Clinical trial NCT03781479
Conditions: Muscular Atrophy, Spinal
Keywords: Type 3
Sponsor: Catalyst Pharmaceuticals, Inc.
Start date: 2019-01-21; Completion date: 2020-07-23
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A two-period, two-treatment, crossover study to evaluate the safety, tolerability and efficacy of amifampridine phosphate in ambulatory patients diagnosed with spinal muscular atrophy (SMA) Type 3.

Detailed description:
This randomized (1:1), double-blind, placebo-controlled, 2-period, 2-treatment, crossover, outpatient study is designed to evaluate the safety, tolerability and efficacy of amifampridine phosphate in ambulatory patients diagnosed with SMA Type 3. The study is planned to include approximately 12 male and female SMA Type 3 patients. The planned duration of participation for each patient is approximately 2 months, based upon length of dose titration and excluding the screening period, which can last up to 14 days. Patients should only be taking the assigned investigational product (amifampridine phosphate 10 mg tablets or matching placebo tablets), no new therapies are permitted during the study.

Arms: arm 1: Oral tablets, 30 to 80 mg per day in divided doses 3 to 4 times a day for 4 weeks arm 2: Oral tablets, 30 to 80 mg per day in divided doses 3 to 4 times a day for 4 weeks
Interventions: intervention 1: Amifampridine Phosphate intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: Amifampridine phosphate tablets 10 mg will be provided in round, white-scored tablets, and containing amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet. intervention 2: Placebo Oral Tablet

Protocol documents:
Prot_000.pdf: 
 
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CLINICAL STUDY PROTOCOL 
Study Title: 
A Randomized, Placebo-Controlled, Crossover Study to 
Evaluate the Safety and Efficacy of Amifampridine Phosphate 
in Ambulatory Patients with Spinal Muscular Atrophy (SMA) 
Type 3 
Protocol Number: 
SMA-001 
Investigational Product: Amifampridine phosphate (3,4-diaminopyridine phosphate) 
IND/EUDRACT 
Number: 
142044 /2017-004600-22 
Indication: 
Spinal Muscular Atrophy Type 3 
External Support: 
Catalyst Pharmaceuticals, Inc. 
Development Phase: 
Phase 2a 
Medical Officer: 
Gary Ingenito, MD, PhD 
Study Design: 
Double-blind, Placebo-controlled, Randomized, Crossover  
Dose: 
15-80 mg total daily dose or placebo equivalent 
Patient Population: 
Ambulatory patients with SMA Type 3 
Version and Date of 
Protocol: 
Version 1.0 dated 20 November 2017 
Version 2.0 dated 12 April 2019 
Version 3.0 dated 27 September 2019 
 
 
Property of Catalyst Pharmaceuticals, Inc. 
CONFIDENTIAL 
May not be divulged, published, or otherwise disclosed to others without prior written 
approval from Catalyst Pharmaceuticals, Inc. 
 
This study will be conducted according to the principles of Good Clinical Practice as 
described in the U.S. Code of Regulations and the International Conference on 
Harmonisation Guidelines, including the archiving of essential documents. 
 
 
 
 
 


 
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1           PROCEDURES IN CASE OF AN EMERGENCY 
Emergency Contact Information 
Role in 
Study 
Name 
Contact Information 
Medical 
Monitor 
Stanley Iyadurai, MD, PhD 
Vice President, Clinical 
Affairs 
Catalyst Pharmaceuticals, Inc. 
355 Alhambra Circle, Suite 1250 
Coral Gables, FL 33134 
Tel: 305-420-3200, ext. 139 
Email: siyadurai@catalystpharma.com 
 
 
 
Contract 
Research 
Organization 
High Research s.r.l. for Italy 
 
 
 
 
Easthorn Clinical Services for 
countries outside Italy 
Viale Abruzzi 13/A 
20131 Milan, Italy 
Tel: +39 02 66712580 
Email: l.cottini@highresearch.it 
 
Obilicev venac 15 
11000 Belgrade, Serbia 
Tel: +381 11 3286 305 
Email: ivana.mucic@easthorn.eu 
Safety 
Reporting 
 
Gary Ingenito, MD, PhD  
Chief Medical Officer 
Catalyst Pharmaceuticals, Inc. 
355 Alhambra Circle, Suite 1250 
Coral Gables, FL 33134 
 
Catalyst Pharmaceuticals, Inc. 
Tel: +1 305-420-3223 
Email: gingenito@catalystpharma.com 


 
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2 
SYNOPSIS 
TITLE OF STUDY: 
A Randomized, Placebo-Controlled, Crossover Study to Evaluate the Safety and Efficacy of 
Amifampridine Phosphate in Ambulatory Patients with SMA Type 3 
PROTOCOL NUMBER: 
SMA-001 
STUDY SITE:  
Up to 3 sites 
PHASE OF DEVELOPMENT: 
Phase 2a 
STUDY RATIONALE: 
The purpose of this study is to evaluate the safety, tolerability, and efficacy of amifampridine 
phosphate in ambulatory patients with SMA Type 3.  
OBJECTIVES: 
Primary 
• 
To characterize the overall safety and tolerability of amifampridine phosphate compared with 
placebo in patients with SMA Type 3; and 
• 
To assess the clinical efficacy of amifampridine phosphate compared with placebo in 
ambulatory patients with SMA Type 3 using the Hammersmith Functional Motor Scale 
Expanded (HFMSE). 
Secondary 
• 
To assess the clinical efficacy of amifampridine phosphate compared with placebo using the 
six-minute walk test, timed tests, and individual quality of life (INQoL) and pediatric quality 
of life inventory (PEDSQoLTM) assessments. 
STUDY DESIGN AND PLAN:  
This randomized (1:1), double-blind, placebo-controlled, 2-period, 2-treatment, crossover, 
outpatient study is designed to evaluate the safety, tolerability and efficacy of amifampridine 
phosphate in ambulatory patients diagnosed with SMA Type 3. The study is planned to include 
approximately 12 male and female SMA Type 3 patients. The planned duration of participation for 
each patient is approximately 2 months, based upon length of dose titration and excluding the 
screening period, which can last up to 14 days. Patients should only be taking the assigned 
investigational product (amifampridine phosphate 10 mg tablets or matching placebo tablets), no 
new therapies are permitted during the study. 
All patients who sign an informed consent will be screened for eligibility to participate in the study, 
and those successfully completing screening will have procedures/assessments (see Table 1) 
completed during Run-in, until an optimized stable dose and frequency of amifampridine 
phosphate is established. At the end of 7 days on a stable daily dose regimen, the patient must show 


 
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≥3-point improvement in HFMSE score to be randomized. On Day 0 (randomization), procedures/ 
assessments (see Table 1) will be conducted to confirm eligibility for randomization, including a 
negative urine pregnancy test. 
Open-label Run-in 
Amifampridine dose will be titrated upward every 3 to 4 days, starting at 15 mg/day, at the 
discretion of the Investigator. Patients will either visit or have telephone/video contact with the site 
for each dose titration and at least one in-person site evaluation at Week 3 of the Run-in period. 
When the Investigator determines that the patient has reached the maximal tolerable dose, the 
patient should demonstrate they can remain on a stable dose and frequency for at least an additional 
7 days.  The Open-label Run-in period may be extended if additional time is needed for dose 
titration. At the end of this period, patients must show a ≥3-point improvement in HFMSE from 
start of Run-in, to be eligible for randomization (Day 0). 
Period 1 (Weeks 1 and 2) 
Patients who have successfully completed the Open-label Run-in and continue to meet all 
inclusion/exclusion criteria will be randomized (1:1 ratio) on Day 0 to receive either amifampridine 
tablets (10 mg as amifampridine phosphate) or placebo tablets for 2 weeks, beginning on Day 0 
after assessments have been performed on open-label medication. Test medication will be 
dispensed by the Catalyst designee, according to the randomization schedule provided. 
Assessments will be performed weekly, in the clinic, as listed in Table 1.  
On the last day of Period 1, patients will be evaluated in the clinic after taking the Period 1 study 
medication. Any remaining Period 1 medication will be collected and study medication for Period 
2 dispensed.   
Period 2 (Weeks 3 and 4) 
Period 2 begins after the patient has taken their dose of Period 1 medication in the clinic and had 
the evaluations listed for end of Week 2 as listed in Table 1.  The Period 2 medication will be the 
alternate study medication (amifampridine or placebo) which was not administered in Period 1.  
Assessments will be performed weekly, in the clinic, as listed in Table 1.  At the end of Weeks 3 
and 4, patients will be evaluated in the clinic after taking the Period 2 study medication.  The end 
of Week 4 represents the end of the study. 
NUMBER OF PATIENTS PLANNED:  
Approximately 12 SMA Type 3 ambulatory patients. 
 
 
 


 
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CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all the following inclusion criteria: 
1. Willing and able to provide written informed consent after the nature of the study has been 
explained and before the start of any research-related procedures. 
2. Male or female between the ages of 6 and 50 years. 
3. Genetically confirmed diagnosis of SMA Type 3. 
4. Able to walk independently for at least 30 meters (objectively measured at screening). 
5. Not taking Nusinersen for the treatment of SMA (Nusinersen should be stopped at least 6 
months before screening).  Salbutamol is permitted only if the dose has been stable during the 
6 months before screening. 
6. Able to swallow oral medication. 
7. Female patients of childbearing potential must have a negative pregnancy test (serum human 
chorionic gonadotropin [HCG] at Screening); and must practice an effective, reliable 
contraceptive regimen during the study and for up to 30 days following discontinuation of 
treatment. 
8. Ability to participate in the study based on overall health of the patient and disease prognosis, 
as applicable, in the opinion of the Investigator; and able to comply with all requirements of 
the protocol, including completion of study questionnaires. 
Individuals who meet any of the following Exclusion Criteria are not eligible to participate 
in the study: 
1. Epilepsy and currently on medication for epilepsy. 
2. An electrocardiogram (ECG) within 6 months before starting treatment that shows 
clinically significant abnormalities, in the opinion of the Investigator. 
3. Breastfeeding or pregnant at Screening or planning to become pregnant at any time 
during the study.  
4. Treatment with an investigational drug (other than amifampridine), device within 6 
months prior to Screening or while participating in this study. 
5. Surgery for scoliosis or joint contractures within the previous 6 months. 
6. Any medical condition that, in the opinion of the Investigator, might interfere with 
the patient’s participation in the study, poses an added risk for the patient, or 
confound the assessment of the patient. 
7. History of drug allergy to any pyridine-containing substances or any amifampridine 
excipient(s). 
8. Less than a 3-point improvement in HFSME from start of the Open label Run -in 
period to end of Run-in (Day 0). 
9. Uncontrolled asthma. 


 
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10. Concomitant use with sultopride. 
11. Concomitant use with medicinal products with a narrow therapeutic window. 
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE, AND REGIMEN:  
The investigational product (IP) is amifampridine, and it will be provided in round, white-scored 
tablets, containing amifampridine phosphate formulated to be the equivalent of 10 mg 
amifampridine base per tablet. Dosing is up to 80 mg/day in 3 or 4 divided doses. 
 
The investigational product, and matching placebo, will be provided by Catalyst Pharmaceuticals, 
Inc., 355 Alhambra Circle, Suite 1250, Coral Gables, Florida, 33134, United States. 
REFERENCE THERAPY, DOSE, ROUTE, AND REGIMEN:  
The reference therapy is a placebo, provided as tablets indistinguishable from amifampridine 
tablets. The placebo will be administered consistent with the dose and dose regimen of the 
investigational product (amifampridine). 
DURATION OF TREATMENT: 
Approximately 8 weeks (depending on length of dose titration and excluding up to 14-day 
screening period). The Run-in phase requires that the patient must be on a stable dose and regimen 
of amifampridine for the last week of Run-in. 
CRITERIA FOR EVALUATION: 
Safety: 
Safety will be assessed by the incidence of treatment-emergent adverse events (TEAEs), including 
serious adverse events (SAEs). Vital signs, 12-lead ECGs, clinical laboratory tests, physical 
examination, and concomitant medications will also be evaluated.  
Efficacy:  
Efficacy will be assessed by comparison of amifampridine versus placebo for: 
Primary - 
• 
Change from baseline in HFMSE total score; 
Secondary - 
• 
Change from baseline in quality of life assessments (INQoL or PEDSQoLTM).  
• 
Change from baseline in 6-minute walk test. 
• 
Timed items (rising from floor, rising from a chair, climbing 4 steps, walking 10 meters). 
STATISTICAL METHODS: 
Sample Size Determination 
The sample size for this study is based on clinical considerations related to the epidemiology of the 
disease, and not on a formal statistical power calculation.  The sample size should be representative 
of a sufficient number of patients to evaluate the study objectives (i.e. safety, tolerability, and 
evidence of efficacy of amifampridine in the target population).  It is anticipated approximately 12 
patients will be randomized. 


 
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Safety Analysis 
Safety analyses will be conducted on the safety population (i.e. all patients who receive at least 
1 dose of amifampridine). The safety analysis will be descriptive and will be presented on observed 
data only. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Only 
treatment-emergent AEs (TEAEs) will be included in the safety analysis. The incidence of TEAEs 
will be summarized by system organ class, preferred term, relationship to treatment, and severity 
by treatment  
All other safety measures including ECGs, vital signs, laboratory tests, physical examination and 
concomitant medications data will also be summarized. 
Efficacy Analysis 
Efficacy analysis will be conducted on 2 datasets: 
• 
Full Analysis Set (FAS): This population consists of all randomized patients who receive 
at least 1 dose of IP (amifampridine or placebo) and have at least one post-treatment 
efficacy assessment. 
• 
Per Protocol (PP): This population is a subset of the FAS population, excluding patients 
with major protocol deviations. The PP population will include all patients who: 
o Have no major protocol deviations or inclusion/exclusion criteria deviations that might 
potentially affect efficacy, and 
o Patients who took at least 80% of the required treatment doses and completed both 
double-blind treatment periods. 
 


 
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3 TABLE OF CONTENTS 
1 PROCEDURES IN CASE OF EMERGENCY ...................................................................2 
2 SYNOPSIS ...........................................................................................................................3 
3 TABLE OF CONTENTS .....................................................................................................8 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................12 
5 ETHICS..............................................................................................................................14 
5.1 Independent Ethics Committee / Institutional Review Board ...................................14 
5.2 Ethical Conduct of Study ..........................................................................................15 
5.3 Patient Information and Informed Consent ...............................................................15 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................15 
7 INTRODUCTION .............................................................................................................16 
7.1 Disease Background ..................................................................................................16 
7.2 Amifampridine ..........................................................................................................18 
7.3 Nonclinical Studies ...................................................................................................19 
7.4 Previous Clinical Studies ..........................................................................................20 
7.4.1 
Amifampridine Phosphate in Healthy Subjects ...........................................20 
7.4.2 
Efficacy of Amifampridine .........................................................................22 
7.4.3 
Safety of Amifampridine and Amifampridine Phosphate ...........................22 
7.4.4 
Overall Risks and Benefits ..........................................................................24 
7.4.5 
Study Rationale ...........................................................................................24 
8 STUDY OBJECTIVES ......................................................................................................25 
8.1.1 
Primary Objectives ......................................................................................25 
8.1.2 
Secondary Objective ....................................................................................25 
9 INVESTIGATIONAL PLAN ............................................................................................25 
9.1.1 
Overall Study Design and Plan ...................................................................25 
9.2 Selection of Study Population ...................................................................................29 
9.2.1 
Inclusion Criteria .........................................................................................29 
9.2.2 
Exclusion Criteria ........................................................................................30 
9.2.3 
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9.2.4 
Patient Identification ...................................................................................31 
9.2.5 
Re-screening ................................................................................................31 
9.3 Treatments .................................................................................................................32 
9.3.1 
Treatments Administered ............................................................................32 
9.3.2 
Identity of Investigational Product ..............................................................32 
9.3.2.1 
Product Characteristics and Labeling ..........................................33 
9.3.2.2 
Storage .........................................................................................33 
9.3.3 
Directions for Administration .....................................................................33 
9.3.4 
Method of Assigning Patients to Treatment Groups ...................................35 
9.3.5 
Selection of Doses Used in the Study .........................................................35 
9.3.6 
Blinding .......................................................................................................35 
9.3.7 
Treatment Compliance ................................................................................35 
9.3.8 
Investigational Product Accountability .......................................................35 
9.3.9 
Return and Disposition of Clinical Supplies ...............................................36 
9.4 Prior and Concomitant Medications .........................................................................36 
9.5 Dietary or Other Protocol Restrictions......................................................................37 
9.5.1 
Dietary Restrictions .....................................................................................37 
9.5.2 
Contraception ..............................................................................................38 
9.6 Safety Variables ........................................................................................................38 
9.6.1 
Adverse Events ............................................................................................38 
9.6.2 
Vital Signs ...................................................................................................38 
9.6.3 
Clinical Laboratory Assessments ................................................................38 
9.6.4 
Pregnancy Testing .......................................................................................39 
9.6.5 
Electrocardiogram (ECG) ............................................................................40 
9.6.6 
Physical Examination ..................................................................................40 
9.7 Efficacy Variables .....................................................................................................41 
9.7.1 
Hammersmith Functional Motor Scale Expanded (HFSME) .....................41 
9.7.2 
6-minute walk test .......................................................................................41 
9.7.3 
Timed Items .................................................................................................41 


 
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9.7.4 
Quality of life Assessment ..........................................................................41 
10.1 Adverse Events ..........................................................................................................42 
10.2 Serious Adverse Events .............................................................................................44 
10.3 Safety Blood Collection ............................................................................................46 
10.4 Pregnancy ..................................................................................................................46 
10.5 Urgent Safety Measures ............................................................................................46 
10.6 Medical Monitor Contact Information ......................................................................47 
11 APPROPRIATENESS OF MEASUREMENTS ................................................................47 
12 STUDY PROCEDURES ....................................................................................................47 
12.1 Screening Visit ..........................................................................................................47 
12.2 Open-label Run-in .....................................................................................................48 
12.3 Period 1 .....................................................................................................................49 
12.3.1 Day 0 ...........................................................................................................49 
12.3.2 Period 1, Days 7 and 14 (or Early Termination Visit) ................................50 
12.4 Period 2, Days 21 and 28 (or Early Termination Visit) ...................................51 
13 DATA QUALITY ASSURANCE ......................................................................................53 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...................53 
14.1 Statistical and Analytical Plans .................................................................................53 
14.1.1 Interim Analyses ..........................................................................................53 
14.2 Analysis Populations .................................................................................................53 
14.3 Primary Endpoint ......................................................................................................54 
14.4 Secondary Endpoints.................................................................................................54 
14.5 Safety Analysis .........................................................................................................54 
14.6 Efficacy Analysis ......................................................................................................55 
14.6.1 Primary Efficacy Endpoint Analyses ..........................................................55 
14.6.2 Secondary Efficacy Endpoint Analyses ......................................................55 
14.7 Determination of Sample Size ..................................................................................56 
14.8 Changes in the Conduct of the Study or Planned Analyses ......................................56 
 


 
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15 COMPENSATION, INSURANCE, AND INDEMNITY .................................................56 
16 CASE REPORT FORMS AND SOURCE DOCUMENTS ..............................................57 
17 STUDY MONITORING AND AUDITING .....................................................................58 
18 RETENTION OF RECORDS ...........................................................................................58 
19 USE OF INFORMATION AND PUBLICATION ...........................................................59 
20 REFERENCES ..................................................................................................................60 
21 INVESTIGATOR RESPONSIBILITIES ..........................................................................65 
21.1 Conduct of Study and Protection of Human Patients ...............................................65 
22 SIGNATURE PAGE .........................................................................................................66 
APPENDIX 1  ..........................................................................................................................67 
APPENDIX 2 ...........................................................................................................................70 
 
List of In-text Tables 
Table 1 Schedule of Events......................................................................................................28 
Table 2 Pediatric Dosing Guidelines .......................................................................................34 
Table 3 Medications Prohibited During Study ........................................................................37 
Table 4 Clinical Laboratory Tests ............................................................................................39 
Table 5 Categories of Severity for Advere Events ..................................................................43 
Table 6 Description of Relationship to Adverse Event Categories .........................................44 
 
List of In-text Figure 
Figure 1. 
Chemical Structure of Amifampridine Phosphate .........................................32 
 


 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
6MWT 
3,4-DAP 
Six-minute walk test 
3,4-diaminopyridine 
 
 
AChR-MG 
Acetylcholine receptor Myasthenia Gravis 
ADL 
Activities of Daily Living 
ADME 
absorption, distribution, metabolism, and excretion 
AE(s) 
adverse event(s) 
 
 
ALS 
amyotrophic lateral sclerosis 
ALT 
alanine aminotransferase  
ANS 
autonomic nervous system 
AST 
aspartate aminotransferase 
ATU 
Autorisations Temporaires d'Utilisation Normative 
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve from time 0 to infinity  
CI 
confidence interval 
Cmax 
peak plasma concentration 
CFB 
Change from baseline 
CMS 
congenital myasthenia syndromes 
CNS 
central nervous system 
CRA(s) 
clinical research associate(s) 
CRF 
CRO 
case report form 
contract research organization 
CYP450 
cytochrome P450 
DBP 
diastolic blood pressure 
ECG(s) 
electrocardiogram(s) 
eCRF 
electronic case report form 
EFNS 
European Federation of Neurological Societies  
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
hERG 
human Ether-à-go-go Related Gene 


 
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HFMSE 
Hammersmith Functional Motor Scale Expanded 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICH E6 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
IEC 
independent ethics committee 
INQoL 
Individual quality of life 
IP 
investigational product 
IRB 
institutional review board 
K+ 
potassium ion 
kg 
Kilogram 
LEMS 
Lambert-Eaton myasthenic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MG 
Myasthenia gravis 
mg 
Milligram 
MI 
myocardial infarction 
mmHg 
millimeters of mercury 
MS 
multiple sclerosis 
NAT 
N-acetyl transferase 
ng/mL 
nanograms per milliliter 
NMJ 
neuromuscular junction 
PEDSQLTM 
pediatric quality of life inventory 
Pgp 
P-glycoprotein 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
per protocol 
QMG 
Quantitative myasthenia gravis examination 
QT 
QT wave 
QTc 
QT wave corrected for heart rate 
REB 
research ethics board 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SMA 
spinal muscular atrophy 
SMN 
Survival motor neuron 


 
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SOPs 
standard operating procedures 
t1/2 
elimination half-life 
TEAE(s) 
treatment emergent adverse event(s) 
TK 
Toxicokinetic 
Tmax 
time to reach maximum plasma concentration 
US 
United States 
 
Definition of Terms:  
Investigational Product (IP): 
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6]). The terms “IP” and “study drug” may be 
used interchangeably in the protocol. 
5 
ETHICS 
5.1 Independent Ethics Committee / Institutional Review Board 
The Investigator will provide the IEC with all appropriate material, including the protocol, 
Investigator Brochure or Package Insert, the Informed Consent Form (ICF) including 
compensation procedures, and any other written information provided to the patients. The 
study will not be initiated and Investigational Product (IP) supplies will not be shipped to the 
site until appropriate documents from the IEC confirming unconditional approval of the 
protocol, the ICF, and all patient recruitment materials are obtained in writing by the 
Investigator, and copies are received at Catalyst or its designee. The approval document 
should refer to the study by protocol title and Catalyst protocol number (if possible), identify 
the documents reviewed, and include the date of the review and approval. The Investigator is 
responsible to ensure that the appropriate reports on the progress of the study are made to the 
IEC in accordance with applicable guidance documents and governmental regulations. 


