar domain (Q1-
Q3) score from baseline through Week 24 among all participants in FAS with baseline 
ALSFRS-R greater than or equal to 36 (Early in disease),  
• Rate of change in CNS-BFS total score from baseline through Week 24 among all 
participants in FAS,  
• Rate of change in CNS-BFS total score from baseline through Week 24 among participants 
in FAS with bulbar dysfunction at baseline defined as an ALSFRS-R bulbar domain (Q1-Q3) 
score of less than 12,  
• Change in HHD upper extremity percentage from baseline through Week 24,  
• Change in HHD lower extremity percentage from baseline through Week 24,  
• Change in log transformed serum NfL from baseline through Week 24 among all participants 
in FAS,  
• Change in log transformed serum NfL from baseline through Week 24 among participants in 
FAS with bulbar dysfunction at baseline defined as an ALSFRS-R bulbar domain (Q1-Q3) 
score of less than 12,  
• Change in log transformed serum NfL from baseline through Week 24 among participants in 
FAS by NfL median baseline split (slow vs fast progressors),  
• Rate of change in ALSFRS-R total score from baseline through Week 24 among participants 
in FAS who were not on Nuedexta at baseline,  
• Rate of change in ALSFRS-R total score from baseline through Week 24 among participants 
in FAS who were not on Nuedexta at baseline and with bulbar dysfunction at baseline 
defined as an ALSFRS-R bulbar domain (Q1-Q3) score of less than 12,  
• Rate of change in CNS-BFS total score from baseline through Week 24 among participants 
in FAS who were not on Nuedexta at baseline,  
• Rate of change in CNS-BFS total score from baseline through Week 24 among participants 
in FAS who were not on Nuedexta at baseline and with bulbar dysfunction at baseline 
defined as an ALSFRS-R bulbar domain (Q1-Q3) score of less than 12,  
• Proportion of participants experiencing no worsening in the CNS-BFS total score from 
baseline through Week 24 among all participants in FAS who were not on Nuedexta at 
baseline,  
• Time to first increase of 5 points or more post baseline in the CNS-BFS total score among all 
participants in FAS who were not on Nuedexta at baseline, and  
• Rate of change in ALSFRS-R total score from baseline through Week 24 among participants 
in FAS who were on Nuedexta at baseline. 
4.2 
Exploratory Endpoints 
The following categories of exploratory endpoints will be evaluated: 
• Rate of change in ALSFRS-R bulbar domain (Q1-Q3) score from baseline through Week 24 
among participants in FAS,  


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• Rate of change in ALSFRS-R bulbar domain (Q1-Q3) score from baseline through Week 24 
among participants in FAS with bulbar dysfunction at baseline defined as an ALSFRS-R 
bulbar domain (Q1-Q3) score of less than 12,  
• Proportion of participants experiencing no worsening in the ALSFRS-R bulbar domain (Q1-
Q3) score from baseline through Week 24 among all participants in FAS with delta-FRS less 
than -0.75 points/month (fast progressors),  
• Rate of change in ALSFRS-R bulbar domain (Q1-Q3) score from baseline through Week 24 
among all participants in FAS with delta-FRS greater than -0.75 points/month (slow 
progressors),  
• Time to first decline of 1 or more points post baseline in the ALSFRS-R bulbar domain (Q1-
Q3) score among participants in FAS with no bulbar dysfunction at baseline defined as an 
ALSFRS-R bulbar domain (Q1-Q3) score of 12,  
• Change in other ALSFRS-R domain scores (fine motor, gross motor, respiratory, and fine 
and gross motor combined),  
• 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, and CNS Lability 
Scale (CNS-LS),  
• Change in plasma concentration of pridopidine and its metabolites,  
• 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. 
Safety Endpoints 
In addition to the safety endpoints described in the M-SAP, the following RGD regimen-specific 
safety endpoint will be evaluated: 
• QT prolongation: Proportion of participants meeting ECG stopping rules or meeting ECG 
monitoring rules 1, 2, or 3 times. 


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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 with the 
clarification that scores will be considered missing in cases of item nonresponse. 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. 
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 acceptable FVC 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. 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. 
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). 


