A Phase 3, Double-blind, Outpatient Crossover Study to Evaluate the Efficacy and Safety of Amifampridine Phosphate (3,4 Diaminopyridine Phosphate) in Patients With Congenital Myasthenic Syndromes (CMS)
Phase: PHASE3
Conditions: Myasthenic Syndromes, Congenital
Sponsor: Catalyst Pharmaceuticals, Inc.

 
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CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 3, Multicenter, Double-blind, Placebo-controlled, 
Randomized, Outpatient Two-period Two-treatment Crossover 
Study to Evaluate the Efficacy and Safety of Amifampridine 
Phosphate (3,4-Diaminopyridine Phosphate) in Patients with 
Congenital Myasthenic Syndromes (CMS) 
Protocol Number: 
CMS-001 
Investigational Product: Amifampridine phosphate (3,4-diaminopyridine phosphate) 
IND/EUDRACT 
Number: 
106263 / 2010-021850-20 
Indication: 
Congenital Myasthenic Syndromes (CMS) 
Sponsor: 
Catalyst Pharmaceuticals, Inc. 
Development Phase: 
Phase 3 
Medical Officer: 
Gary Ingenito, MD, PhD 
Study Design: 
Double-blind, Placebo-controlled, Randomized, Outpatient 
Two-period Two-treatment Crossover 
Dose: 
10-80 mg total daily dose or placebo equivalent 
Patient Population: 
Patients with CMS 
Date of Protocol: 
15 September, 2015 (FINAL) 
Date of Amendment 1: 
2 February 2016 
Date of Amendment 2: 
7 March 2016 
Date of Amendment 3: 
7 July 2016 
Date of Amendment 4: 
25 April 2017 
Date of Amendment 5: 
26 June 2017 
 
CONFIDENTIAL 
May not be divulged, published, or otherwise disclosed to others without prior written 
approval from Catalyst Pharmaceutical, Inc. 
This study will be conducted according to the principles of Good Clinical Practice as 
described in the U.S. Code of Federal 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 
 
Table 1. 
Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Medical Monitor 
Gary Ingenito, MD, PhD, 
Chief Medical Officer 
Catalyst Pharmaceuticals, Inc. 
355 Alhambra Circle, Suite 1250 
Coral Gables, FL  33134 
Tel: +1 305-420-3200, ext. 123 
Email: gingenito@catalystpharma.com 
Clinical Project Lead 
Sumit Verma MD 
Assistant Professor of Pediatrics and 
Neurology, Emory Univeristy School of 
Medicine, Atlanta, GA 
Staff Pediatric Neurologist, 
Children’s Healthcare of Atlanta 
1001 Johnson Ferry Road, Atlanta, GA 
SAE Reporting 
Reported within 24 hours 
24-hour safety hotline: 305-420-3233 
 
To ensure notification in real time, also 
email reports to: 
jrubine@catalystpharma.com and 
gingenito@catalystpharma.com 
 
 

 
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3 
SYNOPSIS 
NAME OF COMPANY: 
Catalyst Pharmaceuticals, Inc. 
355 Alhambra Circle, Suite 1250 
Coral Gables, FL  33134 
NAME OF FINISHED PRODUCT: 
Firdapse® 
NAME OF INVESTIGATIONAL PRODUCT:  
amifampridine phosphate (3,4-diaminopyridine phosphate) 
TITLE OF STUDY: 
A Phase 3, Multicenter, Double-blind, Placebo-controlled, Randomized, Outpatient Two-period 
Two-treatment Crossover Study to Evaluate the Efficacy and Safety of Amifampridine Phosphate 
(3,4-Diaminopyridine Phosphate) in Patients with certain Congenital Myasthenic Syndromes 
(CMS) amenable to treatment. 
PROTOCOL NUMBER: 
CMS-001 
STUDY SITE:  
Multicenter at up to 5 sites in the United States and 3 sites in Canada 
PHASE OF DEVELOPMENT: 
Phase 3 
OBJECTIVES: 
• 
To characterize the overall safety and tolerability of amifampridine phosphate compared with 
placebo in patients with CMS; and 
• 
To assess the clinical efficacy of amifampridine phosphate compared with placebo in patients 
with CMS, based on improvement in subject global impression (SGI) and motor function 
measure (MFM 20 or 32) scores. 
STUDY DESIGN AND PLAN:  
This randomized (1:1), double-blind, placebo-controlled, outpatient two-period, two-treatment 
crossover study is designed to evaluate the efficacy and safety of amifampridine phosphate in 
patients diagnosed with certain genetic subtypes of CMS and demonstrated open label 
(amifampridine phosphate) or history of sustained amifampridine benefit from treatment. After a 
period of unblinded drug escalation/treatment, blinded treatment effect will be assessed in a 
randomized fashion of continuation or cessation of drug, each blinded treatment period separated 
by a stabilization period. The study is planned to include up to 23 male and female patients. The 
planned duration of participation for each patient is approximately 56 days, excluding the screening 
period, which can last up to 14 days.  

 
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All patients will be screened for eligibility to participate in the study. Those successfully 
completing screening will have procedures/assessments (see Table 3) completed on Day 1 of the 
run-in period. Patients who are previously naïve to amifampridine (3,4-DAP) or amifampridine 
phosphate treatment will then begin open-label up-titration of medication, with frequent clinic 
visits/telephone evaluation for up to 4 weeks during run-in period, until stable dose and frequency 
of amifampridine phosphate is achieved for 7 days. At the end of the 7 days of stable dosing, there 
must be demonstrated efficacy as assessed by improvement on the MFM 20 or 32 in order for the 
patient to participate in the randomized two-period, two-treatment crossover portion of the study.  
Patients on a stable dose of amifampridine phosphate with a history of meaningful 
improvement in motor function are eligible immediately for randomization. Those who are 
on a stable pre-trial dose of 3,4-DAP will be transitioned to equivalent dose of amifampridine 
phosphate for 7 days. At this point (labeled Day 0) the patient will be randomized to a Treatment 
Sequence and undergo procedures/assessments (Table 3). Study medication at the stable dose or 
placebo, will be dispensed by the site pharmacist, according to the randomization schedule, 
beginning with the dose following completion of assessments on Day 0 and for the 8 day Period 1.  
Following experimental Period 1, patients will be returned to the stable dose administered at the 
end of the open-label run-in period from days 9-21, followed by Period 2 dosing for 8 days (Days 
22-29). Patients who were on a stable does of amifampriding phosphate with history of meaningful 
improvement prior to randomization in CMS-001, will be returned to the same stable dose from 
days 9-21, followed by Period 2 dosing for 8 days (Days 22-29).  
After completion of Period 2, patients will be eligible for expanded access with restoration of open-
label amifampridine phosphate at the same dose and frequency as established in the run-in phase of 
the study. Patients who were on stable dose of amifampriding phosphate with history of meaningful 
improvement prior to randomization in CMS-001, will be returned to the same stable dose and 
frequency during their participation in the expanded access program.   
Open-label Run-in 
Patients who are naïve to amifampridine or amifampridine phosphate treatment are each potentially 
eligible, but the pathway to enrollment depends upon previous drug exposure and efficacy. For 
those naïve to either, amifampridine phosphate dose may be titrated upward every 3 to 4 days, per 
the dosing guidelines in Table 4, at the discretion of the investigator, for up to 4 weeks, including 1 
week of stable dose and frequency before being randomized to a Treatment Sequence in Period 1. 
Measurements of clinical improvement will be administered at the outset and repeated as clinically 
indicated during the titration period, to assess open-label efficacy. Dosing can be increased or 
decreased by the investigator during the run-in phase. Enrollment and randomization for patients in 
this group of initially drug-naïve patients can only occur after achievement of stable dose for at 
least 7 days with demonstrated 20% or greater improvement in MFM 20 or 32 (depending on the 
age of patient) compared to Day 1 run-in assessment. 

 
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Patients already receiving 3,4-DAP or amifampridine phosphate treatment for CMS, and meeting 
the inclusion and exclusion criteria are eligible to participate in this study. The patient should 
report or investigator judges there is a history of improvement on 3,4-DAP or amifampridine 
phosphate treatment; improvement of at least 20% in MFM 20 or 32 is not a requirement for these 
participants. They can be randomized into Period 1 if on stable dose and frequency of 
amifampridine phosphate for at least 1 week before being randomized to a Treatment Sequence.   
Treatment Group A or B 
Period 1 (Days 1-8) (+1 day) 
Patients who have successfully completed the open-label run-in and continue to meet all 
inclusion/exclusion criteria will be randomized (1:1 ratio) on the last day of the run-in period 
(Day 0) to either Sequence 1 or 2 and commence Period 1 for the respective Treatment Sequence. 
Only after assessments are completed on Day 0, the patient will begin to receive either 
amifampridine phosphate tablets or placebo tablets for 8 days as an outpatient, with a dose of the 
same medication on the day of scheduled study visit (Day 8) in the clinic, in order to facilitate 
efficacy assessments, under double-blind conditions. If the patient is on a BID or TID regimen 
during Period 1, the Day 8 assessments should occur after the same dose that corresponds to when 
assessments were done on Day 0.  Any unused portion of double-blind dispensed drug will be 
returned to the site before dispensing drug for the Re-Stabilization Period.  
Re-Stabilization Period (Days 9-21) (+1 day) 
Patients will be administered amifampridine phosphate at the same dose and frequency established 
as the stable dose in the open-label run-in phase for a 14-day period, under open-label conditions. 
Patients who were on stable dose of amifampriding phosphate with history of meaningful 
improvement prior to randomization in study CMS-001, will be returned to the same stable dose 
and frequency during the re-stabilization period.  
Period 2 (Days 22-29) (+1 day) 
After completion of Period 1 and the re-stabilization period, according to randomization sequence, 
patients will receive the blinded study medication/placebo for Period 2 for 8 days (Day 22 – 29) as 
an outpatient with a dose of the same medication on the day of scheduled study visit (Day 29) in 
the clinic, in order to facilitate efficacy assessments, under double-blind conditions. If the patient is 
on a BID or TID regimen during Period 2, the Day 29 assessments should occur after the same 
dose that corresponds to when assessments were done on Day 0. Any unused portion of double-
blind dispensed drug will be returned to the site before enrolling the patient in the expanded access 
program and dispensing open-label drug.  
During all phases of the study, safety and efficacy assessments will be performed as detailed in the 
Schedule of Assessments in Table 3 and Section 13. 
NUMBER OF PATIENTS PLANNED:  
Approximately 23 patients to enroll in the study. 

 
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CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all of the following inclusion criteria: 
1. Patient or parent 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, or the 
patient’s legal guardian or caregiver with durable power of attorney can provide written 
informed consent.  An assent form must also be signed if in the judgement of the 
IRB/IEC/REB the children are capable of providing assent. 
2. Male or female age 2 years and above. 
3. Body weight ≥10 kg. 
4. Genetically-confirmed CMS involving acetylcholine receptor defect, Rapsyn deficiency, 
MuSK deficiency, Dok-7 deficiency, SYT2 mutations, SNAP25B deficiency, and fast 
channel syndrome. 
5. In patients who are naïve to 3,4-DAP or amifampridine phosphate, MFM 20 or 32 score 
equal or less than 48 or 76, respectively, at Screening 
6. In patients who are naïve to 3,4-DAP or amifampridine phosphate, improvement of >20% in 
MFM 20 or MFM 32 scores after open label period of uptitration of dose 
7. In patients who are previously stabilized on 3,4-DAP or amifampridine phosphate, a 
history of meaningful improvement in motor function (in the opinion of the investigator).  
8. Willingness of patients receiving pyridostigmine, albuterol, ephedrine, or fluoxetine to 
remain on a stable dose of these medications throughout the study interval. 
9. Female patients of childbearing potential must have a negative pregnancy test (serum human 
chorionic gonadotropin [HCG] at Screening); and must practice effective, reliable 
contraceptive regimen during the study. Acceptable methods of contraception include 
hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal 
ring), intrauterine device, barrier methods (diaphragm, condom) with spermicide, or surgical 
sterilization (tubal ligation). 
10. 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. 
Individuals who meet any of the following exclusion criteria are not eligible to participate in 
the study: 
1. CMS subtype diagnosis of acetylcholinesterase deficiency, slow-channel syndrome, LRP4 
deficiency, and plectin deficiency. 
2. Cardiac conduction defects on Screening electrocardiogram (ECG). 
3. Seizure disorder. 
4. Clinically significant abnormal laboratory values at Screening, in the opinion of the 

 
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investigator. 
5. Pregnancy or breastfeeding at Screening or planning to become pregnant at any time during 
the study. 
6. Any systemic bacterial or other infection, which is clinically significant in the opinion of the 
investigator and has not been treated with appropriate antibiotics. 
7. Treatment with an investigational drug (other than 3,4-DAP or amifampridine phosphate), 
device, or biological agent within 30 days before Screening or while participating in this 
study. 
8. Any other 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 confounds the 
assessment of the patient. 
9. History of drug allergy to any pyridine-containing substances or any amifampridine 
phosphate excipient(s). 
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE, AND REGIMEN:  
The investigational product (IP) is amifampridine phosphate tablets 10 mg, and it will be provided 
in round, white-scored tablets, containing amifampridine phosphate formulated to be the equivalent 
of 10 mg amifampridinebase per tablet. The total daily dose will be individually determined by the 
investigator, within the bounds of a total daily dose of 10 mg to 80 mg, divided into doses taken 
2 to 4 times per day as prescribed by the investigator, based on optimal neuromuscular benefit. 
Amifampridine phosphate tablets are to be taken orally by mouth with food throughout the study. 
Children unable to swallow tablets will have the tablets crushed and mixed with a small amount of 
food, and children with a nasogastric or gastrostomy tube will have the tablets crushed and diluted 
in 5 to 10 mL of water and given through the tube. Scored tablet can be split to obtain 5 mg dose, if 
required. 
 
The investigational product, and matching placebo, will be provided by Catalyst Pharmaceuticals, 
Inc., 355 Alhambra Circle, Suite 1250, Coral Gables, Florida, 33134, United States. 
 
REFERENCE THERAPY, DOSE, ROUTE, AND REGIMEN:  
The reference therapy is a placebo, provided as tablets indistinguishable from amifampridine 
tablets. The placebo will be administered consistent with the dose and dose regimen of the 
investigational product (amifampridine phosphate). 
 
DURATION OF TREATMENT: 
Approximately 56 days (excluding up to 14-day screening period) after enrollment. The run-in 
phase requires that the patient must be on a stable dose and dose regimen for the last 7 days of run-

 
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in. 
CRITERIA FOR EVALUATION: 
Safety: 
Safety will be assessed by the incidence of treatment-emergent adverse events (TEAEs), including 
serious adverse events (SAEs). Vital signs, 12-lead ECGs, clinical laboratory tests, physical 
examination, and concomitant medications will also be evaluated. 
Efficacy:  
Efficacy will be assessed by comparison of amifampridine phosphate versus placebo for: 
• 
SGI;  
• 
MFM 20 or 32 (MFM 20 (individual <7 years) and MFM 32 (individual ≥ 7 years)); 
• 
Clinical Global Impression-Severity (CGI-S); and 
• 
Clinical Global Impression-Improvement (CGI-I). 
 
Optional tests to be performed are; 
• 
Stimulated single fiber electromyogram (SFEMG) 
• 
“Slurp” test 
 
STATISTICAL METHODS:  
Sample Size Determination 
Assuming a standardized between-treatment difference of 0.5, 23 patients per sequence 
will ensure power of 90% for the 2-sided test at the 0.05 level using the standard 2-by-2 
crossover analysis.  
Safety Analysis 
Safety analyses will be conducted on the safety population (i.e. all patients who receive at least 
1 dose of amifampridine phosphate or placebo). The safety analysis will be descriptive and will be 
presented on observed data only. 

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Efficacy Analysis 
Efficacy will be described for 2 datasets: 
•
Full Analysis Set (FAS): This population consists of all randomized patients who receive
at least 1 dose of IP (amifampridine phosphate or placebo) and have at least one post-
treatment efficacy assessment.
•
Per Protocol (PP): This population is a subset of the FAS population, excluding patients
with major protocol deviations.
If the PP Population is the same as the FAS, then the results will be presented only for the FAS. 
Exclusion from the FAS and PP Population will be finalized prior to database lock and 
subsequent unblinding. 
Summary statistics will be provided by treatment and period for CGI-I, CGI-S, Change From 
Baseline (CFB) for CGI-S, the optional Slurp Test, and variables associated with the optional 
SFEMG. 
The analysis of CFB for SGI is the primary efficacy analysis and will be performed using the 
standard analysis for a 2-by-2 crossover design. Summary statistics for SGI and CFB for SGI 
will be presented by treatment and period. P-values <0.05 wil be considered statistically 
significant. 
The total score for MFM and the subtotal for each of the three dimensions (Standing and 
transfer, Axial and proximal motor function, and Distal motor function) will be standardized by 
the possible maximum for both MFM 20 and MFM 32. The CFB for these standardized scores 
will be analyzed using the standard analysis for a 2-by-2 crossover design for MFM 20 and 
MFM 32 separately and pooled, with the latter being the secondary and the separate analyses 
being supportive. The total scores, subtotals for each dimension, and the corresponding 
standardized scores will be summarized by treatment and period for MFM 20 and MFM 32 
separately and standardized scores will be summarized by treatment and period for MFM 20 
and MFM 32 pooled. P-values <0.05 wil be considered statistically significant. 

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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 ...................................................................................................10 
5 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................15 
6 ETHICS..............................................................................................................................17 
6.1 Independent Ethics Committee .................................................................................17 
6.2 Ethical Conduct of Study ..........................................................................................18 
6.3 Patient Information and Informed Consent ...............................................................18 
7 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................19 
8 INTRODUCTION .............................................................................................................20 
8.1 Disease Background ..................................................................................................20 
8.2 Amifampridine ..........................................................................................................21 
8.3 Nonclinical Studies ...................................................................................................21 
8.4 Previous Clinical Studies ..........................................................................................23 
8.4.1 
Amifampridine Phosphate in Healthy Subjects ...........................................24 
8.4.2 
Efficacy of Amifampridine in CMS ............................................................26 
8.4.3 
Efficacy of Amifampridine in LEMS ..........................................................28 
8.4.4 
Safety of Amifampridine and Amifampridine Phosphate ...........................29 
8.5 Overall Risks and Benefits ........................................................................................31 
8.6 Study Rationale .........................................................................................................32 
9 STUDY OBJECTIVES ......................................................................................................32 
9.1 Primary Objectives ....................................................................................................32 
10 INVESTIGATIONAL PLAN ............................................................................................32 
10.1 Overall Study Design and Plan .................................................................................32 
10.2 Selection of Study Population ...................................................................................41 
10.2.1 Inclusion Criteria .........................................................................................41 
10.2.2 Exclusion Criteria ........................................................................................42 
10.2.3 Removal of Patients from Treatment or Assessment ..................................42 

 
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10.2.4 Patient Identification and Randomization ...................................................43 
10.2.5 Re-screening ................................................................................................44 
10.3 Treatments .................................................................................................................44 
10.3.1 Treatments Administered ............................................................................44 
10.3.2 Identity of Investigational Product ..............................................................44 
10.3.2.1 
Product Characteristics and Labeling ..........................................45 
10.3.2.2 
Storage .........................................................................................45 
10.3.3 Directions for Administration .....................................................................45 
10.3.4 Method of Assigning Patients to Treatment Groups ...................................47 
10.3.5 Selection of Doses Used in the Study .........................................................48 
10.3.6 Blinding .......................................................................................................48 
10.3.7 Treatment Compliance ................................................................................48 
10.3.8 Investigational Product Accountability .......................................................48 
10.3.9 Return and Disposition of Clinical Supplies ...............................................48 
10.4 Prior and Concomitant Medications .........................................................................49 
10.5 Dietary or Other Protocol Restrictions......................................................................50 
10.5.1 Dietary Restrictions .....................................................................................50 
10.5.2 Contraception ..............................................................................................50 
10.6 Safety Variables ........................................................................................................50 
10.6.1 Adverse Events ............................................................................................50 
10.6.2 Vital Signs ...................................................................................................50 
10.6.3 Clinical Laboratory Assessments ................................................................51 
10.6.4 Pregnancy Testing .......................................................................................51 
10.6.5 Electrocardiogram .......................................................................................51 
10.6.6 Physical Examination ..................................................................................52 
10.7 Efficacy Variables .....................................................................................................53 
10.7.1 Subject Global Impression ..........................................................................53 
10.7.2 Motor Function Measure .............................................................................53 
10.7.3 Clinical Global Impression Scales ..............................................................54 
10.7.4 Stimulated Single Fiber Electromyogram ...................................................54 