 
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5.2 Ethical Conduct of Study 
This study will be conducted in accordance with the following: 
• ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
(ICH E6); and 
• The ethical principles established by the Declaration of Helsinki. 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IEC and will be conducted by scientifically and medically qualified persons. The benefits of 
the study are in proportion to the risks. The rights and welfare of the patients will be 
respected and the Investigators conducting the study do not find the hazards to outweigh the 
potential benefits. Each patient will provide written, informed consent prior to any 
study-related tests or evaluations are performed. 
5.3 Patient Information and Informed Consent 
A properly written and executed ICF, in accordance with the Declaration of Helsinki, ICH E6 
(Section 4.8), and other applicable local regulations, will be obtained for each patient before 
entering the patient into the study. The Investigator will prepare the ICF and provide the 
documents to Catalyst, or designee, for review. The IEC must approve the documents before 
their implementation. A copy of the approved ICF and a copy of the approved patient 
information sheet must also be received by Catalyst, or designee, prior to any study-specific 
procedures being performed. 
The Investigator will provide copies of the signed ICF to each patient and will maintain the 
original in the record file of the patient. 
6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
Before beginning the study, the Investigator must provide to Catalyst or designee, a fully 
executed and signed US Food and Drug Administration (FDA) Form FDA 1572 and a 
Financial Disclosure Form.  All sub-investigators must be listed on Form FDA 1572 and 
provide a Financial Disclosure Form. 
Clinical research associates (CRAs) or trained designees will monitor the site on a periodic 
basis and perform verification of source documentation for a representative sample of 
patients as well as other required review processes. Principal Investigator (PI) will be 
responsible for the timely reporting of serious adverse events (SAEs) to Catalyst, or 


 
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designee, and the IEC. Catalyst Medical Department (or designee) will be responsible for the 
timely reporting of SAEs to appropriate regulatory authorities, as required. 
Laboratory evaluations will be performed at the local laboratory associated with the study 
site.  
7 
INTRODUCTION 
A comprehensive review of amifampridine phosphate is contained in the Investigator 
Brochure supplied by Catalyst (March 2019). Investigators are to review this document 
before initiating this study. 
7.1 
Disease Background 
Spinal Muscular Atrophy (SMA), first described in the 1890s, is an autosomal recessive 
neuromuscular disease characterized by degeneration of alpha motor neurons in the anterior 
horn of spinal cord, leading to progressive denervation atrophy in the involved skeletal 
muscles, with weakness and paralysis. The disease is due to defects in the Survival Motor 
Neuron 1 (SMN1) gene in chromosome 5, with deficiency in the SMN protein, a 
ubiquitously expressed protein, critical to the health and survival of the motor neurons. 
Recent studies suggest that, due to the ubiquity of SMN protein, SMA might be a multi-
system disorder (Hamilton, 2013). The overall incidence of SMA is about 1:6,000-10,000 
live births and approximately one in 50 persons are healthy carriers of a defective SMN1 
gene (Ogino, 2002, Lunn and Wang 2008). The disease usually appears early in life and is 
the leading genetic cause of death in infants and toddlers. In most cases, weakness in the legs 
appears earlier and is generally greater than weakness in the arms. Muscles controlling 
feeding, swallowing, and respiratory function (e.g., breathing, coughing, and clearing 
secretions) may also be affected. The clinical phenotype is classified into four types (1, 2, 3, 
4), on the basis of age of onset and maximum motor function achieved (Munsat and Davies, 
1992 International SMA consortium meeting. (26-28 June 1992, Bonn, Germany). Even 
within the same type, clinical severity is highly variable and essentially depends on the 
number of copies of an alternative gene (SMN2), which may produce a limited amount of 
functional SMN protein, allowing the survival of a variable number of motor neurons. Type 1 
patients usually have two copies of the SMN2 gene, or even one copy only, while most 
Types 3 and 4 patients have three or four copies (Goulet 2013, Kolb 2015).  
SMA Type 1 (Werdnig-Hoffman disease), the most severe form, appears in the first months 
of life, often with a very rapid course (“floppy baby syndrome”), and is usually lethal before 


 
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two years of age. SMA Type 2 also presents very early, before 18 months of age, but 
symptoms are less severe, and these children are able to sit or even to stand unsupported, 
although they do not achieve the ability to walk independently. SMA Types 3 and 4 are the 
least severe forms. In Type 3, symptoms appear after 18 months of age, and severity is highly 
variable. Many patients have only proximal muscle weakness and can stand and walk 
independently, sometimes until the late disease stages. Life expectancy is near normal. SMA 
Type 4 has an adult onset, sometimes after 30 years of age, and muscle weakness, mainly of 
proximal muscles, is relatively mild and slowly progressing, although loss of independent 
walking has been rarely reported (Shababi 2014).  
SMN protein localized in the presynaptic terminals at the neuromuscular junction (NMJ) 
(Dombert 2014) and its role in NMJ development has been tested by the failure of the 
cultured muscle cells derived from SMA patients to cluster acetylcholine receptors (AChRs) 
at the junction (Arnold 2004). In addition, neurofilament accumulation along with poor 
terminal arborization in postnatal diaphragm samples of SMA Type 1 have been reported 
(Kariya 2008).  Further evidence for a possible role of abnormal NMJ in human SMA 
pathology derives from a recent study providing a detailed structural characterization of NMJ 
defects in SMA fetuses (Martinez-Hernandez 2013); main prenatal defects were abnormal 
modification of acetylcholine receptor clustering, irregular accumulation and positioning of 
synaptic vesicles, and atypical nerve terminals in motor endplates of SMA Type 1 samples, 
whereas SMA Type 2 fetuses were similar to controls.  
In SMA mice some findings suggest skeletal muscle fiber disruption, such as increased 
activity of cell death pathways (Mutsaers 2011), abnormal differentiation in muscle satellite 
cells, deficient formation of myotubes, and decreased muscle fiber size (Lee 2011; Hayhurst 
2012). Interestingly, loss of murine SMN specifically in the skeletal muscle causes muscle 
necrosis, paralysis, and death (Cifuentes-Diaz 2001).  
In addition, restoration of SMN in the mature muscle or increasing the muscle mass through 
different molecules have limited therapeutic benefits in SMA mice (Gavrilina 2008; Rose 
2009; Bosch-Marce 2011), further confirming that NMJ maturation defects and abnormal 
synapses are the hallmark of SMA pathology (Kariya 2008).  
There are also data suggesting fatigue and signs of NMJ dysfunction in SMA patients 
(Montes 2010; Wadman. 2012; Montes 2014; Pera 2017).  


 
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Three-Hz repetitive nerve stimulation showed a decremental compound muscle action 
potential in around half of SMA Types 2 and 3 patients, indicating an impaired NMJ 
transmission (Wadman 2012; Pera 2017). Furthermore, fatigue tested through 6MWT and 
expressed as decreased gait speed between first and last minute, is common in SMA Type 3 
patients (Montes 2010; Pera 2017). This 6MWT pattern has not been found in other 
neuromuscular disorders, hence cannot be attributed to muscle weakness alone.  
Based on the results of a randomized, double-blind, placebo-controlled, phase 3 clinical trial 
in SMA Types 1, nusinersen, is an antisense, intrathecally administered product designed to 
bind to the SMN2 pre-mRNA and promote inclusion of exon 7 (Finkel, 2017). It has been 
recently approved for treatment of all SMA types by FDA and European Medicines Agency.  
Furthermore, gene-replacement therapy using intravenous administration of adeno-associated 
virus 9 carrying SMN complementary DNA showed promising results in a small cohort of 
SMA Type 1 patients (Mendell, 2017). However, it is reasonable to assume that a single 
therapeutic solution may not be sufficient, hence combined treatments acting on different 
disease aspects may be beneficial. 
In summary, recent studies in SMA animal models and SMA patients have shown that the 
NMJ displays significant structural and functional defects that precede overt disease 
symptoms, suggesting that impaired NMJ function may contribute to SMA pathogenesis and 
symptoms. Defects in the NMJ appear to precede degeneration of motor neurons suggesting 
that abnormal formation and/or maintenance of this structure may be a key event in disease 
pathogenesis. These defects have been observed at both the pre- and postsynaptic 
components of the NMJ, which likely contribute to the failure to maintain the NMJ and 
muscle innervation in mouse models of SMA. Finally, NMJ dysfunction has been also 
demonstrated in SMA patients, mainly in Type 3 subgroup, contributing to the symptoms 
associated with the disease. 
7.2 
Amifampridine  
Amifampridine (3,4-DAP) is a non-specific voltage-dependent potassium (K+) channel 
blocker. Blockade of K+ channels cause depolarization of the presynaptic membrane and 
slows down or inhibits repolarization. Prolonged depolarization results in opening of slow 
voltage-dependent calcium (Ca2+) channels and allows a subsequent influx of Ca2+. The 
increased concentration of intracellular Ca2+ induces exocytosis of the synaptic vesicles 
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cleft (Maddison, 1998a; Maddison, 1998b). The influx of ACh into the presynaptic cleft 
enhances neuromuscular transmission, providing improved muscle function. 
Over the last 25 years, a considerable amount of clinical experience with amifampridine has 
been gained, which provides a strong body of evidence for its efficacy and safety in the 
treatment of patients with neurologic disorders, including myasthenia gravis (MG), Lambert-
Eaton myasthenic syndrome (LEMS), multiple sclerosis (MS), congenital myasthenia 
syndromes (CMS), downbeat nystagmus, and amyotrophic lateral sclerosis (ALS). 
Amifampridine has been recommended as first-line symptomatic treatment for LEMS by the 
European Federation of Neurological Societies (EFNS) (Skeie, 2006; Skeie, 2010; Lindquist, 
2011) and amifampridine 10 mg (as amifampridine phosphate) (Firdapse® Tablets) is 
marketed for the treatment of LEMS in the European Union (including Norway and Iceland), 
Israel, and Switzerland and the United States of America. The collective body of data 
indicates that amifampridine/ amifampridine phosphate (salt form of amifampridine) is well 
tolerated up to and including 80 mg/day (Firdapse Investigator Brochure, March 2019). 
7.3 Nonclinical Studies 
An extensive nonclinical program assessed the safety and absorption, distribution, 
metabolism, and excretion (ADME) and pharmacokinetic (PK) properties of amifampridine, 
including: 
• Five safety pharmacology studies in central nervous system (rat), respiratory (rat), and 
cardiovascular (telemeterized dogs, in vitro human Ether-à-go-go Related Gene (hERG) 
and rabbit Purkinje fiber)  
• Pharmacokinetics and mass balance in rat and dog  
• In vitro metabolism in human and animal hepatocytes  
• Human hepatic cytochrome P450 (CYP450) inhibition and induction  
• Human P-glycoprotein (Pgp) interaction  
• Single dose toxicity and toxicokinetic (TK) studies in mouse and rat  
• Repeat dose toxicity and TK in rat (28-day, 13-week, and 2-year) and dog studies 
(28-day and 9-month) 
• Reproductive and developmental toxicity in rat and rabbit 
• Six in vitro and in vivo genotoxicity studies 


 
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The main nonclinical findings were CNS and autonomic nervous system (ANS) effects, the 
development of Schwannomas, and histologic changes in muscle tissues after administration 
of amifampridine.  
7.4 Previous Clinical Studies 
Amifampridine has been used for over 25 years in patients with multiple neurologic disorders 
including MG, LEMS, MS, CMS, ALS, congenital forms of nystagmus, and adult idiopathic 
nystagmus (AIN). There are a limited number of published controlled trials with 
amifampridine in these disorders. A review of the literature documents that amifampridine is 
a safe and effective treatment in multiple neurologic disorders and is recommended by the 
EFNS for first-line symptomatic treatment of patients with LEMS (Skeie, 2006; Skeie, 2010; 
Lindquist, 2011). 
7.4.1 Amifampridine Phosphate in Healthy Subjects 
A Phase 1 study with amifampridine phosphate was conducted to investigate the 
bioavailability/bioequivalence and tolerability of amifampridine administered as a phosphate 
salt or free base. In the first part of the study, a pilot tolerance study was conducted in 5 
healthy male volunteers who received a single 10-mg dose of amifampridine phosphate to 
determine tolerability. In the second part of the study, bioequivalence testing was conducted 
in 27 healthy male volunteers. Each subject was randomized to receive either a single dose (2 
 10 mg tablets) of amifampridine as amifampridine phosphate or amifampridine base on one 
occasion and received the alternate treatment following a minimum of 72-hour washout 
period. 
This study demonstrated bioequivalence for area under the plasma concentration-time curve 
from time 0 to infinity (AUC0-∞), with the 90% confidence interval (CI) for the base/salt ratio 
of 93.1% to 113.3% falling within the predefined limits of 80% to 125% for bioequivalence. 
The mean elimination half-life (t1/2) values of amifampridine were 1.8 and 1.6 hours for the 
phosphate free base forms, respectively. Amifampridine peak serum levels (Cmax) was 
64.8 ng/mL for the phosphate form and 57.0 ng/mL for the free base form. Potentially higher 
solubility of the phosphate salt explained the slightly higher Cmax observed for amifampridine 
phosphate compared with the free base. All adverse events (AEs) were mild or moderate, 
transitory and fully reversible. The nature and frequency of side-effects did not differ 
between the salt and free base forms. The most common AE (25 of 40 AEs) in 12 subjects 
was paresthesia, which was mainly minor peri-oral paresthesia. Since paresthesia is well 
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possibly related to investigational product (IP) by the Investigator. The only other AE 
occurring in >1 subject and judged possibly related to amifampridine was abdominal pain (4 
events). Flu-like symptoms (5 events) and feeling of discomfort (2 events) were also reported 
for > 1 subject in the study, however were considered not related to amifampridine treatment. 
The only clinical laboratory test result abnormality reported in the study were minor, 
isolated, and reversible increases in aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT), in a single subject after administration of 20 mg amifampridine 
base. Aside from this 1 subject no other laboratory abnormalities were observed. No 
electrocardiogram (ECG) abnormalities were observed. No deaths occurred in the DAPSEL 
study.  
A Phase 1 open-label, randomized, single-dose, 2-treatment, 2-period crossover study in 46 
healthy volunteers evaluated whether food consumption significantly affected the 
bioavailability of amifampridine phosphate tablets (LMS-001).. Each subject received 20 mg 
amifampridine phosphate on 2 occasions, once fasting and once after consumption of a 
standard high fat breakfast. Each single 20 mg dose of amifampridine phosphate were 
administered 6 days apart. The results from this study indicate co-administration with food 
reduces exposures determined by Cmax and AUC by approximately 40% and 20%, 
respectively. In addition, the time to maximum serum concentrations (Tmax) was increased 2-
fold from approximately 38 minutes (fasted) to 78 minutes (fed). The drug was well tolerated 
with no serious adverse events and only 1 severe event, an episode of gastroenteritis 
unrelated to amifampridine. The most common AEs occurring in ≥ 10% of subjects were: 
oral paresthesia (20 subjects; 43%), peripheral paresthesias (12; 26%), dizziness (5; 11%), 
headache (5; 11%), and oral hypoesthesia (5; 11%). Abdominal pain, nausea, peripheral 
paresthesias, dizziness, and headache were more commonly reported by subjects following 
administration of amifampridine phosphate in the fasted state. In humans, amifampridine is 
exclusively metabolized to a single major metabolite, 3-N-acetyl amifampridine, via N-acetyl 
transferases (NAT) (Catalyst internal in vitro and in vivo studies; data available upon 
request). There are 2 NAT enzymes, NAT1 and NAT2, both of which are principally hepatic 
and both of which are highly polymorphic. These allelic variations lead to slow and fast 
metabolic rates, which have been well characterized in the Caucasian and Asian populations, 
but somewhat less well in African populations (Sabbagh, 2006). Slow acetylators are 
estimated to comprise 50% to 59% of the Caucasian population, with the remainder being 
rapid acetylators (fast + intermediate). Fast acetylators are over represented in Asian 
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African populations (25%) (Cascorbi, 1995). Slow acetylators will accumulate drug to higher 
levels (i.e. higher Cmax) and clear drug more slowly (i.e. longer t1/2), both of which may 
increase the risk of drug related toxicity (Fukino, 2008; Jetter, 2009).  
7.4.2 Efficacy of Amifampridine 
A Phase 3, randomized, double-blind, placebo-controlled study (LMS-002) evaluated the 
efficacy and safety of amifampridine phosphate (30-80 mg total daily dose) versus placebo in 
patients with LEMS. The change in QMG scores from baseline (Day 1, Part 2) to Day 14 
(Part 3) reached statistical significance (p=0.0452), with the least square (LS) mean for QMG 
score increasing by 2.2 in placebo-treated patients, and increasing by 0.4 in amifampridine-
treated patients. For the other primary endpoint, subject global impression (SGI), patients 
randomized to amifampridine on Day 1 reported, on average, that they were “pleased” (SGI 
mean ±SD score of 5.9 ± 1.2) while on treatment. After being switched to placebo tablets, 
their opinions dropped, on average, 2.7 ±2.3 points. The LS mean was -2.6 for the placebo 
group and -0.8 for the amifampridine group, a difference of 1.8 ±0.6 (p=0.0028), 
corresponding to a patient assessment, of “mixed” for the placebo tablets. This substantial 
change in patients’ assessments, to a worsening of their condition while receiving placebo, 
was considered clinically significant. 
In addition to Study LMS-002, 5 randomized, double-blind, placebo-controlled studies and 
1 double-blind study with an active comparator (reported in abstract form only) in 71 patients 
with LEMS are reported in the clinical literature. In all 6 studies, amifampridine (free base 
form) was shown to be more effective for the symptomatic treatment of LEMS compared 
with placebo or active comparator across a number of independent measures of neurological 
function. Supportive data from multiple published uncontrolled investigations and case 
reports demonstrate the long-term benefits of treatment with amifampridine in patients with 
LEMS, and show that discontinuation of amifampridine in a double blind controlled manner 
led to recurrence of underlying symptoms.  Refer to the Firdapse Investigator Brochure 
(March 2019) for further details on these studies. 
7.4.3 Safety of Amifampridine and Amifampridine Phosphate 
Safety data collected from 1,454 patients or healthy volunteers in various studies (e.g. 
controlled study LMS-002, other controlled and uncontrolled published studies of LEMS or 
other neurologic conditions, a 3-year safety surveillance study (ATU), and PK studies) 
demonstrate amifampridine is well tolerated up to and including 80 mg/day (Firdapse 
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safety data were perioral and peripheral paresthesias and gastrointestinal disorders 
(abdominal pain, nausea, diarrhea, epigastralgia).  These events were typically mild or 
moderate in severity, and transient, seldom requiring dose reduction or withdrawal from 
treatment. In the pharmacogenomic study in healthy subjects (classified as either slow 
acetylators or fast acetylators), slow acetylators experienced >80% more drug-related AEs 
compared with fast acetylators (FIR-001). 
Clinically significant or serious adverse events were infrequent in all studies for all 
indications. A total of 12 deaths were reported in the 1,454 patients or healthy subjects. Six 
of 12 deaths were associated with accompanying malignancy (1 of 6 with pulmonary 
embolus as terminal event), 1 due to tracheobronchitis, and 2 due to myocardial infarction 
(MI). Attribution to amifampridine for 2 of 3 deaths from the ATU study was specified as 
unrelated; causality for the third death was not reported. No attribution was specified in the 
academic series, but the author singled out the fatal MI as the only serious incident during 
amifampridine therapy, implying that the 2 deaths due to malignancy, the 1 due to 
malignancy and pulmonary embolus and the 1 due to tracheobronchitis were not related in 
his opinion. The author further states that no pathological findings related to amifampridine 
were found in the patient who died of tracheobronchitis. For 1 of the fatal MIs, the author 
speculates that a “sudden increase of physical activity” with amifampridine may have been a 
contributant (Lundh, 1984; Lundh, 1993); no causality was reported for the other fatal MI 
(Bertorini, 2011). Three deaths occurred in children with CMS, including 2 with fast-channel 
CMS (Beeson, 2005). Although no causal relationship was established with amifampridine, 
the authors advise its use cautiously in children and in fast-channel patients. The other CMS 
death was not thought to be related to amifampridine (Palace, 1991). Overall 7 of 12 deaths 
were not considered related to amifampridine; neither cause nor causality is known for 4 
deaths; and amifampridine may have contributed indirectly to 1 of the MI-related deaths.   
The most frequent clinically significant or serious event was seizure. Ten of 1454 (0.69%) 
individuals exposed to amifampridine experienced seizures. Electroencephalogram (EEG) 
findings, reported for 3 of the 10 patients, did not show epileptiform activity. Three of 10 
seizures occurred in patients with LEMS (3/209; 1.44%), 4 occurred in patients with MS 
(4/774; 0.5%), 1 occurred in a patient with CMS (1/88; 1.14%) (Harper, 2000) and 2 seizures 
were reported in a literature-based study where both MG and LEMS patients were enrolled, 
but the paper did not state the indication (Sanders, 1993; Sanders, 2000; Flet, 2010; McEvoy, 
1989; Boerma, 1995; Bever, 1996).  