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Time at risk for HHD0 and HHD02 will be censored at the Week 24 Visit, if completed, the date 
of consent withdrawal, if withdrawn, or the last date at which vital status is known prior to the 
end of the Week 24 Visit window for participants lost to follow-up. 
HHD global average percentage, HHD0, and HHD02 are 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 
CNS-LS 
The Center for Neurologic Study Lability Scale (CNS-LS, Moore et al. 1997) is a 7-item 
instrument completed by participants for assessing emotional lability. For each item, participants 
are asked to rate the perceived frequency at which they experienced a manifestation of 
pseudobulbar affect (PBA) over the past week on a scale from 1 ("Applies never") to 5 ("Applies 
most of the time"). The total score is the sum of all items (range 7 to 35). Higher scores indicate 
greater emotional lability. A CNS-LS score of 13 or higher may suggest PBA. 


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5.10 Survival 
The primary definition of survival time is the same as described in the M-SAP with the 
clarifications that PAV is defined as more than 22 hours per day of noninvasive or invasive 
mechanical ventilation for more than seven consecutive days, that time at risk should not be 
censored at date of consent withdrawal, and that time at risk should be censored at date last 
known alive. The date of PAV initiation, where applicable, will be imputed as the fifteenth day 
of a month if not specified more precisely. Any participant on PAV at baseline will be censored 
at baseline. A secondary survival endpoint of death alone, independent of any death equivalent 
(including a death equivalent that occurs prior to baseline), is also defined and will be censored 
at the Week 24 Visit if completed or at the earlier of the end of the Week 24 Visit window or 
date last known alive if a Week 24 visit is not completed. An exploratory survival endpoint of 
death or death-equivalent will censor at the earlier of last known PAV-free or last known alive. 
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 RGD participant. The primary analysis of survival will 
evaluate PAV-free survival to the Week 24 Visit time point. 
5.11 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. 
5.12 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,  


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• 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 
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. 
5.13 Pharmacokinetics of Pridopidine 
Plasma samples collected at the Week 4 and Week 24 visits will be analyzed to quantify the 
concentration of pridopidine. Details of the assay technique will be added once the procedures 
are confirmed. 
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 RGD plus placebo 
participants from specified regimens, classified according to their randomized treatment 
assignment. Participants who discontinue study drug but remain in the study will be included 
in the FAS. 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 RGD plus placebo 
participants from specified regimens who are not known to be ineligible for RGD 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 RGD is defined as follows: 


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• 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 
RGD. 
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 sets are specific to RGD: 
• 
Modified Intention-to-treat (mITT) Set: Participants who were randomized within RGD plus 
placebo participants from specified regimens, who received at least one dose of study drug, 
and who completed at least one post-baseline ALSFRS-R assessment, classified according to 
their randomized treatment assignment. Participants who discontinue study drug but remain 
in the study will be included in the mITT. Observations completed after regimen data lock 
are excluded. 
• 
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 related to 
eligibility, treatment, follow-up, or assessment, classified according to the treatment they 
actually received. Final specification of participants included vs. excluded from the EPP 
analysis set will be defined prior to data lock. 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 a time-dependent event, e.g., initiation of a prohibited 
medication or 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. Data from placebo 
participants shared from other regimens will not be truncated due to non-adherence to 
protocol-specified dosing. 
Applicable analysis sets (FAS, mITT, ECM, EPP, STF, and STN) will include shared placebo 
participants from regimens A, B, and C. As only concurrently enrolling regimens are 
contributing to efficacy analyses, the FAS and ECC analysis sets are synonymous in RGD and 
only the FAS analysis set will be referenced. As regimen A is administered by subcutaneous 
injection and regimens B and C are administered orally, only regimens B and C will contribute 
shared placebo participants to the ECM and STN analysis sets. 
6.2 
Baseline Characterization 
The baseline characteristics summarized for participants randomized within RGD are the same as 
specified in the M-SAP with the addition of ALSAQ-40 domain scores and SI, CNS-BFS total 
score, CNS-LS score, King's stage, weight, body mass index (BMI), serum urate concentration, 
serum creatinine concentration, serum NfL concentration, and baseline use of Nuedexta. 
6.3 
Primary Efficacy Analysis and Supportive Analyses 
The primary analysis for RGD 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 


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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 set 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: pridopidine administered orally at a dosage of 45 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 or death equivalent: 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 or death equivalent: 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 
RGD 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 
and Simulation Report" (Appendix 1 to the Master Protocol). RGD 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 or subsets of the FAS analysis set as defined below. Primary estimates and inference for time-
to-event endpoints will be by Kaplan-Meier product-limit estimates and log-rank test (see 
Section 6.5.6 below). Primary estimates and inference for responder endpoints will be by logistic 
regression as described in Section 6.5.5 with missing data handled as indicated in Section 3.6. 
Primary estimates and inference for rate of change of continuous endpoints will be by a random-
slopes linear mixed model (see Section 6.5.3 below). The sequence for testing secondary efficacy 
endpoints is the following: 
1. Time to first decline of 2 points or greater post-baseline in the ALSFRS-R total score 
among participants in FAS with bulbar dysfunction at baseline defined as an ALSFRS-R 
bulbar domain (Q1-Q3) score of less than 12,  