 
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10.7.5 Slurp Test ....................................................................................................55 
11 REPORTING ADVERSE EVENTS .................................................................................55 
11.1 Adverse Events .........................................................................................................55 
11.2 Serious Adverse Events ............................................................................................57 
11.3 Safety Blood Collection ............................................................................................59 
11.4 Pregnancy ..................................................................................................................59 
11.5 Urgent Safety Measures ............................................................................................59 
11.6 Medical Monitor Contact Information ......................................................................60 
12 APPROPRIATENESS OF MEASUREMENTS ...............................................................60 
13 STUDY PROCEDURES ...................................................................................................61 
13.1 Screening Visit ..........................................................................................................61 
13.2 Open-label Run-in .....................................................................................................61 
13.3 Period  1 ....................................................................................................................63 
13.4 Re-stabilization Period ..............................................................................................64 
13.5 Period 2 .....................................................................................................................65 
13.6 Early Discontinuation Visit .......................................................................................66 
14 DATA QUALITY ASSURANCE .....................................................................................67 
15 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................68 
15.1 Determination of Sample Size ..................................................................................68 
15.2 Safety Analysis .........................................................................................................68 
15.3 Adverse Events .........................................................................................................68 
15.4 Laboratory Tests .......................................................................................................68 
15.5 Other Safety Assessments .........................................................................................68 
15.6 Efficacy Analysis ......................................................................................................68 
15.7 Primary Efficacy Analysis ........................................................................................69 
15.8 Secondary Efficacy Analysis ....................................................................................69 
15.9 Changes in the Conduct of the Study ........................................................................69 
16 COMPENSATION, INSURANCE, AND INDEMNITY .................................................70 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ..............................................70 
18 STUDY MONITORING AND AUDITING .....................................................................71 

 
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19 RETENTION OF RECORDS ...........................................................................................71 
20 USE OF INFORMATION AND PUBLICATION ...........................................................72 
21 REFERENCES ..................................................................................................................73 
22 INVESTIGATOR RESPONSIBILITIES ..........................................................................77 
22.1 Conduct of Study and Protection of Human Patients ...............................................77 
23 SIGNATURE PAGE .........................................................................................................78 
24 APPENDICES ...................................................................................................................79 
Appendix 1 
Subject Global Impression (SGI) ................................................................79 
Appendix 2 
Motor Function Measure (MFM 32 or 20) .................................................80 
Appendix 3 
Clinical Global Impression-Severity (CGI-S) .............................................85 
Appendix 4 
Clinical Global Impression-Improvement (CGI-I) .....................................86 
Appendix 5 
Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4 ...................................................................................................................87 
Appendix 6: Protocol Amendment 1 .................................................................................88 
Appendix 7: Protocol Amendment 2 .................................................................................90 
Appendix 8: Protocol Amendment 3 .................................................................................92 
Appendix 9: Protocol Amendment 4 ...............................................................................105 
Appendix 10: Protocol Amendment 5 .............................................................................122 
 
List of In-text Tables 
Table 1. 
Emergency Contact Information .....................................................................2 
Table 2. 
Body Surface Area and Exposure-Based Safety Factors ..............................23 
Table 3. 
Schedule of Events ........................................................................................37 
Table 4. 
Dosing Guidelines .........................................................................................47 
Table 5. 
Medications Prohibited During Study ...........................................................49 
Table 6. 
Clinical Laboratory Tests ..............................................................................51 
Table 7. 
Categories of Severity for CTCAE Criteria ..................................................56 
Table 8. 
Description of Relationship to Adverse Event Categories ............................57 
 
 

 
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List of In-text Figures 
Figure 1. 
Chemical Structure of Amifampridine Phosphate .........................................45 
 

 
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5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
3,4-DAP 
3,4-diaminopyridine 
ACh 
acetylcholine 
AChR 
acetylcholine receptor 
ADL 
Activities of Daily Living 
ADME 
absorption, distribution, metabolism, and excretion 
AE(s) 
adverse event(s) 
AIN 
adult idiopathic nystagmus 
ALS 
amyotrophic lateral sclerosis 
ALT 
alanine aminotransferase  
ANS 
autonomic nervous system 
AST 
aspartate aminotransferase 
ATU 
Autorisations Temporaires d'Utilisation Normative 
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve from time 0 to infinity  
Ca+ 
calcium ion 
CI 
confidence interval 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
Cmax 
peak plasma concentration 
CMG 
congenital myasthenia gravis 
CMS 
congenital myasthenic syndromes 
CNS 
central nervous system 
CRA(s) 
clinical research associate(s) 
CRF 
case report form (paper or electronic) 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP450 
cytochrome P450 
DBP 
diastolic blood pressure 
EC 
European Commission 
ECG(s) 
electrocardiogram(s) 
EFNS 
European Federation of Neurological Societies  
EMG 
Electromyogram 

 
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EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCG 
human chorionic gonadotropin 
hERG 
human Ether-à-go-go Related Gene 
HIPAA 
Health Insurance Portability and Accountability Act 
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 
IVIG 
intravenous immunoglobulin G 
JMS 
juvenile myasthenia gravis 
K+ 
potassium ion 
kg 
kilogram 
LEMS 
Lambert-Eaton myasthenic syndrome 
LRP4 
Low Density Lipoprotein Receptor-Related Protein 4 
LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MFM 
Motor Function Measure 
MG 
Myasthenia Gravis 
MI 
myocardial infarction 
mmHg 
millimeters of mercury 
MS 
multiple sclerosis 
NAT 
N-acetyl transferase 
ng/mL 
nanograms per milliliter 
NMJ 
neuromuscular junction 
PE 
plasma exchange 
Pgp 
P-glycoprotein 
PK 
pharmacokinetic 
PP 
per protocol 

 
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QID 
four times daily 
QMG 
quantitative myasthenia gravis 
QTc 
QT wave corrected for heart rate 
REB 
research ethics board 
SAE(s) 
serious adverse event(s) 
SBP 
systolic blood pressure 
SGI 
subject global impression 
SOPs 
standard operating procedures 
SFEMG 
single fiber electromyogram 
t1/2 
elimination half-life 
TEAE(s) 
treatment emergent adverse event(s) 
TID 
three times daily 
TK 
toxicokinetic 
Tmax 
time to reach maximum plasma concentration 
TPE 
Therapeutic Plasma Exchange 
US 
United States 
 
Definition of Terms:  
Investigational Product (IP): 
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6]). The terms “IP” and “study drug” may be 
used interchangeably in the protocol. 
6 
ETHICS 
6.1 
Independent Ethics Committee 
The investigator will provide the institutional review board (IRB/IEC/REB), independent 
ethics committee (IEC), or research ethics board (REB) with all appropriate material, 
including the protocol, Investigator’s Brochure or Package Insert, the Informed Consent 

 
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Form (ICF) including compensation procedures, child assent form if required, and any other 
written information provided to the patients, including all ICFs and child assent forms 
translated to a language other than the native language of the clinical site. The study will not 
be initiated and Investigational Product (IP) supplies will not be shipped to the site until 
appropriate documents from the IRB/IEC/REB confirming approval of the protocol, the ICF, 
and child assent form (if applicable) are obtained by the investigator. 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. Catalyst will 
ensure that the appropriate reports on the progress of the study are made to the IRB/IEC/REB 
and Catalyst by the investigator 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: 
• US Code of Federal Regulations (CFR) sections that address clinical research studies, 
and/or other national and local regulations, as applicable; 
• ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
(ICH E6); and 
• The ethical principles established by the Declaration of Helsinki. 
6.3 
Patient Information and Informed Consent 
A properly written and executed ICF (and assent if in the judgement of the IRB/IEC/REB the 
children are capable of providing assent), in compliance with the Declaration of Helsinki, 
ICH E6 (Section 4.8), US CFR sections that address clinical research studies, 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 for 
review, or designee. Catalyst and the IRB/IEC/REB must review the documents before their 
implementation. A copy of the approved ICF, and if applicable, a copy of the approved 
patient information sheet and all ICFs translated to a language other than the native language 
of the clinical site must also be received by Catalyst or designee before any study-specific 
procedures being performed. 
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 

 
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health information per country-specific regulations, such as the Health Insurance Portability 
and Accountability Act (HIPAA) in the US, 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. 
The investigator will provide copies of the signed ICF and HIPAA (or similar form) to each 
patient and will maintain the original in the record file of the patient. 
7 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
Before beginning the study, the investigator at each site 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. 
Financial Disclosure Forms must also be completed for all sub-investigators listed on the 
Form FDA 1572 who will be directly involved in the treatment or evaluation of patients in 
this study. 
The study will be administered by and monitored by employees or representatives of 
Catalyst.  The responsible Medical Officer is: 
Gary Ingenito, MD, PhD 
Chief Medical Officer 
Catalyst Pharmaceuticals, Inc. 
Tel: +1 305-420-3200, ext. 123 
Email: gingenito@catalystpharma.com 
 
Clinical research associates (CRAs) or trained designees will monitor the site on a periodic 
basis and perform verification of source documentation for a representative sample of 
patients as well as other required review processes. Catalyst’s Regulatory Affairs Department 
(or designee) will be responsible for the timely reporting of serious adverse events (SAEs) to 
appropriate regulatory authorities as required. 
In multicenter studies, a Coordinating Investigator will be identified who will be responsible 
for study overview. 
Laboratory evaluations will be performed at both central laboratories and the local 
laboratories associated with the study sites. Additional details will be provided in the 
CMS-001 Study Reference Manual. 

 
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8 
INTRODUCTION 
A comprehensive review of amifampridine phosphate is contained in the Firdapse® 
Investigator’s Brochure supplied by Catalyst (February 2015). Investigators are to review this 
document before initiating this study. 
8.1 
Disease Background 
The neuromuscular junction (NMJ) is the specialized synapse between the motor nerve 
terminal and the muscle fiber. Defects in NMJ function present with variable and often 
fluctuant symptoms such as fatigue, muscle weakness, droopy eyelids, double vision, 
swallowing and breathing difficulties. NMJ disorders are both inherited and acquired in 
nature. Congenital myasthenic syndromes (CMS) are a group of heterogeneous inherited 
disorders caused by mutations in genes encoding proteins essential for the integrity of 
neuromuscular transmission. Most CMS are caused by molecular defects in the muscle 
nicotinic acetylcholine receptor, but they can also be caused by mutations in presynaptic 
proteins, mutation in proteins associated with the synaptic basal lamina, defects in endplate 
development and maintenance, or defects in protein glycosylation (Engel, 2007). More than 
20 different genetic mutations at the presynaptic, synaptic, and postsynaptic level of 
neuromuscular junction have been described. 
CMS is rare, estimated at one-tenth that of myasthenia gravis, which in itself is rare 
(estimated at 25 to 125 per million) (Eymard, 2013; Abicht, 2012). Worldwide, 
approximately 2,000 to 3,000 patients have been diagnosed on a molecular level (Schara, 
2012). A recent report on genetically-confirmed CMS cases in the United Kingdom indicates 
a prevalence of 9.2 per million in children under 18 years of age, equally affecting girls and 
boys (Parr, 2014). 
CMS is characterized by fatigable weakness of skeletal muscle (ocular, bulbar, limb 
muscles), with an onset typically at birth or early childhood, although rarely it can manifest 
in adolescence and adulthood (Abicht, 2012; Schara, 2012). Clinically, hypotonia is 
common, as are ophthalmoplegia and ptosis, dysphonia and swallowing disturbance, facial 
paresis, and progressive muscle weakness (Eymard, 2013; Abicht, 2012). The severity and 
clinical course of the disease are highly variable, reflective of the underlying genetic defect. 
The diagnosis and management of children with CMS is challenging and response to 
treatment in CMS depends on the type of defect (pre-synaptic, synaptic, post-synaptic) and 
the kinetics of the channel affected (fast versus slow). Most patients are eligible and respond 
to pharmacologic intervention, including esterase inhibitors, 3,4-diaminopyridine (3,4-DAP), 

 
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ephedrine, fluoxetine or quinidine, and albuterol (Eymard, 2013; Abicht, 2012; Schara, 2012; 
Engel, 2007). The particular therapy is dictated by the diagnosed CMS subtype, as drugs 
beneficial in one subtype can be detrimental in another subtype. 
8.2 
Amifampridine  
Amifampridine (3,4-DAP) is a non-specific voltage-dependent potassium (K+) channel 
blocker used to treat many of the congenital myasthenic syndromes, particularly those with 
defects in choline acetyltransferase, downstream kinase 7, and those where any kind of defect 
causes “fast channel” behavior of the AChR. Its blockade of K+ channels causes 
depolarization of the presynaptic membrane and slows down or inhibits the repolarization 
phase of an action potential. Prolongation of the action potential duration increased opening 
of pre-synaptic slow voltage-dependent calcium (Ca2+) channels, increasing  Ca2+ influx and 
consequent increase in synaptic vesicle exocytosis (quantal content) with each depolarization 
event, 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 in those cases of CMS where defects of 
diminished post-synaptic response are demonstrated or postulated. 
Over the last 25 years, a considerable amount of clinical experience with amifampridine has 
been gained, which provides a strong body of evidence for its efficacy and safety in the 
treatment of patients with neurologic disorders, including MG, CMS, Lambert-Eaton 
myasthenic syndrome (LEMS), multiple sclerosis (MS), downbeat nystagmus, and 
amyotrophic lateral sclerosis (ALS). Amifampridine has been recommended as first-line 
symptomatic treatment for LEMS by the European Federation of Neurological Societies 
(EFNS) (Skeie, 2006; Skeie, 2010; Lindquist, 2011) and amifampridine tablets 10 mg (as 
amifampridine phosphate) (Firdapse® Tablets) is marketed for the treatment of LEMS in the 
European Union (including Norway and Iceland), Israel, and Switzerland. The collective 
body of data indicates that amifampridine/ amifampridine phosphate is well tolerated up to 
and including 80 mg/day (Firdapse Investigator Brochure, February 2015). 
8.3 
Nonclinical Studies 
An extensive nonclinical program assessed the safety and absorption, distribution, 
metabolism, and excretion (ADME) and pharmacokinetic (PK) properties of amifampridine, 
including: 

 
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• Five safety pharmacology studies in central nervous system (rat), respiratory (rat), 
and cardiovascular (telemeterized dogs, in vitro human Ether-à-go-go Related Gene 
(hERG) and rabbit Purkinje fiber)  
• Pharmacokinetics and mass balance in rat and dog  
• In vitro metabolism in human and animal hepatocytes  
• Human hepatic cytochrome P450 (CYP450) inhibition and induction  
• Human P-glycoprotein (Pgp) interaction  
• Single dose toxicity and toxicokinetic (TK) studies in mouse and rat  
• Repeat dose toxicity and toxicokinetic in rat (28-day and 13-week) and  
dog (28-day and 9-month) 
• Reproductive and developmental toxicity in rat and rabbit 
• Six in vitro and in vivo genotoxicity studies 
Safety factors based on data from the 4-week toxicity/TK studies in rat and dog, the 13-week 
toxicity/TK study in rats along with a PK study in fasted rats are presented in Table 2. Peak 
plasma concentration (Cmax) values were used in calculating the exposure-based safety 
factors as the central nervous system (CNS) and autonomic nervous system (ANS) effects are 
correlated to plasma concentration levels. Cmax data from the bioavailability/bioequivalence 
study in healthy volunteers were used to compare with animal Cmax data. Human safety 
factors calculated using mean Cmax from a PK study in fasted rats are 2.8 (male) and 7.8 
(female). The safety factor based on average Cmax in male and female dog versus human is 
1.2 and 1.1, respectively. 

 
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Table 2. Body Surface Area and Exposure-Based Safety Factors 
Species 
NOAEL 
(mg/kg/day) 
Clinical dosea 
(mg/kg/day) 
Cmax  
(ng/mL) 
(M/F) 
Body Surface 
Area-Based 
Safety Factor 
Cmax-Based 
Safety Factor 
(M/F) 
Rat 
PK studyb 
NA 
NA 
179/503 
NA 
2.8/7.8 
Rat  
4-Weekc 
24 
NA  
51.9/80.2 
3.0 
0.8/1.2  
Rat 
13-weekd 
22.5 
NA 
88.5/223 
NA 
NA 
Dog 
4-weeke 
1.9 
NA 
74.9/72.3 
0.8 
1.2/1.1 
Humanf 
NA 
1.3 
64.8 
NA 
NA 
Cmax, peak plasma concentration; F, female; M, male; NA, not available; NOAEL, no observed adverse effect 
level; TID, 3 times daily 
a Based on a 60-kg human and a total daily dose of 80 mg/kg or 20 mg amifampridine phosphate, TID in 
order to calculate body surface area and Cmax based safety factors, respectively. 
b Dose was 24 mg/kg/day, TID in fasted rats; based on fasted first dose. 
c Based on Day 27 of the first 4-week study in rat. 
d Based on Day 92 after third daily dose. 
e Based on Day 0 of the first 4-week study in dog. 
f Bioavailability/Bioequivalent clinical study in fasted healthy volunteers. 
 
The main nonclinical findings of CNS and ANS effects and histologic changes in muscle 
tissues after administration of amifampridine are in accordance with the mechanism of 
action. No new treatment-related findings in the nonclinical program have been observed that 
would limit the use of amifampridine at the planned clinical maximum daily oral dose of 60 
mg (≤16 years of age) and 80 mg (>16 years of age) in this study involving patients with 
CMS. 
8.4 
Previous Clinical Studies 
Amifampridine has been used for over 25 years in patients with multiple neurologic disorders 
including MG, CMS, LEMS, MS, ALS, congenital forms of nystagmus, and adult idiopathic 
nystagmus (AIN). There are a limited number of published controlled trials with 
amifampridine in these disorders. A review of the literature documents that amifampridine is 
a safe and effective treatment in multiple neurologic disorders and is recommended by the 
EFNS for first-line symptomatic treatment of patients with LEMS (Skeie, 2006; Skeie, 2010; 
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8.4.1 Amifampridine Phosphate in Healthy Subjects 
A first in human Phase 1 study (DAPSEL Study, 2006) with amifampridine phosphate was 
conducted to investigate the bioavailability/bioequivalence and tolerability of amifampridine 
administered as a phosphate salt or free base. In the first part of the study, a pilot tolerance 
study was conducted in 5 healthy male volunteers who received a single 10-mg dose of 
amifampridine phosphate to determine tolerability. In the second part of the study, 
bioequivalence testing was conducted in 27 healthy male volunteers. Each patient was 
randomized to receive either a single dose (2 × 10 mg tablets) of amifampridine as 
amifampridine phosphate or amifampridine base and received alternate treatment following a 
minimum of 72-hour washout period. 
This study demonstrated bioequivalence for area under the plasma concentration-time curve 
from time 0 to infinity (AUC0-∞), with the 90% confidence interval (CI) for the base/salt ratio 
of 93.1% to 113.3% falling within the predefined limits of 90% to 125% for bioequivalence. 
The mean elimination half-life (t1/2) of amifampridine was 1.8 hours for the phosphate and 
1.6 hours for the free base form. Amifampridine Cmax was 64.8 ng/mL for the phosphate and 
57.0 ng/mL for the free base form. Potentially improved absorption of the phosphate salt 
explained the slightly higher Cmax observed for amifampridine phosphate compared with the 
free base. All adverse events (AEs) were mild or moderate, transitory and fully reversible. 
The nature and frequency of side-effects did not differ between formulations (phosphate salt 
or base). The most common AE (25 of 40 AEs) was paresthesia, which was mainly minor 
peri-oral paresthesia. Since paresthesia is well recognized as an AE occurring in patients 
treated with amifampridine, all were considered as possibly related to investigational product 
(IP) by the investigator. The only other AE occurring in >1 patient and judged possibly 
related to amifampridine was abdominal pain (4 events). Simple flu (5 events) and feeling of 
discomfort (2 events) were also reported for > 1 patient in the study, however were 
considered not related to amifampridine treatment. 
The only SAEs reported in the study were minor, isolated, and reversible increases in 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which occurred in a 
single patient after administration of 20 mg amifampridine base. Aside from this 1 patient, no 
other laboratory abnormalities were observed. No electrocardiogram (ECG) abnormalities 
were observed. No deaths occurred in the DAPSEL study.  
A Phase 1 study (LMS-001) in healthy volunteers evaluated whether food consumption 
significantly affected the bioavailability of amifampridine phosphate tablets. This was an 
open-label, randomized, single-dose, 2-treatment, 2-period crossover design in 46 healthy 

 
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volunteers. Each patient received 20 mg amifampridine phosphate on 2 occasions, once 
fasting and once after consumption of a standard high fat breakfast. The 2 single 20 mg doses 
of amifampridine phosphate were administered 6 days apart. Data indicate that taking 
amifampridine with food reduces exposures determined by Cmax (maximum serum levels) by 
approximately 40% and AUC by approximately 20%. In addition, the time to maximum 
serum concentrations (Tmax) was increased 2-fold from approximately 38 minutes (fasted) to 
78 minutes (fed). The drug was well tolerated with no serious adverse events and only 1 
severe event, an episode of gastroenteritis unrelated to amifampridine. The most common 
adverse events occurring in ≥ 10% of patients were: oral paresthesia (20 patients; 43%), 
peripheral paresthesias (12; 26%), dizziness (5; 11%), headache (5; 11%), and oral 
hypoesthesia (5; 11%). Abdominal pain, nausea, peripheral paresthesias, dizziness, and 
headache were more commonly reported by patients following administration of 
amifampridine phosphate in the fasted state; therefore, administration with food is 
recommended based on the current study. 
In both Study LMS-001 and DAPSEL, PK parameters were highly variable with 10-fold 
ranges observed in values of Cmax, AUC, and t½ across patients. In humans, amifampridine is 
exclusively metabolized to a single major metabolite, 3-N-acetyl amifampridine, via N-acetyl 
transferases (NAT) (Catalyst internal in vitro and in vivo studies; data available upon 
request). There are 2 NAT enzymes, NAT1 and NAT2, both of which are principally hepatic 
and both of which are highly polymorphic. These allelic variations lead to slow and fast 
metabolism variations, which have been well characterized in the Caucasian and Asian 
populations, but somewhat less well in African populations (Sabbagh, 2006). Slow 
acetylators are estimated to comprise 50% to 59% of the Caucasian population, with the 
remainder being rapid acetylators (fast + intermediate). Fast acetylators are over represented 
in Asian population (92% of Japanese and 80% of Chinese) while they may be under 
represented in African populations (25%) (Cascorbi, 1995). Slow acetylators will accumulate 
drug to higher levels (i.e. higher Cmax) and clear drug more slowly (i.e. longer t1/2), both of 
which may increase the risk of drug related toxicity (Fukino, 2008; Jetter, 2009). It is 
hypothesized that the high variability in amifampridine phosphate PK may be due to NAT 
polymorphisms with slow and fast acetylator phenotypes. In a study (FIR-001) that evaluated 
the effect of acetylator status in 26 healthy subjects (half with fast and half with slow 
acetylator phenotypes), polymorphisms in the NAT system created 3- to 4-fold differences in 
plasma amifampridine levels. Potentially information relating NAT genotype and 
amifampridine phosphate PK could be used to inform dose selection for individual patients 
and to lower incidence of dose-related side effects. 

