Long Term Safety Study of Amifampridine Phosphate in Ambulatory Patients With Spinal Muscular Atrophy (SMA) Type 3
Phase: PHASE2
Conditions: Spinal Muscular Atrophy Type 3
Sponsor: Catalyst Pharmaceuticals, Inc.



 
 
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CLINICAL STUDY PROTOCOL 
Study Title: 
Long Term Safety Study of Amifampridine Phosphate in 
Ambulatory Patients with Spinal Muscular Atrophy (SMA) 
Type 3 
Protocol Number: 
SMA-002 
Investigational Product: Amifampridine phosphate (3,4-diaminopyridine phosphate) 
IND/EUDRACT 
Number: 
142044 / 2018-000160-28 
Indication: 
Spinal Muscular Atrophy Type 3 
External Support: 
Catalyst Pharmaceuticals, Inc. 
Development Phase: 
Phase 2 
Medical Officer: 
Gary Ingenito, MD, PhD 
Study Design: 
Open Label  
Dose: 
15-80 mg total daily dose   
Patient Population: 
Ambulatory patients with SMA Type 3 
Version and Date of 
Protocol: 
Version 2.0 dated 24 July 2018  
Version 3.0 dated 12 April 2019 (amendment) 
 
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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2 
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 
Vaile 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 
 
PhAST Consulting s.r.l.  
 
 
 
 
 
Jonathan Rubine, MD 
Associate Medical Director 
Via Roma 74 - 20060  
Cassina de’ Pecchi (MI) Italy 
Tel. +39.039.9416900 
Fax +39.039.3305126 
Email: ClinicalTrial@phast.it 
 
Catalyst Pharmaceuticals, Inc. 
Tel: 305-420-3233 
Email: 
jrubine@catalystpharma.com 
 