 
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Three patients experienced seizures on a daily dose of ≥90 mg/day (LEMS or MG). No other 
cause was apparent in 2 cases; 1 patient had concurrent toxic serum levels of theophylline 
(McEvoy, 1989; Sanders, 1993). A fourth patient with LEMS had multiple seizures 
following accidental ingestion of 360 mg/day amifampridine for 7 days (prescribed dose 
60 mg/day) (Boerma, 1995). There were potentially contributing conditions in 6 patients, 
specifically, concurrent treatment with theophylline (n=1; LEMS or MG), or coexistent brain 
metastases (n=1; LEMS), epilepsy (n=1; MS) and MS (n=4). In cases where follow-up was 
reported, most seizures did not recur with amifampridine dose reduction or treatment 
withdrawal. In the one accidental overdose case, seizures were controlled with intravenous 
clonazepam and the patient made a full recovery (Boerma, 1995). Note that a seizure rate of 
4% can be expected in the natural course of patients with MS (Engelsen, 1997; Moreau, 
1998; Kinnunen, 1987). Among the 774 MS patients treated with amifampridine included in 
the safety assessment of this report, 4 (0.5%) experienced seizures. 
Other clinically significant or SAEs reported in more than 1 patient were palpitations 
(8/1,454; 0.56%), abnormal liver enzymes (6/1,454; 0.41%), QTc prolongation (2/1,454; 
0.14%), and premature ventricular contraction/increased ventricular extrasystoles (2/1,454; 
0.14%). Each of the following serious or clinically significant events was reported in a single 
patient: chorea, paresthesias, paroxysmal supraventricular tachycardia, cardiac arrest, drug-
induced hepatitis, gastroesophageal reflux, increased lipase and amylase, aspiration 
pneumonia with confusion, and urinary tract infection with confusion. 
7.4.4 Overall Risks and Benefits 
Data on amifampridine treatment in 1,454 patients or healthy volunteers support the 
favorable safety profile of amifampridine (both base and phosphate salt forms) at doses up to 
80 mg per day. Current data demonstrate that amifampridine phosphate has an acceptable 
tolerability profile with a positive risk-benefit in patients treated with amifampridine. Refer 
to the Investigator Brochure (March 2019) for further discussion on benefit/risk of 
amifampridine.  
7.4.5 Study Rationale 
As discussed above in Section 7.4, a considerable amount of clinical experience is available 
with amifampridine and, in December 2009, amifampridine phosphate tablets (10 mg as free 
base), received marketing approval by the European Commission as Firdapse® for the 
symptomatic treatment of patients with LEMS. Case reports, animal data suggest that 
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symptomatic relief through its action on the impaired NMJ transmission. Thus, the purpose 
of this study (SMA-001) is to demonstrate the safety and efficacy of amifampridine in 
patients with Type 3 SMA.  
8 
STUDY OBJECTIVES 
8.1.1 Primary Objectives 
The primary objectives of the study are: 
• To characterize the overall safety and tolerability of amifampridine compared with 
placebo in patients with SMA Type 3; and  
• 
To assess the clinical efficacy of amifampridine compared with placebo in ambulatory 
patients with SMA Type 3 based on change from baseline in the Hammersmith 
Functional Motor Scale Expanded (HFMSE) scores. 
8.1.2 Secondary Objective 
The secondary objective of the study is: 
• To assess the clinical efficacy of amifampridine compared with placebo by using the 
change from baseline in six-minute walk test, timed tests, and quality of life 
assessments; 
9 
INVESTIGATIONAL PLAN 
9.1.1 Overall Study Design and Plan 
This is a stratified, randomized (1:1), double-blind, placebo-controlled, , 2-treatment, 2-
sequence, crossover , outpatient study designed to evaluate the safety, tolerability and 
efficacy of amifampridine in ambulatory patients diagnosed with SMA Type 3. The study 
will include about 12 male and female SMA Type 3 patients,  
The planned duration of participation for each patient is at least 60 days excluding the 
screening period, which can last up to 14 days. 
All patients who sign an informed consent will be screened for eligibility to participate in the 
study: inclusion and exclusion criteria; medical and medication history; complete physical 
exam (including height, weight); vital signs; standard 12-lead ECG, including QTc 
evaluation; clinical laboratory testing; serum pregnancy testing (females of childbearing 
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administration); confirmed molecular diagnosis of SMA; and assessment of serious adverse 
events (SAEs) (Table1) 
Those patients successfully completing screening will have procedures/assessments (see 
Table 1 Schedule of Events) conducted at the start of the Run-in period (Day 1, before 
starting medication) and during Run-in, until stable dose and frequency of amifampridine is 
established for at least 7 days, and at least a 3-point improvement in HFMSE score is 
achieved. Screening and the start of the Run-in period may be combined into a single visit, in 
which case overlapping procedures/assessments will only need to be performed once. On the 
last day of the Run-in period (Day 0), procedures/assessments, as detailed in Table 1 will be 
conducted to confirm eligibility for randomization, including a negative pregnancy test. 
Every attempt should be made to have the same individual perform all assessments for a 
patient throughout the study. 
Randomized patients will be assigned to one of 2 treatment sequences under double-blind 
conditions, either placebo or amifampridine phosphate in Part 1, and then cross-over in Part 2 
to receive the alternate medication which was not taken in Part 1.   
Open-label Run-in 
Amifampridine dose will be titrated upward every 3 to 4 days, starting at 15 mg/day, at the 
discretion of the Investigator. Patients will either visit or have telephone/video contact with 
the site for each dose titration and at least one in-person site evaluation at Week 3 of the Run-
in period.  When the Investigator determines that the patient has reached the maximal 
tolerable and efficacious dose, the patient should demonstrate they can remain on a stable 
dose and frequency for at least an additional 7 days. The Open-label Run-in period may be 
extended if additional time is needed for the dose titration. At the end of this period, patients 
must show at least a 3-point improvement in HFMSE score from start of Run-in, to be 
eligible for randomization (Day 0). 
Randomization 
Patients who continue to meet all the inclusion and exclusion criteria will be randomized on 
the last day of the Run-in period (Day 0). 
Period 1 (Days 1-14) (±1 day for each of Days 7 and 14) 
Patients who have successfully completed the Open-label Run-in and continue to meet all 
inclusion/exclusion criteria will be randomized (1:1 ratio) on Day 0 to receive either 


 
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amifampridine tablets (10 mg as amifampridine phosphate) or placebo tablets for 14 days, 
under double-blind conditions, (blinded medication to start after assessments obtained on 
open-label medication, on Day 0). Test medication will be dispensed by the Catalyst 
designee, according to the randomization schedule provided by Sponsor. All unused 
medication and the container must be brought back to the study site at each clinic visit. 
Safety and efficacy assessments will be made, in the site clinic, on Days 7 and 14 as detailed 
in the Schedule of Assessments in Table 1 and Section 12 STUDY Procedures. 
Period 2 (Days 15-28) (±1 day for each of Days 21 and 28)   
Following the in-clinic assessments on Day 14 of Period 1, the Period 1 study medication is 
collected and the patient should be given the blinded Period 2 medication; either 
amifampridine phosphate or placebo tablets (whichever they did not receive in Period 1) for 
14 days. The Period 2 medication is to start with the next dose after the assessments are 
performed on Day 14 with Period 1 medication. 
Safety and efficacy assessments will be made, in the site clinic, on Days 21 and 28 as 
detailed in the Schedule of Assessments in Table 1 and Section 12 STUDY Procedures.  All 
unused medication and the container must be brought back to the study site at each clinic 
visit, including on Day 28, which represents the end of the study.    
 
 


 
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 Table 1 Schedule of Events 
Study Assessment  
or Event b 
 
Run-in 
Period 1 
Period 2 
Screening 
Start a 
 
Last Visit 
Day 7 
±1 day 
Day 14 
±1 day 
Day 
21 
±1 day 
Day 28 
±1 day 
Days 
-14 to -1 
Day 1 
Week 3 
Day 0 end 
of Run-in 
Informed consent c 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
X 
         
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Complete physical exam 
X 
 
 
X 
 
 
 
X 
Vital signs  
X 
 
X 
X 
X 
X 
X 
X 
12-Lead ECG and QTc evaluation 
X 
 
 
X 
 
 
 
X 
Clinical laboratory tests d 
X 
 
 
X 
 
 
 
X 
Pregnancy test e 
X 
 
 
X 
 
X 
 
X 
Dispense blinded IP f,g 
 
 
 
X 
 
X 
 
 
IP accountability 
 
 
X 
X 
X 
X 
X 
X 
Able to walk 30 meters 
X 
 
 
 
 
 
 
 
INQoL or PEDSQL 
 
 
 
X 
X 
X 
X 
X 
HFMSE 
X 
X 
 
X  
X 
X 
X 
X 
Six-minute walk test 
 
 
 
X 
X 
X 
X 
X 
Time to rise from floor 
 
 
 
X 
X 
X 
X 
X 
Time to rise from chair 
 
 
 
X 
X 
X 
X 
X 
Time to climb 4 stairs 
 
 
 
X 
X 
X 
X 
X 
Time to walk 10 meters 
 
 
 
X 
X 
X 
X 
X 
Adverse events/SAEs h 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Dosing Diary Provided 
 
X 
X 
X 
X 
X 
X 
 
 
ECG = electrocardiogram; HFSME= Hammersmith Functional Motor Scale Expanded; IP = investigational product 
(amifampridine or placebo); INQoL = individual quality of life; PEDSQL = pediatric quality of life inventory; SAE = 
serious adverse event. Footnotes continue on next page. 
a Titrate from starting dose of 15 mg/day, every 3 to 4 days with at least one site visit at Week 3.  Last week of 
run-in, study drug dose and frequency must be stable before being eligible for randomization on Day 0. 
b All safety assessments (vital signs, ECGs, laboratory tests) are to be performed before the dose taken in the 
study clinic unless specified otherwise. All efficacy assessments will be performed at standardized times 
relative to the dose that must be taken in the study clinic on Days 0, 7, 14, 21, and 28 according to the efficacy 
assessments schedule in Section 9.7. 
c Informed consent must be obtained before any study procedures are performed. 


 
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d Clinical laboratory tests include serum chemistry, hematology, and urinalysis. 
e Serum pregnancy tests will be obtained from female patients of childbearing potential only at Screening; urine 
dipstick may be used for the remainder of the study. 
f IP will be administered by the clinic staff during in-clinic visit so assessments can be timed according to IP 
administration.   
g Patients will be provided blinded packages containing amifampridine or placebo depending on their 
randomized sequence of treatment. Collect all open-label medication. 
h SAE reporting commences when informed consent is signed. Non-serious adverse event reporting 
commences on Day 1 of run-in (Section 10). 
 
9.2 Selection of Study Population 
Criteria for participation in the study are provided in Sections 9.2.1 and Exclusion Criteria 
9.2.2 
9.2.1 Inclusion Criteria 
Individuals eligible to participate in this study must meet all the following inclusion criteria: 
1. Willing and able to provide written informed consent after the nature of the study has 
been explained and before the start of any research-related procedures. 
2. Male or female between the ages of 6 and 50 years. 
3. Genetically confirmed diagnosis of SMA Type 3. 
4.  Able to walk independently for at least 30 meters (objectively measured at screening). 
5.  Not taking Nusinersen for the treatment of SMA (Nusinersen should be stopped at 
least 6 months before the screening). Salbutamol is permitted only if the dose has been 
stable for 6 months before screening. 
6. Able to swallow oral medication. 
7. Female patients of childbearing potential must have a negative pregnancy test (serum 
human chorionic gonadotropin [HCG] at screening); and must practice an effective, 
reliable contraceptive regimen during the study and for up to 30 days following 
discontinuation of treatment. 
8. Ability to participate in the study based on overall health of the patient and disease 
prognosis, as applicable, in the opinion of the Investigator; and able to comply with all 
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9.2.2 Exclusion Criteria 
Individuals who meet any of the following exclusion criteria are not eligible to participate in 
the study: 
1. Epilepsy and currently on medication. 
2. An electrocardiogram (ECG) within 6 months before starting treatment that shows 
clinically significant abnormalities, in the opinion of the Investigator. 
3. Breastfeeding or pregnant at Screening or planning to become pregnant at any time 
during the study. 
4. Surgery for scoliosis or joint contractures within the previous 6 months. 
5. Treatment with an investigational drug (other than amifampridine) or device within 6 
months before Screening or while participating in this study. 
6. Any medical condition that, in the opinion of the Investigator, might interfere with 
the patient’s participation in the study, poses an added risk for the patient, or 
confound the assessment of the patient. 
7. History of drug allergy to any pyridine-containing substances or any amifampridine 
excipient(s). 
8. Less than 3-point improvement in HFMSE from start to end of Run-in period. 
9. Uncontrolled asthma. 
10. Concomitant use with sultopride. 
11. Concomitant use with medicinal products with a narrow therapeutic window. 
 
9.2.3 Removal of Patients from Treatment or Assessment 
Patients may withdraw their consent to participate in the study or to receive treatment with IP 
at any time without prejudice. The Investigator must withdraw from the study or from 
treatment with IP any patient who requests to be withdrawn. A patient’s participation in the 
study or treatment with IP may be discontinued at any time at the discretion of the 
Investigator and in accordance with his or her clinical judgment.  
Catalyst must be notified of all patient withdrawals from the study or from treatment with IP 
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either clinical or administrative reasons and to discontinue participation by an individual 
Investigator or site for poor enrollment or noncompliance. 
Reasons for which the Investigator or Catalyst may withdraw a patient from the study 
treatment include, but are not limited to, the following: 
• Patient experiences a serious or intolerable AE; 
• Patient requires medication prohibited by the protocol;  
• Patient becomes pregnant (refer to Section 10.4 
Pregnancy for details on the 
reporting procedures to follow in the event of pregnancy).  
• Patient does not adhere to study requirements specified in the protocol; 
• Patient was erroneously admitted into the study or does not meet inclusion criteria;  
• Patient is lost to follow-up. 
If a patient fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the patient cannot be reached by telephone, a certified letter should 
be sent to the patient requesting contact with the Investigator. This information should be 
recorded in the study records. 
The Investigator or designee must explain to each patient, before enrollment into the study, 
that for evaluation of study results, the patient’s protected health information obtained during 
the study may be shared with Catalyst, regulatory agencies, and IEC. It is the Investigator’s 
(or designee’s) responsibility to obtain written permission to use protected health 
information, per country-specific regulations, from each patient. If permission to use 
protected health information is withdrawn, it is the Investigator’s responsibility to obtain a 
written request, to ensure that no further data will be collected from the patient and the 
patient will be removed from the study. 
9.2.4 Patient Identification 
Each patient will be assigned a unique patient identifier (2 digits for the site and 2 digits for 
each patient enrolled). This unique identifier will be on all CRF pages.  
9.2.5 Re-screening 
Re-screening of screen failures will be allowed, if re-screening is approved by the Medical 
Monitor. Justification of the reason for re-screening must be clearly stated in the patient’s 
source documentation. No new consent would be required if re-screened within 30 days. 


 
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Clinical laboratory tests do not have to be repeated for 30 days, except for pregnancy test. 
Patients may be replaced if discontinued from the study after randomization. 
9.3 Treatments 
9.3.1 Treatments Administered 
Catalyst or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study.  
Investigational product: Amifampridine will be provided in round, white-scored tablets and 
containing amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine 
base per tablet. The product will be provided in bottles of bulk tablets to the Catalyst 
designee who will dispense to the site an amount for each portion of the study, in a patient-
specific labeled bottle. 
Placebo: A placebo equivalent will be provided as tablets indistinguishable from the 
amifampridine tablets. The placebo will be administered consistent with the dose regimen of 
amifampridine. The placebo tablets will be provided in bottles of bulk tablets to the Catalyst 
designee, who will dispense to the site an amount, in a patient-specific labeled bottle. 
9.3.2 Identity of Investigational Product 
The chemical name of amifampridine phosphate is: 
• 3,4-pyridinediamine, phosphate (1:1) diamino-3,4-pyridine, phosphate salt 
• 3,4-diaminopyridine phosphate 
The chemical structure is provided in Figure 1. 
Figure 1. Chemical Structure of Amifampridine Phosphate 
 
H3PO4
N
NH2
NH2
4
1
2
3


 
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9.3.2.1 Product Characteristics and Labeling 
Drug product is formulated as a phosphate salt of amifampridine. Tablets were developed to 
provide the equivalent of 10 mg of amifampridine base for oral administration. Each tablet 
contains amifampridine phosphate, microcrystalline cellulose, colloidal anhydrous silica, and 
calcium stearate. The bottles of tablets are labeled “Amifampridine Phosphate Tablets, 
10 mg.” Placebo will be provided as tablets indistinguishable from amifampridine. 
The tablets of amifampridine and placebo are to be dispensed by the Catalyst designee into 
suitably sized pharmacy containers for patient use. Each bottle provided to patients will be 
labeled to include the compound name (Open-label or study drug, depending on the study 
period), site number, patient ID number, date dispensed, storage instructions, the statement 
‘Caution – New Drug – Limited to investigational use’, trial number, manufacturer name and 
address, and instructions for use. Any additional regional label requirements and translations 
will be included in accordance with local regulations. 
9.3.2.2 
Storage 
At the study site, all IP must be stored under the conditions specified, 20-25○ Celsius (C) 
(excursions between 15-30° may be allowed) and in a secure area accessible only to the 
pharmacist and clinical site personnel. All IP must be stored and inventoried, and the 
inventories must be carefully and accurately documented according to applicable national 
and local regulations, ICH GCP, and study procedures. 
9.3.3 Directions for Administration 
All doses of study treatment will be taken at home, except one of the doses on the day of the 
in-clinic study visits, when it will be administered by study personnel and will be 
administered in the clinic to facilitate timing of efficacy assessments. Test medication should 
be taken every day at approximately the same time, at the dose and frequency instructed by 
Investigator. On the day of an in-clinic study visit (Days 0, 7, 14, 21, and 28), dose 
administration will be the medication the patient has been taking for the previous days, but 
administered by the study personnel 45 minutes before the first efficacy assessment. If the 
patient takes the dose three times a day, the patient should be given specific instructions on 
dosing relative to the time of their visit to assure a dose will be given during the in-clinic visit 
within the required time window.  All safety assessments will be performed before the dose 
is administered to the patient during the in-clinic visit.  Efficacy assessment will be 
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Assessment 
Start Time  
After Dose 
(+ 10 minutes unless 
otherwise specified) 
HFSME 
45 minutes 
6-minute walk test 
Time to rise from floor 
Time to rise from chair 
Time to climb 4 stairs 
Time to walk 10 meters 
Quality of Life Assessment 
After HFSME 
After 6-minute walk 
After rise from floor 
After rise from chair 
After climb stairs 
After 10-meter walk 
 
The dose of amifampridine will be individually determined by the Investigator, within the 
bounds of a total daily dose of 15 mg to 80 mg, divided into doses taken 3 to 4 times per day 
as prescribed by the Investigator, based on optimal neuromuscular benefit. The maximum 
single dose is 20 mg. Amifampridine dose will be titrated upward every 3 to 4 days, starting 
at 15 mg/day, at the discretion of the Investigator. Pediatric dosing guidelines are presented 
in Table 2. 
Table 2 Pediatric Dosing Guidelines 
 
Ages 6 to 16 Years 
Ages >16 years 
Recommended 
starting dose 
5 mg, 3 times per day (15 mg/day total) 
10 mg, 3 times per day (30 mg/ day total) 
Initial dose 
escalation 
May increase dose to 10 mg, 3 times per 
day (30 mg/day total) 
May increase dose to 10 mg, 4 times per 
day (40 mg/day total) 
Subsequent 
dose escalations 
May increase dose to 10 mg, 4 times per 
day (40 mg/day total) 
May continue to titrate dose to 15 mg, 4 
times per day (60 mg/day total) 
May titrate dose up to 20 mg, 4 times per 
day (80 mg/day total) 
Maximum dose: 
60 mg/day 
80 mg/day 
 
Patients will either visit or have telephone/video contact with the site for each dose titration 
and at least one in-person site evaluation at Week 3 of the Run-in period. When the 
Investigator determines that the patient has reached the maximal tolerable dose, the patient 
should demonstrate they can remain on a stable dose and frequency for at least an additional 
7 days.  The Open-label Run-in period may be extended if additional time is needed for dose 