 
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8.4.2 Efficacy of Amifampridine in CMS 
Efficacy of 3,4-DAP in patients with CMS has been reported in the published literature. Few 
clinical studies are reported, with most reports being case series or case reports. An open 
prospective trial conducted by Palace and colleagues (1991) reported improvement with oral 
3,4-DAP in congenital myasthenia syndrome in 16 patients (8 males and 8 females) ranging 
in age from 7 to 47 years. All but 1 patient showed improvement in strength scores, and the 
group as a whole showed highly significant increase in muscle strength. Although this study 
included younger patients, only 2 patients were less than 10 years of age, and genetic 
etiology for congenital myasthenia was unknown with outcome measures largely dependent 
on patient cooperation and motivation. One death of 5-year-old girl with severe congenial 
myasthenia who developed fatal pneumonia after several weeks of 3,4-DAP, though not 
thought to have contributed to this event. Anlar and colleagues (1996) conducted a double-
blinded, placebo-controlled, crossover study investigating the effects of 3,4-DAP in 11 
patients (5-24 years of age) with either a diagnosis of congenital myasthenia gravis (CMG) or 
juvenile myasthenia gravis (JMS). None of the 5 JMS patients responded to 3,4-DAP 
treatment. Five of the 6 CMG patients showed clinical improvement, with placebo effect 
noted in 3 patients. The authors concluded that 3,4-DAP treatment may be beneficial in some 
CMG patients but may have different effects on various presynaptic and postsynaptic defects 
of neuromuscular transmission resulting in CMS. 
With the advancements of whole-exome sequencing, approximately 20 CMS disease genes 
have been identified. Harper and Engel’s open-label uncontrolled study (2000) was the first 
to look at patients with different mutation forms of CMS. With a total of 31 patients, this 
study showed all patients with fast-channel CMS had sustained improvement and about one-
third of AChR deficiency patients had sustained improvement. A handful of case reports and 
case series has also shown the efficacy of 3,4-DAP in different mutation forms of CMS. 
Beeson and colleagues (2005) reported 19 patients with CMS who received 3,4-DAP (doses 
not specified), with 15 maintained on their existing anti-AChE medication. Good response to 
3,4-DAP was observed in CMS due to mutations of the following genes: MuSK (n=1), 
CHRNE (n=4), COLQ (n=1), RAPSN (n=1), and unknown (n=6). For the patient with COLQ-
CMS, a positive effect was found at 26 years of age, with a clear gain of axial and limb 
strength. In a single report (Mazell, 2015), use of 3,4-DAP in a 4-year-old girl with well-
defined CHRNE-CMS showed promising results using stimulated jitter analysis and MFM 
score as outcome measures. In long-term follow-up of 15 COLQ-CMS patients ranging in 
age from 3 to 48 years (mean 19 years), all relapses ended spontaneously or with 3,4-DAP 
(30 to 60 mg daily) or ephedrine with no residual impairment (Wargon, 2012). Associated 

 
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respiratory crises were reported in 3 of the 8 patients. From a pediatric standpoint, this 
adverse event was significant as puberty was identified as a triggering factor in 6 of 
8 patients.  
Two children with RAPSN-CMS improved clinically with the addition of 3,4-DAP in 
conjunction with pyridostigmine (Banwell, 2004). Clinically, both children manifested with 
hypomotility in utero, fatigable ocular and limb weakness since birth, decreased strength 
during viral illness, decremental response on EMG, and absence of AChR antibodies. One 
child had a more severe clinical course with recurrent episodes of respiratory failure, 
contractures, and craniofacial malformations. The addition of 3,4-DAP in this 14-year-old 
boy led to increased endurance and a marked reduction in fatigable weakness. In the second 
child, a 9-year-old girl maintained on pyridostigmine since 4 months of age, experienced 
significant improvement in endurance after treatment with 3,4-DAP, allowing for increased 
activity (i.e. jump rope, run, participate in dance, ride a horse). In another report of 11 
patients with RAPSN-CMS, addition of 3,4-DAP to the pyridostigmine regimen resulted in 
further clinical improvement (Milone, 2009). 
Four reports have evaluated 3,4-DAP in DOK-7-CMS. Ben Ammar and colleagues (2010) 
found that 7 of 9 patients (5 males, 4 females ranging in age from 18 to 69 years) improved 
on 3,4-DAP alone (doses not specified). In another report (Anderson, 2008) where 3 patients 
received 3,4-DAP alone (doses not specified) and 3 patients received 3,4-DAP in 
combination with pyridostigmine or ephedrine, all 6 patients improved with treatment. 
Selcen and colleagues (2008) report 9 patients (3 males, 6 females ranging in age from 5 to 
50 years) who received 3,4-DAP alone (n=4), or in combination with pyridostigmine (n=3) 
or ephedrine (n=2). One of the 2 children improved on 3, 4- DAP (10 mg TID), whereas the 
other child became worse after 3,4-DAP (5 mg TID) was added to her pyridostigmine 
regimen; 4 of 7 adults improved. Lashley and colleagues (2010) report follow-up of 10 
patients with DOK-7-CMS mainly treated with ephedrine, with 2 patients (29 and 42 years of 
age) continued on 3,4-DAP treatment (15 or 30 mg QID). All patients improved over 6 to 
8 months of follow-up. 
With respect to DPAGT1-CMS, Finlayson and colleagues (2013) report 5 patients (2 males, 
3 females ranging in age from 6 to 58 years), with 2 of 3 patients who received 3,4-DAP 
(doses not specified) having a favorable response to treatment. In another report, 2 children 
(both girls, 13 and 14 years of age) who received 3,4-DAP did not improve: one was on 
3,4-DAP (30 mg/day) plus pyridostigmine and the other on 3,4-DAP (10 mg) (Selecen, 
2014). 

 
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Two patients (7 and 48 years of age) with presynaptic CMS (with reduced quantal release) 
who had severe generalized weakness since early infancy initially responded to 3,4-DAP 
(dose not specified) and pyridostigmine, but then became refractory to treatment (Beeson, 
2005). Both patients were wheelchair-bound and had multiple skeletal deformities. The 
younger patient could not speak or swallow and was respirator-dependent. In another report 
(Kinali, 2008), 4 of 5 children with CMS who received pyridostigmine and 3,4-DAP (doses 
not specified) showed a positive response. 
8.4.3 Efficacy of Amifampridine in LEMS 
A Phase 3, randomized, double-blind, placebo-controlled study (LMS-002) evaluated the 
efficacy and safety of amifampridine tablets 10 mg, as amifampridine phosphate (30-80 mg 
total daily dose) versus placebo in patients with LEMS. The study has 4 parts, with the first 
3 parts complete in the clinic (open-label extension ongoing). Patients treated with 
amifampridine phosphate had statistically significant improvement in both primary efficacy 
measures relative to patients treated with placebo. The change in QMG scores from baseline 
(Day 1, Part 2) to Day 14 (Part 3) reached statistical significance (p=0.0452), with the least 
square (LS) mean for QMG score increasing by 2.2 in placebo-treated patients, and 
increasing by 0.4 in amifampridine-treated patients. For the other primary endpoint, subject 
global impression (SGI), patients who were receiving amifampridine on Day 1 reported, on 
average, that they were “pleased” (SGI score of 5.9 ± 1.2) with the test medication while they 
were receiving it. After being switched to placebo tablets, their opinions dropped, on 
average, 2.7 ±2.3 points. The LS mean was -2.6 for the placebo group and -0.8 for the 
amifampridine group, a difference of 1.8 ±0.6 (p=0.0028), corresponding to a patient 
assessment, of “mixed” for the placebo tablets. This substantial change in patients’ 
assessments, to a worsening of their condition while receiving placebo, was considered 
clinically significant. 
In addition to Study LMS-002, 5 randomized, double-blind, placebo-controlled studies and 
1 double-blind study with an active comparator (reported in abstract form only) in 71 patients 
with LEMS are reported in the clinical literature. In all 6 studies, amifampridine (in base 
form) was shown to be more effective for the symptomatic treatment of LEMS compared 
with placebo or active comparator across a number of independent measures of neurological 
function. Supportive data from multiple published uncontrolled investigations and case 
reports demonstrate the long-term benefits of treatment with amifampridine in patients with 
LEMS, and show that removal of patients from drug has led to recurrence of underlying 

 
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symptoms. Refer to the Firdapse Investigator Brochure (February, 2015) for further details 
on these studies. 
8.4.4 Safety of Amifampridine and Amifampridine Phosphate 
Safety data collected from 1,454 patients or healthy volunteers in controlled study LMS-002 
(LEMS) described above in Section 8.4.3, controlled and uncontrolled published studies of 
LEMS or other neurologic conditions, a 3-year safety surveillance study (ATU), and PK 
studies demonstrate amifampridine is well tolerated up to and including 80 mg/day (Firdapse 
Investigator Brochure, February 2015). 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 
contributant (Lundh, 1984; Lundh, 1993); no causality was reported for the other fatal MI 
(Bertorini, 2011). Three deaths occurred in children with CMS, including 2 with fast-channel 
CMS (Beeson, 2005). Although no causal relationship was established with amifampridine, 
the authors advise its use cautiously in children and in fast-channel patients. The other CMS 
death was not thought to be related to amifampridine (Palace, 1991). Overall 7 of 12 deaths 
were not considered related to amifampridine; neither cause nor causality is known for 4 
deaths; and amifampridine may have contributed indirectly to 1 of the MI-related deaths. 

 
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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 
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). No seizures have been reported in patients or healthy volunteers taking Firdapse since 
its commercial approval in December 2009 through 23 December 2014.  
Amifampridine was implicated in at least 4 of these cases of seizure. Three patients 
experienced seizures on a daily dose of ≥90 mg/day (n=3; LEMS or MG). No other cause 
was apparent in 2 cases; 1 patient had concurrent toxic serum levels of theophylline 
(McEvoy, 1989; Sanders, 1993). A fourth patient with LEMS had multiple seizures 
following accidental ingestion of 360 mg/day amifampridine for 7 days (prescribed dose 
60 mg/day) (Boerma, 1995). There were potentially contributing conditions in 6 patients, 
specifically, concurrent treatment with theophylline (n=1; LEMS or MG), or coexistent brain 
metastases (n=1; LEMS), epilepsy (n=1; MS) and MS (n=4). In cases where follow-up was 
reported, most seizures did not recur with amifampridine dose reduction or treatment 
withdrawal. In the one accidental overdose case, seizures were controlled with intravenous 
clonazepam and the patient made a full recovery (Boerma, 1995). Note that a seizure rate of 
4% can be expected in the natural course of patients with MS (Engelsen, 1997; Moreau, 
1998; Kinnunen, 1987). Among the 774 MS patients treated with amifampridine included in 
the safety assessment of this report, 4 (0.5%) experienced seizures. 
Other clinically significant or SAEs reported in more than 1 adult 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. 
Based upon the previous clinical studies involving the use of amifampridine in the treatment 
of Lambert-Eaton myasthenic syndrome (LEMS), there have been reports of provocation of 
bronchial asthma, respiratory failure, or respiratory disorder.  These events are also part of 

 
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CMS symptoms; however, the risk may be more likely when the patient has asthma or 
respiratory disorder as a comorbidity with CMS. 
8.5 
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. Current data demonstrate that amifampridine phosphate salt has an 
acceptable tolerability profile with a positive risk-benefit in patients treated with 
amifampridine.  
Risks of of study involvement have been minimized by: 
1. Patients entering the study may already be on some formulation of 3,4-
diaminopyridine and have demonstrated tolerability or; 
2. Patients naïve to the medication are titrated to a tolerable and effective dose with 
open-label medication, under the observation of the Investigator.  Thus, the 
development of adverse events or lack of efficacy is monitored by the Investigator 
during the step-wise titration and study medication dose can be reduced or 
discontinued at any point in the titration for either safety or lack of efficacy.   
The pharmacokinetic half-life of amifampridine phosphate is short (1.8 hours), 
therefore discontinuation of medication will qickly terminate the effects, and mitigate 
adverse reactions.  
This is a withdrawal study design looking at patient worsening on placebo; which is 
possible due to the short half-life of amifampridine phosphate. Therefore, patients must 
demonstrate a level of efficacy during the open-label titration period.  This further 
reduces patient risk, by not continuing an experimental medication in patients who fail 
to demonstrate a benefit.  
During the placebo withdrawal period, patients who deteriorate to a point that the 
Investigator assess to be lower than their baseline, open-label amifampridine phosphate 
is provided as to rescue the patient.  
Refer to the Firdapse Investigator Brochure (February, 2015) for further information on 
benefit/risk of amifampridine.  

 
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8.6 
Study Rationale 
Clinical trials, case series, and case reports studying the efficacy of 3,4-DAP in patients with 
CMS have shown clinical benefit as described above in Section 8.4.2. Little controlled data 
are reported, and several of these studies had patients without genetic confirmation of CMS 
and lacked sensitive, objective, motor and electrophysiologic outcome measures to study 
efficacy. In light of above mentioned advancements in field of genetics, electrophysiological 
techniques, and motor function measures, a randomized placebo-controlled trial of 3,4-DAP 
in CMS patients is warranted. Thus, the purpose of this study (CMS-001) is to evaluate the 
efficacy and safety of amifampridine phosphate in patients diagnosed with subtypes of CMS. 
9 
STUDY OBJECTIVES 
9.1 
Primary Objectives 
The primary objectives of the study are: 
• To characterize the overall safety and tolerability of amifampridine phosphate 
compared with placebo in patients with CMS; and 
• To assess the clinical efficacy of amifampridine phosphate compared with placebo in 
patients with CMS, based on improvement in subject global impression (SGI) and 
motor function measure (MFM 20 or 32) scores. 
10 
INVESTIGATIONAL PLAN 
10.1 
Overall Study Design and Plan 
This is a randomized (1:1), double-blind, placebo-controlled, outpatient two-period two-
treatment crossover study designed to evaluate the efficacy and safety of amifampridine 
phosphate in patients (2 years of age and above) diagnosed with CMS. The study is planned 
to be conducted at up to 5 sites in the United States and 2 sites in Canada, to include 
approximately 23 male and female patients. The planned duration of participation for each 
patient is approximately 56  days excluding the screening period, which can last up to 
14 days.  
All patients (parent or legal guardian) who sign an informed consent will be screened for 
eligibility to participate in the study, including: inclusion and exclusion criteria; medical and 
medication history; complete physical exam; standard 12-lead ECG; laboratory testing; 
serum pregnancy testing (females of childbearing potential only; result must be negative to 

 
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proceed into the run-in period with open-label IP administration); and CMS genetic testing 
(if not previously done or available).  
Those patients successfully completing initial screening will have procedures/assessments 
(see Table 3) conducted on Day 1 of the run-in period. Those not previously on 3,4-DAP or 
amifampridine phosphate will then embark on an open label up-titration of amifampridine 
phosphate dose based upon clinical benefit (assessed at clinic visit and telephone solicitation) 
for up to 4 weeks during run-in period, until stable dose and frequency of amifampridine 
phosphate is achieved for 7 days. If these patients have demonstrable increase of MFM 20 or 
MFM 32 scores of  >20% during this period of open label uptitration of dose, patients will 
then be randomized to a Treatment Sequence on last day of open-label run-in period (Day 0).  
Patients already receiving 3,4-DAP or amifampridine phosphate treatment for CMS, and 
meeting the applicable inclusion and exclusion criteria are eligible to participate in this study. 
The patient should report or investigator judges there is a history of meaningful improvement 
in motor function on 3,4-DAP or amifampridine phosphate treatment; improvement of at 
least 20% in MFM 20 or 32 is not a requirement for these participants. Patients who are on a 
stable dose of amifampridine phosphate with a history of meaningful improvement in motor 
function, they can be randomized into Period 1. The patient should be on that stable dose and 
frequence of amifampridine phosphate for at least 1 week before being randomized to a 
Treatment Sequence. Those patients who are on a stable dose of 3,4-DAP will be transitioned 
to equivalent dose of amifampridine phosphate for 7 days prior to randomization to 
treatment.   
Procedures/assessments, as detailed in Table 3, will be conducted before starting Period 1 
study medication (i.e. Day 0). Administration of Period 1 study medication (amifampridine 
phosphate or placebo) begins after all assessments have been completed on Day 0. Every 
attempt should be made to have the same individual perform all assessments for a patient 
throughout the study, and after the same dose used for Day 0 assessments. Following Period 
1, patients will be returned to the same stable dose administered at the end of the open-label 
run-in period for days 9-21, followed by Period 2 dosing for 8 days.  Patients who were on a 
stable does of amifampriding phosphate with history of meaningful improvement prior to 
randomization in CMS-001, will be returned to the same stable dose from days 9-21, 
followed by Period 2 dosing for 8 days. After completion of of the study, patients will be 
eligible for expanded access program and receive open-label amifampridine phosphate at the 
same dose and frequency as established in the run-in phase of the study. Patients who were 
on stable dose of amifampriding phosphate with a history of meaningful improvement prior 
to randomization in CMS-001, will be returned to the same stable dose and frequency during 

 
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their participation in the expanded access program.   
Following successful completion of the Run-in and randomization on Day 0, study visits will 
occur on Day 8 (+1 day), Day 21 (+1 day), and Day 29 (+1 day) or, if applicable, early 
discontinuation from the study. Note that should a shift in days occur (i.e. +1 day), then rest 
of schedule must shift to keep sequence and stabilization periods constant. 
Safety and efficacy assessments will be made throughout the study as detailed in the 
Schedule of Assessments in Table 3 and Section 13. 
Open-label Run-in 
Amifampridine phosphate dosing will start on Day 1 of the Open-label Run-in and may be 
titrated upward every 3 to 4 days, per the dosing guidelines in Table 4, at the discretion of the 
investigator, for up to 4 weeks, with 1 week of stable dose and frequency before being 
randomized to a Treatment Sequence. Measurements of clinical improvement will be 
administered during the final period of dosing stability. Dosing can be increased or decreased 
by the investigator during the run-in phase prior to the last week of stable dosing. 
Randomization can only occur after the patient has been on a stable dose for at least 7 days. 
For patients naïve to 3,4-DAP or amifampridine phosphate, a second screening event prior to 
randomization requires at least a 20% interval improvement in MFM 20 or 32 (scale use 
depends upon the age of patient), compared to Day 1 of the run-in period, to be eligible for 
randomization. 
Patients already receiving amifampridine phosphate treatment for CMS meeting the inclusion 
and exclusion criteria are eligible to participate in this study. They must have a medical 
history showing improvement on amifampridine phosphate treatment; improvement of at 
least 20% in MFM 20 or 32 is not a requirement for these participants. They can be 
randomized into Period 1 if on stable dose and frequency for 1 week before being 
randomized to a Treatment Sequence.  
Those patients who are on a stable dose of 3,4-DAP with a history of meaningful 
improvement will be transitioned to equivalent dose of amifampridine phosphate for 7 days 
prior to randomization to treatment. Improvement of at least 20% in MFM 20 or 32 is not a 
requirement for these participants. 