 
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SYNOPSIS 
TITLE OF STUDY: 
Long Term Safety Study of Amifampridine Phosphate in Ambulatory Patients with Spinal 
Muscular Atrophy (SMA) Type 3 
PROTOCOL NUMBER: 
SMA-002 
STUDY SITES:  
Up to 3 sites 
PHASE OF DEVELOPMENT: 
Phase 2a 
STUDY RATIONALE: 
The purpose of this study is to evaluate the long-term safety and tolerability of amifampridine 
phosphate in ambulatory patients with SMA Type 3 who completed Protocol SMA-001 or. who 
benefit from the medication but were not meet the criteria enter the double-blind portion of SMA-
001. 
OBJECTIVES: 
Primary 
• 
To characterize the long-term safety and tolerability of amifampridine phosphate in 
patients SMA Type 3 
Secondary 
• 
To assess the clinical efficacy of amifampridine phosphate over time in patients with SMA 
Type 3 based on changes in quality of life (QoL)  
STUDY DESIGN AND PLAN:  
This is a long-term extension study for patients who participated in Protocol SMA-001 where the 
efficacy and safety of amifampridine was evaluated, in ambulatory patients with SMA Type 3. The 
planned duration of participation for each patient is approximately 2 years (i.e. until amifampridine 
is approved by Regulatory Agencies for the treatment of SMA Type 3 or the development program 
is discontinued for this indication). 
All patients who have completed study SMA-001 and sign an informed consent may enroll in the 
long-term study.  Those patients who demonstrated benefit after completing the dose titration 
period but failed to meet the randomization criteria on Day 0 (end of the Run-in period for SMA-
001 may also be eligible for this study.  The evaluations at the end of participation in Study SMA-
001 will as baseline for the Long-Term study. 
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The optimal dose and schedule for amifampridine from the end of the Run-in Period from Study 
SMA-001 will initially be used for each patient. The Investigator may adjust the dose of 
amifampridine during the course of this trial, in order to optimize neuromuscular benefit for the 
patient. Clinic visits for safety assessment and for evaluation of QoL will be made at Months 3, 6, 
9, 12, 15, 21 and 27.  Additional visits may occur at the discretion of the Investigator.   
NUMBER OF PATIENTS PLANNED:  
About 12 SMA Type 3 ambulatory patients will be studied. 
CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all the following inclusion criteria: 
1. Participated in the SMA-001 study 
2. 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. 
3. Female patients of childbearing potential must have a negative pregnancy test (urine 
human chorionic gonadotropin [HCG] at the end of SMA-001 study); and must practice an 
effective, reliable contraceptive regimen during the study and for up to 30 days following 
discontinuation of treatment. 
4. 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 met any of the exclusion criteria in the original protocol or those listed below are 
not eligible to participate in the study: 
1. Epilepsy and currently on medication. 
2. Uncontrolled asthma. 
3. Concomitant use with sultopride. 
4. Concomitant use with medicinal products with a narrow therapeutic window. 
5. Clinically significant abnormalities in 12 lead ECG, in the opinion of the Investigator. 
6.  Breastfeeding or pregnant at Screening or planning to become pregnant at any time during 
the study. 
7. Intolerable amifampridine-related side effects   
8. Treatment with an investigational drug (other than amifampridine) or device while 
participating in this study. 
9. 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. 
10. History of drug allergy to any pyridine-containing substances or any amifampridine 
excipient(s). 
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INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE, AND REGIMEN:  
The investigational product (IP) is amifampridine tablets 10 mg, 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 will be provided by Catalyst Pharmaceuticals, Inc., 355 Alhambra 
Circle, Suite 1250, Coral Gables, Florida, 33134, United States. 
REFERENCE THERAPY, DOSE, ROUTE, AND REGIMEN:  
None 
DURATION OF TREATMENT: 
Amifampridine will be continued for a period of up to 2 years or until the drug is approved by 
Regulatory Agencies or until the development of the drug is discontinued for this indication.  
CRITERIA FOR EVALUATION: 
Safety (primary endpoint): 
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 findings, and concomitant medications will also be evaluated.  
Efficacy (secondary endpoint):  
Efficacy will be assessed by changes in QoL over time. 
STATISTICAL METHODS: 
Sample Size Determination 
The study is not powered with respect to any endpoint, but is a study to assess long term safety and 
lack of tolerance to the effects of amifampridine on QoL.    
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). The 
incidence of TEAEs will be summarized by system organ class, preferred term, relationship to 
treatment, and severity.  
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 all patients who receive at least 1 dose of amifampridine 
and have at least one post-treatment efficacy assessment. The efficacy analysis will be descriptive 
and will be presented on observed data only. 
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4 TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 PROCEDURES IN CASE OF AN EMERGENCY ............................................................2 
3 SYNOPSIS ...........................................................................................................................3 
4 TABLE OF CONTENTS .....................................................................................................6 
5 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................10 
6 ETHICS..............................................................................................................................11 
6.1 Independent Ethics Committee / Institutional Review Board ...................................11 
6.2 Ethical Conduct of Study ..........................................................................................12 
6.3 Patient Information and Informed Consent ...............................................................12 
7 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................13 
8 INTRODUCTION .............................................................................................................13 
8.1 Effectiveness in SMA and Other Indications ............................................................14 
8.2 Safety of Amifampridine and Amifampridine Phosphate .........................................15 
8.3 Overall Risks and Benefits ........................................................................................16 
8.4 Study Rationale .........................................................................................................17 
9 STUDY OBJECTIVES ......................................................................................................17 
9.1 Primary Objective .....................................................................................................17 
9.2 Secondary Objective .................................................................................................17 
10 INVESTIGATIONAL PLAN ............................................................................................18 
10.1 Overall Study Design and Plan .................................................................................18 
10.2 Selection of Study Population ...................................................................................20 
10.2.1 Inclusion Criteria .........................................................................................20 
10.2.2 Exclusion Criteria ........................................................................................20 
10.2.3 Removal of Patients from Treatment or Assessment ..................................21 
10.2.4 Patient Identification ...................................................................................22 
10.3 Treatments .................................................................................................................22 
10.3.1 Treatments Administered ............................................................................22 
10.3.2 Identity of Investigational Product ..............................................................22 
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10.3.2.1 
Product Characteristics and Labeling ..........................................23 
10.3.2.2 
Storage .........................................................................................23 
10.3.3 Directions for Administration .....................................................................23 
10.3.4 Method of Assigning Patients to Treatment Groups ...................................24 
10.3.5 Selection of Doses Used in the Study .........................................................24 
10.3.6 Blinding .......................................................................................................24 
10.3.7 Treatment Compliance ................................................................................24 
10.3.8 Investigational Product Accountability .......................................................24 
10.3.9 Return and Disposition of Clinical Supplies ...............................................24 
10.4 Prior and Concomitant Medications .........................................................................25 
10.5 Dietary or Other Protocol Restrictions......................................................................26 
10.5.1 Dietary Restrictions .....................................................................................26 
10.5.2 Contraception ..............................................................................................26 
10.6 Safety Variables ........................................................................................................26 
10.6.1 Adverse Events ............................................................................................26 
10.6.2 Vital Signs ...................................................................................................26 
10.6.3 Clinical Laboratory Assessments ................................................................27 
10.6.4 Pregnancy Testing .......................................................................................28 
10.6.5 Electrocardiogram (ECG) ............................................................................28 
10.6.6 Physical Examination ..................................................................................29 
10.7 Efficacy Variables .....................................................................................................29 
10.7.1 Quality of life assessment ............................................................................29 
11 REPORTING ADVERSE EVENTS .................................................................................30 
11.1 Adverse Events .........................................................................................................30 
11.2 Serious Adverse Events ............................................................................................32 
11.3 Safety Blood Collection ............................................................................................34 
11.4 Pregnancy ..................................................................................................................34 
11.5 Urgent Safety Measures ............................................................................................34 
11.6 Medical Monitor Contact Information ......................................................................35 
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12 APPROPRIATENESS OF MEASUREMENTS ...............................................................35 
13 STUDY PROCEDURES ...................................................................................................35 
13.1 Start of Long Term Study .........................................................................................35 
13.2 End of Months 3, 6, 9, 12, 15, 21 and 27 in Long Term Study ................................36 
13.2.1 End of Study Visit .......................................................................................37 
14 DATA QUALITY ASSURANCE .....................................................................................37 
15 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................38 
15.1 Statistical and Analytical Plans .................................................................................38 
15.1.1 Interim Analyses ..........................................................................................38 
15.2 Analysis Populations .................................................................................................38 
15.3 Primary Endpoint ......................................................................................................38 
15.4 Secondary Endpoint ..................................................................................................38 
15.5 Safety Analysis .........................................................................................................38 
15.6 Determination of Sample Size ..................................................................................39 
15.7 Changes in the Conduct of the Study or Planned Analyses ......................................39 
16 COMPENSATION, INSURANCE, AND INDEMNITY .................................................39 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ..............................................40 
18 STUDY MONITORING AND AUDITING .....................................................................41 
19 RETENTION OF RECORDS ...........................................................................................41 
20 USE OF INFORMATION AND PUBLICATION ...........................................................42 
21 REFERENCES ..................................................................................................................43 
22 INVESTIGATOR RESPONSIBILITIES ..........................................................................45 
22.1 Conduct of Study and Protection of Human Patients ...............................................45 
23 SIGNATURE PAGE .........................................................................................................46 
 
