HEALEY ALS Platform Trial - Regimen D Pridopidine
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Merit E. Cudkowicz, MD

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 
 
 
 

HEALEY ALS Platform Trial  
Regimen-Specific Appendix D, Pridopidine 
 
Version  2.0,  15-July-2021 
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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 
compliance will be assessed at in clinic study visits through bottle counts and will be 

 
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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 
participants from concurrently enrolling regimens. Analyses of ALSFRS-R bulbar subdomain, 

 
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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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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-
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https://doi.org/10.1213/01.ane.0000226133.85114.91. 
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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. 
 
 
 
 