 
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Treatment Group A or B 
Period 1 (Days 1-8) (+1 day) 
Patients who successfully complete the open-label run-in and continue to meet all 
inclusion/exclusion criteria will be randomized (1:1 ratio) on the last day of the run-in period 
(Day 0) to either Sequence 1 or 2. Subjects randomized to Sequence 1 will receive Treatment 
A (amifampridine phosphate or placebo) in Period 1 and Treatment B (the other treatment) in 
Period 2. Subjects randomized to Sequence 2 will receive Treatment B (amifampridine or 
placebo) in Period 1 and Treatment A (the other treatment) in Period 2. Study medication 
(amifampridine phosphate tablets or placebo tablets) for Period 1 will be dispensed on Day 0, 
the last day of the Run-in, by the site pharmacist, according to the randomization schedule. 
The administration of blinded medication will begin only after completion of all 
assessments of Day 0. The Day 0 assessments are performed while taking a dose of 
open-label amifampridine phosphate in the clinic, 40 minutes before starting the 
assessments.   Any supply of open-label amifampridine phosphate should be collected by the 
study site and stored before dispensing the Period 1 blinded medication.   
The patient will receive either blinded amifampridine phosphate tablets or placebo tablets for 
8 days as an outpatient, and a dose of the same medication on the day of scheduled study 
visit (Day 8) in the clinic, in order to facilitate efficacy assessments, under double-blind 
conditions. If the patient is on a BID or TID regimen during Period 1, the Day 8 assessments 
should occur after the same dose that corresponds to when assessments were done on Day 0.  
All unused medication and the container must be brought back to the study site at the end of 
Period 1. The Day 8 medication is the same as double-blind medication taken for the 
previous Period 1 days. Any unused portion of dispensed drug will be returned to the 
pharmacy before dispensing drug for the Re-Stabilization Period. A dose of medication for 
Day 8 must be administered by research study staff, in the clinic, in order to perform 
evaluations within specified time periods, as described in Section 10.3.3. 
Re-stabilization Period (Days 9-21) (+1 day) 
After Day 8 in-clinic evaluations, patients will return to open-label study drug, through Day 
21 (same dose and frequency as at the end of run-in), as prescribed by investigator and 
dispensed by research pharmacist. No dose adjustments may occur. Patients who were on 
stable dose of amifampriding phosphate with history of meaningful improvement prior to 
randomization in CMS-001, will be returned to the same stable dose and frequency during 
the re-stabilization period.  

 
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Period 2 (Days 22-29) (+1 day) 
Study medication will be dispensed by the site pharmacist on the last day of the Stabilization 
Period (i.e. Day 21), according to the randomization schedule. Patients will start the 
blinded study medication only after completion of all of the Day 22 assessments, while 
taking open-label medication, 40 minutes before starting assessments. 
Per the crossover design, patients will receive the double-blind study medication (either 
amifampridine phosphate tablets or placebo tablets) during Period 2, for 8 days (Day 22 – 29) 
as an outpatient with a dose of the same medication on the day of scheduled study visit (Day 
29), administered by study personnel in the clinic, to facilitate efficacy assessments, under 
double-blind conditions. If the patient is on a BID or TID regimen during Period 2, the Day 
29 assessments should occur after the same dose that corresponds to when assessments were 
done on Day 0. Any unused portion of dispensed drug will be returned to the site before 
enrolling the patient in the expanded access ptogram and dispensing open-label drug. 
  

 
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Table 3. 
Schedule of Events 
 
 
Run-in  
(up to 4 weeks) a 
Period I 
Re-stabilization 
Period II 
 
Screeningqr 
Start of  
Last 
 
 
Run-in 
Visit 
Days 1-8 
Days 9-21 
 
Study Assessment  
or Event d 
Days  
-14 to -1 
Day 1 
 
Day 0b, c 
Days 1-7 
Day 8 c 
(+1 d) 
Days 9-20 
Day 21 c  
(+1 d) 
Days 22-29 
Informed consent e 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
X 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
Medical history 
X 
 
X f 
 
 
 
 
 
CMS genetic testing g 
X 
 
 
 
 
 
 
 
Complete physical exam h 
X 
 
 
 
 
 
 
 
Abbreviated physical exam i 
 
 
X 
 
X 
 
X 
 
Vital signs 
X 
 
X 
 
X 
 
X 
 
12-Lead ECG  
X 
 
 
 
 
 
 
 
Clinical laboratory tests 
X 
 
X 
 
X 
 
 
 
Pregnancy test j 
X 
 
X 
 
 
 
X 
 
IP dispense 
 
X 
X k 
 
X l, 
 
X k 
X 
IP Administration m,p 
 
X 
 
X n 
X n 
X n 
Xn 
X n 
 
 

 
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Table 3. 
Schedule of Events 
 
 
Run-in  
(up to 4 weeks) a 
Period I 
Re-stabilization 
Period II 
 
Screeningqr 
Start of  
Last 
 
 
Run-in 
Visit 
Days 1-8 
Days 9-21 
 
Study Assessment  
or Event d 
Days  
-14 to -1 
Day 1 
 
Day 0b, c 
Days 1-7 
Day 8 c 
(+1 d) 
Days 9-20 
Day 21 c  
(+1 d) 
Days 22-29 
IP accountability 
 
 
X 
 
X 
 
X 
 
 
 
SGI (patient/parent/ 
guardian/caregiver) 
 
 
X 
 
X 
 
X 
 
 
MFM 20 or 32 (depending  
on age of patient) 
X 
X 
X 
 
X 
 
X 
 
CGI-S 
X 
 
X 
 
X 
 
X 
 
CGI-I 
 
 
X 
 
X 
 
X 
 
Stimulated single fiber EMGo 
X 
 
 
 
X 
 
 
 
Slurp Testo 
X 
 
X 
 
X 
 
X 
 
Adverse eventsn 
X 
X 
X 
 
X 
 
X 
 
Concomitant medications 
X 
X 
X 
 
X 
 
X 
 
CGI, Clinical Global Impression; CGI-I, Clinical Global Impression-Improvement; CMS, congenital myasthenic snydromes; CRF, case report form; EMG, 
electromyogram; IP, investigational product (amifampridine phosphate or placebo); MFM 20 or 32, motor function measure; SAE, serious adverse event; SGI, Subject 
Global Impression 
a The first dose will be administered on Day 1. For the last 7 days of run-in, study drug dose must be stable before patient is eligible for randomization.  

 
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Table 3. 
Schedule of Events 
 
 
Run-in  
(up to 4 weeks) a 
Period I 
Re-stabilization 
Period II 
 
Screeningqr 
Start of  
Last 
 
 
Run-in 
Visit 
Days 1-8 
Days 9-21 
 
Study Assessment  
or Event d 
Days  
-14 to -1 
Day 1 
 
Day 0b, c 
Days 1-7 
Day 8 c 
(+1 d) 
Days 9-20 
Day 21 c  
(+1 d) 
Days 22-29 
b All assessments and results must be available before randomization on Day 0. 
c In-clinic visit. 
d All safety assessments (vital signs, laboratory tests) are to be performed before the dose administered to the patient during the scheduled in-clinic visit unless specified 
otherwise. All efficacy assessments will be performed at standardized times relative to the dosing time of the day according to the efficacy assessments schedule in 
Section 10.7. 
e Informed consent must be obtained before any study procedures are performed. 
f Any changes since the Screening Visit will be noted. 
g CMS genetic testing will be conducted if not previously done or available. If previously done, a copy of the results should be included in the patient’s CRF.  
h Complete physical examination includes evaluation of all major body systems, including weight at all visits and height at Screening only (Section 10.6.6). 
i An abbreviated physical exam may be performed as clinically indicated.  
j Serum pregnancy tests will be obtained from female patients of childbearing potential only at Screening; urine dipstick for the remainder of the study. 
k Patients will be provided blinded packages containing amifampridine phosphate or placebo depending on their group assignment. 
l Open-label amifampridine phosphate will be dispensed at the Day 8 visit after all dosing and assessments have been completed for Period 1. Patient to get open-label 
amifampridine phosphate at the same dose and frequency as at the last run-in visit. 
m Rescue dose amifampridine phosphate will be available in case of worsening symptoms in patients previously well-controlled on the drug during open-label run-in or 
during stabilization. 
n SAE reporting commences when informed consent is signed. Non-serious adverse event reporting commences on Day 1 of run-in (Section 11). 
o  Stimulated single fiber EMG and Slurp test are optional assessments. 
p It is recommended that doses of IP be taken with food. 
q Screening and Day 1 visit may be cominbed into a single visit. 
 

 
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Period II 
 
 
Day 29 c 
(+1 d) 
Early  
Discontinuation c 
Study Assessment or Event d 
 
X 
Complete physical exam h 
X 
 
Abbreviated physical exam 
 
X 
Vital signs 
X 
X 
12-Lead electrocardiogram (ECG)  
X 
X 
Clinical laboratory tests 
X 
X 
Pregnancy test j 
X 
X 
IP dispense 
 
 
IP administration 
X 
X 
IP accountability 
X 
X 
Subject Global Impression (SGI, patient/parent/guardian/caregiver) 
X 
X 
Motor function measure (MFM) 20 or 32 (depending on age of patient) 
X 
X 
Clinical Global Impression-Severity (CGI-S) 
X 
X 
Clinical Global Impression-Improvement (CGI-I) 
X 
X 
Stimulated single fiber electromyogram (EMG)o 
X 
X 
Slurp testo 
X 
X 
Adverse eventsn 
X 
X 
Concomitant medications 
X 
X 

 
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10.2 Selection of Study Population 
Criteria for participation in the study are provided in Sections 10.2.1 and 10.2.2. 
10.2.1 Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following inclusion 
criteria: 
1. Patient or parent 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, 
or the patient’s legal guardian or caregiver with durable power of attorney can provide 
written informed consent. An assent form must also be signed if, in the judgement of 
the IRB/IEC/REB, children are capable of providing assent. 
2. Male or female 2 years of age and above. 
3. Body weight ≥10 kg. 
4. Genetically-confirmed CMS involving acetylcholine receptor defect, Rapsyn 
deficiency, MuSK deficiency, Dok-7 deficiency, SYT2 mutations, SNAP25B 
deficiency, and fast channel syndrome. 
5. In patients who are naïve to 3,4-DAP or amifampridine phosphate, MFM 20 or 32 score 
equal or less than 48 or 76, respectively, at Screening 
6. In patients who are naïve to 3,4-DAP or amifampridine phosphate, improvement of 
>20% in MFM 20 or MFM 32 scores after open label period of uptitration of dose 
7. In patients previously stabilized on 3,4-DAP or amifampridine phosphate, history of 
meaningful improvement in motor function (in the opinion of the investigator).  
8. Willingness of patients receiving pyridostigmine, albuterol, ephedrine, or fluoxetine to 
remain on a stable dose of these medications throughout the study interval. 
9. Female patients of childbearing potential must have a negative pregnancy test (serum 
human chorionic gonadotropin [HCG] at Screening); and must practice effective, 
reliable contraceptive regimen during the study. Acceptable methods of contraception 
include hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or 
vaginal ring), intrauterine device, barrier methods (diaphragm, condom) with spermicide, or 
surgical sterilization (tubal ligation). 

 
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10. 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. 
10.2.2 Exclusion Criteria 
Individuals who meet any of the following exclusion criteria are not eligible to participate in 
the study: 
1. CMS subtype diagnosis of acetylcholinesterase deficiency, slow-channel syndrome, 
LRP4 deficiency, and plectin deficiency. 
2. Cardiac conduction defects on Screening ECG. 
3. Seizure disorder. 
4. Clinically significant abnormal laboratory values at Screening, in the opinion of the 
investigator. Pregnancy or breastfeeding at Screening or planning to become pregnant at 
any time during the study. 
5. Pregnancy or breastfeeding at Screening or planning to become pregnant at any time 
during the study. 
6. Any systemic bacterial or other infection, which is clinically significant in the opinion 
of the investigator and has not been treated with appropriate antibiotics. 
7. Treatment with an investigational drug (other than amifampridine or amifampridine 
phosphate), device, or biological agent within 30 days before Screening or while 
participating in this study. 
8. Any other 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. 
9. History of drug allergy to any pyridine-containing substances or any amifampridine 
phosphate excipient(s). 
10.2.3 Removal of Patients from Treatment or Assessment 
Patients/parent/guardian 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.  

 
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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; or 
• Patient becomes pregnant (refer to Section 11.4 for details on the reporting 
procedures to follow in the event of pregnancy). 
Reasons for which the investigator or Catalyst may withdraw a patient from the study 
include, but are not limited to, the following: 
• Patient does not adhere to study requirements specified in the protocol; 
• Patient was erroneously admitted into the study or does not meet inclusion criteria; or 
• Patient is lost to follow-up. 
If a patient fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the patient cannot be reached by telephone, a certified letter should 
be sent to the patient requesting contact with the investigator. This information should be 
recorded in the study records. 
The investigator or designee must explain to each patient (parent/guardian), 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 and Randomization 
Each patient will be assigned a unique patient identification number. Upon signing of the 
ICF, subjects will be assigned an ID composed of a two digit site number and a two digit 
subject number (e.g. site 1 subject 1 would be assigned 01-01). Screen failures that are 
allowed to be re-screend will keep the same site assigned ID. There are no plans to replace 
subjects that drop out of the study.  

 
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Randomization will be across sites to maintain the 1:1 ratio of drug:placebo assignment. The 
assignments to treatment (amifampridine phosphate or placebo) will be based on a computer-
generated randomization code. A central point of contact will be provided to the site 
pharmacist to obtain the treatment sequence for the subject to be enrolled in Period 1 on the 
last day of the run-in period (Day 0). 
10.2.5 Re-screening 
Re-screening of screen failures will be allowed, if re-screening is approved by the Medical 
Monitor. Justification of the reason for re-screening must be clearly stated in the patient’s 
source documentation. No new consent would be required if re-screened within 30 days.  
10.3 Treatments 
10.3.1 Treatments Administered 
Catalyst or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study.  
Investigational product: Amifampridine phosphate tablets 10 mg will be provided in round, 
white-scored tablets, and containing amifampridine phosphate formulated to be the 
equivalent of 10 mg amifampridine base per tablet. The product will be provided to the 
pharmacy department, who will dispense the necessary amount for each part of the study. 
Placebo: A placebo equivalent will be provided as tablets indistinguishable from the 
amifampridine phosphate tablets. The placebo will be administered consistent with the dose 
regimen of amifampridine phosphate.  
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 site pharmacy department into suitably sized pharmacy 
bottles for patient use. Placebo will be provided as tablets indistinguishable from 
amifampridine phosphate. The amifampridine phosphate tablets and placebo tablets will be 
clearly labeled and the pharmacist is responsible for dispensing the amifampridine phosphate 
tablets or placebo tablets, as needed, for each patient. 
Each bottle will be labeled to include the compound name, site number, patient ID number, 
date dispensed, storage instructions, the statement ‘Caution – New Drug – Limited by 
Federal law to investigational use,’ trial number, manufacturer name and address, and area 
for instructions for use.  
10.3.2.2 
Storage 
At the study site, all IP must be stored at room temperature (20-25 degrees Celsius) and in a 
secure area accessible only to the designated pharmacist and clinical site personnel. All IP 
must be stored and inventoried, and the inventories must be carefully and accurately 
documented according to applicable national and local regulations, ICH GCP, and study 
procedures. 
10.3.3 Directions for Administration 
All doses of study treatment will be taken at home, except during the in-clinic study visit. If 
the patient takes the IP two or more times a day, then the patient should be given specific 
instructions on dosing relative to the time of their clinic visit to assure a dose will be given 
H3PO4
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NH2
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during the in-clinic visits. A dose must be administered in the clinic in order to facilitate 
efficacy assessments. All safety assessments (vital signs, laboratory tests) are to be 
performed before the dose administered to the patient during the scheduled in-clinic visit. All 
efficacy assessments will be performed at standardized times relative to the dose 
administered in the clinic. In this case, the dose will be 40 minutes before the first efficacy 
assessment. 
Assessment 
Start Time  
After Dose* 
(± 10 minutes unless 
otherwise specified) 
SGI 
40 minutes 
MFM 20 or 32 
after SGI 
Sitmulated Single fiber EMG^ 
after SGI 
Slurp test^, CGI-S and CGI-I 
At end of assessments 
 
 
*Administration of medication represents Time 0 (minutes) 
 
 
^Optional test  
If the stimulated single fiber EMG (optional assessment) is not to be performed, then the 
slurp test (also optional), CGI-S and CGI-I assessments should be done following completion 
of the MFM.   
The dose of amifampridine phosphate will be individually determined by the investigator, 
within the bounds of a total daily dose of 10 mg to 80 mg, divided into doses taken 2 to 
4 times per day generally taken with food (e.g. breakfast, lunch, dinner, and snack before 
bed) as prescribed by the investigator, based on optimal neuromuscular benefit (see Table 4). 
All doses of study medication will be taken orally by mouth, with the following exceptions: 
• children unable to swallow tablets will have the tablets crushed and mixed with a 
small amount of food; and 
• children with a nasogastric or gastrostomy tube will have the tablets crushed and 
diluted in 5 to 10 mL of water and given through the tube. 

 
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Table 4. Dosing Guidelines 
 
Childrena 
 
Ages up to 3 Years 
Ages 3 to 16 Years 
Ages >16 years 
Recommended 
starting dose 
1 mg/kg/day, 3 times per 
day (to a maximum of 
5 mg, 3 times a day) 
5 mg, 3 times per day 
(15 mg/day total) 
10 mg, 3 times per day 
(30 mg/ day total) 
Initial dose 
escalation 
May increase dose to 
1 mg/kg, 4 times per day 
May increase dose to 
10 mg, 3 times per day 
(30 mg/day total) 
May increase dose to 
10 mg, 4 times per day 
(40 mg/day total) 
Subsequent dose 
escalations 
May increase dose by 
1 mg/kg/day to the 
maximum daily dose of 
60 mg/day 
May increase dose to 
10 mg, 4 times per day 
(40 mg/day total) 
May continue to titrate 
dose to 15 mg, 4 times per 
day (60 mg/day total) 
May titrate dose up to 
20 mg, 4 times per day 
(80 mg/day total) 
Maximum dose: 
60 mg/day 
60 mg/day 
80 mg/day 
a Study medication will be crushed and mixed with a small amount of food for children unable to swallow 
tablets, and children with a nasogastric or gastrostomy tube will have the tablets crushed and diluted in 5 to 
10 mL of water and given through the tube. 
 
Titration during the run-in phase will be at investigator’s discretion per guidelines in Table 4. 
The investigator may contact the patient every 3 to 4 days to evaluate clinical improvement 
and determine if an adjustment of study dose is needed. During double-blind, placebo-
controlled treatment, rescue dose amifampridine phosphate will be available in case of 
worsening symptoms to a level that is worse than their baseline, prior to treatment. The Chief 
Medical Officer needs to be contacted to discuss breaking the blind. 
10.3.4 Method of Assigning Patients to Treatment Groups 
Patients will be randomized on the last day of the open-label run-in period (Day 0) to either 
Treatment Sequence 1 or 2, in a 1:1 ratio. Based upon the Treatment Sequence assigned, 
patients will receive either amifampridine phosphate or placebo in Period 1 and the other 
treatment in Period 2. A stabilization period using open-label amifampridine phosphate will 
occur between switches of amifampridine phosphate and placebo. IP will be administered 
under double-blind conditions for each Sequence.  
The randomization code will be provided by Catalyst or designee to the site Pharmacist. 
Details will be included in the Pharmacy Manual.  

 
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10.3.5 Selection of Doses Used in the Study 
The amifampridine phosphate dose is 10 mg to 80 mg total daily dose, given in 2 to 4 divided 
doses, with no single dose >15 mg in patients up to 16 years of age or >20 mg in patients 
>16 years of age. 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 a double-blind study where both the patients (parent/guardian/caregiver) and 
investigator will be blinded to treatment assignment. 
10.3.7 Treatment Compliance 
Patients will be instructed to return all IP containers and remaining study 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 study site pharmacy is responsible for maintaining accurate records (including dates and 
quantities) of IP(s) received, patients to whom IP is dispensed (patient-by-patient dose 
specific accounting), IP returned, and IP lost or destroyed. The investigator, study site 
pharmacy 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. 
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 a 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. 