 
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 List of Appendices 
APPENDIX  1  PROTOCOL VERSION  3.0 .........................................................................47 
 
 
List of In-text Tables 
Table 1 Schedule of Events......................................................................................................19 
Table 2 Clinical Laboratory Tests ............................................................................................28 
Table 3 Categories of Severity of Adverse Events ..................................................................31 
Table 4 Description of Relationship to Adverse Event Categories .........................................32 
 
List of In-text Figure 
Figure 1 Chemical Structure of Amifampridine Phosphate .....................................................23 
 
 
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5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
Abs 
Antibodies 
Ach 
Acetylcholine 
AChR 
Acetylcholine receptor 
ADL 
Activities of Daily Living 
AE(s) 
adverse event(s) 
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase 
ATU 
Autorisations Temporaires d'Utilisation Normative 
CMS 
congenital myasthenia syndromes 
CRA(s) 
clinical research associate(s) 
CRF 
CRO 
case report form 
contract research organization 
CTFG 
Clinical Trial Facilitation Group 
DBP 
diastolic blood pressure 
ECG(s) 
electrocardiogram(s) 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCG 
human chorionic gonadotropin 
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 
IP 
investigational product 
IRB 
institutional review board 
K+ 
potassium ion 
kg 
kilogram 
LEMS 
Lambert-Eaton myasthenic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MG 
Myasthenia Gravis 
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MI 
myocardial infarction 
mmHg 
millimeters of mercury 
MS 
multiple sclerosis 
MuSK 
muscle-specific receptor tyrosine kinase 
MuSK-MG 
muscle-specific receptor tyrosine Kinase-Myasthenia Gravis 
PI 
Principal Investigator 
PK 
pharmacokinetic 
QoL 
Quality of life 
REB 
research ethics board 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SMA 
spinal muscular atrophy 
 
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. 
6 
ETHICS 
6.1 
Independent Ethics Committee / Institutional Review Board 
The Investigator will provide the Independent Ethics Committee (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 
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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. 
6.2 
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 being performed. 
6.3 
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. 
 