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2. Proportion of participants experiencing no worsening in the ALSFRS-R bulbar domain 
(Q1-Q3) score from baseline through Week 24 among all participants in FAS,  
3. Rate of change in respiratory function as measured by slow vital capacity (SVC) 
maximum percent predicted from baseline through Week 24 among participants in FAS 
with bulbar dysfunction at baseline defined as an ALSFRS-R bulbar domain (Q1-Q3) 
score of less than 12,  
4. Time to first decline post baseline of 1 point or greater in the ALSFRS-R bulbar domain 
(Q1-Q3) score among all participants in FAS, and  
5. Time to death or death equivalent through Week 24 among all participants in FAS. 
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. 
All secondary efficacy analyses specified here for hierarchical testing will also be analyzed in the 
mITT analysis set as sensitivity analyses. 
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, SVC, HHD upper extremity, lower extremity, and 
global average percentages, FVC by home spirometry, serum creatinine, serum NfL, ALSAQ-40 
domain scores and SI, CNS-BFS total score, and CNS-LS score) are revised from those specified 
in the M-SAP to include a main effect of treatment and main effects of centered baseline 
Nuedexta use, centered site of symptom onset (bulbar vs. non-bulbar), and their interactions with 
visit as additional covariates. 
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, centered baseline edaravone use 
and centered baseline edaravone × visit interaction, centered baseline Nuedexta use and centered 
baseline Nuedexta use × visit interaction, and centered site of symptom onset (bulbar vs. non-
bulbar) and centered site of symptom onset × 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, centered baseline edaravone use, centered baseline Nuedexta use, and centered site 


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of symptom onset) 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 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  
                NDX|visit bulbar|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, edv is an indicator of edaravone use at baseline, NDX is an indicator of baseline 
use of Nuedexta centered at the sample median, and bulbar is an indicator of bulbar site of onset 
centered at the sample median. 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: pridopidine administered orally at a dosage of 45 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. 


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• 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. 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, SVC, HHD upper extremity, lower extremity, and global 
average percentages, FVC by home spirometry, quantitative voice characteristics, serum 
creatinine, serum NfL, ALSAQ-40 domain scores and SI, CNS-BFS total score, and CNS-LS 
score) are revised from those specified in the M-SAP to include a main effect of treatment and 
main effects of centered baseline Nuedexta use, centered site of symptom onset (bulbar vs. non-
bulbar), and their interactions with visit as additional covariates 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, centered baseline edaravone use and centered baseline edaravone use × month 
interaction, centered baseline Nuedexta use and centered baseline Nuedexta use × month 
interaction, and centered site of symptom onset (bulbar vs. non-bulbar) and centered site of 
symptom onset × 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, centered baseline edaravone use, 
centered baseline Nuedexta use, and centered site of symptom onset) 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 


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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  
                NDX|month bulbar|month / solution cl; 
  random intercept month / subject=regimen type=un; 
  random intercept month / subject=id type=un; 
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: pridopidine administered orally at a dosage of 45 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 this analysis is supportive of inference from the Bayesian shared-parameter, 
repeated-measures model for the primary endpoint and is primary for the secondary endpoint of 
rate of change in SVC. 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. 


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6.5.4 Time to First Evidence of Bulbar Dysfunction 
The time to first evidence of bulbar dysfunction will be compared between treatments by 
Kaplan-Meier product-limit estimates and log-rank test in the subset of participants with an 
ALSFRS-R bulbar domain (Q1-Q3) score of 12 at the Baseline Visit in the FAS, mITT, ERO, 
and EPP samples. If greater than 10% of participants develop bulbar dysfunction after baseline, 
treatments will be compared by Cox proportional hazards regression adjusting for time since 
ALS symptom onset, delta-FRS, use of riluzole at baseline, use of edaravone at baseline, and use 
of Nuedexta at baseline with a random gamma-distributed regimen-specific frailty term. If 
convergence is not obtained, then the frailty term will be dropped. A separate supportive analysis 
will include centered baseline serum NfL level as an additional covariate. 
6.5.5 Responder Analysis 
Analysis of responder endpoints will use logistic regression. The dependent variable will be 
whether the participant is a responder or not, while the independent variables will be treatment 
group, baseline ALSFRS-R score, site of onset (any bulbar vs. non-bulbar), riluzole use at 
baseline, edaravone use at baseline, and delta-FRS. A separate supportive analysis will include 
centered baseline serum NfL level as an additional covariate. 
6.5.6 Survival and Time to Clinical Events 
Survival and time to hospitalizations and clinical events will be analyzed in the FAS, mITT, 
ECM, ERO, EPP, STF, 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 
addition of baseline age as a 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. 
6.5.7 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 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 