 
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10.4 
Prior and Concomitant Medications 
All prescription and over-the-counter medications and herbal and nutritional supplements 
taken by a patient for 14 days before the Screening visit will be recorded on the designated 
case report form (CRF).  
The investigator may prescribe additional medications during the study, as long as 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 prohibited during the study are listed in Table 5. 
Table 5. 
Medications Prohibited During Study 
Any investigational product (other than amifampridine phosphate) or an investigational medical 
device within 30 days before Screening 
 
The following medicinal products should be use with caution in patients taking 
amifampridine phosphate: 
Medicinal products known to cause cardiac QT prolongation 
Medicinal products known to lower epileptic threshold 
Medicinal products with atropinic effects  
The concomitant use of amifampridine phosphate and medicinal products with atropinic 
effects may reduce the effect of both active substances and should be taken into 
consideration. Medicinal products with atropinic effects include tricyclic anti-depressants, 
most H1 atropinic anti-histamines, anticholinergic, anti-Parkinson medicinal products, 
atropinic antispasmodics, disopyramide, phenothiazine neuroleptics and clozapine.  
Medicinal products with cholinergic effects  
The concomitant use of amifampridine phosphate and medicinal products with cholinergic 
effects (e.g. direct or indirect cholinesterase inhibitors) may lead to an increased effect of 
both products and should be taken into consideration.  
Non-depolarizing muscle relaxant acting medicinal products  

 
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The concomitant use of amifampridine phosphate and medicinal products with non-
depolarizing muscle relaxant effects (e.g. mivacurium, pipercurium) may lead to a decreased 
effect of both products and should be taken into consideration.  
Depolarizing muscle relaxant acting medicinal products  
The concomitant use of amifampridine phosphate and medicinal products with depolarizing 
muscle relaxant effects (e.g. suxamethonium) may lead to a decreased effect of both products 
and should be taken into consideration. 
 
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 must use effective forms of 
contraception, such as condom for males or occlusive cap (diaphragm or cervical/vault caps) 
for females, during the study. 
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 3 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 3 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 
rate in breaths per minute. Weight (kg) and temperature in degrees Celsius (°C) will also be 
measured. Clinically significant changes from baseline will be recorded as AEs. 

 
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10.6.3 Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are provided in Table 3 
for the tests required by Protocol. The scheduled clinical laboratory tests are listed in Table 6. 
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. 
Table 6. 
Clinical Laboratory Tests 
Liver Function Tests 
Renal Function Tests 
Electrolytes 
Other 
Alkaline phosphatase 
Blood urea nitrogen 
Sodium 
Pregnancy test, if 
applicable 
ALT (SGPT) 
Creatinine  
Potassium 
AST (SGOT) 
 
Chloride 
CMS genetic testing a 
 
 
Calcium 
 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CMS, congenital 
myasthenic syndromes; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic 
transaminase. 
a At Screening, if not previously done or available. If previously done, a copy of the CMS genetic testing 
results should be included in the patient’s CRF. 
 
10.6.4 Pregnancy Testing 
Female patients of childbearing potential will have a serum (at Screening) or urine pregnancy 
test at any other time points specified in the Schedule of Events (Table 3) and in Section 13. 
Female patients with a positive pregnancy test at Screening do not meet eligibility criteria for 
enrollment.  
Refer to Section 11.4 for details on the reporting procedures to follow in the event of 
pregnancy. 
10.6.5 Electrocardiogram 
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 3) and in Section 13. Clinically significant changes from baseline will be recorded 
as AEs.  
10.6.6 Physical Examination 
A complete physical examination will be performed at the time points specified in the 
Schedule of Events in Table 3 and in Section 13. Complete physical examination will include 
assessments of general appearance as well as the following: 
• 
Head 
• 
Eyes 
• 
Ears 
• 
Nose 
• 
Throat 
• 
Cardiovascular 
• 
Dermatologic 
• 
Lymphatic 
• 
Respiratory 
• 
Gastrointestinal 
Weight will be measured with each physical examination throughout the study. Height will 
be measured at screening only. 
Other body systems may be examined. Clinically significant changes from baseline will be 
recorded as AEs. 
An abbreviated physical examination may be performed as clinically indicated. The 
procedures and assessments for performing an abbreviated physical examination will be at 
the discretion of the investigator. 

 
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10.7 
Efficacy Variables 
The timing of required evaluation is described in the Schedule of Events in Table 3 according 
to the sequence listed below. 
Assessment 
Start Time  
After Dose* 
(± 10 minutes unless 
otherwise specified) 
SGI 
40 minutes 
MFM 20 or 32 
after SGI 
Stimulated Single fiber EMG 
after MFM 
Slurp test, CGI-S and CGI-I 
At end of assessments 
 
 
*Administration of medication represents Time 0 (minutes) 
If the stimulated single fiber EMG (optional assessment) is not to be performed, then the 
slurp test (also optional), CGI-S and CGI-I assessments should be done following completion 
of the MFM.   
10.7.1 Subject Global Impression 
The SGI (Farrar, 2001) is a 7-point scale on which the patient rates their global impression of 
the effects of a study treatment (1 = terrible to 7 = delighted). The SGI will be assessed by 
the patient or the patient’s parent/guardian/caregiver if the patient is unable to complete the 
SGI. The SGI has demonstrated concordance with the physician’s assessment of 
improvement (Dodick, 2007). Instructions for the SGI are provided in Appendix 1 and the 
CMS-001 Study Reference Manual. 
10.7.2 Motor Function Measure 
The standard MFM 32 (Bérard, 2005) evaluates the severity and progression of motor 
function and is applicable to all degrees of disease severity, in both ambulant and 
nonambulant patients. It is not, however, well suited as an outcome measure in young 
children because of the time required to complete the MFM and difficulty in completion in 
terms of childrens’ cognitive and motor development. A short-form (MFM 20) (de Lattre, 
2013) will be used in this study for patients 2 years up to 7 years of age, with each of 20 
items scored on a 4-point Likert scale (based on patient’s best abilities without assistance): 
standing and transfers (8 items); axial and proximal motor function (8 items); and distal 
motor function (4 items). Total MFM 20 score ranges from 0 to 60. The MSM 32 will be 
used for patients 7 years of age and older, with each of 32 items scored on a 4-point Likert 

 
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scale (based on patient’s best abilities without assistance): standing and transfers (13 items), 
axial and proximal motor function (12 items), and distal motor function (7 items). Total 
MFM 32 score ranges from 0 to 96. Higher MFM 20 or 32 scores indicate more functional 
improvement. 
MFM 20 or 32 will be administered at the protocol specified time points by the same well 
trained evaluator throughout the study. Instructions for conducting the MFM 20 and MFM 32 
are provided in Appendix 2 and Appendix 3, respectively, and in the CMS-001 Study 
Reference Manual. 
10.7.3 Clinical Global Impression Scales 
The CGI score is a 2-part observer-rated instrument that assesses 1) severity of the patient’s 
disease (CGI-S) at a given point in time and 2) change from baseline (CGI-I). This 
instrument is widely used and well validated (Busner, 2009). The investigator will complete 
the 7-point CGI-S based on his/her experience of severity in the CMS population as a whole 
as the point of reference. Instructions for the CGI-S are contained in Appendix 4 and the 
CMS-001 Study Reference Manual. 
The CGI-I captures the investigator’s global impression of the patient’s improvement or 
worsening from baseline status. The 7-point scale is scored by the investigator based on 
changes in symptoms, behavior, and functional abilities. Instructions for the CGI-I are 
contained in Appendix 5 and the CMS-001 Study Reference Manual. 
10.7.4 Stimulated Single Fiber Electromyogram 
Stimulated single fiber EMG is a method to assess the integrity of the neuromuscular 
junction. The principal of stimulated single fiber EMG is to measure the time variability of 
the muscle fiber action potentials as they are generated by the discharges of the motor neuron 
(SFEMG using voluntary activation) versus the variability of a single muscle fiber potential 
(SFEMG using motor axonal stimulation). In infants, young children, or patients having 
difficulty in making a controlled activation, stimulated jitter analysis is preferable. From a 
technical standpoint, facial muscles such as the frontalis and orbicularis oculi are the easiest 
to record by stimulating the distal branch of the facial nerve supplying them with a 
monopolar needle electrode. The latter has less associated stimulation artifact and better 
control of the stimulating impulse. Since the recordings are made with a disposable 
concentric needle electrode, the term “jitter analysis” is preferred as being semantically more 
correct than single fiber EMG. Stimulated jitter analysis will be performed by a certified 
electromyographer. Local anesthetic agent will be applied to the site of needle electrode 

 
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examination 30 minutes before the procedure. Not all patients can tolerate the procedure so 
this test is optional. 
10.7.5 Slurp Test 
Patient’s with neuromuscular disorders experience increasing weakness of bulbar-innervated 
muscles that may result in aspiration or catastrophic airway compromise. The “Slurp” test is 
a non-invasive way of assessing bulbar function (Hudspeth 2006), particularly in children. 
Four ounces (120 mL) of water is placed in a cup. The patient is instructed to drink the entire 
contents of the cup through a standard flex straw as quickly as possible, making a loud 
slurping sound at the end. The duration of time from the start of drinking the water to the 
slurp sound will be measured. This test is optional. Slurp tests will be initiated during the up-
titration phase by parents or investigators until reliable performance is achieved, thereafter 
only at identified places in the protocol timeline.  
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 course of the study. 
• Pre-existing medical conditions judged by the investigator to have worsened in 
severity or frequency or changed in character during the study. 
• Complications that occur as a result of non-drug protocol-imposed interventions.  
An adverse drug reaction is any AE for which there is a reasonable possibility that the IP 
caused the AE. “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the IP and the AE. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis. 
The study period during which all non-serious AEs will be reported begins after informed 
consent is obtained and the first administration of study drug through the last visit (Study 
Day 29) or at the early termination visit. After informed consent but prior to initiation of 
study treatment, only SAEs associated with any protocol-imposed interventions will be 
reported. The criteria for determining, and the reporting of SAEs is provided in Section 11.2. 

 
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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.  
The investigator will determine the severity of each AE using the following Common 
Terminology Criteria for Adverse Events (CTCAE) v 4 grades defined in Table 7 (the event 
will be recorded on the source documents and AE CRF) (Appendix 5). Events that are 
CTCAE grades 4 and 5 are serious events and require completion of both an SAE form and 
AE CRF. Adverse events that do not have a corresponding CTCAE term will be assessed 
according to the general guidelines for grading used in the CTCAE v4 as stated below. 
Table 7. 
Categories of Severity for CTCAE Criteria 
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 ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
** Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 

 
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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 8. 
Table 8. 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 eCRF, using Medical Dictionary for Regulatory Activities 
(MedDRA) terminology. 
11.2 
Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 
1 or more of the following criteria: 
• Is fatal 
• Is life threatening 
• Note: Life-threatening refers to an event that places the patient at immediate risk 
of death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death 

 
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• Requires or prolongs in-patient hospitalization 
• 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.  
For this study, a generalized tonic-clonic convulsion/seizure is to be considered an SAE. 
The reporting period for SAEs begins after informed consent is obtained and continues 
through 4 weeks after the last dose or at the early discontinuation 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. 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 to Catalyst. 
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 eCRF and in the patient’s medical record. 
For some SAEs, Catalyst 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 of any death or SAE occurring at any time after a 
patient has discontinued, or terminated study participation, if felt to be related to prior study 
treatment. Catalyst should also be notified if the investigator should become aware of the 
development of cancer, or of a congenital anomaly, in a subsequently conceived offspring of 
a patient that participated in this study.  
Reporting of SAEs to the IRB, IEC or REB will be done in compliance with the standard 
operating procedures and policies of the IRB, IEC or REB and with applicable regulatory 
requirements. Adequate documentation must be provided showing that the IRB IEC or REB 
was properly and promptly notified as required. 

 
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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. 
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. 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 
IRB/EC/REB 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 within 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 CMS-001 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. 
Gary Ingenito, MD, PhD 
Chief Medical Officer 
Catalyst Pharmaceuticals, Inc. 
Tel: +1 305-420-3200, ext. 123 
Email: gingenito@catalystpharma.com 
 
12 APPROPRIATENESS OF MEASUREMENTS 
The measures of safety used in this study are routine clinical and laboratory procedures.The 
efficacy measures use a variety of approaches to evaluate changes in neuromuscular function 
and muscle strength. These standardized tests have been previously used for determination of 
response to therapeutic intervention in patients with MG and in other indications and, thus, are 
relevant for use in this study in patients with CMS. 

 
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13 STUDY PROCEDURES 
13.1 Screening Visit 
An ICF must be signed and dated by the patient, parent or legal guardian, the investigator or 
designee, and witness (if required) before any study-related procedures are performed. Refer 
to Section 10.4 for prohibited medications. 
After ICF signed, the patient will be screened for enrollment into the study. The study 
activities listed below will be performed during the 1 to 14 days that constitute the Screening 
visit. 
• Informed Consent; 
• Assessment of Inclusion/Exclusion criteria; 
• Demographics (sex, race, ethnic origin, age); 
• Medical history, including allergy history and number of hospitalizations or ER visits 
in last 6 months; 
• CMS genetic testing, if not previously done and report available; 
• Standard resting 12-lead ECG; 
• Complete physical examination including weight and height;  
• Vital signs (seated position), including systolic blood pressure (SBP), diastolic blood 
pressure (DBP), heart rate, respiration, and body temperature;  
• Clinical laboratory tests; 
• For females of child bearing potential, a serum pregnancy test will be taken at 
Screening.; 
• MFM 20 or 32; 
• Stimulated single fiber EMG (optional); 
• CGI-S; 
• Slurp test (optional); 
• Assessment of SAEs; and 
• Assessment of concomitant medications. 
13.2 
Open-label Run-in 
Patients, previously not on amifampridine phosphate treatment for CMS may visit the study 
site for weekly visits for up to 4 weeks throughout the run-in period for the assessments and 

 
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procedures listed in Table 3. Efficacy measurements will be performed during or at the end 
of run-in to document improvement or maintenance of optimal benefit of study drug. 
Additional visits or telephonic interactions are allowed as necessary. 
At the end of this period (Day 0), patients must have been on a stable dose and frequency for 
7 days and show at least a 20% improvement in MFM 20 or 32 (depending on the age of 
patient) from Day 1 of Run-in.  
Patients aleady receiving amifampridine phosphate treatment for CMS meeting the inclusion 
and exclusion criteria are eligible to participate in this study. They can be randomized into 
Period 1 if on stable dose and frequency for 1 week before being randomized to a Treatment 
Sequence. Improvement of at least 20% in MFM 20 or 32 is not a requirement for these 
participants.  
Patients who are deemed eligible will be administered amifampridine phosphate for Day 0 at 
the study site, by the study personnel, and have the assessments/procedures listed below 
completed, in relation to the time of receiving study medication on Day 0, before 
randomization. 
• Confirmation of Inclusion/Exclusion criteria; 
• Assessment of AEs/SAEs; 
• Abbreviated physical exam with weight; 
• Vital signs (seated position), including SBP, DBP, heart rate, respiration, and body 
temperature; 
• Clinical laboratory tests;  
• Urine pregnancy test in females of childbearing potential only; 
• Concomitant medications; 
• IP accountability; 
• Efficacy assessments, including: 
o MFM 20 or 32; 
o SGI (patient/parent/guardian/caregiver); 
o CGI-S;  
o CGI-I; and 
o Slurp test (optional). 

 
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Assessment 
Start Time  
After Dose* 
(± 10 minutes unless 
otherwise specified) 
SGI 
40 minutes 
MFM 20 or 32 
after SGI 
Slurp test, CGI-S and CGI-I 
At end of assessments 
 
 
*Administration of medication represents Time 0 (minutes) 
The site pharmacy will dispense bottles containing blinded amifampridine phosphate or 
placebo tablets, depending on the patient’s Treatment Sequence assignment, for daily 
outpatient administration for 7 days (Days 1-7). Administration of blinded study medication 
will begin with  the next scheduled dose following the Day 0 baseline assessment on open-
label medication. (see Section 13.3). 
13.3 
Period  1 
Administration will be continued on an outpatient basis for a total of 7 days (Days 1-7).  
On Day 8 (+1) patients will be given a dose of the same study medication as the previous 7 
days by the study personnel, at the site, so that the assessments/procedures listed below will 
be completed in relation to the time of study medication dosing. 
• Assessment of AEs/SAEs; 
• Abbreviated physical exam with weight; 
• Vital signs (seated position), including SBP, DBP, heart rate, respiration, and 
body temperature; 
• Clinical laboratory tests; 
• Concomitant medications; 
• IP accountability; 
• Efficacy assessments, including: 
o MFM 20 or 32; 
o SGI (patient/parent/guardian/caregiver); 
o Stimulated Single fiber EMG (optional); 
o CGI-S;  
o CGI-I; and 

 
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o Slurp test (optional). 
 
Assessment 
Start Time  
After Dose* 
(± 10 minutes unless 
otherwise specified) 
SGI 
40 minutes 
MFM 20 or 32 
after SGI 
Stimulated Single fiber EMG 
after MFM 
Slurp test, CGI-S and CGI-I 
At end of assessments 
 
 
*Administration of medication represents Time 0 (minutes) 
If the stimulated single fiber EMG (optional assessment) is not to be performed, then the 
slurp test (also optional), CGI-S and CGI-I assessments should be done following completion 
of the MFM. 
Open-label amifampridine phosphate will be dispensed at the Day 8 visit for administration 
during the stabilization period, starting with the next scheduled dose after Day 8 assessments 
(see Section 13.4). 
13.4 
Re-stabilization Period 
Patients will return to their prior open-label amifampridine phosphate dose established in the 
run-in phase for 2 weeks, Day 9 through Day 21. 
Patients will report to the study site on Day 21 (+1 day) and have the assessments/procedures 
listed below completed. 
• Assessment of AEs/SAEs; 
• Abbreviated physical exam with weight; 
• Vital signs (seated position), including SBP, DBP, heart rate, respiration, and 
body temperature; 
• Urine pregnancy test in females of childbearing potential only; 
• Concomitant medications; 
• IP accountability; 
• Efficacy assessments, including: 
o MFM 20 or 32; 

 
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o SGI (patient/parent/guardian/caregiver); 
o CGI-S;  
o CGI-I; and 
o Slurp test (optional). 
Assessment 
Start Time  
After Dose* 
(± 10 minutes unless 
otherwise specified) 
SGI 
40 minutes 
MFM 20 or 32 
after SGI 
Slurp test, CGI-S and CGI-I 
At end of assessments 
 
 
 
*Administration of medication represents Time 0 (minutes) 
A The slurp test (optional), CGI-S and CGI-I assessments should be done following 
completion of the MFM. 
 
The site will dispense bottles containing amifampridine phosphate or placebo tablets, 
depending on the patient’s Treatment Sequence assignment, for Period 2 (Days 22-28). 
Administration of blinded study medication will begin with the next scheduled dose after 
Day 21 assessments are completed (see Section 13.5). 
13.5 
Period 2 
Patients will the blinded study medication they did not receive in Period 1. Administration 
will be continued on an outpatient basis for a total of 7 days (Days 22-28). 
Patients will report to the study site on Day 29 (+1 day) and receive a dose of the same study 
medication they received for the previous 7 days, under the supervision of the study 
personnel, in order to time the following assessments/procedures in relation to the medication 
dose. 
• Assessment of AEs/SAEs; 
• Complete physical exam with weight; 
• Vital signs (seated position), including SBP, DBP, heart rate, respiration, and 
body temperature; 
• Standard resting 12-lead ECG; 
• Clinical laboratory tests; 

 
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• Urine pregnancy test in females of childbearing potential only; 
• Concomitant medications; 
• IP accountability; 
• Efficacy assessments, including: 
o MFM 20 or 32; 
o SGI (patient/parent/guardian/caregiver); 
o Stimulated single fiber EMG (optional); 
o CGI-S; 
o CGI-I; and 
o Slurp test (optional). 
Assessment 
Start Time  
After Dose* 
(± 10 minutes unless 
otherwise specified) 
SGI 
40 minutes 
MFM 20 or 32 
after SGI 
Stimulated Single fiber EMG 
after MFM 
Slurp test, CGI-S and CGI-I 
At end of assessments 
 
 
*Administration of medication represents Time 0 (minutes) 
If the stimulated single fiber EMG (optional assessment) is not to be performed, then the slurp 
test (also optional), CGI-S and CGI-I assessments should be done following completion of the 
MFM. 
After completion of the above procedures/assessments, patients will be eligible for an 
expanded access program. 
13.6 Early Discontinuation Visit 
Any patient that discontinues from the study, regardless of the reason, will be requested to 
complete all Early Discontinuation visit assessments/procedures as listed below after the last 
dose of IP. Every reasonable effort should be made to contact any patient who is lost to 
follow-up. 
• Assessment of AEs/SAEs; 
• Complete physical examination with weight; 

 
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• Vital signs (seated position), including SBP, DBP, heart rate, respiration, and 
body temperature; 
• Standard resting 12-lead ECG; 
• Clinical laboratory tests; 
• Urine pregnancy test in females of childbearing potential only; 
• Concomitant medications; 
• IP accountability; and 
• Efficacy assessments, including: 
o MFM 20 or 32; 
o SGI (patient/parent/guardian/caregiver); 
o Stimulated Single fiber EMG (optional); 
o CGI-S; 
o CGI-I; and 
o Slurp test (optional). 
The date of the last dose of study medication should be recorded in relation to Early 
Discontinuation assessments. 
 
14 DATA QUALITY ASSURANCE 
Catalyst personnel or designees will visit the study site before initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, CRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs.  
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on CRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records.  
Data quality control and analysis will be performed by Catalyst or a designee, based on a 
predefined analysis plan. 