 
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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, both remotely and with onsite visits, 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 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.  
8 
INTRODUCTION 
Information on disease background, amifampridine, previously completed nonclinical and 
clinical studies of amifampridine, is described in the Introduction of SMA-001 and in the 
Investigator Brochure supplied by Catalyst (March 2019). Investigators are to review this 
document before initiating this study.  
Amifampridine is a non-specific voltage-dependent potassium (K+) channel blocker. 
Blockade of K+ channels causes 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 containing 
acetylcholine (ACh), thus releasing an increased level of ACh into the synaptic cleft 
(Maddison, 1998a; Maddison, 1998b). The influx of ACh into the presynaptic cleft enhances 
neuromuscular transmission, providing improved muscle function. 
Mori et al. (2012) found that amifampridine improved neuromuscular transmission by 
predominantly increasing ACh release in the neuromuscular junction of in mice with MG 
induced by antibodies against muscle-specific kinase (MuSK).  Furthermore, a mouse model 
of MuSK-myasthenia gravis (MG), amifampridine significantly enhanced neuromuscular 
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transmission after 1 week of treatment without exacerbating loss of endplate AChRs 
(Morsch et al. 2013).  
Multiple studies were conducted to evaluate the cardiac safety, pharmacokinetics and 
toxicity profile in rats and dogs. Reproductive and developmental toxicity studies with 
amifampridine were also conducted in rats and rabbit as well a variety of in vitro and in vivo 
genotoxicity studies, and in vitro metabolism/transporter studies. The main nonclinical 
findings related to amifampridine were central and autonomic nervous system effects, the 
development of Schwannomas, and histologic changes in muscle tissues. Below is an 
abbreviated summary of the effectiveness of amifampridine in MuSK-MG and overall safety 
in other patient populations. 
8.1 
Effectiveness in SMA and Other Indications 
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. 
Small studies have demonstrated the beneficial effects of amifampridine in patients with 
muscle-specific receptor tyrosine kinase-myasthenia gravis (MuSK-MG) in 2 children, who 
achieved some benefit (Skjei, 2013) and 1 adult (Evoli, 2016).  Following 4 months of 
treatment, the authors report the adult patient had obvious improvement of ptosis, decreased 
neck weakness and arm fatigability. In an Investigator-Sponsored MuSK-MG randomized, 
double-blind, placebo-controlled, cross-over study conducted in Italy, 7 MuSK-MG patients 
demonstrated statistically significantly higher functional performance in all validated 
assessment scales when they were administered amifampridine compared to placebo. 
Tolerability to amifampridine was excellent (unpublished data). 
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).  
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8.2 
Safety of Amifampridine and Amifampridine Phosphate 
Safety data collected from 1,454 patients or healthy volunteers in controlled study LMS-002 
[(Lambert-Eaton myasthenic syndrome LEMS)], controlled and uncontrolled published 
studies of LEMS or other neurologic conditions, a 3-year safety surveillance study (ATU), 
and pharmacokinetic (PK) studies demonstrate amifampridine is well tolerated up to and 
including 80 mg/day (Firdapse Investigator Brochure, March 2019). The most common 
adverse events observed from the clinical 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 
contributor (Lundh, 1984; Lundh, 1993); no causality was reported for the other fatal MI 
(Bertorini, 2011). Three deaths occurred in children with congenital myasthenia syndromes 
(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. A total of 10 (0.69%) 
patients out of 1,454 patients or healthy subjects experienced seizures or convulsions after 
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treatment with amifampridine. Electroencephalogram 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).  
Three patients (LEMS or MG) experienced seizures on a daily dose of ≥90 mg/day. 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 and multiple sclerosis (MS) (n=1); 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). 
It is noteworthy 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. 
8.3 
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 formulations) at doses up 
to 80 mg per day. To date, current data demonstrate that amifampridine phosphate has an 
acceptable tolerability profile with a positive risk-benefit in patients treated with 
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amifampridine for patients with LEMS and CMS, but longer-term studies are needed in 
patients with SMA. Amifampridine phosphate has also been approved for LEMS in the EU 
since 2009, so there is a well established safety history.  
Patients with SMA Type 3 would already have been treated with amifampridine for several 
weeks as they come from the SMA-001 protocol before entering SMA-002 study.  Therefore, 
the tolerability of amifampridine phosphate and clinical benefit would already be established, 
minimizing risk. 
8.4 
Study Rationale 
A considerable amount of clinical experience is available with amifampridine and, in 
December 2009, amifampridine tablets 10 mg, as amifampridine phosphate, received 
marketing approval by the European Commission as Firdapse® for the symptomatic 
treatment of patients with LEMS. Case reports, animal data suggest that amifampridine may 
also have clinical utility in patients with SMA Type 3, providing symptomatic relief through 
its action on the impaired NMJ transmission. The present long-term extension study will 
evaluate safety and tolerability of amifampridine on clinical laboratory test variables, ECGs, 
AEs, vital signs, physical examinations and the effects on quality of life (QoL) score over 
several months in patients with SMA Type 3. This information is needed to demonstrate that 
the product is safe and provides continued benefit to patients with SMA Type 3.   
9 
STUDY OBJECTIVES 
9.1 
Primary Objective 
The primary objective of the study is: 
• 
To evaluate the long-term safety and tolerability of amifampridine in patients with SMA 
Type 3. 
9.2 
Secondary Objective 
The secondary objective of the study is: 
• 
To assess the clinical efficacy of amifampridine phosphate over time in patients with SMA 
Type 3 based on changes in QoL.  
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10 
INVESTIGATIONAL PLAN 
10.1 
Overall Study Design and Plan 
This open label outpatient extension study is designed to evaluate the long-term safety, 
tolerability of amifampridine in patients diagnosed with SMA Type 3. In addition, evaluation 
of the effects of amifampridine on the QoL will be made. The study will enroll those patients 
who have completed the SMA-001 study and after all final evaluations for that study have 
been completed, or those who demonstrated benefit after completing the dose titration period 
but failed to meet the randomization criteria on Day 0 of SMA-001.  
The duration of participation for each patient is expected to be at least 12 months as patients 
may continue in the study until amifampridine is approved by Regulatory Agencies or the 
clinical development of amifampridine is terminated for this indication. In addition to 
amifampridine, patients will continue to receive previous concomitant medications, as 
needed.  
After a new informed consent is signed and inclusion / exclusion criteria for the current 
protocol are satisfied, eligible patients will be given the optimal dose and dosing schedule 
that was identified in the Run-in Period from Protocol SMA-001.   
The findings from the physical exam (including vital signs, weight); 12-lead ECG; clinical 
laboratory test results (including pregnancy testing) and any ongoing adverse events will be 
used as the baseline for the Long-Term safety evaluation.   
The efficacy measurement is QoL which will be completed every 3 or 6 months. Safety and 
tolerability assessments will be made every 3 or 6 months or more frequently at the 
discretion of the Investigator. The study will continue until amifampridine is approved by 
Regulatory Agencies or until development of the product for this indication is halted. The 
Investigator may alter the dose and dosing frequency during the Long-Term Study as well as 
schedule additional clinic visits for any reason.   
Patients will be seen in the clinic at the end of Months 3, 6, 9, 12, 15, 21 and 27 as detailed in 
the Schedule of Assessments in Table 1 and Section 13. In between the 3-or 6-month visits, 
patients may also have telephone/video contact with the site, or unscheduled visits, if needed. 
Any unused medication must be returned to the clinic at each visit for drug accountability, 
and an additional supply will be dispensed. 
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The study will be completed when amifampridine is approved by Regulatory Agencies for 
Spinal Muscular Atrophy or the clinical development of amifampridine is terminated for this 
indication. 
Table 1 Schedule of Events 
Study Assessment  
or Event  
Screening 
and 
Enrollment* 
End of Study Month ± 1 week 
3 
6 
9 
12 
15 
21 
27 
EoSg 
Informed consent a 
x 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
Complete physical exam b 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs  
x 
x 
x 
x 
x 
x 
x 
x 
x 
12-Lead ECG  
x 
x 
x 
x 
x 
x 
x 
x 
x 
Clinical laboratory tests c 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test d 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Amifampridine Treatment 
 
x 
x 
x 
x 
x 
x 
x 
 
QoL  
x 
x 
x 
x 
x 
x 
x 
x 
x 
Dispense IP e 
x 
x 
x 
x 
x 
x 
x 
 
 
IP accountability 
 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events/SAEs f 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
EoS= End of Study is the patients last visit to the site and discontinuation of study medication; 
IP=investigational product; QoL=quality of life; SAE=serious adverse event.  
a Informed consent must be obtained before any study procedures are performed. 
b Complete physical examination includes evaluation of all major body systems, including weight at 
all visits (Section 10.6.6). 
c Clinical laboratory tests include serum chemistry, hematology, and urinalysis. 
d Urine pregnancy tests will be obtained from female patients of childbearing potential. 
e Pharmacist will dispense sufficient amount of medication until the next clinic visit. All unused 
medication must be returned to the clinic for drug accountability. 
f SAE reporting commences after informed consent is signed. Non-serious adverse event reporting 
commences after the first dose of study drug for the current Long-Term Study. 
g EoS or early termination visit if the last visit does not coincide the scheduled 3- or 6-month visit. 
*These data may be obtained from Study SMA-001. If data not available, then the assessment should 
be repeated. 
 