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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 random-
slopes model for the secondary outcome of SVC. 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. 
6.5.8 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. 
6.5.9 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 
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 use × B-spline 
interaction, centered baseline edaravone use and centered baseline edaravone use × B-spline 
interaction, centered baseline Nuedexta use and centered baseline Nuedexta use × B-spline 
interaction, and centered site of symptom onset (bulbar vs. non-bulbar) and centered site of 
symptom onset × 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. 


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6.5.10 Placebo Multiple Imputation 
Placebo multiple imputation analyses are the same as specified in the M-SAP with the addition 
of baseline serum NfL level as a covariate and will be applied to the mixed model repeated-
measures analysis of ALSFRS-R total score and the random-slopes analysis of SVC in the FAS 
analysis set. 
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 random-slopes linear mixed model for SVC in the FAS analysis set. A 
separate analysis will include centered baseline serum NfL level as an additional covariate in 
both imputation stages. 
6.5.11 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. 
6.5.12 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 ALSFRS-R total score and SVC 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 43 kg, 43 to less than 56 kg, 56 to less than 77 kg, 77 to less than 150 kg, 
150 kg or more),  


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• BMI (less than 18.5 kg/m2, 18.5 to less than 25 kg/m2, 25 to less than 30 kg/m2, 30 to less 
than 40 kg/m2, 40 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 [eGFR 30 to 59 mL/min/1.73m2], stage 4 
[eGFR 15 to 29 mL/min/1.73m2], stage 5 [eGFR less than 15 mL/min/1.73m2]),  
• Time since onset of weakness (less than 18 months vs. 18 months or longer),  
• El Escorial and time since onset of weakness (El Escorial definite and less than 18 months 
vs. not both),  
• Baseline symptom severity (all ALSFRS-R questions scored 2 or greater vs. any question 
scored 0 or 1),  
• Early disease state (all ALSFRS-R questions scored 2 or greater, SVC 80%-predicted or 
greater, and time since symptom onset less than 24 months vs. not meeting all three criteria),  
• Baseline serum urate concentration (less than 5.5 mg/dL vs. 5.5 mg/dL or greater),  
• Baseline plasma 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. 
6.5.13 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. 
6.5.14 Pharmacokinetic Analyses of Pridopidine 
Plasma concentrations of pridopidine 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 pridopidine 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 pridopidine, if deemed appropriate. The population 
pharmacokinetic analysis will be performed by Prilenia and reported in a separate modelling 
report. 


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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 treatment 
initiation to either the Final Safety Visit if completed, the date of death if the participant dies, 40 
days after last study contact if the participant early terminates or is lost to follow-up, or the date 
of first dose of study drug during participation in the OLE, if so exposed. The interval is 
inclusive except for adverse events that occur on the day of treatment initiation and are known to 
precede first exposure to study drug. 
In addition to summaries specified in the M-SAP, TEAEs will be summarized by Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term for fatal 
TEAEs, 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), 
and TEAEs and serious TEAEs stratified by the following subgroups: baseline riluzole use, 
baseline edaravone use, age, sex, race, ethnicity, weight, BMI, and CKD stage. Subgroup 
classifications will be the same as described in Section 6.5.12 Subgroup Analyses except that the 
"other" group will be retained regardless of prevalence. 
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 will be 
estimated as differences rather than ratios and will include comparison-wise 95% confidence 
intervals with variance estimates obtained by the delta method. 
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 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 
will be included in shift tables along with visit-specific shifts. 
Potential drug-induced liver injury (DILI), including cases that potentially meet the Hy’s law 
criteria, will be reported as distinct safety lab outcomes. Three potential DILI criteria will be 
defined: 
• ALT or AST >3xULN with TBL >1.5xULN 
• AST or ALT >3xULN with TBL >2xULN 
• AST or ALT >3xULN with TBL >2xULN and ALP <2xULN (potential Hy’s Law cases) 
where ALT is alanine transaminase level, AST is aspartate transaminase level, TBL is total 
bilirubin level, ALP is alkaline phosphatase level, ULN is upper level of normal, and all levels 
are measured on the same day. 