 
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15 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
15.1 Determination of Sample Size 
Assuming a standardized between-treatment difference of 0.5, 23 patients per sequence will 
ensure power of 90% for the 2-sided test at the 0.05 level using the standard 2-by-2 crossover 
analysis.  
15.2 Safety Analysis 
Safety analyses will be conducted on the safety population (i.e. all patients who receive at 
least 1 dose of amifampridine phosphate or placebo). The safety analysis will be descriptive 
and will be presented on observed data only. All safety data, and corresponding Change 
From Baseline (CFB) if appropriate, will be listed. 
15.3 Adverse Events 
All treatment-emergent adverse events (TEAEs) will be summarized by the treatment at the 
time of onset. Counts and percentages will be presented by treatment for each observed 
system organ class (SOC) and preferred term (PT) as defined in MedDRA. Summaries by 
level of severity and relationship to treatment will be presented by treatment at the time of 
occurrence. Listings of all deaths, SAEs, and discontinuations due to AE will be provided. 
15.4 Laboratory Tests 
For each laboratory parameter, descriptive statistics will be presented for the observed value 
and CFB by treatment at the time of the assessment. The frequency and percentage of 
patients who experience abnormal (i.e. outside of reference ranges) laboratory values will be 
presented by treatment at the time of the assessment. Clinically significant abnormalities will 
be collected as AEs. 
15.5 Other Safety Assessments 
Summary statistics for vital signs, physical examinations, and ECG parameters will be 
presented by treatment at the time of the assessment. 
15.6 
Efficacy Analysis 
The following provides a summary of the planned statistical analyses. Details will be 
provided in a separate Statistical Analysis Plan (SAP), which will be finalized prior to 
unblinding. Any inconsistency between the SAP and the protocol will be noted in the SAP.  
Efficacy analyses will be performed for 2 datasets: 

 
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Full Analysis Set (FAS): This population consists of all randomized patients who receive at 
least 1 dose of IP (amifampridine phosphate or placebo) and have at least one post-treatment 
efficacy assessment. 
Per Protocol (PP): This population is a subset of the FAS population, excluding patients with 
major protocol deviations. 
If the PP Population is the same as the FAS, then the results will be presented only for the 
FAS. Exclusion from the FAS and PP Population will be finalized prior to database lock and 
subsequent unblinding. 
In addition to the following, summary statistics will be provided by treatment and period for 
CGI-I, CGI-S, Change From Baseline (CFB) for CGI-S, the optional Slurp Test, and 
variables associated with the optional SFEMG. 
15.7 Primary Efficacy Analysis 
The analysis of CFB for SGI is the primary efficacy analysis and will be performed using the 
standard analysis for a 2-by-2 crossover design. Summary statistics for SGI and CFB for SGI 
will be presented by treatment and period. P-values <0.05 wil be considered statistically 
significant. 
15.8 Secondary Efficacy Analysis 
The total score for MFM and the subtotal for each of the three dimensions (Standing and 
transfer, Axial and proximal motor function, and Distal motor function) will be standardized 
by the possible maximum for both MFM 20 and MFM 32. The CFB for these standardized 
scores will be analyzed using the standard analysis for a 2-by-2 crossover design for 
MFM 20 and MFM 32 separately and pooled, with the latter being the secondary and the 
separate analyses being supportive. The total scores, subtotals for each dimension, and the 
corresponding standardized scores will be summarized by treatment and period for MFM 20 
and MFM 32 separately and standardized scores will be summarized by treatment and period 
for MFM 20 and MFM 32 pooled. P-values <0.05 wil be considered statistically significant. 
15.9 Changes in the Conduct of the Study  
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. In these circumstances, immediate approval 
of the chairman of the IRB/IEC/REB must be sought, and the investigator should inform 
Catalyst and the full IRB/IEC/REB within 2 working days after the emergency occurs. 

 
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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 IRB/IEC/REB 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 
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. The 
treating physician should bill the patient’s health insurance company or other third party 
payer for the cost of this medical treatment. 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. In some jurisdictions, Catalyst 
is obligated by law to pay for study-related injuries without prior recourse to third party 
payer billing. If this is the case, Catalyst will comply with the law. 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS 
The CRO data management department or designees will perform all data management 
activities, including the writing of a data management plan outlining the systems and 
procedures to be used. 
Study data on will be captured on CRFs and 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 sign the completed CRF 
casebook to verify its accuracy.  

 
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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 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 a 
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.  
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 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, but not less than 15 years. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 

 
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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 for 
the full 15 years. 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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Lundh H, Nilsson O, Rosen I, Johansson S. (1993). Practical aspects of 3,4-diaminopyridine 
treatment of the Lambert-Eaton myasthenic syndrome . Acta Neurol Scand , 
88[2]:136-140. 
Maddison P, Newsom-Davis J, Mills KR. (1998a). 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. 
Maddison P, Newsom-Davis J, Mills KR. (1998b). Maddison P, Newsom-Davis J, Mills KR. 
Distribution of electrophysiological abnormality in Lambert-Eaton myasthenic 
syndrome. J Neurol Neurosurg Psychiatry, 65:213-217. 
Mazell S, Verma S. (Submitted for 62nd AANEM Annual meeting ). Clinical and jitter 
change during oral amifampridine phosphate treatment in Congenital Myasthenia 
Gravis. . (Abstract). 
McEvoy KM, Windebank AJ, Daube JR, Low PA. (1989). 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. 
Milone M, Shen XM, Selcen D, Ohno K, et al. (2009). Myasthenic syndrome due to defects 
in rapsyn: clinical and molecular findings in 39 patients. Neurology, 73(3):228-235. 
Moreau T, Sochurkova D, Lemesle M, Madinier G, et al. (1998). Epilepsy in patients with 
multiple sclerosis: radiological-clinical correlations. Epilepsia, 39[8]:893-896. 

 
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Oh SJ, Claussen GG, Hatanaka Y, Morgan MB. (2009). 3,4-Diaminopyridine is more 
effective than placebo in a randomized, double-blind, cross-over drug study in LEMS. 
Muscle Nerve, 40[5]:795-800. 
Palace J, Wiles CM, Newsom-Davis J. (1991). 3,4-Diaminopyridine in the treatment of 
congenital (hereditary) myasthenia. J Neurol Neurosurg Psychiatry, 54[12]:1069-
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Parr JR, Andrew MJ, Finnis M, Beeson D, Vincent A, Jayawant S. (2014). How common is 
childhood myasthenia? The UK incidence and prevalence of autoimmune and 
congenital myasthenia. Arch Dis Child, 99(6):539–542. 
Pasnoor M, W. G. (2010). Clincal findings in MuSK-antibody positive myasthenia gravis: A 
U.S. experience. Muscle & Nerve, 41:370-374. 
Sabbagh A, Darlu P. (2006). SNP selection at the NAT2 locus for an accurate prediction of 
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Sanders DB, Howard JF Jr, Massey JM. (1993). 3,4-Diaminopyridine in Lambert-Eaton 
myasthenic syndrome and myasthenia gravis. Ann N Y Acad Sci, 681:588-590. 
Sanders DB, Massey JM, Sanders LL, Edwards LJ. (2000). A randomized trial of 3,4-
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Selcen D, M. M. (2008). Dok 7 myasthenia: phenotypic and molecular genetic studies in 16 
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Skeie GO, Apostolski S, Evoli A, Gilhus NE, et al. (2006). Guidelines for the treatment of 
autoimmune neuromuscular transmission disorders. . Eur J Neurol, 13[7]:691-699. 
Skeie GO, Apostolski S, Evoli A, Gilhus NE, et al. (2010). Guidelines for the treatment of 
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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 in the course of 
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’s 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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23 SIGNATURE PAGE 
Protocol Title: A Phase 3, Multicenter, Double-blind, Placebo-controlled, Randomized, 
Outpatient Two-period Two-treatment Crossover Study to Evaluate the Efficacy and Safety 
of Amifampridine Phosphate (3,4-Diaminopyridine Phosphate) in Patients with Congenital 
Myasthenic Syndromes (CMS) 
Protocol Number: CMS-001 
I have read the forgoing protocol and agree to conduct this study as outlined. I agree to 
conduct the study in compliance with all applicable regulations and guidelines, including 
ICH E6, as stated in the protocol, and other information supplied to me. 
 
 
 
Investigator Signature 
 
Date 
 
Printed name:  
 
 
Accepted for Catalyst: 
On behalf of Catalyst, I confirm that Catalyst, as a sponsor will comply with all obligations 
as detailed in all applicable regulations and guidelines. I will ensure that the Investigator is 
informed of all relevant information that becomes available during the conduct of this 
protocol.  
 
 
 
Medical Monitor Signature 
 
Date 
Printed name: 
Gary Ingenito, MD, PhD 
 
Chief Medical Officer 
 
Catalyst Pharmaceuticals, Inc. 

 
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24 APPENDICES 
Appendix 1 
Subject Global Impression (SGI) 
The SGI will be assessed at the protocol-specified time points (see Table 3) by the patient or 
the patient’s parent/guardian/caregiver if the patient is unable to complete the SGI.  
Using the 7-point scale below, rate your impression of the effects of the study medication 
during the preceding week on your physical well being.  
 
1=Terrible 
2= Mostly dissatisfied 
3= Mixed 
4=Partially satisfied 
5= Mostly satisfied  
6= Pleased 
7= Delighted  
 
Refer to the CMS-001 Study Reference Manual for additional information. 
 

 
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Appendix 2 
Motor Function Measure (MFM 32 or 20) 
The MFM 32 will be used to evaluate the severity and progression of motor function in 
patients 7 years of age and older. For patients 2 years up to 6 years of age, the MFM 20 will 
be used to evaluate the severity and progression of motor function.   The MFM 32 or 20 
(depending on age) will be administered at the protocol specified time points (see Table 3) by 
the same well trained evaluator throughout the study.  
Each of the 32 items listed below will be graded using a 4-point Likert scale based on the 
patient’s best abilities without any assistance: 
0 
Cannot initiate the task 
1 
Partially performs the task 
2 
Performs the movement incompletely, or completely but imperfectly (compensatory 
movements, position maintained for an insufficient duration of time, slowness,        
uncontrolled movement) 
3 
Performs the task fully and “normally”; the movement is controlled, mastered, 
directed, and performed at constant speed 
 
The 20 motor function measures comprising the MFM20 are marked with  (child <7 years 
old) 
Total score ranges from 0 to 96 when summing the 32 items and from 0 to 60 when summing 
the 20 items. 
 
 

 
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Items MFM 32 (from 7 to 60 years 
 
 Items MFM 20 (child <7 years old) 
1.   SUPINE, HEAD IN MIDLINE POSITION: holds the head for 5 seconds in midline position and 
turns it completely from one side to the other. 
comments : 
2.  SUPINE: raises the head and maintains the raised position for 5 second 
comments :  
3.   SUPINE: flexes the hip and knee more than 90o by raising the foot during the whole 
movement 
comments : 
side : 
right : ❑ 
left : ❑ 
4.   SUPINE, LEG SUPPORTED BY EXAMINER: from the plantar flexion, dorsiflexes 
the foot to at least 90° in relation to the lower part of the leg. 
comments: 
side : 
right : ❑ 
left : ❑ 
5.   SUPINE: raises the hand and moves it to the opposite shoulder. 
comments: 
 
side : 
right : ❑ 
left : ❑ 
6.    SUPINE, LOWER LIMBS HALF-FLEXED, KNEECAPS AT THE ZENITH AND 
FEET RESTING ON THE MAT SLIGHTLY APART: maintains for 5 seconds the starting 
position then raises the pelvis ; the lumbar spine, the pelvis and the thighs are aligned and the 
feet slightly apart. 
comments: 
7.   SUPINE: turns over into prone and frees both upper limbs from under the trunk. 
comments: 
side : 
right : ❑ 
left : ❑ 
8.   SUPINE: without upper limb support sits up. 
comments: 
9.   SEATED ON THE MAT: without upper limb support, maintains the seated position 
for 5 seconds and is then capable of maintaining contact 5 seconds between the two hands. 
comments: 

 
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Items MFM 32 (from 7 to 60 years 
 
 Items MFM 20 (child <7 years old) 
10.   Seated on the mat, THE tennis ball placed in front of the PERSON without upper limb support, 
leans forward, touches the ball and sits back again. 
comments: 
11.   SEATED ON THE MAT: without upper limb support, stands up. 
comments: 
12.   STANDING: without upper limb support, sits down on the chair with the feet 
slightly apart. 
comments: 
13.  SEATED ON THE CHAIR: without upper limb support nor leaning against the back 
of the chair, maintains the seated position for 5 seconds, with the head and trunk in midline 
position. 
comments: 
14.  SEATED ON THE CHAIR OR IN THE WHEELCHAIR, HEAD IN FLEXION: 
from head in complete flexion, raises the head then maintains it raised for 5 seconds, the head 
stays in midline position throughout the movement and the holding position. 
comments: 
15.  SEATED ON THE CHAIR OR IN THE WHEELCHAIR, FOREARMS ON THE 
TABLE BUT NOT ELBOWS: places both hands on top of the head at the same time while the 
head and trunk remain in midline position. 
comments: 
16.  SEATED ON THE CHAIR OR IN THE WHEELCHAIR, THE PENCIL ON THE 
TABLE: without moving the trunk, reaches the pencil with one hand, forearm and hand off the 
table with the elbow in full extension at the end of the movement. 
comments: 
side : 
 
 
 
 
right : ❑ 
left : ❑ 
17.  SEATED ON THE CHAIR OR IN THE WHEELCHAIR, 10 COINS ON THE TABLE: successively 
picks up and holds 10 coins in one hand during a 20-second period. 

 
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Items MFM 32 (from 7 to 60 years 
 
 Items MFM 20 (child <7 years old) 
comments: 
side : 
right : ❑ 
left : ❑ 
18.   SEATED ON THE CHAIR OR IN THE WHEELCHAIR, ONE FINGER 
PLACED IN THE CENTER OF THE FIXED CD: goes round the edge of the CD with the same 
finger without hand support on the table. 
comments: 
side : 
right : ❑ 
left : ❑ 
19.  SEATED ON THE CHAIR OR IN THE WHEELCHAIR, THE PENCIL ON THE 
TABLE: picks up the pencil and draws a continuous series of loops inside the frame and over its full 
length touching the top and bottom line of the frame. 
 
Trial n° 1 
 
Trial n° 2 
comments: 
side : 
right : ❑ 
left : ❑ 
20.  SEATED ON THE CHAIR OR IN THE WHEELCHAIR, HOLDING THE SHEET 
OF PAPER: tears the sheet of paper folded in 4, beginning from the fold edge. 
comments: 
 
21.   SEATED ON THE CHAIR OR IN THE WHEELCHAIR, THE TENNIS BALL   ON THE 
TABLE: picks up the ball, and turns the hand over completely holding the ball. 
comments: 
 
side : 
 
 
 
 
right : ❑ 
left : ❑ 
22.   SEATED ON THE CHAIR OR IN THE WHEELCHAIR, ONE FINGER PLACED IN THE 
CENTER OF THE DIAGRAM: raises the finger and places it successively on the 8 drawings without 
touching the lines. 
comments: 
 
side : 
 
 
 
 
right : ❑ 
left : ❑ 

 
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23.   SEATED ON THE CHAIR OR IN THE WHEELCHAIR, UPPER LIMBS ALONG THE TRUNK: 
places the two forearms and/or the hands on the table at the same time without moving the trunk. 
comments 
24.   SEATED ON THE CHAIR: without upper limb support, stands up with the feet slightly apart. 
comments 
25.  STANDING WITH UPPER LIMB SUPPORT ON EQUIPMENT: without upper limb support, 
maintains a standing position for 5 seconds with the feet slightly apart, the head, trunk and limbs in midline 
position 
comments: 
26.  STANDING WITH UPPER LIMB SUPPORT ON EQUIPMENT: without upper limb support, raises 
the foot for 10 seconds. 
comments: 
 
side support: 
 
right : ❑ 
left : ❑ 
27.   STANDING: without support, touches the floor with one hand and stands up again. 
comments: 
28.  STANDING WITHOUT SUPPORT: takes 10 steps forward on both heels. 
comments: 
29.  STANDING WITHOUT SUPPORT: takes 10 steps forward on a line. 
comments: 
 
30.  STANDING WITHOUT SUPPORT: runs 10 meters. 
comments: 
31. STANDING ON ONE FOOT WITHOUT SUPPORT: hops 10 times in place. 
comments: 
side support : 
 
 
right : ❑ 
 
left : ❑ 
32.   STANDING WITHOUT SUPPORT: without upper limb support, manages to squat and gets up 
twice in a row. 
comments: 
 

 
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Appendix 3 
Clinical Global Impression-Severity (CGI-S) 
The CGI-S will be used to assess the severity of the patient’s disease. The investigator will 
complete the 7-point CGI-S, based on his/her experience of severity in the CMS population 
as a whole as the point of reference, at the protocol-specified time points (see Table 3). 
Considering your total clinical experience with this particular population, how ill is the 
patient at this time? 
 
1 = Normal, not at all ill 
2 = Borderline ill 
3 = Mildly ill 
4 = Moderately ill 
5 = Markedly ill 
6 = Severely ill 
7 = Among the most extremely ill patients 
 
Refer to the CMS-001 Study Reference Manual for additional information.  

 
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Appendix 4 
Clinical Global Impression-Improvement (CGI-I) 
The CGI-I will be used to capture the investigator’s global impression of the patient’s 
improvement or worsening from baseline status. The investigator will complete the 7-point 
CGI-I, based on changes in symptoms, behavior, and functional abilities, at the protocol-
specified time points (see Table 3). 
 
Rate total improvement whether or not, in your judgment, it is due entirely to drug treatment. 
Compared to the patient’s condition at baseline, how much has it changed? 
1 = Very much improved 
2 = Much improved 
3 = Minimally improved 
4 = No change 
5 = Minimally worse 
6 = Much worse 
7 = Very much worse 
 
Refer to the CMS-001 Study Reference Manual for additional information. 

 
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Appendix 5 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4 
 
Refer to: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf  
 
 

 
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Appendix 6: Protocol Amendment 1 
 
PURPOSE:  The purpose of this amendment is as follows: 
Administrative change to clarify  the original intent of a reasonable duration of time (at least 
3 months) between the last SGI and MFM 20 or MFM 30 assessments and the first incidence 
of these assessments in this protocol.  
 
Risk: these administrative changes provide clarity on duration between testing to avoid 
testing bias, adding no additional risk to the patient. 
 
MODIFICATIONS TO PROTOCOL: 
• Bold and underlined text:   
Changed Text 
• Bold and strike through text:  
Deleted Text 
• Bold and italicized text:  
 
Added Text 
 
On Page 1, under Date of Protocol, added text to indicate this is protocol amendent 1. 
Amendment 1: 2 February 2016 
On Page 5, first paragraph folowing header, added text: 
They must have not been previously assessed for improvement in subject global impression 
(SGI) and motor function measure (MFM 20 or 32) scores within 3 months prior to 
participating in this study to avoid testing bias. 
 
On Page 34, third paragraph under the header Open-label Run-in, deleted text: 
Patients already receiving amifampridine phosphate treatment for CMS meeting the inclusion 
and exclusion criteria are eligible to participate in this study. They can be randomized into 
Period 1 if on stable dose and frequency for 1 week before being randomized to a Treatment 
Sequence. They must have a medical history showing improvement on amifampridine 
phosphate treatment:  improvement of at least 20% in MFM 20 or 32 is not a requirement for 
these participants and will not be administered to minimize potential for testing bias. 
 

 
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On Page 62, third paragraph under section 13.2, text was added: 
Patients aleady receiving amifampridine phosphate treatment for CMS meeting the inclusion 
and exclusion criteria are eligible to participate in this study. They can be randomized into 
Period I if on stable dose and frequency for 1 week before being randomized to a Treatment 
Group. They must have a medical history showing improvement on amifampridine phosphate 
treatment: improvement of at least 20% in MFM 20 or 32 is not a requirement for these 
participants. They must have not been previously assessed for improvement in subject global 
impression (SGI) and motor function measure (MFM 20 or 32) scores within 3 months prior 
to participating in this study to avoid testing bias. 
 
 

 
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Appendix 7: Protocol Amendment 2 
 
PURPOSE:  The purpose of this amendment is as follows: 
Administrative changes to correct the use of the the term1)  “sequence” from “period”  and 2) 
outpatient versus office visit.  
Risk: these administrative changes provide clarity, adding no additional risk to the patient. 
 
MODIFICATIONS TO PROTOCOL: 
• Bold and underlined text:   
Changed Text 
• Bold and strike through text:  
Deleted Text 
• Bold and italicized text:  
 
Added Text 
 
On Page 1, under Date of Protocol, added text to indicate this is protocol amendent 2. 
Amendment 2: 7 March 2016 
 
On page 6: 
PeriodSequence II (Day 29) (+1 day) 
 
On page 44, first paragraph: 
A central point of contact will be provided to the site pharmacist to obtain the treatment 
sequence for the subject to be enrolled in Period ISequence on the last day of the run-in 
period (Day 0). 
 