 
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titration. At the end of this period, patients must show a ≥3-point improvement in HFMSE 
from start of Run-in, to be eligible for randomization (Day 0). 
9.3.4 Method of Assigning Patients to Treatment Groups 
Patients will be randomized on the last day of the open-label run-in period (Day 0), in a 1:1 
ratio, to 1 of 2 treatment sequences (amifampridine for Period 1 and placebo for Period 2 or 
placebo for Period 1 and amifampridine for Period 2. IP will be administered under double-
blind conditions. Randomized patients who discontinue after initiation of treatment may be 
replaced. 
The randomization code will be provided to the unblinded Catalyst designee. Details will be 
included in the Pharmacy Manual.  
9.3.5 Selection of Doses Used in the Study 
Amifampridine is given in 3 or 4 divided doses, with no single dose 20 mg and the 
maximum daily dose of 80 mg. Safety of a single maximum dose of 20 mg is based on 
completed animal and in vitro pharmacology, PK, and toxicology studies.  Previous studies 
with amifampridine in this dose range have shown clinical benefit in other neurologic 
disorders (LEMS, MG). 
9.3.6 Blinding 
This is a double-blind, treatment cross-over study where both the patient and Investigator 
will be blinded to treatment assignment. 
9.3.7 Treatment Compliance 
Patients will be instructed to complete a daily Dosing Diary of study medication taken and 
bring the Diary, all IP containers, and remaining test medication at each study visit. Patient 
compliance with the dosing regimen will be assessed by reconciliation of the used and 
unused IP. The quantity dispensed, returned, used, lost, etc., must be recorded on the 
medication dispensing log provided for the study. 
9.3.8 Investigational Product Accountability 
The study site staff is responsible for maintaining accurate records (including dates and 
quantities) of IP(s) received, patients to whom IP is dispensed (patient-by-patient dose 
specific accounting), IP returned, and IP lost or destroyed. The Investigator and the study site 
staff must retain all unused or expired study supplies until the study monitor (on-site CRA) 
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9.3.9 Return and Disposition of Clinical Supplies 
Unused IP must be kept in a secure location for accountability and reconciliation by the study 
monitor. The Investigator or designee must provide an explanation for any destroyed or 
missing IP or study materials. 
Unused IP may be destroyed on site, per the site’s standard operating procedures, but only 
after Catalyst has granted approval for drug destruction. The monitor must account for all IP 
in a formal reconciliation process prior to IP destruction. All IP destroyed on site must be 
documented. Documentation must be provided to Catalyst and retained in the Investigator 
study files. If the site is unable to destroy IP appropriately, the site can return unused IP to 
Catalyst upon request. The return of IP or IP materials must be accounted for on a Study 
Drug Return Form provided by Catalyst. 
All IP and related materials should be stored, inventoried, reconciled, and destroyed or 
returned according to applicable regulations and study procedures. 
9.4 
Prior and Concomitant Medications 
All prescription and over-the-counter medications and herbal and nutritional supplements 
taken by a patient for 14 days before the Screening visit will be recorded on the designated 
CRF. Additionally, the stop date of any medications the patient was taking within 6 months 
before Screening that are excluded or restricted by the protocol will be recorded.  
The Investigator may prescribe additional medications during the study, if the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be 
notified of the use of any contraindicated medications immediately thereafter. Any 
concomitant medications added or discontinued during the study should be recorded on the 
CRF. 
Medications that are contraindicated when combined with amifampridine phosphate are: 
• Medicinal products with narrow therapeutic window 
• Sultopride 
Amifampridine phosphate should be used with caution when combined with the following 
products: 
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• Medicinal products with atropinic effects 
• Medicinal products with cholinergic effects 
• Non depolarizing muscle relaxant acting medicinal products 
• Depolarizing muscle relaxant acting medicinal products. 
 
Medications prohibited during the study are listed in Table 3. 
Table 3. 
Medications Prohibited During Study 
Nusinersen must be stopped at least 6 months before screening. Salbutamol, is permitted only 
if the dose has been stable for 6 months before screening.  
Any investigational product (other than amifampridine) or an investigational medical device within 
6 months before Screening. 
Medications that are contraindicated when combined with amifampridine phosphate are: 
• Medicinal products with narrow therapeutic window 
• Sultopride 
Amifampridine phosphate should be used with caution when combined with the following 
products: 
• Medicinal products known to lower the epileptic threshold 
• Medicinal products with atropinic effects 
• Medicinal products with cholinergic effects 
• Non depolarizing muscle relaxant acting medicinal products 
• Depolarizing muscle relaxant acting medicinal products. 
 
9.5 Dietary or Other Protocol Restrictions 
9.5.1 Dietary Restrictions 
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9.5.2 Contraception 
Sexually active males and females of childbearing potential and their partners must use 
effective forms of contraception, such as condom for males or occlusive cap (diaphragm or 
cervical/vault caps) for females, during the study.   
9.6 Safety Variables 
Safety in this study will be determined from evaluation of AEs/SAEs, vital signs, clinical 
laboratory test results, ECGs, including QTc evaluation, and physical examination findings. 
Pregnancy testing is also required for females of childbearing potential. The timing of the 
required evaluations is described in the Schedule of Events in Table 1 and in Section 12 
STUDY Procedures. 
9.6.1 Adverse Events 
The determination, evaluation and reporting of AEs will be performed as outlined in Section 
10.  
 
9.6.2 Vital Signs 
Specific visits for obtaining vital signs are provided in Table 1 and in Section 12 STUDY 
Procedures. Vital signs will be measured while in a sitting position, after resting for 5 
minutes, and include systolic blood pressure (SBP), diastolic blood pressure (DBP) measured 
in millimeters of mercury (mmHg), heart rate in beats per minute, respiration rate in breaths 
per minute. Body weight (kg) and temperature in °C will also be measured. Clinically 
significant changes from baseline will be recorded as AEs. 
9.6.3 Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are provided in Table 1 
Schedule of Events for the tests required by Protocol. The scheduled clinical laboratory tests 
are listed in Table 4.  All abnormal clinical laboratory test result pages should be initialed 
and dated by an Investigator, along with a comment for each abnormal result indicating 
whether or not it is clinically significant. Any abnormal test results determined to be 
clinically significant by the Investigator should be repeated (at the Investigator’s discretion) 
until the cause of the abnormality is determined, the value returns to baseline or to within 
normal limits, or the Investigator determines that the abnormal value is no longer clinically 
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Each clinically significant laboratory result should be recorded as an AE. The diagnosis, if 
known, associated with abnormalities in clinical laboratory tests that are considered clinically 
significant by the Investigator will be recorded on the AE CRF. 
Table 4 Clinical Laboratory Tests  
Blood Chemistry 
Hematology 
Urine Tests 
Other 
Albumin  
Hemoglobin  
Appearance 
Pregnancy test, if applicable 
Alkaline phosphatase  
Hematocrit  
Color 
ALT (SGPT) 
WBC count 
pH 
 
AST (SGOT) 
RBC count 
Specific gravity 
 
Direct bilirubin 
Platelet count 
Ketones 
 
Total bilirubin 
Differential cell count  
Protein  
 
BUN 
 
Glucose  
 
Calcium 
 
Bilirubin 
 
Chloride 
 
Nitrite 
Total cholesterol 
 
Urobilinogen 
 
CO2 or bicarbonate 
 
Blood in urine 
 
Creatine phosphokinase 
 
 
 
Creatinine 
 
 
 
Glucose 
 
 
 
GGT 
 
 
LDH 
 
 
Phosphorus 
 
 
 
Potassium 
 
 
Total protein  
 
 
 
Sodium  
 
 
 
Uric acid 
 
 
 
 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CO2, carbon 
dioxide; GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase; RBC, red blood cell; SGOT, serum 
glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase; WBC, white blood cell. 
 
9.6.4 Pregnancy Testing 
Female patients of childbearing potential will have a serum (at Screening) or urine pregnancy 
test at any other time points specified in the Schedule of Events (Table 1) and in Section 12 
STUDY Procedures. Female patients with a positive pregnancy test at Screening do not meet 
eligibility criteria for enrollment. Additional pregnancy tests will be performed at any visit in 
which pregnancy status is in question. 
Refer to Section 10.4 Pregnancy for details on the reporting procedures to follow in the 
event of pregnancy. 


 
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9.6.5 Electrocardiogram (ECG) 
A standard 12-lead safety ECG (single tracing) will be recorded with the patient resting 
comfortably in the supine position at the time points specified in the Schedule of Events 
(Table 1 Schedule of Events) and in Section 12 STUDY Procedures. The QTc interval should 
be evaluated. Clinically significant changes from baseline will be recorded as AEs.  
9.6.6 Physical Examination 
A complete physical examination is to be performed at each clinic visit or, if applicable, at 
early discontinuation from the study. Complete physical examination will include 
assessments of general appearance as well as the following: 
• Head 
• Eyes 
• Ears 
• Nose 
• Throat 
• Cardiovascular 
• Dermatologic 
• Lymphatic 
• Respiratory 
• Gastrointestinal 
• Musculoskeletal 
Weight will be measured with each physical examination throughout the study. Height (cm.) 
will be measured at screening only. 
Other body systems may be examined. Clinically significant changes from baseline will be 
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9.7 
Efficacy Variables 
The timing of required evaluation is described in the Schedule of Events in Table 1 Schedule 
of Events following the sequence listed below. 
Assessment 
Start Time  
After Dose 
(+ 10 minutes unless 
otherwise specified) 
HFSME 
45 minutes 
6-minute walk test 
Time to rise from floor 
Time to rise from chair 
Time to climb 4 stairs 
Time to walk 10 meters 
Quality of Life Assessment 
After HFSME 
After 6-minute walk 
After rise from floor 
After rise from chair 
After climb stairs 
After 10-meters walk 
 
9.7.1 Hammersmith Functional Motor Scale Expanded (HFSME) 
The HFSME (Appendix 1) assess motor function (e.g. lying, rolling, sitting, crawling, 
attaining standing, walking, running, and jumping) in order of progressive difficulty, with 
higher values showing higher function abilities.  The HFSME was expanded from the 
original 20-item Hammersmith functional motor scale by incorporating 13 relevant items to 
eliminate the “ceiling” effect of the original scale when applied to ambulant SMA patients.  
Each item scores 2 for unaided, 1 for assistance, and 0 for inability.  A total score is 
calculated by summing the scores of the individual items. The total score can range from 0 
(all activities failed) to 66 (all activities achieved unaided).  The HFSME shows good test-
retest reliability and correlation with other clinical measures in SMA, especially in Type 3 
(Montes, 2015). 
9.7.2 6-minute walk test 
This is a test of endurance which has been validated for ambulant patients with SMA 
(Montes, 2010).  Participants are instructed to walk as fast as possible along a 25-meter linear 
marked course for 6 minutes.  Meters walked are recorded. 
9.7.3   Timed items 
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• Rising from a chair – the time required to stand from a seated position 
• Climbing 4 steps – the time required to climb 4 standardized steps 
• Walking 10 meters – the time required to walk 10 meters as fast as possible 
9.7.4   Quality of life assessment 
The Individualized Quality of Life for neuromuscular disease (INQoL) or the Pediatric 
Quality of Life (PEDSQLTM) will be assessed for adult or pediatric patients, respectively. 
Each QoL evaluation is available in the local language for the appropriate sites.  
10 Reporting Adverse Events 
 10.1 Adverse Events 
For this protocol, a reportable AE is any untoward medical occurrence (e.g. sign, symptom, 
illness, disease or injury) in a patient administered the IP or other protocol-imposed 
intervention, regardless of attribution. This includes: 
• AEs not previously observed in the patient that emerge during the study. 
• Pre-existing medical conditions judged by the Investigator to have worsened in 
severity or frequency or changed in character during the study. 
• Complications that occur as a result of non-drug protocol-imposed interventions. 
An adverse drug reaction is any AE for which there is a reasonable possibility that the IP 
caused the AE. “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the IP and the AE. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis. 
The study period during which all non-serious AEs will be reported begins after the first 
administration of study drug through the termination visit or at the early termination visit. 
After informed consent but prior to initiation of study treatment, only SAEs associated with 
any protocol-imposed interventions will be reported. The criteria for determining, and the 
reporting of SAEs is provided in Section 10.2 Serious Adverse Events 
The Investigator should follow all unresolved AEs until the events are resolved or stabilized, 
the patient is lost to follow-up, or it has been determined that the study treatment or 
participation is not the cause of the AE. Resolution of AEs (with dates) should be 
documented on the appropriate CRF page(s) and in the patient’s medical record. 


 
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The Investigator responsible for the care of the patient or qualified designee will assess AEs 
for severity, relationship to IP, and seriousness (refer to Section 10.2 Serious Adverse Events 
for SAE definition). Severity (as in mild, moderate or severe headache) is not equivalent to 
seriousness, which is based on patient/event outcome or action criteria usually associated 
with events that pose a threat to a patient’s life or functioning. Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations.  
The Investigator will determine the severity of each AE using grades defined in Table 5 
Categories of Severity for Adverse Events (the event will be recorded on the source 
documents and AE CRF). Events that are Grades 4 and 5 are serious events and require 
completion of both an SAE form and AE CRF.  
Table 5 Categories of Severity for Adverse Events 
Severity 
Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**. 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated. 
Note: Grade 4 and 5 
adverse events should 
always be reported as 
serious adverse events 
Grade 5 
Death related to AE. 
Activities of Daily Living (ADL) 
* Instrumental ADLs refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
** Self-care ADLs refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
The Investigator will suggest the relationship of an AE to the IP and will record it on the 
source documents and AE CRF, using the relationship categories defined in Table 6. 


 
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Table 6 Description of Relationship to Adverse Event Categories  
Relationship 
Category 
Description 
Not Related 
Exposure to the IP has not occurred 
OR 
The administration of the IP and the occurrence of the AE 
are not reasonably related in time  
OR 
The AE is considered likely to be related to an etiology other 
than the use of the IP; that is, there are no facts [evidence] or 
arguments to suggest a causal relationship to the IP. 
Possibly 
Related 
The administration of the IP and the occurrence of the AE 
are reasonably related in time 
AND 
The AE could be explained equally well by factors or causes 
other than exposure to the IP. 
Probably 
Related 
The administration of IP and the occurrence of the AE are 
reasonably related in time  
AND 
The AE is more likely explained by exposure to the IP than 
by other factors or causes. 
 
In order to classify AEs and diseases, preferred terms will be assigned by the sponsor to the 
original terms entered in the CRF, using Medical Dictionary for Regulatory Activities 
(MedDRA) terminology. 
10.2 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 
1 or more of the following criteria: 
• Is fatal 
• Is life threatening 
• Note: Life-threatening refers to an event that places the patient at immediate risk 
of death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death 
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• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect, that is, an AE that occurs in the child or fetus 
of a patient exposed to IP prior to conception or during pregnancy 
• Is an important medical event or reaction.  
The reporting period for SAEs begins after informed consent is obtained and continues 
through 4 weeks after the last visit.  
Any SAE, whether or not considered related to study drug, must be reported within 24 hours 
of knowledge of the event by forwarding (fax, email) the study-specific SAE Report Form to 
Catalyst and CRO. The Investigator should not wait to collect information that fully 
documents the SAE before notifying Catalyst. As additional information becomes available, 
including but not limited to the outcome of the SAE and any medication or other therapeutic 
measures used to treat the event, it must be reported within 24 hours in a follow-up report. 
The Investigator should follow all unresolved SAEs until the events are resolved or 
stabilized, the patient is lost to follow-up, or it has been determined that the study treatment 
or participation is not the cause of the AE. Resolution of AEs (with dates) should be 
documented in the CRF and in the patient’s medical record. 
For some SAEs, Catalyst and/or designee may follow up by telephone, fax, email, and/or a 
monitoring visit to obtain additional case details deemed necessary to appropriately evaluate 
the SAE report (e.g. hospital discharge summary, consultant report, autopsy report). 
At the last scheduled visit, the Investigator should instruct each patient to report any 
subsequent SAEs that the patient’s personal physician(s) believes might be related to prior 
study treatment. 
The Investigator should notify Catalyst and CRO of any death or SAE occurring at any time 
after a patient has discontinued, or terminated study participation, if felt to be related to prior 
study treatment. Catalyst should also be notified if the Investigator should become aware of 
the development of cancer, or of a congenital anomaly, in a subsequently conceived offspring 
of a patient that participated in this study.  
Reporting of SAEs to the IEC will be done in compliance with the standard operating 
procedures and policies of the IEC and with applicable regulatory requirements. Adequate 
documentation must be provided showing that the IEC was properly and promptly notified as 
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10.3 
Safety Blood Collection 
Patients who experience a serious or severe AE should have, at the discretion of the 
Investigator, a blood sample drawn for safety labs as soon as possible after the AE began. 
Additional blood sampling may be performed at any time during the study if warranted to 
monitor patient safety. 
10.4 
Pregnancy 
Pregnancy in a patient or partner should be reported within 24 hours of the site becoming 
aware of the pregnancy by fax or email of the Pregnancy Reporting Form in the study 
reference materials to Catalyst. In addition, pregnancy in a patient is also reported on the End 
of Study CRF. The Investigator must make every effort to follow the patient through 
resolution of the pregnancy (delivery or termination) and to report the resolution on the 
follow-up form (Pregnancy Reporting Form: Additional Information in the study reference 
materials). In the event of pregnancy in the partner of a study patient, the Investigator should 
make every reasonable attempt to obtain the woman’s consent for release of protected health 
information. 
10.5 
Urgent Safety Measures 
The regulations governing clinical trials state that the sponsor and Investigator are required to 
take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
subjects, the sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the subjects against any immediate hazard. The sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IEC is notified at the same time. The reporting period for urgent safety measures is the period 
from the time of signing of the ICF through the completion of the last study visit. 
Investigators are required to report any urgent safety measures to the Sponsor or designee 
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Examples of situations that may require urgent safety measures include discovery of the 
following: 
• An immediate need to revise IP administration (i.e. modified dose amount or 
frequency not defined in protocol). 
• Lack of study scientific value, or detrimental study conduct or management. 
• Discovery that the quality or safety of IP does not meet established safety 
requirements. 
 
10.6 
Medical Monitor Contact Information 
The Investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the study Medical 
Monitor is listed below. 
Stanley Iyadurai, MD, PhD 
Vice President, Clinical Affairs 
Catalyst Pharmaceuticals, Inc. 
Tel: +1 305-420-3239 
Email: siyadurai@catalystpharma.com 
 
11 APPROPRIATENESS OF MEASUREMENTS 
The measures of safety used in this study are routine clinical and laboratory procedures. 
The efficacy measures use a variety of approaches to evaluate changes in neuromuscular 
function and muscle strength. These standardized tests have been previously used for 
determination of response to therapeutic intervention in patients with SMA and thus are 
relevant for use in this study in ambulatory patients with SMA. 
 
12 STUDY PROCEDURES 
12.1 
Screening Visit 
An ICF must be signed and dated by the patient and parents for patients with age < 18 years, 
the Investigator or designee, and witness (if required) before any study-related procedures are 
performed. Refer to Section 9.4 for prohibited medications. 