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6.6.3 ECG Results 
Summaries of ECG parameters and findings are the same as specified in the M-SAP with the 
additional of summaries of the proportion of participants meeting ECG stopping rules or meeting 
ECG monitoring rules 1, 2, or 3 times. 
6.6.4 Vital Signs and Weight 
Summaries and analyses of vital signs and weight are the same as specified in the M-SAP. 
6.6.5 Suicidality 
Summaries of suicidality are the same as specified in the M-SAP. 
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 RGD vs. final screening for a non-RGD 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 RGD screen failure will 
be summarized separately for all participants screened for RGD 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. 
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 as the number of days from dose initiation to drug withdrawal, inclusive, less any 
day(s) during which use of study drug was interrupted. 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. 


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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 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 and 
listed. 
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 
with the following clarifications. 
Three levels of validation will be used: 
Level 1: Replication of results by an independent programmer. 
Level 2: When a macro is used to generate multiple results, one result will be replicated by 
an independent programmer. 
Level 3: Log files will be inspected for error messages and / or relevant warnings. 
A separate validation document will be created in which the validation level applied for each 
analysis is specified. The level of validation will be based on whether the result is considered 
core or supplementary. Core results will be based on validation level 1 or level 2. Supplementary 
results will be based on level 3 validation. Examples of core results include primary and key 


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secondary efficacy and safety endpoints. Examples of supplementary results include exploratory 
efficacy endpoints, selected sensitivity analyses, and selected sensitivity analysis data sets for 
secondary efficacy endpoints. Any analyses that fail due to small sample size or lack of 
convergence will be omitted with comment rather than programmed separately to find a post-
hoc, work-around solution. 
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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Signed: 10/6/2022 5:22:09 PM
Electronic Record and Signature Disclosure: 
      Accepted: 10/6/2022 5:21:25 PM
      ID: 9a39b89a-10c4-4de5-9c8b-dfa0376bc793
In Person Signer Events
Signature
Timestamp
Editor Delivery Events
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Agent Delivery Events
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Intermediary Delivery Events
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Certified Delivery Events
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Carbon Copy Events
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Witness Events
Signature
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Notary Events
Signature
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Envelope Summary Events
Status
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Envelope Sent
Hashed/Encrypted
10/6/2022 4:56:55 PM
Certified Delivered
Security Checked
10/6/2022 5:21:25 PM
Signing Complete
Security Checked
10/6/2022 5:22:09 PM
Completed
Security Checked
10/7/2022 9:50:18 AM
Payment Events
Status
Timestamps
Electronic Record and Signature Disclosure


ELECTRONIC RECORD AND SIGNATURE DISCLOSURE  
From time to time, Insight OBO The Massachusetts General Hospital (we, us or Company) may 
be required by law to provide to you certain written notices or disclosures. Described below are 
the terms and conditions for providing to you such notices and disclosures electronically through 
the DocuSign system. Please read the information below carefully and thoroughly, and if you can 
access this information electronically to your satisfaction and agree to this Electronic Record and 
Signature Disclosure (ERSD), please confirm your agreement by selecting the check-box next to 
‘I agree to use electronic records and signatures’ before clicking ‘CONTINUE’ within the 
DocuSign system. 
 
Getting paper copies  
At any time, you may request from us a paper copy of any record provided or made available 
electronically to you by us. You will have the ability to download and print documents we send 
to you through the DocuSign system during and immediately after the signing session and, if you 
elect to create a DocuSign account, you may access the documents for a limited period of time 
(usually 30 days) after such documents are first sent to you. After such time, if you wish for us to 
send you paper copies of any such documents from our office to you, you will be charged a 
$0.00 per-page fee. You may request delivery of such paper copies from us by following the 
procedure described below. 
 
Withdrawing your consent  
If you decide to receive notices and disclosures from us electronically, you may at any time 
change your mind and tell us that thereafter you want to receive required notices and disclosures 
only in paper format. How you must inform us of your decision to receive future notices and 
disclosure in paper format and withdraw your consent to receive notices and disclosures 
electronically is described below. 
 