On Page 63, paragraph under table: 
The site will dispense bottles containing amifampridine phosphate or placebo tablets, 
depending on the patient’s Treatment Group assignment, for daily outpatient administration 
for 7 days (Days 1-7). Administration of blinded study medication will begin with the first 
morning dose on Day 1 of Period ISequence (see Section 13.3). 
 
On Page 63, under section 13.3, Period I: 

 
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On Day 1, patients will begin administration of randomized study medication (amifampridine 
phosphate or placebo tablets) with the first morning dose. Administration will be continued 
on an outpatient basis for a total of 78 days (Days 1-78). 
 
 

 
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Appendix 8: Protocol Amendment 3 
PURPOSE:  The purpose of this amendment is as follows: 
To increase the age range eligible for the study, expand the statistical analysis section of the 
protocol, increase the number of patients in the study, and update previous instructional 
language regarding dosing on the days of clinic evaluations. 
Risk: these administrative changes provide clarity, adding no additional risk to the patient. 
 
MODIFICATIONS TO PROTOCOL: 
• Bold and underlined text:   
Changed Text 
• Bold and strike through text:  
Deleted Text 
• Bold and italicized text:  
 
Added Text 
 
On Page 1, under Date of Protocol, added text to indicate this is protocol amendent 3. 
Amendment 3: 7 July 2016 
On Page 2, under Contact Information, changed text with updated Catalyst phone number.  
Tel: +1 305 420-3200, ext. 123 
On Page 3, under Study Site, changed text to 5 sites. 
Multicenter at up to 5 sites in the United States 
On Page 3, under Objectives, changed word children for patients. 
• To characterize the overall safety and tolerability of amifampridine phosphate 
compared with placebo in patients with CMS; and 
• To assess the clinical efficacy of amifampridine phosphate compared with 
placebo in patients with CMS, based on improvement in subject global 
impression (SGI) and motor function measure (MFM 20 or 32) scores. 
On Page 3, under Study Design and Plan, deleted 10 male and female patients and added 23. 
The study is planned to include up to 23 male and female patients. The planned 
duration of participation for each patient is approximately 56 days, excluding the 
screening period, which can last up to 14 days.  
 
On Page 4, under Name of Invesigational Product, deleted 7 days and added 8 days. 

 
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Study medication at the stable dose or placebo, will be dispensed by the site pharmacist, 
according to the randomization schedule, beginning the morning of Day 1 for the 8 day 
Period 1.  Following experimental Period 1, patients will be returned to the stable dose 
administered at the end of the open-label run-in period from days 9-21, followed by 
Period 2 dosing for 8 days (Days 22-29). 
On Page 4, under Name of Invesigatinal Product, changed text from 7 days to 8 days. 
Study medication at the stable dose or placebo, will be dispensed by the site pharmacist, 
according to the randomization schedule, beginning the morning of Day 1 for the 8 day 
Period 1.  Following experimental Period 1, patients will be returned to the stable dose 
administered at the end of the open-label run-in period from days 9-21, followed by 
Period 2 dosing for 8 days (Days 22-29). 
On Page 4, under Name of Invesigatinal Product, changed ±1 and added ±2. 
Patients taking open-label amifampridine phosphate following completion of Study Day 
29 visit will return to the study site for a final safety assessment on Day 36 (±2 days). 
On Page 5, under Name of Invesigatinal Product, added “at least”. 
They can be randomized into Period 1 if on stable dose and frequency of amifampridine 
phosphate for at least 1 week before being randomized to a Treatment Sequence. 
On Page 5, under Period 1 (Day 1-8) (+1day), added text. 
7 days as an outpatient, and a dose of the same medication on the day of scheduled 
study visit on Day 8 in the clinic in order to facilitate efficacy assessments, under 
double-blind conditions. If the patient is on a BID or TID regimen during Period 1, then 
any planned dosing following the dose given by study personnel in the clinic should be 
completed on Day 8 with tablets dispensed for Period 1 after all scheduled visit 
assessments are completed. Any unused portion of dispensed drug will be returned to 
the pharmacy before dispensing drug for the Re-Stabilization Period. 
On Page 6, under Period 2 (Days 22-29) (±2days), added text.  
blinded study appropriate medication/placebo for Period 2 for 7 days (Day 22 – 28) as an 
outpatient and a dose of the same medication on the day of scheduled study visit on Day 29 
in the clinic in order to facilitate efficacy assessments, under double-blind conditions. If 
the patient is on a BID or TID regimen during Period 2, then any planned dosing 
following the dose given by study personnel in the clinic should be completed on Day 29 
with tablets dispensed for Period 2 after all scheduled visit assessments are completed. Any 
unused portion of dispensed drug will be returned to the pharmacy before dispensing 
open-label drug to begin dosing on Day 30 through the Final Safety Asssessment on Day 
36. 

 
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Follow-up and Final Safety Assessment (Days 30-36) (±2 days) 
Patients will be administered amifampridine phosphate at the same dose and frequency 
established as the stable dose in the open-label run in phase until Day 36± 2 days, under 
open-label conditions. 
On Page 6, after Final Safety Assessment (Day 36) (±2 days) changed ±1 and added ±2. 
Final Safety Assessment (Day 36) (±2 days) 
Patients taking open-label amifampridine phosphate following Study Day 29 visit will 
return to the study site for a final safety assessment on Day 36 (±2 days). 
On Page 6, under Name of Investigational Products, change from 2 to 7 years of age. 
2. Male or female age 2 years and above. 
On Page 7, under Name of Investigational Products, deleted “two forms of”.  
9.  Female patients of childbearing potential must have a negative pregnancy test (serum 
human chorionic gonadotropin [HCG] at Screening); and must practice two forms of 
effective, reliable contraceptive regimen during the study. Acceptable methods of 
contraception include hormonal contraception (i.e., birth control pills, injected hormones, 
dermal patch or vaginal ring), intrauterine device, barrier methods (diaphragm, condom) with 
spermicide, or surgical sterilization (tubal ligation). 
On Page 7, under Criteria for Inclusion and Exclusion, deleted text. 
4. Abnormal liver function tests at Screening. 
5. Abnormal kidney function tests at Screening. 
6. Abnormal electrolyte values at Screening.  
On Page 7, under Criteria for Inclusion and Exclusion, added text. 
4. Clinically significant abnormal laboratory values at Screening, in the opinion of the 
investigator. 
On Page 9, under Criteria for Evaluation, change from word child to individual.  
• MFM 20 or 32 (MFM 20 (individual <7 years) and MFM 32 (individual ≥ 7 years)); 
On Page 9, under Criteria for Evaluation, deleted words “head area” and added face.  
An approximate 20-minute video will be obtained at each protocol specified time point 
and the patient’s face will be evaluated for ptosis, extra-ocular movements, facial 
strength (i.e. smile, eye closure, puffing cheeks), and speech; as age permits. 
On Page 9, under Statistical Methods, deleted text.  
The sample size for this study is based on clinical considerations related to the epidemiology 

 
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of the disease and not on a formal statistical calculation.  
On Page 9, under Statistical Methods, changed sample size.  
Assuming a standardized between-treatment difference of 0.5, 23 patients per sequence 
will ensure power of 90% for the 2-sided test at the 0.05 level using the standard 2-by-2 
crossover analysis. 
On Page 10, under Efficacy Analysis, deleted text. 
The variability of outcome variables in this rare disease is unknown and the available sample 
size is such that there is almost certainly insufficient power to observe differences that will be 
found to be statistically significant. Thus, no formal statistical testing will be done. 
On Page 10, under Efficacy Analysis, changed text. 
If the PP Population is the same as the FAS, then the results will be presented only for 
the FAS. Exclusion from the FAS and PP Population will be finalized prior to database 
lock and subsequent unblinding. 
Summary statistics will be provided by treatment and period for CGI-I, CGI-S, Change 
From Baseline (CFB) for CGI-S, the optional Slurp Test, and variables associated with 
the optional SFEMG. 
The analysis of CFB for SGI is the primary efficacy analysis and will be performed 
using the standard analysis for a 2-by-2 crossover design. Summary statistics for SGI 
and CFB for SGI will be presented by treatment and period. P-values <0.05 wil be 
considered statistically significant. 
The total score for MFM and the subtotal for each of the three dimensions (Standing 
and transfer, Axial and proximal motor function, and Distal motor function) will be 
standardized by the possible maximum for both MFM 20 and MFM 32. The CFB for 
these standardized scores will be analyzed using the standard analysis for a 2-by-2 
crossover design for MFM 20 and MFM 32 separately and pooled, with the latter being 
the secondary and the separate analyses being supportive. The total scores, subtotals for 
each dimension, and the corresponding standardized scores will be summarized by 
treatment and period for MFM 20 and MFM 32 separately and standardized scores will 
be summarized by treatment and period for MFM 20 and MFM 32 pooled. P-values 
<0.05 wil be considered statistically significant. 
On Page 20, under Investigator and Study Administrative Structure, changed text with 
updated Catalyst phone number.  
Tel: +1 305 420-3200, ext. 123 
On page 32, under Study Rationale, deleted and added text.  
Clinical trials, case series, and case reports studying the efficacy of 3,4-DAP in patients with 
CMS have shown clinical benefit as described above in Section 8.4.2. Little controlled data 
are reported in infants and young patients, and several of these studies had patients without 
genetic confirmation of CMS and lacked sensitive, objective, rapid motor and 

 
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electrophysiologic outcome measures to study efficacy especially in infants and young 
children. In light of above mentioned advancements in field of genetics, electrophysiological 
techniques, and motor function measures, a randomized placebo-controlled trial of 3,4-DAP 
in CMS patients is warranted. Thus, the purpose of this study (CMS-001) is to evaluate the 
efficacy and safety of amifampridine phosphate in patients diagnosed with subtypes of CMS. 
On page 32, under Primary Objectives, change word children to patients. 
• To characterize the overall safety and tolerability of amifampridine phosphate compared 
with placebo in patients with CMS; and 
• To assess the clinical efficacy of amifampridine phosphate compared with placebo in 
patients with CMS, based on improvement in subject global impression (SGI) and motor 
function measure (MFM 20 or 32) scores. 
On page 32, under Overall Study Design and Plan, deleted and added text.  
This is a randomized (1:1), double-blind, placebo-controlled, outpatient two-period two-
treatment crossover study designed to evaluate the efficacy and safety of amifampridine 
phosphate in children patients (2-17 years of age and above) diagnosed with CMS. The 
study is planned to be conducted at up to 35 sites in the United States and will include up to 
approximately 10 23 male and female patients. The planned duration of participation for 
each patient is approximately 56 days excluding the screening period, which can last up to 
14 days.  
On page 34, under Overall Study Design and Plan, added text. 
After completion of of the study, patients will be eligible for expanded access program and 
receive open-label amifampridine phosphate at the same dose and frequency as established 
in the run in phase of the study. 
On Page 35, under Treatment Group A or B, added text.  
Beginning on Day 1 of Period 1, the patient will receive either amifampridine phosphate 
tablets or placebo tablets for 7 days as an outpatient, and a dose of the same medication on 
the day of scheduled study visit on Day 8 in the clinic in order to facilitate efficacy 
assessments, under double-blind conditions. If the patient is on a BID or TID regimen 
during Period 1, then any planned dosing following the dose given by study personnel in 
the clinic should be completed on Day 8 with tablets dispensed for Period 1, after all 
scheduled visit assessments are completed. All unused medication and the container must 
be brought back to the study site at the end of Period 1. The Day 8 medication is the same 
as double-blind medication taken for the previous Period 1 days 

 
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On Page 37, under Table 3, text changed from Every Week to Start of Run-in.  
Start of Run-in 
On Page 37, Table 3 under Day 1, text deleted  
(+1d) 
On Page 37, Table 3 X on IP accountability and Day 1, deleted. 
X 
On Page 38, Table 3 under Day 1, text deleted  
(+1d) 
On page 38, Table 3, under Screening, Stimulated Single Fiber EMG, added text. 
X 
On Page 39, Table 3, after d, added text. 
dose administered to the patient during the scheduled in-clinic visit 
On Page 39, Table 3, after l, added text. 
after all dosing and assessments have been completed for Period 1. 
On Page 39, Table 3, after m, added text.  
Open-label amifampridine phosphate will be dispensed at the Day 29 visit after all dosing 
and assessments have been completed for Period 2. Patient to get open-label 
amifampridine phosphate at the same dose and frequency as at the last run-in visit. 
On Page 39, Table 3, after q, added text.  
It is recommended that doses of IP be taken with food. 
On Page 38, Table 3, after r, added text.  
Screening and Day 1 visit may be cominbed into a single visit. 
On Page 40, Table 3, under Complete physical exam, added text. 
Abbreviated physical exam  
On Page 41, under Inclusion Criteria, changed text.  
2. Male or female 2 years of age and above. 
On Page 41, under Inclusion Criteria, added text.  

 
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4. Genetically-confirmed CMS involving acetylcholine receptor defect, Rapsyn 
deficiency, MuSK deficiency, Dok-7 deficiency, SYT2 mutations, SNAP25B 
deficiency, and fast channel syndrome. 
On Page 42, under Exclusion Criteria, added text.  
4. Clinically significant abnormal laboratory values at Screening, in the opinion of 
the investigator 
On Page 45, under Exclusion Criteria, deleted text. 
4. Abnormal liver function tests at Screening. 
5. Abnormal kidney function tests at Screening. 
6. Abnormal electrolyte values at Screening.  
On Page 44, under Directions for Administration, added text.  
All doses of study treatment will be taken at home, except during the in-clinic study visit. If 
the patient takes the IP two or more times a day, then the patient should be given specific 
instructions on dosing relative to the time of their clinic visit to assure a dose will be given 
during the in-clinic visit. A dose must be administered in the clinic in order to facilitate 
efficacy assessments. All safety assessments (vital signs, laboratory tests) are to be 
performed before the dose administered to the patient during the scheduled in-clinic visit. 
All efficacy assessments will be performed at standardized times relative to the dose 
administered in the clinic. In this case, the dose will be 40 minutes before the first efficacy 
assessment. 
On Page 46, in the table, changed text. 
45 minutes after SGI 
140 minutes after MFM 
160 minutes after video 
On Page 46, under table, added text.  
At the end of the MFM testing, the patient’s face will be evaluated for ptosis, extra-ocular 
movements, facial strength (i.e. smile, eye closure, puffing cheeks), and speech, as age 
permits. 
If the stimulated single fiber EMG (optional assessment) is not to be performed, then the 
slurp test (also optional), CGI-S and CGI-I assessments should be done following 
completion of the video of the patient’s face.   

 
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On Page 46, under table third paragraph, deleted text. 
as dispensed with food  
On Page 47, under Method of Assigning Patients to Treatment Groups, deleted text. 
Subjects randomized to Sequence I will receive Treatment A (amifampridine 
phosphate) in Period 1 and Treatment B (placebo) in Period 2. Subjects randomized to 
Sequence II will receive Treatement B (placebo) in Period 1 and Treatment A 
(amifampridine phosphate) in period 2.  
On Page 47, under Method of Assigning Patients to Treatment Groups, added text. 
Based upon the Treatment Sequence assigned, patients will receive either amifampridine 
phosphate or placebo in Period 1 and the other treatment in Period 2. 
On Page 52, in the table, changed text. 
45 minutes after SGI 
140 minutes after MFM 
160 minutes after video 
On Page 52, under Table, added text.  
At the end of the MFM testing, the patient’s face will be evaluated for ptosis, extra-ocular 
movements, facial strength (i.e. smile, eye closure, puffing cheeks), and speech, as age 
permits. 
If the stimulated single fiber EMG (optional assessment) is not to be performed, then the 
slurp test (also optional), CGI-S and CGI-I assessments should be done following 
completion of the video of the patient’s face.   
On Page 52, under Table, deleted text.  
The MFM testing will be videod. At the end of the MFM testing, the patient’s head area 
will be evaluated for ptosis, extra-ocular movements, facial strength (i.e. smile, eye 
closure, puffing cheeks), and speech. 
If the stimulated single fiber EMG (optional assessment) is not to be performed, then 
the slurp test (also optional), CGI-S and CGI-I assessments should be done following 
completion of the video of the patient’s head area. 
On Page 59, under Pregnacy, changed text. 
Drug Exposure via Parent Form Pregnancy Reporting Form 

 
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On Page 60, under Medical Monitor Contact Information, changed text.  
Tel: +1 305 420-3200, ext. 123 
On Page 61, under Screening Visit, deleted text. 
After patient’s parent or legal guardian has signed an ICF signed, the patient will be 
screened for enrollment into the study. The study activities listed below will be 
performed during the 1 to 14 days that constitute the Screening visit. 
On Page 61, under Screening Visit, added text.  
• CMS genetic testing, if not previously done and report available 
• Stimulated single fiber EMG 
On Page 61, under Screening Visit, deleted text. 
• 
SGI (patient/parent/guardian/caregiver); 
On Page 62, under Open-label Run-in, deleted text. 
They must have a medical history showing improvement on amifampridine 
phosphate treatment: 
On Page 63, deleted text from table. 
45 minutes after SGI 
140 minutes after MFM 
Stimulated Single fiber EMG 160 minutes  
On Page 63, under Table, added text. 
At the end of the MFM testing, the patient’s face will be evaluated for ptosis, extra-
ocular movements, facial strength (i.e. smile, eye closure, puffing cheeks), and speech, 
as age permits. 
On Page 63, under Table, deleted text. 
The MFM testing will be videod. At the end of the MFM testing, the patient’s head 
area will be evaluated for ptosis, extra-ocular movements, facial strength (i.e. smile, 
eye closure, puffing cheeks), and speech. 
If the stimulated single fiber EMG (optional assessment) is not to be performed, 
then the slurp test (also optional), CGI-S and CGI-I assessments should be done 
following completion of the video of the patient’s head area. 
On Page 63, under Period 1, deleted text and added text 
On Day 8 (+1) patients will be given a dose of their the same study medication as the 
previous 7 days study medication by the study personnel, at the site, so that the 

 
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assessments/procedures listed below will be completed in relation to the time of study 
medication dosing of the study medication. 
On Page 64, in the table, changed text. 
45 minutes after SGI 
140 minutes after MFM 
160 minutes after video 
On Page 64, under table added text.  
At the end of the MFM testing, the patient’s face will be evaluated for ptosis, extra-
ocular movements, facial strength (i.e. smile, eye closure, puffing cheeks), and speech, 
as age permits 
On Page 64, under table deleted text. 
The MFM testing will be videod. At the end of the MFM testing, the patient’s head 
area will be evaluated for ptosis, extra-ocular movements, facial strength (i.e. smile, 
eye closure, puffing cheeks), and speech. 
On Page 65, under Re-stabilization Period, deleted and added text. 
• Clinical laboratory tests; 
• Urine pregnancy test (dipstick) in females of childbearing potential only; 
On Page 65, deleted text from table. 
45 minutes after SGI 
140 minutes after MFM 
Stimulated Single fiber EMG 160 minutes  
On Page 65, under Table deleted and added text  
At the end of the MFM testing, the patient’s face will be evaluated for ptosis, extra-
ocular movements, facial strength (i.e. smile, eye closure, puffing cheeks), and speech, 
as age permits The MFM testing will be videod. At the end of the MFM testing, the 
patient’s head area will be evaluated for ptosis, extra-ocular movements, facial 
strength (i.e. smile, eye closure, puffing cheeks), and speech. 
If the stimulated single fiber EMG (optional assessment) is not to be performed, 
then tThe slurp test (optional), CGI-S and CGI-I assessments should be done 
following completion of the video of the patient’s face. 
On Page 66, under Period 2, added text. 
Patients will report to the study site on Day 29 (+1 day) and receive a dose of the 
same study medication they received for the previous 7 days, under the supervision of 

 
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the study personnel, in order to time the following and the assessments/procedures 
listed below will be completed in relation to the medication dose. 
On Page 67, under Period 2, changed text. 
• 
Complete Abbreviated physical exam with weight; 
On Page 67, under Period 2, changed text 
• Stimulated Ssingle fiber EMG; 
On Page 67, on Table, deleted and added text.  
45 minutes after SGI 
140 minutes after MFM 
160 minutes after video 
On Page 67, under Safety Follow-Up, changed text. 
Patients taking open-label amifampridine phosphate, following Study Day 29 visit, 
will return to the study site on Day 36 (±2+1 days) for a final safety assessment, 
including: 
On Page 67, under Safety Follow-Up, deleted text. 
• 
Clinical laboratory tests; 
On Page 67, under Safety Follow-Up, added text. 
• 
IP accountability. 
On Page 70, under Determination of Sample Size, changed text. 
15.1 
Determination of Sample Size 
Assuming a standardized between-treatment difference of 0.5, 23 patients per sequence 
will ensure power of 90% for the 2-sided test at the 0.05 level using the standard 2-by-2 
crossover analysis.  
15.2 
Safety Analysis 
Safety analyses will be conducted on the safety population (i.e. all patients who receive 
at least 1 dose of amifampridine phosphate or placebo). The safety analysis will be 
descriptive and will be presented on observed data only. All safety data, and 
corresponding Change From Baseline (CFB) if appropriate, will be listed. 
15.3 
Adverse Events 
All treatment-emergent adverse events (TEAEs) will be summarized by the treatment 
at the time of onset. Counts and percentages will be presented by treatment for each 