 
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After patients have signed an ICF, they will be screened for enrollment into the study. The 
study activities listed below will be performed during the 14 days that constitute the 
Screening visit. 
• Informed Consent; 
• Inclusion/Exclusion criteria; 
• Demographics (sex, race, ethnic origin, age); 
• Medical history, including allergy history; 
• Standard resting 12-lead ECG; 
• Complete physical examination including weight and height;  
• Vital signs (seated position), including SBP, DBP, heart rate, respiration, and body 
temperature;  
• Clinical laboratory tests including hematology, chemistry, and urinalysis; 
• Serum pregnancy test in females of childbearing potential only; 
• HFSME; 
• Walk 30 meters; 
• SAEs;  
• Concomitant medications. 
12.2 Open-label Run-in 
Amifampridine dose will be titrated upward every 3 to 4 days, starting at 15 mg/day, at the 
discretion of the Investigator. Patients will either visit or have telephone/video contact with 
the site for each dose titration and at least one in-person site assessment at Week 3 of the 
Run-in period (Table 1). When the Investigator determines that the patient has reached the 
maximal tolerable dose, the patient should demonstrate they can remain on a stable dose and 
frequency for at least an additional 7 days.  The Open-label Run-in period may be extended if 
additional time is needed for dose titration. At the end of this period, patients must show a 
≥3-point improvement in HFMSE from start of Run-in, to be eligible for randomization 
(Day 0). 
Patients should be given a Drug Dosing Diary to record each dose of their open-label 
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Additional visits are allowed as necessary. Screening visit and start of Run-in (Day 1) may be 
combined into a single visit. 
12.3 Period 1 
12.3.1 Day 0 
Patients who are deemed eligible for continuation will have the assessments/procedures listed 
below completed on Day 0 after taking a supervised dose of their medication for that day 
during the clinic visit, so that the assessments can occur in the prescribed relation to the time 
of medication administration.  
• Confirmation of Inclusion/Exclusion criteria; 
• Assessment of AEs/SAEs; 
• Complete physical exam with weight; 
• Vital signs (seated position), including SBP, DBP, heart rate, respiration, and body 
temperature; 
• Standard resting 12-lead ECG; 
• Clinical laboratory tests including hematology, chemistry, and urinalysis;  
• Urine pregnancy test in females of childbearing potential only; 
• Concomitant medications; 
• Collect patient Drug Dosing Diary and perform IP accountability of open-label 
medication; 
• Efficacy assessments following in-clinic dose of open-label medication as listed below: 
 


 
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Order of Assessment at Each 
Study Visit (when applicable) 
Start Time  
After Dose 
(+ 10 minutes unless 
otherwise specified) 
HFSME 
45 minutes 
6-minute walk test 
Time to rise from floor 
Time to rise from chair 
Time to climb 4 stairs 
Time to walk 10 meters 
Quality of Life Assessment 
After HFSME 
After 6-minute walk 
After rise from floor 
After rise from chair 
After climb stairs 
After 10-meters walk 
 
• 
INQoL for neuromuscular disease or the PEDSQLTM assessments will be completed 
for adult or pediatric patients, respectively after the six other assessments have been 
made. 
• Randomization to Treatment Sequence 
All open-label IP should be collected from the patient. The Investigator will dispense bottles 
containing amifampridine or placebo tablets, depending on the patient’s randomization 
assignment, for daily outpatient administration for 14 days (Days 1-14), starting after 
completion of all assessments on Day 0.   
Patients should be given a Drug Dosing Diary to record each dose of their double-blind 
medication and instructions on how to complete the form. 
Patients continue administration of blinded study medication (amifampridine or placebo) 
until the Day 14 visit.  
12.3.2 Period 1, Days 7 and 14 (or Early Termination Visit) 
Patients will report to the study site on Days 7 and 14 (±1 day) and have the 
assessments/procedures listed below completed. Study personnel will administer a dose of 
the patient’s blinded medication at the clinic on Days 7 and 14, so assessments can be 
performed according to the specified times in relation to the time of dose administration. The 
medication administered by study personnel should be the same as what the patient has been 
taking for Period 1. If the patient is taking study medication 3 or 4 times a day, the visit 
needs to be arranged such that one of the doses is administered by the study site personnel, 
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• Assessment of AEs/SAEs; 
• Vital signs (seated position), including SBP, DBP, heart rate, respiration, and body 
temperature; 
• Urine pregnancy test in females of childbearing potential (only on Day 14); 
• Concomitant medications;  
• Collect patient Drug Dosing Diary and perform IP accountability (a new Drug Dosing 
Diary is given to the patient on Days 7 and 14); 
• Efficacy assessments following in-clinic dose of double-blind medication as listed 
below: 
 
Order of Assessment at Each 
Study Visit (when applicable) 
Start Time  
After Dose 
(+ 10 minutes unless 
otherwise specified) 
HFSME 
45 minutes 
6-minute walk test 
Time to rise from floor 
Time to rise from chair 
Time to climb 4 stairs 
Time to walk 10 meters 
Quality of Life Assessment 
After HFSME 
After 6-minute walk 
After rise from floor 
After rise from chair 
After climb stairs 
After 10-meters walk 
 
• 
INQoL for neuromuscular disease or the PEDSQLTM assessments will be completed 
for adult or pediatric patients, respectively after the six other assessments have been 
made. 
On Day 14, all Period 1 study medication should be collected after the assessments have been 
performed, and study medication for Period 2 dispensed.  The first dose of Period 2 
medication is to be administered after the assessments are completed and at the time of the 
next regularly scheduled dose.  
12.4 Period 2, Days 21 and 28 (or Early Termination Visit) 
Patients will report to the study site on Days 21 and 28 (±1 day) and have the 
assessments/procedures listed below completed. Study personnel will administer a dose of 
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performed according to the specified times in relation to the time of dose administration. The 
medication administered by study personnel should be the same as what the patient has been 
taking for Period 2. If the patient is taking study medication 3 or 4 times a day, the visit 
needs to be arranged such that one of the doses is administered by the study site personnel. 
• Assessment of AEs/SAEs; 
• Complete physical exam (Day 28 only); 
• Vital signs (seated position), including SBP, DBP, heart rate, respiration, and body 
temperature; 
• 12-lead ECG (Day 28 only); 
• Clinical laboratory tests (Day 28 only); 
• Urine pregnancy test in females of childbearing potential (Day 28 only); 
• Concomitant medications;  
• Collect patient Drug Dosing Diary and perform IP accountability (a new Drug Dosing 
Diary is given to the patient on Day 21); 
• Efficacy assessments following in-clinic dose of double-blind medication as listed 
below: 
 
Order of Assessment at Each 
Study Visit (when applicable) 
Start Time  
After Dose 
(+ 10 minutes unless 
otherwise specified) 
HFSME 
45 minutes 
6-minute walk test 
Time to rise from floor 
Time to rise from chair 
Time to climb 4 stairs 
Time to walk 10 meters 
Quality of Life Assessment 
After HFSME 
After 6-minute walk 
After rise from floor 
After rise from chair 
After climb stairs 
After 10-meters walk 
 
• 
INQoL for neuromuscular disease or the PEDSQLTM assessments will be completed 
for adult or pediatric patients, respectively after the six other assessments have been 
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On Day 28, all Period 2 study medication should be collected after the assessments have been 
performed. This represents the end of the study.  
13 DATA QUALITY ASSURANCE 
Catalyst personnel or designees will visit the study site before initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, CRFs, monitoring requirements, and procedures for reporting AEs/SAEs.  
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on CRFs 
from source documents, adherence to protocol, randomization AE/SAE reporting, and drug 
accountability records.  
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
14.1 
Statistical and Analytical Plans 
14.1.1 Interim Analyses 
No interim analyses are planned. 
14.2 
Analysis Populations 
The following analysis populations will be defined for the study: 
• Safety Population: The safety population will consist of all subjects who are enrolled 
in the study and have received at least one dose of amifampridine and includes 
subjects who begin the Run-in period regardless of whether they are randomized to 
double blind medication on Day 0. 
• Full Analysis Set (FAS): This population consists of all randomized subjects who 
receive at least 1 dose of IP (amifampridine or placebo) and have at least one post-
treatment efficacy assessment. Subjects will be compared for efficacy according to 
the treatment to which they were randomized, regardless of the treatment actually 
received. 
• Per Protocol (PP): This population is a subset of the FAS population, excluding 
subjects with major protocol deviations. The PP population will include all FAS 
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o Have no major protocol deviations or inclusion/exclusion criteria deviations that 
might potentially affect efficacy, and 
o Subjects who took at least 80% of the required treatment doses.  
o The PP population will be determined before database lock and unblinding 
subject treatment codes. 
The FAS population will be the primary analysis set for all effectiveness analyses.  The 
safety population will be used for the analysis of all safety variables and baseline 
characteristics. The PP population will be used for selected effectiveness analyses. 
14.3 
Primary Endpoint  
The primary efficacy endpoint of the study is the change in HFMSE score from Day 0 
(baseline) for SMA subjects treated with amifampridine and placebo. 
14.4 Secondary Endpoints  
The secondary efficacy endpoints of the study are: 
• the six-minute walk test  
• timed tests  
• quality of life assessments 
 
14.5 
Safety Analysis  
Prior to analysis, all AEs will be coded using the MedDRA coding dictionary. Based on these 
coded terms, TEAEs and SAEs will be summarized using system organ class and preferred 
terms, as well as by relationship to treatment. All AEs will be listed, regardless of whether 
they were study treatment related.     
Vital signs will be summarized using descriptive statistics (mean, standard deviation, median, 
minimum, maximum, and number of non-missing observations) by time point.  Changes 
from baseline will also be summarized by post-dose time point.   
Clinical laboratory parameters will be summarized using descriptive statistics (mean, 
standard deviation, median, minimum, maximum, and number of non-missing observations) 
by time point.  Changes from baseline will also be summarized by post-dose time point.  In 
addition, a shift table will be constructed to show the shifts in laboratory results by parameter 
relative to the normal ranges.  The number and percentage of subjects with the following 
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low/high, high/low, high/normal, and high/high. Similar shift tables will also be constructed 
for physical exam results. ECG results will be summarized in a shift table with the following 
shifts presented: normal/normal, normal/abnormal, abnormal/normal and 
abnormal/abnormal. A table of descriptive statistics for QTc interval by treatment, day and 
period will be created. 
Additional safety analyses may be performed as described in the SAP for the study. 
14.6 
Efficacy Analysis  
14.6.1 Primary Efficacy Endpoint Analyses 
The change-from-baseline scores [Change From Baseline (CFB)7 = HFMSE7 – HFMSE0, 
CFB14 = HFMSE14 – HFMSE0, CFB21 = HFMSE21 – HFMSE0, CFB28 = HFMSE28 – 
HFMSE0] will be analyzed using a mixed effects linear model. Treatment (amifampridine 
(A) or placebo (P)) and Sequence (A/P or P/A) and the Treatment by Sequence interaction 
will enter the model as fixed effects. Subject within Sequence will enter the model as a 
random effect with a block diagonal covariance structure. Population marginal means1 will 
be estimated for each of the four Period and Sequence combinations.   
Other analyses may be carried out as specified in the Statistical Analysis Plan.  
14.6.2 Secondary Efficacy Endpoint Analyses  
The quantitative secondary efficacy endpoints (6-minute walk test, Time-to-rise-from-floor, 
Time-to-rise-from chair, Time-to-climb-4-stairs, and Time-to-walk-10 meters) will be 
analyzed as the HFSME is analyzed. The four CFB scores will be analyzed with a linear 
mixed model. Treatment and Sequence will be entered as fixed effects. Subject within 
Sequence will be entered as a random effect with a block-diagonal covariance structure. 
Population marginal means will be estimated for each of the four Period and Sequence 
combinations. 
Results from INQoL questionnaires and PEDSQLTM inventory of disease specific symptoms 
will be summarized with descriptive statistics (n, mean, standard deviation, minimum, 
median, and maximum) per time point (Days 0, 7, 14, 21, and 28) and CFB, using the Day 0 
                                                 
 
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response as the baseline level). The subscales of the QoL questionnaires will be similarly 
summarized. 
14.7 
Determination of Sample Size 
The sample size for this study is based on clinical considerations related to the epidemiology 
of the disease, and not on a formal statistical power calculation.  The sample size should be 
representative of a sufficient number of patients to evaluate the study objectives (i.e. safety, 
tolerability, and evidence of efficacy of amifampridine in the target population).  It is 
anticipated approximately 12 patients will be randomized.  
 
14.8  Changes in the Conduct of the Study or Planned Analyses 
Any change in study conduct considered necessary by the Investigator will be made only 
after consultation with Catalyst., who will then issue a formal protocol amendment to 
implement the change. The only exception is when an Investigator considers that a patient’s 
safety is compromised without immediate action.  
Protocol amendments that influence patient risk or the study objectives, or require revision of 
the ICF, must receive approval from the IEC prior to their implementation. 
When a protocol amendment substantially alters the study design or the potential risks or 
burden to patients, the ICF will be amended and approved by Catalyst and the IEC, and all 
active patients must again provide informed consent. 
Note: If discrepancies exist between the text of the statistical analysis as planned in the 
protocol, and the final SAP, a protocol amendment will not be issued, and the SAP will 
prevail. 
15 
COMPENSATION, INSURANCE, AND INDEMNITY 
There will be no charge to study patients to be in this study. Catalyst will pay all costs of 
tests, procedures, and treatments that are part of this study (as included in the site budget). In 
addition, after IEC approval, Catalyst may reimburse the cost of travel for study-related 
visits. Catalyst will not pay for any hospitalizations, tests, or treatments for medical problems 
of any sort, whether or not related to the study patient’s disease that are not part of this study. 
Costs associated with hospitalizations, tests, and treatments should be billed and collected in 
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The Investigator should contact Catalyst immediately upon notification that a study patient 
has been injured by the IP or by procedures performed as part of the study. Any patient who 
experiences a study-related injury should be instructed by the Investigator to seek medical 
treatment at a pre-specified medical institution if possible, or at the closest medical treatment 
facility if necessary. The patient should be given the name of a person to contact to seek 
further information about, and assistance with, treatment for study-related injuries. If the 
patient has followed the Investigator’s instructions, Catalyst will pay for reasonable and 
necessary medical services to treat the injuries caused by the IP or study procedures, if these 
costs are not covered by health insurance or another third party that usually pays these costs.  
16 
CASE REPORT FORMS AND SOURCE DOCUMENTS 
The CRO data management department or designee will perform all data management 
activities, including the writing of a data management plan outlining the systems and 
procedures to be used. 
Electronic case report forms (eCRFs) will be provided. The eCRF system, and procedures, 
and electronic signatures follow ICH requirements and applicable laws and local regulations. 
All system users will be trained on the eCRF before being granted system access. In the 
event of an entry error, or if new information becomes available, users will correct the value 
by deselecting the erroneous response and then selecting or entering the factual response. The 
documented audit trail will include the reason for the change, the original value, the new 
value, the time of the correction and the identity of the operator. 
In the application, study data on the eCRFs will be verified to the source data, which 
necessitates access to all original recordings, laboratory reports, and patient records. 
In addition, all source data should be attributable (signed and dated). The Investigator must 
therefore agree to allow direct access to all source data. Patients must also allow access to 
their medical records, and patients will be informed of this and will confirm their agreement 
when giving informed consent. The Investigator must review and electronically sign the 
completed eCRF casebook to verify its accuracy. A CRA designated by Catalyst will 
compare the eCRFs in the application with the original source documents at the study site 
and evaluate them for completeness and accuracy before designating them as “Source Data 
Verified” in the application. If an error is discovered at any time or a clarification is needed, 
the Data Manager, CRA, or designee, will create an electronic query on the associated field. 
Site personnel will then answer the query by either correcting the data or responding to the 


 
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query. The Data Manager or CRA will then review the response and determine either to close 
the query or re–query the site if the response does not fully address the question. This process 
will be repeated until all open queries are answered and closed. 
The Investigator will then electronically sign the casebook, specifying that the information 
on the eCRFs is accurate and complete. An electronic copy of the site’s casebooks will be 
sent to the site for retention with other study documents.  
17 
STUDY MONITORING AND AUDITING 
Qualified individuals approved and/or designated by Catalyst will monitor all aspects of the 
study according to GCP and SOPs for compliance with applicable government regulations. 
The Investigator agrees to allow these monitors direct access to the clinical supplies, 
dispensing, and storage areas and to the clinical files, including original medical records, of 
the study patients, and, if requested, agrees to assist the monitors. The Investigator and staff 
are responsible for being present or available for consultation during routinely scheduled site 
visits conducted by Catalyst or its designees.  
Members of Catalyst’s GCP Quality Department or designees may conduct an audit of the 
clinical site at any time before, during, or after completion of the study. The Investigator will 
be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other regulatory agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify Catalyst immediately. 
The Investigator will ensure that the auditors have access to the clinical supplies, study site 
facilities, original source documentation, and all study files. 
18 
RETENTION OF RECORDS 
The Investigator must retain all study records required by Catalyst and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a Catalyst 
representative before disposal of any study records and must notify Catalyst of any change in 
the location, disposition or custody of the study files. The Investigator/institution must take 
measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (e.g. patient charts) 
as well as any original source documents that are electronic as required by applicable 
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All study records must be retained for at least 2 years after the last approval of a marketing 
application in an ICH region and until (1) there are no pending or contemplated marketing 
applications in an ICH region or (2) at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IP. The Investigator/institution should retain 
patient identifiers and records for at least 15 years after the completion or discontinuation of 
the study. Patient files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice. These documents should be retained 
for a longer period, however, if required by the applicable regulatory requirements or by a 
Catalyst agreement. Catalyst must be notified and will assist with retention should 
Investigator/institution be unable to continue maintenance of patient files. It is the 
responsibility of Catalyst to inform the Investigator /institution as to when these documents 
no longer need to be retained. 
19 
USE OF INFORMATION AND PUBLICATION 
Catalyst recognizes the importance of communicating medical study data and therefore 
encourages their publication in reputable scientific journals and at seminars or conferences. 
The details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this study will be described in the Clinical Trial 
Agreement between Catalyst and the institution of the Investigator. 


 
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20 
REFERENCES 
Arnold AS, Gueye M, Guettier-Sigrist S, Courdier-Fruh I, Coupin G, Poindron P, Gies JP. 
Reduced expression of nicotinic AChRs in myotubes from spinal muscular atrophy I patients. 
Lab Invest. 84(10):1271-1278, 2004. 
Bertorini TE, Rashed H, Zeno M, et al. Effects of 3-4 diaminopyridine (DAP) in motor 
neuron diseases. J Clin Neuromusc Dis 12[3], 129-137. 2011. 
 
Beeson D, Hantaï D, Lochmüller H, Engel AG.  126th International Workshop: Congenital 
Myasthenic Syndromes, 24–26 September 2004, Naarden, The Netherlands.  Neuromuscul 
Disord. 15:498-512, 2005. 
 
Bever CT, Anderson PA, Leslie J, Panitch HS, et al. Treatment with oral 3,4 diaminopyridine 
improves leg strength in multiple sclerosis patients: results of a randomized, double-blind, 
placebo-controlled, crossover trial. Neurology 47[6], 1457-1462. 1996.  
 
Boerma CE, Rommes JH, van Leeuwen RB, Bakker J. Cardiac arrest following an iatrogenic 
3,4-diaminopyridine intoxication in a patient with Lambert-Eaton myasthenic syndrome. J 
Toxicol Clin Toxicol 33[3], 249-251, 1995.  
 
Bosch-Marcé M, Wee CD, Martinez TL, Lipkes CE, Choe DW, Kong L, Van Meerbeke JP, 
Musarò A, Sumner CJ. Increased IGF-1 in muscle modulates the phenotype of severe SMA 
mice. Hum Mol Genet. 20(9):1844-53, 2011.   
 
Cascorbi I, Drakoulis N, Brockmoller J, Maurer A, et al. Arylamine N-acetyltransferase 
(NAT2) mutations and their allelic linkage in unrelated Caucasian individuals: correlation 
with phenotypic activity. Am J Hum Genet 57[3], 581-592, 1995.  
 
Cifuentes-Diaz C1, Frugier T, Tiziano FD, Lacène E, Roblot N, Joshi V, Moreau MH, Melki 
J. Deletion of murine SMN exon 7 directed to skeletal muscle leads to severe muscular 
dystrophy. J Cell Biol. 152(5):1107-1114, 2001. 
 
Dombert B, Sivadasan R, Simon CM, Jablonka S, Sendtner M. Presynaptic localization of 
Smn and hnRNP R in axon terminals of embryonic and postnatal mouse motoneurons. PLoS 
One. 9(10): e110846, 2014. 
 
Engelsen BA, Gronning M. Epileptic seizures in patients with multiple sclerosis. Is the 
prognosis of epilepsy underestimated? Seizure 6[5], 377-382, 1997. 
 


 
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Evoli A, Alboini PE, Damato V, Iorio R. 3,4-Diaminopyridine may improve myasthenia 
gravis with MuSK antibodies. Neurology. 86(11):1070–1071, 2016. 
 
Flet L, Polard E, Guillard O, Leray E, et al. 3,4-Diaminopyridine safety in clinical practice: 
an observational, retrospective cohort study. J Neurol. 2010.  
Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, 
Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop 
K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC.  Nusinersen 
versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. ENDEAR Study Group. N 
Engl J Med. 377(18):1723-1732, 2017. 
Fukino K, Sasaki Y, Hirai S, Nakamura T, et al. Effects of N-acetyltransferase 2 (NAT2), 
CYP2E1 and Glutathione-S-transferase (GST) genotypes on the serum concentrations of 
isoniazid and metabolites in tuberculosis patients. J Toxicol Sci 33[2]: 187-195, 2008.  
Gavrilina TO, McGovern VL, Workman E, Crawford TO, Gogliotti RG, DiDonato CJ, 
Monani UR, Morris GE, Burghes AH.  Neuronal SMN expression corrects spinal muscular 
atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic 
effect.  Hum Mol Genet. 17(8):1063-1075, 2008.  
Goulet BB, Kothary R, Parks RJ. At the "junction" of spinal muscular atrophy pathogenesis: 
the role of neuromuscular junction dysfunction in SMA disease progression. Curr Mol 
Med.;13(7):1160-1174; 2013. 
Hamilton G, Gillingwater TH. Spinal muscular atrophy: going beyond the motor neuron. 
Trends Mol Med:19(1):40-50, 2013. 
Harper CM, Engel AG.  Treatment of 31 congenital myasthenic syndrome (CMS) patients 
with 3,4-diaminopyridine (DAP).  Neurology 54(Suppl 3): A395, 2000. 
Hayhurst M1, Wagner AK, Cerletti M, Wagers AJ, Rubin LL. A cell-autonomous defect in 
skeletal muscle satellite cells expressing low levels of survival of motor neuron protein. Dev 
Biol. 368(2):323-334. 2012. 
Jetter A, Kinzig M, Rodamer M, Tomalik-Scharte D, et al. Phenotyping of N-
acetyltransferase type 2 and xanthine oxidase with caffeine: when should urine samples be 
collected? Eur J Clin Pharmacol 65[4]: 411-417. 2009.  
 
Kariya S, Park GH, Maeno-Hikichi Y, Leykekhman O, Lutz C, Arkovitz MS, Landmesser 
LT, Monani UR. Reduced SMN protein impairs maturation of the neuromuscular junctions in 
mouse models of spinal muscular atrophy. Hum Mol Genet.17(16):2552-2569, 2008. 


 
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Kinnunen E, Koskenvuo M, Kaprio J, Aho K. Multiple sclerosis in a nationwide series of 
twins. Neurology 37[10]:1627-1629. 1987. 
 
Kolb SJ, Kissel JT. Spinal Muscular Atrophy. Neurol Clin.33(4):831-846, 2015. 
 
Lee YI, Mikesh M, Smith I, Rimer M, Thompson W.  A cell-autonomous defect in skeletal 
muscle satellite cells expressing low levels of survival of motor neuron protein. Dev Biol. 
356(2):432-444, 2011.  
Lindquist S, Stangel M. Update on treatment options for Lambert-Eaton myasthenic 
syndrome: focus on use of amifampridine. Neuropsychiatr Dis Treat 7: 341-349, 2011. 
 
Lundh H, Nilsson O, Rosen I, Johansson S. Practical aspects of 3,4-diaminopyridine 
treatment of the Lambert-Eaton myasthenic syndrome. Acta Neurol Scand 88[2]: 136-140, 
1993.  
 