Consequences of changing your mind  
If you elect to receive required notices and disclosures only in paper format, it will slow the 
speed at which we can complete certain steps in transactions with you and delivering services to 
you because we will need first to send the required notices or disclosures to you in paper format, 
and then wait until we receive back from you your acknowledgment of your receipt of such 
paper notices or disclosures. Further, you will no longer be able to use the DocuSign system to 
receive required notices and consents electronically from us or to sign electronically documents 
from us. 
 
All notices and disclosures will be sent to you electronically  
Electronic Record and Signature Disclosure created on: 3/31/2020 3:10:31 PM
Parties agreed to: Ben Saville, PhD, Eric A. Macklin, PhD, Merit Cudkowicz, MD, Munish Mehra, MSc, PhD, Sabrina Paganoni, MD, PhD, Suzanne Hendrix, PhD, Y Pa


Unless you tell us otherwise in accordance with the procedures described herein, we will provide 
electronically to you through the DocuSign system all required notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided or made 
available to you during the course of our relationship with you. To reduce the chance of you 
inadvertently not receiving any notice or disclosure, we prefer to provide all of the required 
notices and disclosures to you by the same method and to the same address that you have given 
us. Thus, you can receive all the disclosures and notices electronically or in paper format through 
the paper mail delivery system. If you do not agree with this process, please let us know as 
described below. Please also see the paragraph immediately above that describes the 
consequences of your electing not to receive delivery of the notices and disclosures 
electronically from us. 
 
How to contact Insight OBO The Massachusetts General Hospital:  
You may contact us to let us know of your changes as to how we may contact you electronically, 
to request paper copies of certain information from us, and to withdraw your prior consent to 
receive notices and disclosures electronically as follows: 
To contact us by email send messages to: jhenrique@mgh.harvard.edu 
 
To advise Insight OBO The Massachusetts General Hospital of your new email address  
To let us know of a change in your email address where we should send notices and disclosures 
electronically to you, you must send an email message to us at jhenrique@mgh.harvard.edu and 
in the body of such request you must state: your previous email address, your new email 
address.  We do not require any other information from you to change your email address.  
If you created a DocuSign account, you may update it with your new email address through your 
account preferences.  
 
To request paper copies from Insight OBO The Massachusetts General Hospital  
To request delivery from us of paper copies of the notices and disclosures previously provided 
by us to you electronically, you must send us an email to jhenrique@mgh.harvard.edu and in the 
body of such request you must state your email address, full name, mailing address, and 
telephone number. We will bill you for any fees at that time, if any. 
 
To withdraw your consent with Insight OBO The Massachusetts General Hospital  
To inform us that you no longer wish to receive future notices and disclosures in electronic 
format you may: 


i. decline to sign a document from within your signing session, and on the subsequent page, 
select the check-box indicating you wish to withdraw your consent, or you may; 
ii. send us an email to jhenrique@mgh.harvard.edu and in the body of such request you must 
state your email, full name, mailing address, and telephone number. We do not need any other 
information from you to withdraw consent..  The consequences of your withdrawing consent for 
online documents will be that transactions may take a longer time to process.. 
 
Required hardware and software  
The minimum system requirements for using the DocuSign system may change over time. The 
current system requirements are found here: https://support.docusign.com/guides/signer-guide-
signing-system-requirements.  
 
Acknowledging your access and consent to receive and sign documents electronically  
To confirm to us that you can access this information electronically, which will be similar to 
other electronic notices and disclosures that we will provide to you, please confirm that you have 
read this ERSD, and (i) that you are able to print on paper or electronically save this ERSD for 
your future reference and access; or (ii) that you are able to email this ERSD to an email address 
where you will be able to print on paper or save it for your future reference and access. Further, 
if you consent to receiving notices and disclosures exclusively in electronic format as described 
herein, then select the check-box next to ‘I agree to use electronic records and signatures’ before 
clicking ‘CONTINUE’ within the DocuSign system. 
By selecting the check-box next to ‘I agree to use electronic records and signatures’, you confirm 
that: 
 
You can access and read this Electronic Record and Signature Disclosure; and 
 
You can print on paper this Electronic Record and Signature Disclosure, or save or send 
this Electronic Record and Disclosure to a location where you can print it, for future 
reference and access; and 
 
Until or unless you notify Insight OBO The Massachusetts General Hospital as described 
above, you consent to receive exclusively through electronic means all notices, 
disclosures, authorizations, acknowledgements, and other documents that are required to 
be provided or made available to you by Insight OBO The Massachusetts General 
Hospital during the course of your relationship with Insight OBO The Massachusetts 
General Hospital.