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10.2 Selection of Study Population 
Patients who complete Protocol SMA-001 or who have demonstrated benefit after completing 
the dose titration period but failed to meet randomization criteria for SMA-001 and who meet 
the inclusion and exclusion criteria for participation in the current study will be eligible. 
10.2.1 Inclusion Criteria 
Individuals eligible to participate in this study must meet all the following inclusion criteria: 
1. Participated in the SMA-001 study 
2. 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. 
3. Female patients of childbearing potential defined according to the Clinical Trial 
Facilitation Group - CTFG guidelines* must have a negative pregnancy test (urine 
human chorionic gonadotropin [HCG] at the end of SMA-001 study); and must 
practice an effective, reliable contraceptive regimen during the study and for up to 30 
days following discontinuation of treatment. 
4. 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. 
* According to CTFG guidelines a woman is considered of childbearing potential, i.e. fertile, 
following menarche and until becoming post-menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
10.2.2 Exclusion Criteria 
Individuals who met any of the exclusion criteria in the original protocol or those listed 
below are not eligible to participate in the study: 
1. Epilepsy and currently on medication. 
2. Uncontrolled asthma. 
3. Concomitant use with sultopride. 
4. Concomitant use with medicinal products with a narrow therapeutic window. 
5. Clinically significant abnormalities in 12 lead ECG, in the opinion of the Investigator. 
  
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6. Breastfeeding or pregnant at Screening or planning to become pregnant at any time 
during the study. 
7. Intolerable amifampridine-related side effects   
8. Treatment with an investigational drug (other than amifampridine) or device while 
participating in this study. 
9. 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. 
10. History of drug allergy to any pyridine-containing substances or any amifampridine 
excipient(s). 
10.2.3 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 
as soon as possible. Catalyst also reserves the right to discontinue the study at any time for 
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 11.4 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 
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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 IRB/IEC/REB. 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. 
10.2.4 Patient Identification 
Each patient will be assigned a unique patient identifier (2 digit for the site and 2 digit for 
each patient enrolled). This unique identifier will be on all CRF pages.  
10.3 Treatments 
10.3.1 Treatments Administered 
Catalyst or its designee will provide the study site with a supply of Investigational product: 
amifampridine tablets 10 mg at various intervals sufficient for the completion of the study. 
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. 
10.3.2 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. 
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Figure 1. 
Chemical Structure of Amifampridine Phosphate 
 
10.3.2.1 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.” 
The tablets 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, 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 area for instructions for use. Regional label requirements and 
translations should be used in accordance with local regulations. 
10.3.2.2 
Storage 
All IP must be stored under the conditions specified, 20-25○ Celsius (C) (excursions between 
15-30°may be permitted) and in a secure area accessible only to the pharmacist. 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. 
10.3.3 Directions for Administration 
All doses of study drug will be taken as outpatients. Study drug should be taken every day at 
approximately the same time, on empty stomach or with small amount of food (crackers) 
since food significantly delays the absorption of the drug and will slow onset of action, at the 
dose and frequency instructed by Investigator. 
The dose of amifampridine will be based on optimal neuromuscular benefit determined from 
the Run-in Period from SMA-001 or may be modified as the discretion of the Investigator. 
H3PO4
N
NH2
NH2
4
1
2
3
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The maximum single dose is 20 mg.  The dose range for patients 6 to 16 years of age is 15 to 
60 mg and for those 17 years and older, the range is from 30 to 80 mg daily. The daily dose 
of amifampridine can be adjusted during this long-term at the discretion of the Investigator. 
10.3.4 Method of Assigning Patients to Treatment Groups 
All patients will receive open label amifampridine. Details on study drug preparation, 
dispensing medication will be included in the Pharmacy Manual.  
10.3.5 Selection of Doses Used in the Study 
Initially, the daily amifampridine dose will be the one that was determined at the end of the 
Run-in Period from SMA-001. The usual range is 20 to 80 mg total daily dose, given in 3 or 
4 divided doses, with no single dose >20 mg. Safety of a single maximum dose of 20 mg is 
based on completed animal and in vitro pharmacology, PK, and toxicology studies.  
10.3.6 Blinding 
This is an open label study.  
10.3.7 Treatment Compliance 
Patients will be instructed to take study medication as directed and bring 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. 
10.3.8 Investigational Product Accountability 
The  Catalyst designee is responsible for maintaining accurate records (including dates and 
quantities) of IP received and sending IP to the site.  The clinical site is responsible for 
maintaining accurate records for IP dispensed, returned, and IP lost or destroyed. The 
Investigator, study site coordinator or designee must retain all unused or expired study 
supplies until the study monitor (on-site CRA) has confirmed the accountability data. 
10.3.9 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. 
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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. 
10.4 
Prior and Concomitant Medications 
All prescription and over-the-counter medications and herbal and nutritional supplements 
taken during the Long-Term study will be recorded on the designated CRF.  All prior 
medications taken within 14 days of initiation of this study are to be recorded on the CRF 
which is also recorded in the appropriate CRF pages of Study SMA-001 as concomitant 
medication. 
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: 
• 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 
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• Depolarizing muscle relaxant acting medicinal products. 
10.5 Dietary or Other Protocol Restrictions 
10.5.1 Dietary Restrictions 
There are no dietary restrictions for patients during any part of this study. 
10.5.2 Contraception 
Sexually active males and females of childbearing potential and their partners must use 
effective forms of contraception, including: combined hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, transdermal); progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable or implantable); 
intrauterine device; intrauterine hormone-releasing system; bilateral tual occlusion; 
vasectomised partner; sexual abstinence.   
According to CTFG guidelines a woman is considered of childbearing potential, i.e. fertile, 
following menarche and until becoming post-menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause.  
10.6 Safety Variables 
Safety in this study will be determined from evaluation of AEs/SAEs, vital signs 
assessments, clinical laboratory assessments, ECGs, and physical examinations. 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 13. 
10.6.1 Adverse Events 
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 11.  
10.6.2 Vital Signs 
Specific visits for obtaining vital signs are provided in Table 1 and in Section 13. Vital signs 
will be measured while in a sitting position, after resting for 5 minutes, and include SBP and 
DBP measured in millimeters of mercury (mmHg), heart rate in beats per minute, respiration 
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rate in breaths per minute. Weight (kg) and temperature in degrees C will also be measured. 
Clinically significant changes from baseline will be recorded as AEs. 
10.6.3 Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are provided in Table 1 
for the tests required by Protocol. The scheduled clinical laboratory tests are listed in Table 2. 
In brief, clinical laboratory evaluations are to be performed every 3 to 6 months. These tests 
can be performed more frequently at the discretion of the Investigator. 
All abnormal clinical laboratory 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 significant. 
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. 
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Table 2 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-glutamyl transferase; LDH, lactate dehydrogenase; RBC, red blood cell; SGOT, serum 
glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase; WBC, white blood cell. 
 