Lundh H, Nilsson O, Rosen I. Treatment of Lambert-Eaton syndrome: 3,4-diaminopyridine 
and pyridostigmine. Neurology 34[10]: 1324-1330, 1984.  
 
Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 371(9630):2120-33, 2008 
 
Maddison P, Newsom-Davis J, Mills KR. Effect of 3,4-diaminopyridine on the time course 
of decay of compound muscle action potential augmentation in the Lambert-Eaton 
myasthenic syndrome. Muscle Nerve 21[9]: 1196-1198, 1998a. 
 
Maddison P, Newsom-Davis J, Mills KR. Distribution of electrophysiological abnormality in 
Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 65: 213-217, 1998b. 
 
Mah JK, Thannhauser JE, Kolski H, Dewey D. Parental stress and quality of life in children 
with neuromuscular disease. Pediatric Neurology 39:102–107, 2008.  
Martínez-Hernández R, Bernal S, Also-Rallo E, Alías L, Barceló MJ, Hereu M, Esquerda JE, 
Tizzano EF. Synaptic defects in type I spinal muscular atrophy in human development. J 
Pathol. 229(1):49-61, 2013.  
McEvoy KM, Windebank AJ, Daube JR, Low PA. 3,4-Diaminopyridine in the treatment of 
Lambert-Eaton myasthenic syndrome. N Engl J Med 321[23]: 1567-1571, 1989.  
 
Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, Lowes L, 
Alfano L, Berry K, Church K, Kissel JT, Nagendran S, L'Italien J, Sproule DM, Wells C, 
Cardenas JA, Heitzer MD, Kaspar A, Corcoran S, Braun L, Likhite S, Miranda C, Meyer K, 


 
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Foust KD, Burghes AHM, Kaspar BK.  Single-Dose Gene-Replacement Therapy for Spinal 
Muscular Atrophy.  N Engl J Med. 377(18):1713-1722, 2017. 
 
Montes J, McDermott MP, Martens WB, Dunaway S, Glanzman AM, Riley S, et al. Six-
minute walk test demonstrates motor fatigue in spinal muscular atrophy. Neurology 
74(10):833–838, 2010. 
Montes J, Dunaway S, Garber CE, Chiriboga CA, De Vivo DC, Rao AK. Leg muscle 
function and fatigue during walking in spinal muscular atrophy type 3. Muscle Nerve 
50(1):34–39, 2014. 
Montes J, Glanzman AM, Mazzone ES, Martens WB, Dunaway S, Pasternak A, Riley SO, 
Quigley J, Pandya S, De Vivo DC, Kaufmann P, Chiriboga CA, Finkel RS, Tennekoon GI, 
Darras BT, Pane M, Mercuri E, Mcdermott MP. Pediatric Neuromuscular Clinical Research 
Network, Muscle Study Group, SMA Europe. Spinal muscular atrophy functional composite 
score: A functional measure in spinal muscular atrophy. Muscle Nerve. 52(6):942-947, 2015.  
Moreau T, Sochurkova D, Lemesle M, Madinier G, et al. Epilepsy in patients with multiple 
sclerosis: radiological-clinical correlations. Epilepsia 39[8]: 893-896, 1998. 
 
Munsat TL, Davies KE. International SMA consortium meeting. (26-28 June 1992, Bonn, 
Germany). Neuromuscul Disord. 2(5-6):423-428, 1992. 
Mutsaers CA1, Wishart TM, Lamont DJ, Riessland M, Schreml J, Comley LH, Murray LM, 
Parson SH, Lochmüller H, Wirth B, Talbot K, Gillingwater TH. Reversible molecular 
pathology of skeletal muscle in spinal muscular atrophy. Hum Mol Genet. 20(22):4334-44, 
2011. 
Ogino S, Leonard DG, Rennert H, Ewens WJ, Wilson RB. Genetic risk assessment in carrier 
testing for spinal muscular atrophy. Am J Med Genet 110: 301–307, 2002. 
Palace J, Wiles CM, Newsom-Davis J. 3,4-Diaminopyridine in the treatment of congenital 
(hereditary) myasthenia. J Neurol Neurosurg Psychiatry 54[12]: 1069-1072, 1991. 
 
Pasnoor M, Wolfe GI, Nations S, Trivedi J, et al. Clincal findings in MuSK-antibody positive 
myasthenia gravis: A U.S. experience.  Muscle & Nerve 41: 370 – 374, 2010. 
 
Pera MC, Luigetti M, Pane M, Coratti G, Forcina N, Fanelli L, Mazzone ES, Antonaci L, 
Lapenta L, Palermo C, Ranalli D, Granata G, Lomonaco M, Servidei S, Mercuri E. 6MWT 
can identify type 3 SMA patients with neuromuscular junction dysfunction. Neuromuscul 
Disord. 27(10):879-882, 2017. 
Rose FF Jr, Mattis VB, Rindt H, Lorson CL. Delivery of recombinant follistatin lessens 
disease severity in a mouse model of spinal muscular atrophy. Hum Mol Genet 15;18(6):997-
1005, 2009. 
 


 
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Sabbagh A, Darlu P. SNP selection at the NAT2 locus for an accurate prediction of the 
acetylation phenotype. Genet Med 8[2]: 76-85, 2006.  
 
Sanders DB, Massey JM, Sanders LL, Edwards LJ. A randomized trial of 3,4-
diaminopyridine in Lambert-Eaton myasthenic syndrome. Neurology 54[3]: 603-607, 2000.  
 
Sanders DB, Howard JF Jr, Massey JM. 3,4-Diaminopyridine in Lambert-Eaton myasthenic 
syndrome and myasthenia gravis. Ann N Y Acad Sci 681: 588-590, 1993.  
 
Sansone VA, Panzeri M, Montanari M, Apolone G, Gandossini S, Rose MR, Politano L, 
Solimene C, Siciliano G, Volpi L, Angelini C, Palmieri A, Toscano A, Musumeci O, 
Mongini T, Vercelli L, Massa R, Panico MB, Grandi M, Meola G. Italian validation of 
INQoL, a quality of life questionnaire for adults with muscle diseases. Eur J Neurol. 
17:1178–1187, 2010. 
 
Skjei KL, Lennon VA, Kuntz NL: Muscle specific kinase autoimmune myasthenia gravis in 
children: A case series. Neuromuscul Disorders 23(11):874-882, 2013. 
 
Skeie GO, Apostolski S, Evoli A, Gilhus NE, et al. Guidelines for the treatment of 
autoimmune neuromuscular transmission disorders. Eur J Neurol 17[7]: 893-902, 2010. 
 
Skeie GO, Apostolski S, Evoli A, Gilhus NE, et al. Guidelines for the treatment of 
autoimmune neuromuscular transmission disorders. Eur J Neurol 13[7]: 691-699, 2006.  
 
Shababi M1, Lorson CL, Rudnik-Schöneborn SS. Spinal muscular atrophy: a motor neuron 
disorder or a multi-organ disease? J Anat. 224(1):15-28, 2014. 
Uzark K, King E, Cripe L, Spicer R, Sage J, Kinnett K, Wong B, Pratt J, Varni JW. Health- 
related quality of life in children and adolescents with Duchenne muscular dystrophy. 
Pediatrics.130: e1559–1566, 2012.  
 
Varni JW, Limbers CA. The pediatric quality of life inventory: measuring pediatric health- 
related quality of life from the perspective of children and their parents. Pediatr Clin North 
Am 56:843–863, 2009.  
 
Vincent KA, Carr AJ, Walburn J, Scott DL, Rose MR. Construction and validation of a 
quality of life questionnaire for neuromuscular disease (INQoL). Neurology 68:1051–1057, 
2007. 
 
Wadman RI, Vrancken AF, van den Berg LH, van der Pol WL. Dysfunction of the 
neuromuscular junction in spinal muscular atrophy types 2 and 3. Neurology 79(20):2050–
2055, 2012. 


 
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21 
INVESTIGATOR RESPONSIBILITIES 
21.1 
Conduct of Study and Protection of Human Patients 
The Investigator will ensure that: 
• He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of patients. 
• He or she will personally conduct or supervise the study. 
• He or she will inform any potential patients that the drug is being used for 
investigational purposes and he or she will ensure that the requirements relating to 
obtaining informed consent in compliance with ICH E6 (Section 4.8), and other 
applicable local regulations, are met.  
• He or she will report to the sponsor adverse experiences that occur during the 
investigation in compliance with the standard operating procedures and policies of the 
EC and with applicable regulatory requirements. 
• He or she has read and understands the information in the Investigator Brochure, 
including potential risks and side effects of the drug. 
• His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments. 
• He or she will ensure that adequate and accurate records are kept in accordance with 
ICH and GCP requirements and to ensure those records are available for inspection. 
• He or she will ensure that the IEC complies with ICH and GCP requirements, and 
other applicable regulations, and conducts initial and ongoing reviews and approvals 
of the study. He or she will also ensure that any change in research activity and all 
problems involving risks to human patients or others are reported to the IEC. 
Additionally, he or she will not make any changes in the research without IEC 
approval, except where necessary to eliminate apparent immediate hazards to human 
patients. 
• He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent ICH and GCP requirements. 
• He or she agrees to comply with electronic signature requirements in accordance with 
ICH requirements and applicable laws and local regulations. 




 
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Appendix 1 : Hammersmith Functional Motor Scale for SMA 
 
 
 


 
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APPENDIX 2: Protocol Version 2.0 
PURPOSE: The purpose of this version is as follows: 
To add an additional site, update medical monitor information, and update product 
information, based upon FDA approval. 
Risk: these administrative changes provide clarity, adding no additional risk to the patient. 
 
MODIFICATIONS TO PROTOCOL: 
• Bold and underlined text: 
 
Changed Text 
• Bold and strike through text: 
Deleted Text 
• Bold and italicized text: 
 
Added Text 
 
On Page 1, under Clinical Study Protocol,  
IND Number was updated  106263 142044   
Version and Date of Protocol, added text to indicate this is protocol Version 2.0 
Version 2.0 dated 12 April 2019 
Footer was updated to reflect new version information 
 
Section 1 Procedures in Case of an Emergency, under Medical Monitor, changed the Name 
and Contact Information number. 
Gary Ingenito, Chief Medical Officer 
ext. 123 
gingenito@catalystpharma.com 
Stanley Iyadurai, Vice President, Clinical Affairs 
ext. 139 
siyadurai@catalystpharma.com 
 
Section 1 Procedures in Case of an Emergency, Investigators Name and Contact Information 
were removed.  


 
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Section 1 Procedures in Case of an Emergency, under Contract Research Organization, 
information was added 
For Italy, email l.cottini@highresearch.it was added. 
 
Section 1 Procedures in Case of an Emergency, CRO information was added  
Easthorn Clinical Services for countries outside Italy 
Obilicev venac 15 
11000 Belgrade, Serbia 
Tel: +381 11 3286 305 
Email: ivana.mucic@easthorn.eu 
 
Section 1 Procedures in Case of an Emergency, Safety Reporting, changed address for 
PhAST Consulting Srl 
Via A. Gramsci 10 
20090 Monza, Italy 
 
Via Roma 74 - 20060  
Cassina de’ Pecchi (MI) Italy 
 
Section 2 Synopsis, under Study Site, deleted reference to single site, to reflect added site 
Single site in Italy 
Up to 3 sites 
 
Section 2 Synopsis, Criteria for Inclusion and Exclusion, the following were removed: 
2. Concomitant use of medicinal products with a known potential to cause QTc 
prolongation. 
3. Patients with long QT syndromes. 
 
Section 2 Synopsis, Criteria for Inclusion and Exclusion, criteria 4 was updated 
 to include the note (objectively measured at screening). 


 
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Table of Contents, two items with no corresponding sections were removed: 
2.   Male or Female between the ages of 6 and 50 years 
3.   Genetically confirmed diagnosis of SMA Type 3 
 
Reference to Table 3 Medications Prohibited During Study, was added to the Table of 
Contents. Table references throughout the document have been corrected accordingly. 
 
Appendix 2, Quality of Life Assessments was removed, and Appendix 2. Protocol Version 
2.0  history has been added to Table of Contents. 
 
Section 7.2 Amiphampridine, United States of America was added as a market, and Firdapse 
Investigator Brochure date was updated. 
. and the United States of America. 
June 2017 March 2019). 
 
The date for the Investigator Brochure (June 2017 March 2019) was updated in the 
following sections:  7, 7.2,  7.4.3, and 7.4.4. 
 
Section 9.1.1 Overall Study Design and Plan, deleted phrase with single site reference. 
The study is planned to be conducted at a single site; and will include about 12 male and 
female SMA Type 3 patients, 
 
Section 9.1.1 Overall Study Design and Plan, Error! Reference source not found. was 
corrected to Table 1. 
 
Table 1 Schedule of Events, was updated to include a column for Week 3. 
 


 
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Section 9.2.1 Inclusion Criteria, criteria 4 was updated to include the note (objectively 
measured at screening). 
 
Section 9.2.2 Exclusion Criteria, the following were removed: 
2. Concomitant use of medicinal products with a known potential to cause QTc 
prolongation. 
3. Patients with long QT syndromes. 
 
Section 9.3.2.2 Storage, the following was added: 
(excursions between 15-30° may be allowed) 
 
Section 9.4 Prior and Concomitant Medications, the following was deleted: 
Medications known to prolong QTc interval (e.g. fluoroquinolone antibiotics) should be 
used with caution, if required by the patient. 
 
Table 4 Clinical Laboratory Tests, blood chemistry item has been updated: 
CO2 or bicarbonate 
 
Table 4 Clinical Laboratory Tests, under the column Urine Tests, text was changed: 
Hemoglobin   Blood in urine 
 
 
Section 9.7.4 Quality of Life Assessment, the following has been added and deleted: 
Each QoL evaluation is available in the local language for the appropriate sites. 
(Appendix 2) 
 
Section 10.6 Medical Monitor Contact Information was updated to reflect the changes made 
on Section 2 Synopsis. 
Gary Ingenito, MD, PhD 
Chief Medical Officer 
Catalyst Pharmaceuticals, Inc. 


 
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Tel: +1 305-420-3223 
Email: gingenito@catalystpharma.com 
 
Stanley Iyadurai, MD, PhD 
Vice President, Clinical Affairs 
Catalyst Pharmaceuticals, Inc. 
Tel: +1 305-420-3239 
Email: siyadurai@catalystpharma.com 
 
 
Section 13, Data Quality Assurance, the following sentence was deleted: 
A separate unblinded CRA may verify records at the site. 
 
Section 22, Signature Page, information below the Medical Monitor Signature was updated.  
Gary Ingenito, MD, PhD 
Chief Medical Officer 
 
Stanley Iyadurai, MD, PhD 
Vice President, Clinical Affairs 
 
Appendix 2, Quality of Life Assessments, has been removed. 
Appendix 2. Protocol Version 2.0 has been added to record changes made to this protocol. 
 
 
 
 
 
 
 


 
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APPENDIX 3: Protocol Version 3.0 
PURPOSE: The purpose of this version is as follows: 
To reconcile mismatches between Protocol SMA-001 and Protocol SMA-002. 
Risk: these administrative changes provide clarity, adding no additional risk to the patient. 
 
MODIFICATIONS TO PROTOCOL: 
On Page 1, under Clinical Study Protocol,  
Version and Date of Protocol, added text to indicate this is protocol Version 3.0 
Version 3.0 dated 27 September 2019 
Footer was updated to reflect new version information 
 
On Page 3 Jonathan Rubine contact details were replaced by Gary Ingenito’s. 
 
Section 2 Synopsis, Criteria for Inclusion and Exclusion, the following were added: 
9. Uncontrolled asthma. 
10. Concomitant use with sultopride. 
11. Concomitant use with medicinal products with a narrow therapeutic window. 
 
Section 2 Synopsis, Criteria for Inclusion and Exclusion, criteria 4 was updated 
4. Treatment with an investigational drug (other than amifampridine), device, or 
biological agent within 6 months prior to Screening or while participating in this study. 
 
to read as follows in order to match Protocol section 9.2.2 
 
4. Treatment with an investigational drug (other than amifampridine), device within 6 
months prior to Screening or while participating in this study. 
 
Section 9.2.2. Exclusion Criteria, the following were added: 


 
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9. Uncontrolled asthma. 
10. Concomitant use with sultopride. 
11. Concomitant use with medicinal products with a narrow therapeutic window. 
 
Section 9.4 Prior and Concomitant Medications, the following was 
inserted: 
Medications that are contraindicated when combined with amifampridine phosphate are: 
• Medicinal products with narrow therapeutic window 
• Sultopride 
Amifampridine phosphate should be used with caution when combined with the following 
products: 
• Medicinal products known to lower the epileptic threshold 
• Medicinal products with atropinic effects 
• Medicinal products with cholinergic effects 
• Non depolarizing muscle relaxant acting medicinal products 
• Depolarizing muscle relaxant acting medicinal products. 
 
Table 3 updated. 
Appendix 3. Protocol Version 3.0 has been added to record changes made to this protocol. 
 

SAP_001.pdf: 
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Protocol SMA-001
Statistical Analysis Plan ver 1.0
Version Date: 11MAY2020
PROTOCOL SMA-001
A Randomized, Placebo-Controlled, Crossover Study to Evaluate the
Safety and Efficacy of Amifampridine Phosphate in Ambulatory Patients
with Spinal Muscular Atrophy (SMA) Type 3
STATISTICAL ANALYSIS PLAN
Version 1.0
11 May 2020
CONFIDENTIAL
Submitted to:
Gary Ingenito, MD, PhD
Chief Medical Officer
Catalyst Pharmaceuticals, Inc.
355 Alhambra Circle, Suite 1500
Coral Gables, FL 33134




Catalyst Pharmaceuticals, Inc.
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Protocol SMA-001
Statistical Analysis Plan ver 1.0
Version Date: 11MAY2020
2
Modification History
Unique Identifier
for this Version
Date of the
Document
Version
Author
Significant Changes from
Previous Authorized Version
0.1
11MAR2020
Claudio Iannacone
n.a.
0.2
30APR2020
Claudio Iannacone
Previous released used for internal
revision and comments from
Catalyst Pharmaceuticals.
Minor changes done to the
methodology text.
Added summary tables of each
individual item of HFMSE
Provided shells of all line listings
1.0
11MAY2020
Claudio Iannacone
Approved version.


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Protocol SMA-001
Statistical Analysis Plan ver 1.0
Version Date: 11MAY2020
3
List of Abbreviations and Definitions of Terms
Abbreviation
Definition
6MWT
Six-minute walk test
3,4-DAP
3,4-diaminopyridine
AChR-MG
Acetylcholine receptor Myasthenia Gravis
ADL
Activities of Daily Living
ADME
absorption, distribution, metabolism, and excretion
AE(s)
adverse event(s)
ALS
amyotrophic lateral sclerosis
ALT
alanine aminotransferase
ANS
autonomic nervous system
AST
aspartate aminotransferase
ATU
Autorisations Temporaires d'Utilisation Normative
AUC
area under the plasma concentration-time curve
AUC0-∞
area under the plasma concentration-time curve from time 0 to infinity
BMI
Body mass index
CI
confidence interval
Cmax
peak plasma concentration
CFB
Change from baseline
CMS
congenital myasthenia syndromes
CNS
central nervous system
CRA(s)
clinical research associate(s)
CRF
case report form
CRO
contract research organization
CYP450
cytochrome P450
DBP
diastolic blood pressure
ECG(s)
electrocardiogram(s)
eCRF
electronic case report form
EFNS
European Federation of Neurological Societies
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
hERG
human Ether-à-go-go Related Gene
HFMSE
Hammersmith Functional Motor Scale Expanded
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use
ICH E6
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6


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Protocol SMA-001
Statistical Analysis Plan ver 1.0
Version Date: 11MAY2020
Abbreviation
Definition
IEC
independent ethics committee
INQoL
Individual quality of life
IP
investigational product
IRB
institutional review board
K+
potassium ion
kg
Kilogram
LEMS
Lambert-Eaton myasthenic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MG
Myasthenia gravis
mg
Milligram
MI
myocardial infarction
mmHg
millimeters of mercury
MS
multiple sclerosis
NAT
N-acetyl transferase
ng/mL
nanograms per milliliter
NMJ
neuromuscular junction
PEDSQLTM
pediatric quality of life inventory
Pgp
P-glycoprotein
PI
Principal Investigator
PK
Pharmacokinetic
PPAS
per protocol analysis set
QMG
Quantitative myasthenia gravis examination
QT
QT wave
QTc
QT wave corrected for heart rate
REB
research ethics board
SAE(s)
serious adverse event(s)
SAF
safety analysis set
SAP
statistical analysis plan
SAS
Statistical Analysis System (software)
SBP
systolic blood pressure
SMA
spinal muscular atrophy
SMN
Survival motor neuron
SOPs
standard operating procedures
t1/2
elimination half-life
TEAE(s)
treatment emergent adverse event(s)
TK
Toxicokinetic
Tmax
time to reach maximum plasma concentration


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Protocol SMA-001
Statistical Analysis Plan ver 1.0
Version Date: 11MAY2020
Abbreviation
Definition
US
United States
WHO-DD
World Health Organization – Drug Dictionary


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Protocol SMA-001
Statistical Analysis Plan ver 1.0
Version Date: 11MAY2020
TABLE OF CONTENTS
1
Statistical Analysis Plan Signature Form
2
2
Modification History
3
3
List of Abbreviations and Definitions of Terms
4
4
Introduction
9
4.1
Background
9
5
Trial Design
10
5.1
Study Objectives
10
5.2
Study Design
11
5.3
Study Drug Dosage and Administration
11
6
Sample Size, Randomization and Blinding
11
6.1
Sample Size
11
6.2
Randomization and Blinding
11
7
Selection and Discontinuation of Patients
12
7.1
Inclusion Criteria
12
7.2
Exclusion Criteria
12
7.3
Removal of Patients from Treatment or Assessment
13
8
Schedule of Events
13
9
Study Endpoints
13
9.1
Efficacy Endpoints
13
9.1.1
Hammersmith Functional Motor Scale Expanded (HFMSE)
13
9.1.2
6-minute walk test
13
9.1.3
Timed items
13
9.1.4
Quality of life assessment
14
9.2
Safety Endpoints
14
10
Data Analysis and Statistical Considerations
14
10.1
Analysis Populations
14
10.2
General Statistical Considerations
14
10.3
Multiple Comparisons/ Multiplicity
15
10.4
Examination of Subgroups
15
10.5
Interim Analysis
15
10.6
Final Analysis
15
10.7
Retests, Unscheduled Visits and Early Termination Data
15
10.8
Windowing Conventions
15
10.9
Demographic Characteristics and Medical History
15
10.9.1
Demographic Characteristics
15
10.9.2
Medical History
15
10.10 Medication and Treatment Analysis
16
10.10.1
Patient Disposition and Accountability
16


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10.10.2
Duration of Treatment and Compliance
16
10.10.3
Concomitant Medications
17
10.11 Efficacy Analyses
17
10.12 Safety Data
18
10.12.1
Adverse Events
18
10.12.2
Vital Signs and Body Weight
21
10.12.3
12-Lead ECG
21
10.12.4
Physical Examination
22
10.12.5
Laboratory Tests
22
10.12.5.1 Laboratory Specific Derivations
23
10.13 Protocol Deviations
24
11
Data Handling
24
11.1
Multicenter Sites
24
11.2
Handling of Missing Data
24
12
Changes from the Protocol
24
13
Table Shells and Specifications
25
13.1
Table Specifications
25
13.1.1 Table Format Specification
25
13.2
Line Listings Specifications
25
14
Programming Conventions for Outputs
25
Appendix 1: Schedule of Events
27
Appendix 2: INQoL and PedsQL Scaling and Scoring
29


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4
Introduction
This Statistical Analysis Plan (SAP) is based on study procedures and analyses from the protocol,
Version 1.0, dated 20 November 2017. This SAP takes as well into account the following protocol
versions/amendments:
-
Version 2.0, dated 12 April 2019
-
Version 3.0, dated 27 September 2019
Table shells and mock listings corresponding to the contents of this document will be prepared and
included with the final version. This document, with table shells and mock listings, will be reviewed
prior to final unblinded analyses, and revised if necessary.
4.1
Background
Spinal Muscular Atrophy (SMA), first described in the 1890s, is an autosomal recessive
neuromuscular disease characterized by degeneration of alpha motor neurons in the anterior horn of
spinal cord, leading to progressive denervation atrophy in the involved skeletal muscles, with
weakness and paralysis. The disease is due to defects in the Survival Motor Neuron 1 (SMN1) gene
in chromosome 5, with deficiency in the SMN protein, a ubiquitously expressed protein, critical to
the health and survival of the motor neurons.
Recent studies suggest that, due to the ubiquity of SMN protein, SMA might be a multisystem
disorder (Hamilton, 2013). The overall incidence of SMA is about 1:6,000-10,000 live births and
approximately one in 50 persons are healthy carriers of a defective SMN1 gene (Ogino, 2002, Lunn
and Wang 2008). The disease usually appears early in life and is the leading genetic cause of death
in infants and toddlers. In most cases, weakness in the legs appears earlier and is generally greater
than weakness in the arms. Muscles controlling feeding, swallowing, and respiratory function (e.g.,
breathing, coughing, and clearing secretions) may also be affected. The clinical phenotype is
classified into four types (1, 2, 3, 4), on the basis of age of onset and maximum motor function
achieved (Munsat and Davies, 1992 International SMA consortium meeting. (26-28 June 1992, Bonn,
Germany). Even within the same type, clinical severity is highly variable and essentially depends on
the number of copies of an alternative gene (SMN2), which may produce a limited amount of
functional SMN protein, allowing the survival of a variable number of motor neurons. Type 1 patients
usually have two copies of the SMN2 gene, or even one copy only, while most Types 3 and 4 patients
have three or four copies (Goulet 2013, Kolb 2015). SMA Type 1 (Werdnig-Hoffman disease), the
most severe form, appears in the first months of life, often with a very rapid course (“floppy baby
syndrome”), and is usually lethal before two years of age. SMA Type 2 also presents very early,
before 18 months of age, but symptoms are less severe, and these children are able to sit or even to
stand unsupported, although they do not achieve the ability to walk independently. SMA Types 3 and
4 are the least severe forms. In Type 3, symptoms appear after 18 months of age, and severity is
highly variable. Many patients have only proximal muscle weakness and can stand and walk
independently, sometimes until the late disease stages. Life expectancy is near normal. SMA Type 4
has an adult onset, sometimes after 30 years of age, and muscle weakness, mainly of proximal
muscles, is relatively mild and slowly progressing, although loss of independent walking has been
rarely reported (Shababi 2014). SMN protein localized in the presynaptic terminals at the
neuromuscular junction (NMJ) (Dombert 2014) and its role in NMJ development has been tested by
the failure of the cultured muscle cells derived from SMA patients to cluster acetylcholine receptors
(AChRs) at the junction (Arnold 2004). In addition, neurofilament accumulation along with poor
terminal arborization in postnatal diaphragm samples of SMA Type 1 have been reported (Kariya


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2008). Further evidence for a possible role of abnormal NMJ in human SMA pathology derives from
a recent study providing a detailed structural characterization of NMJ defects in SMA fetuses
(Martinez-Hernandez 2013); main prenatal defects were abnormal modification of acetylcholine
receptor clustering, irregular accumulation and positioning of synaptic vesicles, and atypical nerve
terminals in motor endplates of SMA Type 1 samples, whereas SMA Type 2 fetuses were similar to
controls. In SMA mice some findings suggest skeletal muscle fiber disruption, such as increased
activity of cell death pathways (Mutsaers 2011), abnormal differentiation in muscle satellite cells,
deficient formation of myotubes, and decreased muscle fiber size (Lee 2011; Hayhurst 2012).
Interestingly, loss of murine SMN specifically in the skeletal muscle causes muscle necrosis,
paralysis, and death (Cifuentes-Diaz 2001). In addition, restoration of SMN in the mature muscle or
increasing the muscle mass through different molecules have limited therapeutic benefits in SMA
mice (Gavrilina 2008; Rose 2009; Bosch-Marce 2011), further confirming that NMJ maturation
defects and abnormal synapses are the hallmark of SMA pathology (Kariya 2008). There are also data
suggesting fatigue and signs of NMJ dysfunction in SMA patients (Montes 2010; Wadman. 2012;
Montes 2014; Pera 2017).
Three-Hz repetitive nerve stimulation showed a decremental compound muscle action potential in
around half of SMA Types 2 and 3 patients, indicating an impaired NMJ transmission (Wadman
2012; Pera 2017). Furthermore, fatigue tested through 6MWT and expressed as decreased gait speed
between first and last minute, is common in SMA Type 3 patients (Montes 2010; Pera 2017). This
6MWT pattern has not been found in other neuromuscular disorders, hence cannot be attributed to
muscle weakness alone. Based on the results of a randomized, double-blind, placebo-controlled,
phase 3 clinical trial in SMA Types 1, nusinersen, is an antisense, intrathecally administered product
designed to bind to the SMN2 pre-mRNA and promote inclusion of exon 7 (Finkel, 2017). It has been
recently approved for treatment of all SMA types by FDA and European Medicines Agency.
Furthermore, gene-replacement therapy using intravenous administration of adeno-associated virus 9
carrying SMN complementary DNA showed promising results in a small cohort of SMA Type 1
patients (Mendell, 2017). However, it is reasonable to assume that a single therapeutic solution may
not be sufficient, hence combined treatments acting on different disease aspects may be beneficial. In
summary, recent studies in SMA animal models and SMA patients have shown that the NMJ displays
significant structural and functional defects that precede overt disease symptoms, suggesting that
impaired NMJ function may contribute to SMA pathogenesis and symptoms. Defects in the NMJ
appear to precede degeneration of motor neurons suggesting that abnormal formation and/or
maintenance of this structure may be a key event in disease pathogenesis. These defects have been
observed at both the pre- and postsynaptic components of the NMJ, which likely contribute to the
failure to maintain the NMJ and muscle innervation in mouse models of SMA. Finally, NMJ
dysfunction has been also demonstrated in SMA patients, mainly in Type 3 subgroup, contributing to
the symptoms associated with the disease.
5
Trial Design
5.1
Study Objectives
The primary objectives of the study are:

To characterize the overall safety and tolerability of amifampridine compared with placebo in
patients with SMA Type 3; and


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
To assess the clinical efficacy of amifampridine compared with placebo in ambulatory patients
with SMA Type 3 based on change from baseline in the Hammersmith Functional Motor Scale
Expanded (HFMSE) scores.
The secondary objective of the study is to assess the clinical efficacy of amifampridine compared
with placebo by using the change from baseline in six-minute walk test, timed tests, and quality of
life assessments;
5.2
Study Design
This is a stratified, randomized (1:1), double-blind, placebo-controlled, 2-treatment, 2-sequence,
crossover study.
Patients will be randomized (1:1) to one of two sequences:
AP: Amifampridine (Period 1) followed by Placebo (Period 2)
PA: Placebo (Period 1) followed by Amifampridine (Period 2)
Patients will be randomized on the last day of the open-label run-in period (Day 0).
IP will be administered under double-blind conditions. Randomized patients who discontinue after
initiation of treatment may be replaced. The planned duration of participation for each patient is
approximately 2 months, based upon length of dose titration and excluding the screening period,
which can last up to 14 days.
The study is planned to be conducted in two investigational sites; and will include about 12 male and
female SMA Type 3 patients.
5.3
Study Drug Dosage and Administration
The IP is amifampridine, and it will be provided in round, white-scored tablets, containing
amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet.
Dosing is up to 80 mg/day in 3 or 4 divided doses.
A placebo equivalent will be provided as tablets indistinguishable from the amifampridine tablets and
will be administered consistent with the dose regimen of amifampridine.
6
Sample Size, Randomization and Blinding
6.1
Sample Size
The sample size for this study was based on clinical considerations related to the epidemiology of the
disease, and not on a formal statistical power calculation. It is anticipated approximately 12 patients
will be randomized with 6 patients per treatment sequence.
6.2
Randomization and Blinding
Patients will be randomized to one of two sequences:
AP: Amifampridine (Period 1) followed by Placebo (Period 2)
PA: Placebo (Period 1) followed by Amifampridine (Period 2)
This is a double-blind study where all involved parties will be blinded to randomized assignment to
the two sequences.


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7
Selection and Discontinuation of Patients
7.1
Inclusion Criteria
Individuals eligible to participate in this study must meet all the following inclusion criteria:
1. Willing and able to provide written informed consent after the nature of the study has been
explained and before the start of any research-related procedures.
2. Male or female between the ages of 6 and 50 years.
3. Genetically confirmed diagnosis of SMA Type 3.
4. Able to walk independently for at least 30 meters (objectively measured at screening).
5. Not taking Nusinersen for the treatment of SMA (Nusinersen should be stopped at least 6
months before the screening). Salbutamol is permitted only if the dose has been stable for 6
months before screening.
6. Able to swallow oral medication.
7. Female patients of childbearing potential must have a negative pregnancy test (serum human
chorionic gonadotropin [HCG] at screening); and must practice an effective, reliable
contraceptive regimen during the study and for up to 30 days following discontinuation of
treatment.
8. Ability to participate in the study based on overall health of the patient and disease prognosis,
as applicable, in the opinion of the Investigator; and able to comply with all requirements of
the protocol, including completion of study questionnaires.
7.2
Exclusion Criteria
Individuals who meet any of the following exclusion criteria are not eligible to participate in the
study:
1. Epilepsy and currently on medication.
2. An electrocardiogram (ECG) within 6 months before starting treatment that shows clinically
significant abnormalities, in the opinion of the Investigator.
3. Breastfeeding or pregnant at Screening or planning to become pregnant at any time during
the study.
4. Surgery for scoliosis or joint contractures within the previous 6 months.
5. Treatment with an investigational drug (other than amifampridine) or device within 6
months before Screening or while participating in this study.
6. Any medical condition that, in the opinion of the Investigator, might interfere with the
patient’s participation in the study, poses an added risk for the patient, or confound the
assessment of the patient.
7. History of drug allergy to any pyridine-containing substances or any amifampridine
excipient(s).
8. Less than 3-point improvement in HFMSE from start to end of Run-in period.
9. Uncontrolled asthma.
10. Concomitant use with sultopride.
11. Concomitant use with medicinal products with a narrow therapeutic window.


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7.3
Removal of Patients from Treatment or Assessment
Patients may withdraw their consent to participate in the study or to receive treatment at any time
without prejudice. The investigator or Catalyst may withdraw a patient from the treatment or from
the study at any time.
8
Schedule of Events
The schedule of clinical procedures and assessments conducted during the study is presented in
Appendix 1.
9
Study Endpoints
9.1
Efficacy Endpoints
The following efficacy assessments will be performed as described in the Schedule of Events
(Appendix 1), following the sequence in the following listed below.
Order of Assessment at Each Study Visit
(when applicable)
Start Time After Dose
(+10 minutes unless
otherwise specified)
HFMSE
45 minutes
6-minute walk test
After HFSME
Time to rise from floor
After 6-minute walk
Time to rise from chair
After rise from floor
Time to climb 4 stairs
After rise from chair
Time to walk 10 meters
After climb stairs
Quality of Life Assessment
After 10-meters walk
9.1.1
Hammersmith Functional Motor Scale Expanded (HFMSE)
The HFMSE assess motor function (e.g. lying, rolling, sitting, crawling, attaining standing, walking,
running, and jumping) in order of progressive difficulty, with higher values showing higher function
abilities. The HFMSE was expanded from the original 20-item Hammersmith functional motor scale
by incorporating 13 relevant items to eliminate the “ceiling” effect of the original scale when applied
to ambulant SMA patients. Each item scores 2 for unaided, 1 for assistance, and 0 for inability. A
total score is calculated by summing the scores of the individual items. The total score can range from
0 (all activities failed) to 66 (all activities achieved unaided). The HFMSE shows good test-retest
reliability and correlation with other clinical measures in SMA, especially in Type 3.
9.1.2
6-minute walk test
This is a test of endurance which has been validated for ambulant patients with SMA. Participants
are instructed to walk as fast as possible along a 25-meter linear marked course for 6 minutes. Meters
walked are recorded.
9.1.3
Timed items
a)
Rising from floor – the time required in rising from the supine position


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b)
Rising from a chair – the time required to stand from a seated position
c)
Climbing 4 steps – the time required to climb 4 standardized steps
d)
Walking 10 meters – the time required to walk 10 meters as fast as possible
9.1.4
Quality of life assessment
The Individualized Quality of Life for neuromuscular disease (INQoL) or the Pediatric Quality of
Life (PEDSQL) will be assessed for adult or pediatric patients, respectively.
9.2
Safety Endpoints
Safety endpoints include treatment-emergent adverse events (AEs), vital signs, physical examination,
clinical laboratory tests (hematology, chemistry and urinalysis), and ECGs, and each corresponding
CFB as appropriate.
10 Data Analysis and Statistical Considerations
Statistical tables and by-patient data listings will be prepared using SAS System (SAS Institute,
Cary, North Carolina, USA), Version 9.4 under Windows 10 PRO.
10.1 Analysis Populations
The following analysis populations have been defined for this clinical study:
a)
Enrolled Population (EP): all patients who provided informed consent for this study.
b)
Safety Population (SAF): the safety population consists of all subjects who are enrolled in the
study and have received at least one dose of amifampridine and includes subjects who begin
the Run-in period regardless of whether they are randomized to double blind medication on
Day 0.
c)
Full Analysis Set (FAS): this population consists of all randomized subjects who receive at
least one dose of IP (amifampridine or placebo) and have at least one post-treatment efficacy
assessment. Subjects will be compared for efficacy according to the treatment to which they
were randomized, regardless of the treatment actually received.
d)
Per-Protocol Population (PPAS): this population is a subset of the FAS population, excluding
subjects with major protocol deviations. The PPAS population will include all FAS subjects
who:
-
Have no major protocol deviations or inclusion/exclusion criteria deviations that
might potentially affect efficacy, and
-
Subjects who took at least 80% of the required treatment doses.
The PPAS population will be determined before database lock and unblinding subject treatment
codes.
The FAS population will be the primary analysis set for all effectiveness analyses. The safety
population will be used for the analysis of all safety variables and baseline characteristics. The PPAS
population will be used for selected effectiveness analyses. The results obtained in PPAS population
set will be seen as supportive of those obtained in the FAS population.
10.2 General Statistical Considerations
The following standards will be applied for the analyses unless otherwise specified.
Simple summary statistics (descriptive statistics) for continuous data will be n (number of non-
missing observations), mean, median, standard deviation, minimum, and maximum.


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The frequency count and percentage will be used to summarize categorical data. Summary statistics
will be presented by treatment by period and overall.
Summary statistics for all safety and efficacy variables will be presented by sequence, except for
tables related to incidence of AEs which will be presented by treatment group.
All tables of baseline and demographic data will be presented by sequence.
All data collected will be presented in the by-patient data listings, sorted by patient and by period and
day, where appropriate.
P-values <0.05 will be considered as statistically significant.
95% confidence interval will be calculated as appropriate.
Change From Baseline (CFB) will be summarized for efficacy and safety assessments, where
Baseline is defined as Day 0.
10.3 Multiple Comparisons/ Multiplicity
No alpha adjustment for multiple comparisons will be introduced, because only the comparison
between amifampridine and placebo group on the primary efficacy endpoint will be considered as
confirmatory.
10.4 Examination of Subgroups
No subgroup analyses are foreseen for this study.
10.5 Interim Analysis
There will be no Interim Analysis for this study.
10.6 Final Analysis
All final, planned analyses identified in this SAP will be performed by SPARC Consulting, Milan,
Italy on behalf of Catalyst Pharmaceuticals following Sponsor Authorization of this Statistical
Analysis Plan, Database Lock, Sponsor Authorization of Analysis Sets and Unblinding of Study
Treatment.
10.7 Retests, Unscheduled Visits and Early Termination Data
In general, for by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled
measurements will not be included in by-visit summaries.
Listings will include scheduled, unscheduled and early discontinuation data.
10.8 Windowing Conventions
Actual dates of visits will be used for calculations of time intervals. No visit windowing will be
performed for this study. Out-of-window visits will not be reallocated to the nearest timepoint.
10.9 Demographic Characteristics and Medical History
10.9.1 Demographic Characteristics
Demographic parameters, including age, gender, race, body weight, height, and BMI at Screening,
will be summarized for the SAF analysis set.
10.9.2 Medical History
Summary analysis will involve the SAF analysis set.


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SMA history parameters, including time in years from onset of SMA symptoms, previous treatments
for SMA and SMN gene analysis results will be summarized by treatment sequence.
Time from onset of SMA symptoms will be calculated as the difference in years from the year of the
date of informed consent and the year of onset of SMA symptoms reported in CRF.
All verbatim terms reported in the Medical History form will be assigned to a Preferred Term (PT)
and will be classified by the primary System Organ Class (SOC) according to the Medical Dictionary
for Regulatory Activities (MedDRA) thesaurus, version 23.
Previous diseases are those reported in the “Medical History” form of the eCRF with item “Present
at study start?” flagged as “No”.
Concomitant diseases are those reported in the “Medical History” form of the eCRF with item
“Present at study start?” flagged as “Yes” or “Unknown”.
The following data will be presented by treatment sequence:
a) A default frequency table showing the number and percentage of patients who exhibited an
abnormality by single body system;
b) A default frequency table showing the number and percentage of patients who exhibited at
least one previous disease and the previous diseases by primary SOC and PT;
c) A default frequency table showing the number and percentage of patients who exhibited at
least one concomitant disease and the concomitant diseases by primary SOC and PT;
Medical history will be listed for all enrolled patients.
10.10Medication and Treatment Analysis
10.10.1Patient Disposition and Accountability
The number and percentage of randomized patients who are in the SAF, FAS, and PPAS analysis set,
and who complete each treatment period will be presented by treatment sequence. The number and
percentage of patients who discontinue dosing prematurely, along with the primary reason that dosing
was discontinued prematurely, will be presented by period and treatment at the time of
discontinuation.
10.10.2 Duration of Treatment and Compliance
Duration of treatment during the open-label period will be summarized for the Safety Population.
The duration of treatment during the open-label run-in period is the date of Day 0 minus date of first
study dose+1.
Duration of treatment during the double-blind periods will be summarized for the Safety Population
by treatment and by period and pooled.
For Period 1, the duration of treatment is the (date of Day 14 minus date of Day 0)+1; for patients
who discontinue during Period 1, the duration of treatment during Period 1 is the (date of the last dose
during Period 1 minus the date of Day 0) +1.
For Period 2, the duration of treatment is the (date of Day 28 minus date of Day 14)+1; for patients
who discontinue during Period 2, the duration of treatment during Period 2 is the (date of the last dose
during Period 2 minus the date of Day 14)+1.
The overall duration during the double-blind periods will be obtained for each treatment by adding
the durations for the periods during which the patient received each treatment.
Compliance is 100%*(Number consumed)/(Number prescribed). “Number consumed” is from Study
Drug Accountability and “Number prescribed” is number of tablets to have been taken daily duration.