10.6.4 Pregnancy Testing 
Female patients of childbearing potential will have a urine pregnancy test at the end of the 
double-blind period on Day 10 and at other time points specified in the Schedule of Events 
(Table l) and in Section 13. Female patients with a positive pregnancy test at end of the 
double-blind study are not eligible for enrollment. Additional pregnancy tests will be 
performed at any visit in which pregnancy status is in question. 
Refer to Section 11.4 for details on the reporting procedures to follow in the event of 
pregnancy. 
10.6.5 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 
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(Table 1) and in Section 13. Clinically significant changes from baseline will be recorded as 
AEs.  
10.6.6 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 
Body weight will be measured with each physical examination throughout the study.  
Other body systems may be examined. Clinically significant changes from baseline will be 
recorded as AEs. 
10.7 
Efficacy Variables 
Every 3 or 6 months, each patient will be assessed with the QoL questionnaire.  
10.7.1 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.  
For the purposes of this study, the same QoL assessment instrument must be used throughout 
the study even if he/she becomes an adult. Each QoL evaluation is available in the local 
language for the appropriate sites.  
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11 REPORTING ADVERSE EVENTS 
11.1 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. 
All ongoing non-serious AEs, even those which began under Protocol SMA-001, will be 
reported from the end of the double-blind study (SMA-001) or from Day 0 for those not 
randomized to double blind medication in SMA-001 through the termination visit or at the 
early termination visit and will be recorded on the AE page of the eCRF. All ongoing SAEs 
from SMA-001 will be reported. The criteria for determining, and the reporting of new SAEs 
is provided in Section 11.2. 
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 Section 11.2 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.  
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The Investigator will determine the severity of each AE using grades defined in Table 3 
Categories of Severity of 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 3 Categories of Severity of 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 4  
Description of Relationship to Adverse Event Categories. 
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Table 4  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. 
11.2 
Serious Adverse Events 
A serious adverse event 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 
• Requires or prolongs in-patient hospitalization 
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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 for the current 
SMA-002 study 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 its designee PhAST Consulting s.r.l.. 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 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 its designee PhAST Consulting s.r.l 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 and its designee PhAST 
Consulting s.r.l 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 
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documentation must be provided showing that the IEC was properly and promptly notified as 
required. 
11.3 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 has 
occurred. 
Additional blood sampling may be performed at any time during the study if warranted to 
monitor patient safety. 
11.4 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 and its designee PhAST Consulting s.r.l.  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. 
11.5 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 with 24 hours. 
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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. 
 
11.6 Medical Monitor Contact Information 
Contact information and additional requirements will be provided in the SMA-002 Study 
Reference Manual. 
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 
 
12 APPROPRIATENESS OF MEASUREMENTS 
The measures of safety used in this study are routine clinical and laboratory procedures. 
The efficacy measure is based on the QoL assessment.  
13 REPORTING ADVERSE EVENTS STUDY PROCEDURES 
13.1 Start of Long Term Study 
An ICF for the Long-Term Study 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.  
The following procedures are to be performed as schedule for either the Day 0 (in the case 
where patient was not randomized) or the Day 28 visit for the SMA-001 protocol and can 
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serve as baseline for the Long-Term study. Any procedure not performed for SMA-001 
protocol needs to be completed before the patient can be enrolled in this trial. 
• Informed Consent for SMA-002; 
• Inclusion/Exclusion criteria for the current study must be verified; 
• Standard 12-lead ECG after 5 minutes in the supine position; 
• Complete physical examination including weight;  
• Vital signs (seated position), including SBP, DBP, heart rate, respiration, and body 
temperature;  
• Clinical laboratory tests including hematology, chemistry, and urinalysis; 
• Urine pregnancy test in females of childbearing potential only; 
• QoL (use data from Day 0 of SMA-001 for those patients not randomized in SMA-
001); 
• AEs;  
• Concomitant medications. 
13.2 
End of Months 3, 6, 9, 12, 15, 21 and 27 in Long Term Study  
The following assessments and procedures will be determined at the end of Months 3, 6, 9, 
12, 15, 21 and 27. Each month has a clinic visit window of ± 1 week. Additional visits are 
allowed as necessary. 
• Assessment of AEs/SAEs; 
• Complete physical exam with weight; 
• Vital signs (seated position), including SBP, DBP, heart rate, respiration, and body 
temperature; 
• Standard 12-lead ECG after 5 minutes in the supine position; 
• Clinical laboratory tests including hematology, chemistry, and urinalysis;  
• Urine pregnancy test in females of childbearing potential only; 
• Concomitant medications; 
• IP accountability of medication; 
• QoL  
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All IP should be collected from the patient at each visit, in order to perform drug 
accountability. The investigator or her/his designee will dispense sufficient amifampridine 
for daily outpatient administration for 90 days (or 180 days from Months 15 to 27).   
Patients may continue to receive amifampridine until the study is terminated, the patient 
decides to withdraw from the study, or the development program is discontinued for this 
indication.  
13.2.1 End of Study Visit  
Patients will report to the study site at the end of the study and have the assessments and 
procedures listed below completed.  This visit may be incorporated at the scheduled 3-or 6-
month visit. 
• Assessment of AEs/SAEs; 
• Complete physical exam with weight; 
• Vital signs (seated position), including SBP, DBP, heart rate, respiration, and body 
temperature; 
• 12-Lead ECG; 
• Clinical laboratory tests; 
• Urine pregnancy test in females of childbearing potential only; 
• Concomitant medications;  
• IP accountability; 
• 
QoL   
14 DATA QUALITY ASSURANCE 
Catalyst personnel or designees will visit or telephone the study site before initiation of the 
study to review with the site personnel information about the IP, protocol and other 
regulatory document requirements, 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, AE/SAE reporting, and drug accountability 
records. 
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15 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
15.1 Statistical and Analytical Plans 
15.1.1 Interim Analyses 
No interim analyses are planned. 
15.2 Analysis Populations 
The analysis population in this study is the safety population and will consist of all patients 
who are enrolled in the Long-Term study and have received at least one dose of 
amifampridine.     
15.3 Primary Endpoint 
The primary endpoint of the study is safety and tolerability of amifampridine at Months 3, 6, 
9, 12, 15, 21 and 27.  For more details see Section 15.5 below. 
15.4 
Secondary Endpoint  
The secondary endpoint of the study is the QoL scores at Months 3, 6, 9, 12, 15, 21 and 27.  
15.5 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 
shifts will be presented: normal/normal, normal/low, normal/high, low/low, low/normal, 
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 
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shifts presented: normal/normal, normal/abnormal, abnormal/normal and 
abnormal/abnormal. A table of descriptive statistics for QTc will be created. 
Additional safety analyses may be performed as described in the Statistical Analysis Plan 
(SAP) for the study. 
15.6 Determination of Sample Size 
The study is not powered with respect to any endpoint and no hypothesis is being tested.  
15.7 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 IRB/IEC/REB, 
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. 
16 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 
the way that such costs are usually billed and collected. 
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 
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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. 
17 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 
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. 
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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.  
18 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 monitoring will take place on site as well as remotely as the monitors can view all 
clinical data electronically and can follow-up with any queries for more information. 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. 
19 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 
regulatory requirements.  
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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. 
20 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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21 REFERENCES 
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 2005;15: 498-512. 
 
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.  
 
Engelsen BA, Gronning M. Epileptic seizures in patients with multiple sclerosis. Is the 
prognosis of epilepsy underestimated? Seizure 6[5], 377-382. 1997. 
 
Evoli A, Alboini PE, Damato V, Iorio R. 3,4-Diaminopyridine may improve myasthenia 
gravis with MuSK antibodies. Neurology. 2016;86(11):1070–1 
 
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.  
 
Harper CM, Engel AG.  Treatment of 31 congenital myasthenic syndrome (CMS) patients 
with 3,4-diaminopyridine (DAP).  Neurology 2000;54(Suppl 3): A395 
 
Kinnunen E, Koskenvuo M, Kaprio J, Aho K. Multiple sclerosis in a nationwide series of 
twins. Neurology 37[10], 1627-1629. 1987. 
 
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.  
 
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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. 
 
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.  
 
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. 
 
Mori S1, Kishi M, Kubo S, Akiyoshi T, Yamada S, Miyazaki T, Konishi T, Maruyama N, 
Shigemoto K. 3,4-Diaminopyridine improves neuromuscular transmission in a MuSK 
antibody-induced mouse model of myasthenia gravis. J Neuroimmunol. 245, 75-78, 2012. 
 
Morsch M1, Reddel SW, Ghazanfari N, Toyka KV, Phillips WD. Pyridostigmine but not 3,4-
diaminopyridine exacerbates ACh receptor loss and myasthenia induced in mice by muscle-
specific kinase autoantibody. J Physiol. 591, 2747-2762, 2013. 
 