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Compliance during the double-blind periods will be summarized for the Safety Population by
treatment and by period. The compliance during the double-blind periods will be obtained for each
treatment by performing the same calculations for the periods during which the patient received each
treatment.
10.10.3Concomitant Medications
All prescription and over-the-counter medications and herbal and nutritional supplements taken by a
patient for 14 days before the Screening visit will be recorded on the designated CRF. Additionally,
the stop date of any medications the patient was taking within 6 months before Screening that are
excluded or restricted by the protocol will be recorded.
The Investigator may prescribe additional medications during the study, if the prescribed medication
is not prohibited by the protocol. In the event of an emergency, any needed medications may be
prescribed without prior approval, but the medical monitor must be notified of the use of any
contraindicated medications immediately thereafter. Any concomitant medications added or
discontinued during the study should be recorded on the CRF.
Concomitant medications will be only listed for all enrolled patients.
10.11Efficacy Analyses
The primary assessment of efficacy will be performed using the CFB in HFMSE total score.
Secondary assessments of efficacy will be performed using the following endpoints:
1.
CFB in 6-minute walk test (meters);
2.
CFB in rising from floor (seconds);
3.
CFB in rising from a chair (seconds);
4.
CFB in climbing 4 steps (seconds);
5.
CFB in walking 10 meters (seconds);
6.
CFB in the INQoL subscales scores:
Symptoms (section 1):
a) Weakness
b) Muscle “locking”
c) Pain
d) Fatigue
e) Droopy eyelids
f)
Double vision
g) Swallowing difficulties
Life domains (section 2):
a) Activities
b) Independence
c) Social relationship
d) Emotions
e) Body image
Life domains (section 3):
a) Perceived treatment effects
b) Expected treatment effects


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Quality of Life
7.
CFB in the PEDSQL score (where applicable).
The individual domain scores in INQoL and PedsQL will be calculated using the scoring algorithms
outlined in Appendix 2.
The efficacy assessments will be summarized by sequence and period.
The change-from-baseline scores [Change From Baseline (CFB)7 = HFMSE7 – HFMSE0, CFB14 =
HFMSE14 – HFMSE0, CFB21 = HFMSE21 – HFMSE0, CFB28 = HFMSE28 – HFMSE0] will be
analyzed using a mixed effects linear model. Treatment (amifampridine (A) or placebo (P)) and
Sequence (A/P or P/A) and the Treatment by Sequence interaction will enter the model as fixed
effects. Subject within Sequence will enter the model as a random effect with a block diagonal
covariance structure. The 95% confidence interval (CI) based on this model will be presented for the
difference in the Least Squares (LS) means. The analysis will be performed using SAS PROC
MIXED to incorporate the random effects model.
A summary statistics on the CFB in the individual items score of the HFMSE will be also provided
by sequence and period.
The quantitative secondary efficacy endpoints (6-minute walk test, Time-to-rise-from-floor, Time-
to-rise-from chair, Time-to-climb-4-stairs, and Time-to-walk-10 meters) will be analyzed as the
HFMSE is analyzed. The four CFB scores will be analyzed with a linear mixed model. Treatment
and Sequence will be entered as fixed effects. Subject within Sequence will be entered as a random
effect with a block-diagonal covariance structure. The 95% confidence interval (CI) based on this
model will be presented for the difference in the Least Squares (LS) means. The analyses will be
performed using SAS PROC MIXED to incorporate the random effects model.
Results from INQoL questionnaires and PEDSQL inventory of disease specific symptoms will be
summarized with descriptive statistics (n, mean, standard deviation, minimum, median, and
maximum) per time point (Days 0, 7, 14, 21, and 28) and CFB, using the Day 0 response as the
baseline level). The subscales of the INQoL questionnaires will be similarly summarized.
Analysis of the primary efficacy endpoint will be perfomed both in the FAS and in PPAS analysis
set. Analysis on FAS analysis set will be considered as primary while analysis in the PPAS will be
used as supportive of the FAS results.
Analysis of secondary efficacy endpoints will be performed only in the FAS analysis set.
10.12Safety Data
Summaries of safety data will be presented for the SAF analysis set using observed data only, i.e.
without imputation. All observed safety data will be listed.
10.12.1Adverse Events
For this protocol, a reportable AE is any untoward medical occurrence (e.g. sign, symptom, illness,
disease or injury) in a patient administered the IP or other protocol-imposed intervention, regardless
of attribution. This includes:

AEs not previously observed in the patient that emerge during the study.

Pre-existing medical conditions judged by the Investigator to have worsened in severity or
frequency or changed in character during the study.

Complications that occur as a result of non-drug protocol-imposed interventions.


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An adverse drug reaction is any AE for which there is a reasonable possibility that the IP caused the
AE. “Reasonable possibility” means there is evidence to suggest a causal relationship between the IP
and the AE.
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series of terms
relating to a diagnosis.
The study period during which all non-serious AEs will be reported begins after the first
administration of study drug through the termination visit or at the early termination visit. After
informed consent but prior to initiation of study treatment, only SAEs associated with any protocol-
imposed interventions will be reported. The criteria for determining, and the reporting of SAEs is
provided in Protocol Section 10.2.
The Investigator should follow all unresolved AEs until the events are resolved or stabilized, the
patient is lost to follow-up, or it has been determined that the study treatment or participation is not
the cause of the AE. Resolution of AEs (with dates) should be documented on the appropriate CRF
page(s) and in the patient’s medical record.
The Investigator responsible for the care of the patient or qualified designee will assess AEs for
severity, relationship to IP, and seriousness (refer to Protocol Section 10.2 for SAE definition).
Severity (as in mild, moderate or severe headache) is not equivalent to seriousness, which is based
on patient/event outcome or action criteria usually associated with events that pose a threat to a
patient’s life or functioning. Seriousness (not severity) serves as a guide for defining regulatory
reporting obligations.
The Investigator will determine the severity of each AE using grades defined in Table 1 (the event
will be recorded on the source documents and AE CRF). Events that are Grades 4 and 5 are serious
events and require completion of both an SAE form and AE CRF.
Table 1 - Categories of Severity for Adverse Events
Severity
Description
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic
observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated;
limiting age-appropriate instrumental ADL*.
Grade 3
Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling;
limiting self-care ADL**.
Grade 4
Life-threatening consequences; urgent
intervention indicated.
Note: Grade 4 and 5
adverse events should
always be reported as
serious adverse events
Grade 5
Death related to AE.
Activities of Daily Living (ADL)
* Instrumental ADLs refer to preparing meals, shopping for groceries or clothes, using the telephone,
managing money, etc.
**Self-care ADLs refer to bathing, dressing and undressing, feeding self, using the toilet, taking
medications, and not bedridden.


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A treatment-emergent adverse event (TEAE) is any AE that emerges after randomization having been
previously absent, or worsens relative to the previous periods. All AEs will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA), Version 23.0. All treatment-emergent
adverse events (TEAEs) will be summarized by the treatment at the time of onset. Counts and
percentages will be presented by treatment for each observed system organ class (SOC) and preferred
term (PT) as defined in MedDRA. A patient having more than one TEAE with the same PT in a given
time period will be counted only once in the incidence calculation for that PT for that time period.
Similarly, if a patient has more than one TEAE in the same SOC in a given time period, the patient
will be counted only once in the total number of patients with a TEAE for that SOC for that time
period. TEAEs will summarized only for the treatment at onset unless it worsens at subsequent
period(s) or recurs after having resolved at a previous period; in each of these situations, the TEAE
will be considered a new TEAE and summarized for both treatments.
Each TEAE will be assessed with respect to severity and relationship to treatment. The relationship
of an AE will be recorded using the specified relationship categories described in Table 2.
Table 2 - Description of relationship to adverse events categories
Relationship
Category
Description
Not Related
Exposure to the IP has not occurred
OR
The administration of the IP and the occurrence of the AE are not
reasonably related in time
OR
The AE is considered likely to be related to an etiology other than the
use of the IP; that is, there are no facts [evidence] or arguments to
suggest a causal relationship to the IP.
Possibly
Related
The administration of the IP and the occurrence of the AE are
reasonably related in time
AND
The AE could be explained equally well by factors or causes other
than exposure to the IP.
Probably
Related
The administration of IP and the occurrence of the AE are reasonably
related in time
AND
The AE is more likely explained by exposure to the IP than by other
factors or causes.
The following summary tables will be provided:
1. An overview of TEAEs including the number of TEAEs, related TEAEs, TESAEs, related
TESAEs, TEAEs leading to premature discontinuation, TEAEs leading to hospitalization,
life-threatening TEAEs, number of patients with at least one TEAE, at least one related TEAE,
at least one TESAE, at least one related TESAE, at least one TEAE leading to premature
discontinuation, at least one TEAE leading to hospitalization, at least one life-threatening
TEAE, and at least one TEAE leading to death


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2. Summary of all TEAEs by treatment group, Primary SOC and PT
3. Summary of all related TEAEs by treatment group, Primary SOC and PT
4. Summary of all TESAEs by treatment group, Primary SOC and PT
5. Summary of all related TESAEs by treatment group, Primary SOC and PT
6. Summary of all TEAEs leading to hospitalization by treatment group, Primary SOC and PT
7. Summary of all life-threatening TEAEs by treatment group, Primary SOC and PT
8. Summary of all TEAEs leading to premature discontinuation by treatment group, Primary
SOC and PT
9. Summary of all TEAEs by treatment group, Primary SOC and PT and maximum severity
The following individual data listings will be produced:
1. A listing of all TEAEs
2. A listing of all TESAEs
3. A listing of all IMP related TEAEs
4. A listing of all IMP related TESAEs
5. A listing of all TEAEs leading to hospitalization
6. A listing of all life-threatening TEAEs
7. A listing of TEAEs leading to premature discontinuation
8. A listing of all TEAEs leading to death
9. A listing of all AEs started before the first dose of study drug intake
10. A listing of all AEs started after the first dose of study drug intake but before the date of
randomization (Day 0)
10.12.2 Vital Signs and Body Weight
Vital signs, including sitting blood pressure (systolic and diastolic; mmHg), sitting heart rate
(beats/minute), body temperature (oC), respiration rate (breaths/minute), and weight (kg) will be
summarized using descriptive statistics by sequence and period for both the observed values and CFB.
Height will be recorded at Screening visit only.
BMI will be calculated at Screening visit according to the following formula:
BMI (kg/m^2) = ((body weight (kg)/(height (m))^2).
Height and BMI will be summarized using descriptive statistics by sequence.
10.12.3 12-Lead ECG
Analysis will be performed in the SAF analysis set.
A standard 12-lead ECG will be recorded at Screening, Days 0 and Day 28 visit.
Each tracing will be classified as “Normal tracing”, “Abnormal tracing (not clinically significant)”,
“Abnormal tracing (clinically significant)”, or “Unknown”.
A summary of the assessments will be provided by sequence and period. Clinically significant
changes from baseline will be recorded as AEs.
ECG abnormalities reported will be coded using MedDRA thesaurus version 23.0, and the terms
listed for all enrolled patients.


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10.12.4 Physical Examination
Summary analysis will involve the SAF analysis set.
A complete physical examination is to be performed at Screening, Days 0, and Day 28.
These assessments will be summarized by sequence and period using counts and percentages.
All verbatim terms reported in the Physical Examination form will be assigned to a Preferred Term
(PT) and will be classified by the primary System Organ Class (SOC) according to the Medical
Dictionary for Regulatory Activities (MedDRA) thesaurus, version 23.
A summary table containing the frequency and percentage of patients who exhibited at least one
abnormality as well as of the abnormalities reported at Screening, Day 0 and Day 28 by primary SOC
and PT will be prepared by treatment sequence.
Physical examination abnormalities will be listed for all patients.
10.12.5 Laboratory Tests
For blood chemistry and hematology, descriptive statistics will be presented for the observed value
and CFB by sequence and visit. The frequency and percentage of patients who experience abnormal
(i.e. outside of reference ranges) laboratory values and clinically significant abnormalities will be
presented by sequence and visit.
Moreover shift tables from screening to each time-point, with regard to the laboratory normal range
(low, normal and high), will be presented for all parameters of blood chemistry and hematology by
sequence. The laboratory parameters to be collected are given below in Table 3.
Table 3 - Clinical Laboratory Tests
Blood Chemistry
Haematology
Urine Tests
Albumin
Haemoglobin
Appearance
Alkaline phosphatase
Haematocrit
Color
ALT (SGPT)
WBC count
pH
AST (SGOT)
RBC count
Specific gravity
Direct bilirubin
Platelet count
Ketones
Total bilirubin
Differential cell count
Protein
BUN
Glucose
Calcium
Bilirubin
Chloride
Nitrite
Total cholesterol
Urobilinogen
CO2
Hemoglobin
Creatine phosphokinase
Creatinine
Glucose
GGT
LDH
Phosphorus
Potassium
Total protein
Sodium
Uric acid
Urinalysis parameters will not be included in summary tables.


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All laboratory parameters will be listed for all patients.
10.12.5.1 Laboratory Specific Derivations
For each laboratory parameter, where appropriate, the reported values will be converted into SI units
and if needed boundary values for reference ranges will be converted as well.
Conversion to SI will be provided using textbook ranges: SI Unit Conversion Guide, M. Laposata,
NEJM, 1992.
To convert from the conventional unit to the SI unit, multiply by the conversion factor:
Table 4 - Clinical Laboratory Tests SI Conversion Factors
Component
Conventional
Unit
Conversion
Factor
SI Unit
Hematology
RBC count
x 106/µL
1
x 1012/L
WBC count
x 103/µL
1
x 109/L
Neutrophils
x 103/µL
1
x 109/L
Lymphocytes
x 103/µL
1
x 109/L
Monocytes
x 103/µL
1
x 109/L
Eosinophils
x 103/µL
1
x 109/L
Basophils
x 103/µL
1
x 109/L
Platelet count
x 103/µL
1
x 109/L
Hemoglobin
g/dL
10
g/L
Hematocrit
%
0.01
Proportion of 1.0
Biochemistry
Albumin
g/dL
10
g/L
Alkaline phosphatase (ALP)
U/L
1
U/L
ALT (SGPT)
U/L
1
U/L
AST (SGOT)
U/L
1
U/L
Direct Bilirubin
mg/dL
17.104
µmol/L
Total Bilirubin
mg/dL
17.104
µmol/L
BUN
mg/dL
0.357
mmol/L
Calcium
mg/dL
0.25
mmol/L
Chloride
mEq/L
1.0
mmol/L
Total cholesterol
mg/dL
0.02586
mmol/L
CO2
mEq/L
1
mmol/L
Creatinine phosphokinase
U/L
0.01667
µkat/L
Creatinine
mg/dL
88.4
µmol/L
Glucose
mg/dL
0.05551
mmol/L


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Component
Conventional
Unit
Conversion
Factor
SI Unit
Gamma-GT
U/L
1
U/L
LDH
U/L
0.01667
µkat/L
Phosphorus
mg/dL
0.3229
mmol/L
Potassium
mEq/L
mg/dL
1.0
0.2558
mmol/L
Total protein
g/dL
10
g/L
Sodium
mEq/L
1.0
mmol/L
Uric acid
mg/dL
59.48
µmol/L
10.13Protocol Deviations
All the protocol deviations will be discussed case by case by the clinical team during the review of
the data before the lock of the study database and described in the Blind Data Review Report.
However, the following protocol deviations are anticipated to be considered as major:

Inclusion and exclusion criteria not respected;

Received treatment other than they were randomized to;

Missing information on IMP administration that does not allow calculation of IMP
exposure/compliance;

Overall study treatment compliance < 80%;

Missing data for the primary endpoint (CFB in HFMSE total score);

Use of prohibited medications during study (see Protocol Section 9.4).
The number and percentage of patients with each type of protocol deviation will be presented by
treatment.
11 Data Handling
11.1 Multicenter Sites
This study is conducted by multiple Investigators in two investigational sites.
Site-related differences will not be evaluated and presented in the statistical output as the study does
not foresee a randomization stratified by Centre.
11.2 Handling of Missing Data
If a patient discontinues during a double-blind treatment period and assessments are made
upon discontinuation, then these values will be used as the assessments for that period.
Otherwise, missing data due to discontinuation will not be imputed. Missing safety data will
not be imputed.
Handling of missing data in INQoL is provided in the Appendix 2.
12
Changes from the Protocol
No changes from the statistical analyses planned in the study protocol have been introduced in this
SAP.


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13
Table Shells and Specifications
13.1 Table Specifications
Tables will be provided as defined by the table shells.
Similar tables based on different populations will have the same number, except for the last digit.
All output will be generated by SAS and exported into a Microsoft Word document in RTF format.
All output will be in landscape orientation. Left and right margins will be 2 cm from the side; the top
and bottom margins will be 2.5 cm. Font size will be Courier New 7 pt.
The header containing the sponsor name (Catalyst Pharmaceuticals) and protocol number will appear
on the top left corner of each page of the output. The page number, in the format of “Page x of y”,
will appear on the top right corner of the output, where y = last page of corresponding output.
Column headers in tables include the total possible numbers to be included in summaries for that
table, designated as “(N=XX)”.
The SAS program name, the date of the creation of the output (run date) and the reference to the data
listing(s) from which the table is derived will appear on the bottom left corner as follows:
Source: [program name].sas, Run on ddmmmyyyy
Source: Listing(s) xx.x.x, xx.x.x
13.1.1 Table Format Specification
Maximum and minimum values will be reported with the same number of decimal places as collected.
Means and medians will be reported to one additional decimal place. Standard deviations and standard
errors will be reported to two decimal places more than the collected data. Percentages will be
reported with one decimal place.
Data in the tables are formatted as follows:
Text fields in the body of the tables and listings will be left-justified.
When no data are available for a table, an empty page with the title will be produced with suitable
text. Example: THERE WERE NO SERIOUS ADVERSE EVENTS.
13.2 Line Listings Specifications
Individual line listings will be provided as defined by the listing shells.
All output will be generated by SAS and exported into a Microsoft Word document in RTF format.
All output will be in landscape orientation. Left and right margins will be 2 cm from the side; the top
and bottom margins will be 2.5 cm. Font size will be Courier New 7 pt.
The header containing the sponsor name (Catalyst Pharmaceuticals) and protocol number will appear
on the top left corner of each page of the output. The page number, in the format of “Page x of y”,
will appear on the top right corner of the output, where y = last page of corresponding output.
The SAS program name and the date of the creation of the output (run date) will appear on the bottom
left corner as follows:
Source: [program name].sas, Run on ddmmmyyyy.
14
Programming Conventions for Outputs
Outputs will be presented according to the standard SPARC’s layout of tables and line listings.
Dates & Times: depending on data available, dates and times will take the form ddmmmyyyy
hh:mm (i.e. 01JAN2019 10:20)
Spelling Format: English US.
Listings: all listings will be ordered by the following (unless otherwise indicated in the template):


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
Site ID

Randomization number

Sequence (where applicable)

Study visit

Study treatment

Date and hours (where applicable)

For listings where non-randomized patients are included, these will appear in a category
after the randomized treatment groups labelled ‘Not Randomized’.
In all listings missing data will be reported, according to the variable type, as follows:
-
Character variables and dates will be presented as empty fields
-
Numerical variables will be presented with a “-“


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Appendix 1: Schedule of Events
Study Assessment
or Event b
Run-in
Period 1
Period 2
Screening
Start a
Last Visit
Day 7
±1 day
Day 14
±1 day
Day 21
±1 day
Day 28
±1 day
Days
-14 to -1
Day 1
Day 0 end of
Run-in
Informed consent c
X
Inclusion/Exclusion Criteria
X
X
Randomization
X
Medical history
X
Complete physical exam
X
X
X
Vital signs
X
X
X
X
X
X
12-Lead ECG and QTc evaluation
X
X
X
Clinical laboratory tests d
X
X
X
Pregnancy test e
X
X
X
X
Dispense blinded IP f,g
X
X
IP accountability
X
X
X
X
X
Able to walk 30 meters
X
INQoL or PEDSQL
X
X
X
X
X
HFMSE
X
X
X
X
X
X
X
Six-minute walk test
X
X
X
X
X
Time to rise from floor
X
X
X
X
X
Time to rise from chair
X
X
X
X
X
Time to climb 4 stairs
X
X
X
X
X
Time to walk 10 meters
X
X
X
X
X
Adverse events/SAEs h
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
Patient Dosing Diary Provided
X
X
X
X
X
ECG = electrocardiogram; HFSME= Hammersmith Functional Motor Scale Expanded; IP = investigational product
(amifampridine or placebo); INQoL = individual quality of life; PEDSQL = pediatric quality of life inventory; SAE =
serious adverse event.
a Titrate from starting dose of 15 mg/day, every 3 to 4 days with at least one site visit at Week 3. Last week of run-in, study drug dose and frequency must be
stable before being eligible for randomization on Day 0.
b All safety assessments (vital signs, ECGs, laboratory tests) are to be performed before the dose taken in the study clinic unless specified otherwise. All efficacy
assessments will be performed at standardized times relative to the dose that must be taken in the study clinic on Days 0, 7, 14, 21, and 28 according to the
efficacy assessments schedule.
c Informed consent must be obtained before any study procedures are performed.


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d Clinical laboratory tests include serum chemistry, hematology, and urinalysis.
e Serum pregnancy tests will be obtained from female patients of childbearing potential only at Screening; urine dipstick may be used for the remainder of the
study.
f IP will be administered by the clinic staff during in-clinic visit so assessments can be timed according to IP administration.
g Patients will be provided blinded packages containing amifampridine or placebo depending on their randomized sequence of treatment. Collect all open-label
medication.
h SAE reporting commences when informed consent is signed. Non-serious adverse event reporting commences on Day 1 of run-in.


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Appendix 2: INQoL and PedsQL Scaling and Scoring
Scaling and scoring
INQoL_English.pdf
Scaling and scoring
of PedsQL English.pdf