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. 
 
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.  
 
Skjei KL, Lennon VA, Kuntz NL: Muscle specific kinase autoimmune myasthenia gravis in 
children: A case series. Neuromuscul Disorders 2013 Nov;23(11):874-882 
 
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.  
 
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22 INVESTIGATOR RESPONSIBILITIES 
22.1 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, or any persons used as controls, that the 
drugs are 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 
IRB/IEC/REB 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 IRB/IEC/REB 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 IRB/IEC/REB. Additionally, he or she will not make any changes in 
the research without IRB/IEC/REB 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  PROTOCOL VERSION  3.0  
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 
 
CLINICAL STUDY PROTOCOL,  
IND Number was updated  106263 142044   
Version and Date of Protocol, added text to indicate this is protocol Version 3.0 
Version 3.0 dated 12 April 2019 (amendment) 
Footer was updated to reflect new version information 
 
Section numbers have been added to  
2 PROCEDURES IN CASE OF AN EMERGENCY  and  3 SYNOPSIS. 
Other section numbers in the remainder of the document have been adjusted accordingly. 
 
Section 2, PROCEDURES IN CASE OF AN EMERGENCY, under Medical Monitor, 
changed the Name and Contact Information. 
Gary Ingenito, Chief Medical Officer 
ext. 123 
gingenito@catalystpharma.com 
Stanley Iyadurai, MD, PhD 
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Vice President, Clinical Affairs 
ext. 139 
siyadurai@catalystpharma.com 
 
Section 2, PROCEDURES IN CASE OF AN EMERGENCY, Investigators Name and 
Contact Information section were removed.  
 
Section 2, PROCEDURES IN CASE OF AN EMERGENCY, under Contract Research 
Organization, for High Research s.r.l., the phrase  for Italy  was added. 
 
Section 2, PROCEDURES IN CASE OF AN EMERGENCY, under Contract Research 
Organization, additional CRO contact information was added as follows : 
 
Easthorn Clinical Services for countries outside Italy 
Obilicev venac 15 
11000 Belgrade, Serbia 
Tel: +381 11 3286 305 
Email: ivana.mucic@easthorn.eu 
 
Section 2, PROCEDURES IN CASE OF AN EMERGENCY, Safety Reporting, changed 
address for PhAST Consulting s.r.l. 
Via A. Gramsci 10 
20090 Monza, Italy 
 
Via Roma 74 - 20060  
Cassina de’ Pecchi (MI) Italy 
 
Section 3 SYNOPSIS, under Study Sites, changed reference to single site, to reflect added 
sites 
Single site in Italy 
Up to 3 sites 
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Section 3 SYNOPSIS, under Phase of Development, added ‘a’ to Phase 3a 
 
On Page 3 SYNOPSIS, Criteria for Inclusion and Exclusion, the following were removed: 
5.  Concomitant use of medicinal products with a known potential to cause QTc 
prolongation. 
7. Subjects with congenital QT syndromes. 
 
Section 4  TABLE OF CONTENTS, has been updated with the following: 
Sections 2 PROCEDURES IN CASE OF AN EMERGENCY and 3 SYNOPSIS have been 
included, other section numbers in the remainder of the document have been adjusted. 
 
Appendix 1 Quality of Life Assessments was removed, and APPENDIX 1  PROTOCOL 
VERSION 3.0  history has been added to Table of Contents. 
 
Section 8 INTRODUCTION, and Section 8.2, the Firdapse Investigator Brochure date was 
updated 
June 2017 March 2019 
 
Section 10.2.2 Exclusion Criteria, the following were removed: 
5.  Concomitant use of medicinal products with a known to cause QTc prolongation. 
8. Subjects with congenital QT syndromes. 
 
Section 10.3.2.2 Storage, the following was added: 
(excursions between 15-30° may be permitted) 
 
Section 10.4 Prior and Concomitant Medications, the following were removed: 
• Medicinal products known to prolong QTe interval 
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• Medicinal products with a narrow therapeutic window 
 
Table 2 Clinical Laboratory Tests, Blood Chemistry item has been updated: 
CO2 or bicarbonate 
 
Table 2 Clinical Laboratory Tests, under the column Urine Tests, text was changed: 
Hemoglobin   Blood in urine 
 
Section 10.7.1 Quality of life assessment, the following has been changed: 
A copy of the Quality of Life assessments is in Appendix 1.  
Each QoL evaluation is available in the local language for the appropriate sites. 
 
Section 11.6 Medical Monitor Contact Information, changed the Name and Contact 
Information. 
Gary Ingenito, Chief Medical Officer 
ext. 123 
gingenito@catalystpharma.com 
Stanley Iyadurai, MD, PhD 
Vice President Clinical Affairs 
Catalyst Pharmaceuticals, Inc. 
Tel: +1 305-420-3239 
Email: siyadurai@catalystpharma.com 
 
Section 13.1 Start of Long Term Study, protocol number was added: 
• QoL (use data from Day 0 of SMA-001 for those patients not randomized in SMA-
001); 
 
Section 23, Signature Page, information below the Medical Monitor Signature was updated.  
Gary Ingenito, MD, PhD 
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Chief Medical Officer 
 
Stanley Iyadurai, MD, PhD 
Vice President Clinical Affairs 
Catalyst Pharmaceuticals, Inc. 
 
Appendix 1 Quality of Life Assessments has been removed. 
Appendix 1 Protocol Version 3.0 has been added to record changes made to this protocol.  
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