 
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observed system organ class (SOC) and preferred term (PT) as defined in MedDRA. 
Summaries by level of severity and relationship to treatment will be presented by 
treatment at the time of occurrence. Listings of all deaths, SAEs, and discontinuations 
due to AE will be provided. 
15.4 
Laboratory Tests 
For each laboratory parameter, descriptive statistics will be presented for the observed 
value and CFB by treatment at the time of the assessment. The frequency and 
percentage of patients who experience abnormal (i.e. outside of reference ranges) 
laboratory values will be presented by treatment at the time of the assessment. 
Clinically significant abnormalities will be collected as AEs. 
15.5 
Other Safety Assessments 
Summary statistics for vital signs, physical examinations, and ECG parameters will be 
presented by treatment at the time of the assessment. 
15.6 
Efficacy Analysis 
The following provides a summary of the planned statistical analyses. Details will be 
provided in a separate Statistical Analysis Plan (SAP), which will be finalized prior to 
unblinding. Any inconsistency between the SAP and the protocol will be noted in the 
SAP.  
Efficacy analyses will be performed for 2 datasets: 
Full Analysis Set (FAS): This population consists of all randomized patients who 
receive at least 1 dose of IP (amifampridine phosphate or placebo) and have at least one 
post-treatment efficacy assessment. 
Per Protocol (PP): This population is a subset of the FAS population, excluding patients 
with major protocol deviations. 
If the PP Population is the same as the FAS, then the results will be presented only for 
the FAS. Exclusion from the FAS and PP Population will be finalized prior to database 
lock and subsequent unblinding. 
In addition to the following, summary statistics will be provided by treatment and 
period for CGI-I, CGI-S, Change From Baseline (CFB) for CGI-S, the optional Slurp 
Test, and variables associated with the optional SFEMG. 
15.7 
Primary Efficacy Analysis 

 
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The analysis of CFB for SGI is the primary efficacy analysis and will be performed 
using the standard analysis for a 2-by-2 crossover design. Summary statistics for SGI 
and CFB for SGI will be presented by treatment and period. P-values <0.05 wil be 
considered statistically significant. 
15.8 
Secondary Efficacy Analysis 
The total score for MFM and the subtotal for each of the three dimensions (Standing 
and transfer, Axial and proximal motor function, and Distal motor function) will be 
standardized by the possible maximum for both MFM 20 and MFM 32. The CFB for 
these standardized scores will be analyzed using the standard analysis for a 2-by-2 
crossover design for MFM 20 and MFM 32 separately and pooled, with the latter being 
the secondary and the separate analyses being supportive. The total scores, subtotals for 
each dimension, and the corresponding standardized scores will be summarized by 
treatment and period for MFM 20 and MFM 32 separately and standardized scores will 
be summarized by treatment and period for MFM 20 and MFM 32 pooled. P-values 
<0.05 wil be considered statistically significant. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 9: Protocol Amendment 4 
PURPOSE:  The purpose of this amendment is as follows: 
To formally remove the videotaping of patients from the protocol, clarify the start and stop 
times of Periods 1 and 2, blinded medication dosing, and remove the Day 36 visit.  The 
patient is either on a stable dose of amifampridine phosphate or has been titrated over a 
period of 4 weeks. Also, the patient is observed on open label medication for 2 weeks during 
the restabilization period.  Therefore, the Day 36 visit on open label medication adds no new 
information to the efficacy or safety profile of amifampridine phosphate and the patient may 
go directly into the expanded access program. 
Risk: these administrative changes provide clarity, adding no additional risk to the patient. 
 
MODIFICATIONS TO PROTOCOL: 
• Bold and underlined text:   
Changed Text 
• Bold and strike through text:  
Deleted Text 
• Bold and italicized text:  
 
Added Text 
 
On Page 1, under Clinical Study Protocol, added text 
Date of Amendment 4: 
25 April 2017 
On Page 3, under Study Site, added text  
Multicenter at up to 5 sites in the United States and 3 sites in Canada 
On Page 4, under Name of Investigational Product, added text  
Patients on a stable dose of amifampridine phosphate with a history of meaningful 
improvement in motor function are eligible immediately for randomization. 
On Page 4, under Name of Investigational Product, added and deleted text  
Study medication at the stable dose or placebo, will be dispensed by the site pharmacist, 
according to the randomization schedule, beginning the morning of Day with the dose 
following completion of assessments on Day 0 and 1 for the 8 day Period 1. 
On Page 4, under Name of Investigational Product, added text   
Patients who were on a stable does of amifampriding phosphate with history of meaningful 
improvement prior to randomization in CMS-001, will be returned to the same stable dose 
from days 9-21, followed by Period 2 dosing for 8 days (Days 22-29). 
On Page 4, under Name of Investigational Product, added text 

 
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Patients who were on stable dose of amifampriding phosphate with history of meaningful 
improvement prior to randomization in CMS-001, will be returned to the same stable dose 
and frequency during their participation in the expanded access program.   
On Page 4, under Name of Investigational Product, deleted text 
Patients taking open-label amifampridine phosphate following completion of Study Day 
29 visit will return to the study site for a final safety assessment on Day 36 (±2 days). 
On Page 5, under Name of Investigational Product, added and deleted text 
Measurements of clinical improvement will be administered at the outset and during this 
time, timed repeated as clinically indicated during the titration period, to demonstrate 
assess open-label efficacy 
On Page 5, under Name of Investigational Product, deleted text 
They must have not been previously assessed for improvement in subject global 
impression (SGI) and motor function measure (MFM 20 or 32) scores within 3 months 
prior to participating in this study to avoid testing bias. 
On Page 5, under Name of Investigational Product, deleted and added text  
Patients already receiving 3,4-DAP or amifampridine phosphate treatment for CMS, and 
meeting the inclusion and exclusion criteria are eligible to participate in this study. if they 
have a medicalThe patient should report or investigator judges there is a history of 
improvement on 3,4-DAP or amifampridine phosphate treatment; improvement of at least 
20% in MFM 20 or 32 is not a requirement for these participants.  
On Page 5, under Name of Investigational Product, added and deleted text 
Beginning on Day 1 of Period 1Only after assessments are completed on Day 0, the patient 
will begin to receive either amifampridine phosphate tablets or placebo tablets for 7 8 days as 
an outpatient, and with a dose of the same medication on the day of scheduled study visit 
(Day 8) in the clinic, in order to facilitate efficacy assessments, under double-blind 
conditions. If the patient is on a BID or TID regimen during Period 1, then any planned 
dosing following the dose given by study personnel in the clinic should be completed on 
Day 8 with tablets dispensed for Period 1 after all scheduled visit assessments are 
completed.the Day 8 assessments should occur after the same dose that corresponds to 
when assessments were done on Day 0.  Any unused portion of double-blind dispensed drug 
will be returned to the pharmacy site before dispensing drug for the Re-Stabilization Period. 
 
 
 

 
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On Page 5, under Re-Stabilization Period (Days 9-21) (+1 day), added text Patients who 
were on stable dose of amifampriding phosphate with history of meaningful improvement 
prior to randomization in CMS-001, will be returned to the same stable dose and frequency 
during the re-stabilization period. 
On Page 6, under Period 2 (Days 22-29) (+1 day) 
After completion of Period 1 and the re-stabilization period, according to randomization 
sequence, patients will receive the blinded study medication/placebo for Period 2 for 7 8 days 
(Day 22 – 2829) as an outpatient and with a dose of the same medication on the day of 
scheduled study visit (Day 29) in the clinic, in order to facilitate efficacy assessments, under 
double-blind conditions. If the patient is on a BID or TID regemen regimen during Period 2, 
then any planned dosing following the dose given by study personnel in the clinic should 
be completed on Day 29 with tablets dispensed for Period 2 after all scheduled visit 
assessments are completedthe Day 29 assessments should occur after the same dose that 
corresponds to when assessments were done on Day 0. Any unused portion of double-blind 
dispensed drug will be returned to the pharmacy site before enrolling the patient in the 
expanded access program and dispensing open-label drug. to begin dosing on Day 30 
through the Final Safety Asssessment on Day 36. 
Follow-up and Final Safety Assessment (Days 30-36) (±2 days) 
Patients will be administered amifampridine phosphate at the same dose and frequency 
established as the stable dose in the open-label run-in phase until Day 36± 2 days, under 
open-label conditions. 
 
Final Safety Assessment (Day 36) (±2 days) 
Patients taking open-label amifampridine phosphate following Study Day 29 visit will 
return to the study site for a final safety assessment on Day 36 (±2 days). 
On Page 6, under Name of Investigational Product, added text 
1. Patient or parent 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, or the patient’s legal guardian or caregiver with durable power of 
attorney can provide written informed consent.  An assent form must also be signed if 
in the judgement of the IRB/IEC/REB the children are capable of providing assent. 
 
 

 
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On Page 7, under Criteria for Inclusion and Exclusion, added text  
5. 
In patients who are naïve to 3,4-DAP or amifampridine phosphate, MFM 20 or 32 
score equal or less than 48 or 76, respectively, at Screening. 
6. 
In patients who are naïve to 3,4-DAP or amifampridine phosphate, improvement of 
>20% in MFM 20 or MFM 32 scores after open label period of uptitration of dose 
7. 
In patients who are previously stabilized on 3,4-DAP or amifampridine phosphate, a 
history of meaningful improvement in motor function (in the opinion of the investigator). 
On Page 7, under Name of Investigational Product, added text 
8. Willingness of patients receiving pyridostigmine, prednisone, albuterol, ephedrine, 
or fluoxetine to remain on a stable dose of these medications throughout the study 
interval. 
On Page 8, under Duration of Treatment, deleted and added text 
Up to Approximately 6356 days (excluding up to 14-day screening period) after enrollment. 
On Page 9, under Efficacy, deleted text  
• Patient video of the face; 
 
Videography, using standardized technology and equipment, will be used to evaluate 
patient progress. An approximate 20-minute video will be obtained at each protocol 
specified time point and the patient’s face will be evaluated for ptosis, extra-ocular 
movements, facial strength (i.e. smile, eye closure, puffing cheeks), and speech; as age 
permits. 
On Page 8, under Criteria for Inclusion and Exclusion, deleted and added text 
7.  
Treatment with an investigational drug (other than amifampridine 3,4-DAP 
or amifampridine phosphate), device, or biological agent within 30 days 
before Screening or while participating in this study. 
8.  
Any other 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 confounds the assessment of the patient. 
9. 
History of drug allergy to any pyridine-containing substances or any 
amifampridine phosphate excipient(s). 
9.10. History of drug allergy to any pyridine-containing substances or any 
amifampridine or amifampridine phosphate excipient(s). 

 
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On Page 18, under 6.1 Independent Ethics Committee, deleted and added text 
 (IRBIRB/IEC/REB) 
On Page 19, under 6.3 Patient Information and Informed Consent, deleted and added text 
 (IRBIRB/IEC/REB) 
On Page 32, under 10.1 Overall Study Design and Plan, deleted and added text 
The study is planned to be conducted at up to 5 sites in the United States and 2 sites in 
Canada, and willto include approximately 23 male and female patients 
On Page 33, under 10.1 Overall Study Design and Plan, deleted and added text 
The planned duration of participation for each patient is approximately 56 up to 63 days 
excluding the screening period, which can last up to 14 days. 
All patients who have had a(parent or legal guardian) who sign an informed consent will be 
screened for eligibility to participate in the study, including: inclusion and exclusion criteria; 
medical and medication history; complete physical exam; standard 12-lead ECG; laboratory 
testing; serum pregnancy testing (females of childbearing potential only; result must be 
negative to proceed into the run-in period with open-label IP administration); and CMS 
genetic testing (if not previously done or available).  
On Page 33, under 10.1 Overall Study Design and Plan, deleted and added text 
Patients already receiving 3,4-DAP or amifampridine phosphate treatment for CMS, and 
meeting the applicable inclusion and exclusion criteria are eligible to participate in this 
study. The patient should report or investigator judges there is a history of meaningful 
improvement in motor function on 3,4-DAP or amifampridine phosphate treatment; 
improvement of at least 20% in MFM 20 or 32 is not a requirement for these participants. 
Patients who are on a stable dose of amifampridine phosphate with a history of 
meaningful improvement in motor function, they can be randomized into Period 1. The 
patient should be on that stable dose and frequence of amifampridine phosphate for at 
least 1 week before being randomized to a Treatment Sequence. Patients on a stable dose 
of amifampridine phosphate with history of meaningful improvement in motor function 
are eligible immediately to randomization, while Tthose patients who are on a stable dose 
of 3,4-DAP will be transitioned to equivalent dose of amifampridine phosphate for 7 days 
prior to randomization to treatment.   
 
 

 
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On Page 33 and 34, under 10.1 Overall Study Design and Plan, deleted and added text 
Administration of Period 1 study medication (amifampridine phosphate or placebo) begins 
with the morning dose the day after randomization (i.e. Day 1)after all assessments have 
been completed on Day 0. Every attempt should be made to have the same individual 
perform all assessments for a patient throughout the study, and at approximately the same 
time of dayafter the same dose used for Day 0 assessments. Following Period 1, patients 
will be returned to the same stable dose administered at the end of the open-label run-in 
period for days 9-21, followed by Period 2 dosing for 8 days. Patients will be taking open-
label amifampridine phosphate following Study Day 29 visit and will return to the study 
site for a final safety assessment on Day 36 (±2 days day). Patients who were on a stable 
does of amifampriding phosphate with history of meaningful improvement prior to 
randomization in CMS-001, will be returned to the same stable dose from days 9-21, 
followed by Period 2 dosing for 8 days. After completion of of the study, patients will be 
eligible for expanded access program and receive open-label amifampridine phosphate at the 
same dose and frequency as established in the run-in phase of the study. Patients who were 
on stable dose of amifampriding phosphate with history of meaningful improvement prior 
to randomization in CMS-001, will be returned to the same stable dose and frequency 
during their participation in the expanded access program.   
Following successful completion of the Run-in and randomization on Day 0, study visits will 
occur on Day 8 (+1 day), Day 21 (+1 day), and Day 29 (+1 day), and Day 36 (±2 days) 
(final safety assessment) or, if applicable, early discontinuation from the study. Note that 
should a shift in days occur (i.e. +1 day), then rest of schedule must shift to keep sequence 
and stabilization periods constant. 
On Page 34, under Open-Label Run-in, moved text  
Patients already receiving amifampridine phosphate treatment for CMS meeting the inclusion 
and exclusion criteria are eligible to participate in this study. They must have a medical 
history showing improvement on amifampridine phosphate treatment; improvement of 
at least 20% in MFM 20 or 32 is not a requirement for these participants. They can be 
randomized into Period 1 if on stable dose and frequency for 1 week before being 
randomized to a Treatment Sequence. They must have a medical history showing 
improvement on amifampridine phosphate treatment:  improvement of at least 20% in 
MFM 20 or 32 is not a requirement for these participants. 
On Page 34, under Open-Label Run-in, added text  

 
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Those patients who are on a stable dose of 3,4-DAP with a history of meaningful 
improvement will be transitioned to equivalent dose of amifampridine phosphate for 7 days 
prior to randomization to treatment. Improvement of at least 20% in MFM 20 or 32 is not 
a requirement for these participants. 
On Page 35, under Period 1 (Days 1-8) (+1 day), deleted and added text  
The administration of blinded medication will begin only after completion ofng all 
assessments of Day 0. The Day 0 assessments are performed while taking a dose of 
open-label amifampridine phosphate in the clinic, 40 minutes before starting the 
assessments.    
On Page 35, under Period 1 (Days 1-8) (+1 day), deleted and added text.  
Study medication (amifampridine phosphate tablets or placebo tablets) for Period 1 will be 
dispensed on Day 0, the last day of the Run-in, by the site pharmacist, according to the 
randomization schedule., with The administration of blinded medication will to begin with 
the morning dose the day after randomization (i.e. Day 1)only after completing all 
assessments of the Day 0. The Day 0 assessments are performed while taking  a dose of 
open-label amifampridine phophatephosphate in the clinic, 40 minutes before starting the 
assessments.  Beginning on Day 1 of Period 1, t Any supply of open-label amifampridine 
phosphate should be collected by the study site and stored before dispensing the Period 1 
blinded medication.   
The patient will receive either blinded amifampridine phosphate tablets or placebo tablets for 
7 8 days as an outpatient, and a dose of the same medication on the day of scheduled study 
visit (Day 8) in the clinic, in order to facilitate efficacy assessments, under double-blind 
conditions. If the patient is on a BID or TID regimen during Period 1, then any planned 
dosing following the dose given by study personnel in the clinic should be completed on 
Day 8 with tablets dispensed for Period 1, after all scheduled visit assessments are 
completed.the Day 8 assessments should occur after the same dose that corresponds to 
when assessments were done on Day 0.   
On Page 35, under Re-stabilization Period (Days 9-21) (+1 day), deleted text 
After Day 8 in-clinic evaluations, patients will return to open-label study drug the next day, 
from Day 9 through Day 21 (same dose and frequency as at the end of run-in), as prescribed 
by investigator and dispensed by research pharmacist. 
On Page 35, under Re-stabilization Period (Days 9-21) (+1 day), added text 

 
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No dose adjustments may occur. Patients who were on stable dose of amifampriding 
phosphate with history of meaningful improvement prior to randomization in CMS-001, 
will be returned to the same stable dose and frequency during the re-stabilization period. 
On Page 36, under Period 2 (Days 22-29) (+1 day), deleted and added text 
Study medication will be dispensed by the site pharmacist on the last day of the Stabilization 
Period (i.e. Day 21), according to the randomization schedule. Patients will start the blinded 
study medication with the morning dose on Day 22after completing all of the Day 22 
assessments, while on taking open-label medication, 40 minutes before starting 
assessments 
Per the crossover design, patients will receive the double-blind study medication (either 
amifampridine phosphate tablets or placebo tablets) during Period 2, for 7 8 days (Day 22 – 
289) as an outpatient and with a dose of the same medication on the day of scheduled study 
visit (Day 29), administered by study personnel in the clinic, to facilitate efficacy 
assessments, under double-blind conditions. If the patient is on a BID or TID regimen during 
Period 2, then any planned dosing following in-clinic treatment should be completed on 
Day 29 with tablets dispensed for Period 2, after all scheduled visit assessments are 
completed.the Day 29 assessments should occur after the same dose that corresponds to 
when assessments were done on Day 0. Any unused portion of dispensed drug will be 
returned to the pharmacy site before dispensing drug to begin dosing on Day 30 until 
Final Safety Asssessment on Day 36enrolling the patient in the expanded access ptogram 
and dispensing open-label drug. 
Final Safety Assessment (Day 36) (±2 days) 
Patients taking open-label amifampridine phosphate following Study Day 29 visit will return 
to the study site on Day 36 (±2 days) for a final safety assessment, as described in the 
Schedule of Assessments in Table 3 and Section 13.  
On Page 37, on Table 3. Schedule of Events, between IP dispense and Days 22-29 
deleted text  
Xm 
On Page 37, on Table 3. Schedule of Events, IP Administration added and deleted text 
IP Administration n,qm,p 
On Page 37, on Table 3. Schedule of Events, between IP Administration and Days 1-7, 
deleted and added  

 
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X on 
On Page 37, on Table 3. Schedule of Events, between IP Administration and Day 8 c 
(+1 d), deleted and added 
X on 
On Page 37, on Table 3. Schedule of Events, between IP Administration and Days 9-20, 
deleted and added  
X on 
On Page 37, on Table 3. Schedule of Events, between IP Administration and Day 21 c  
(+1 d), deleted and added 
XoXn 
On Page 37, on Table 3. Schedule of Events, between IP Administration and Days 22-29, 
deleted and added  
X on 
On Page 38, on Table 3. Schedule of Events, deleted row  
Patient 
video 
X 
 
X 
 
X 
 
X 
 
 
On Page 38, on Table 3. Schedule of Events, deleted text 
mOpen-label amifampridine phosphate will be dispensed at the Day 29 visit after all 
dosing and assessments have been completed for Period 2. Patient to get open-label 
amifampridine phosphate at the same dose and frequency as at the last run-in visit. 
 
On Page 39, on Table 3. Schedule of Events, deleted text 
nm 
Rescue dose amifampridine phosphate will be available in case of worsening 
symptoms in children previously well-controlled on the drug during open-label run-in or 
during stabilization after completion of Sequence I. 
on 
SAE reporting commences when informed consent is signed. Non-serious adverse 
event reporting commences on Day 1 of run-in (Section 111111). 
po    Stimulated single fiber EMG and Slurp test are optional assessments. 

 
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qp 
It is recommended that doses of IP be taken with food. 
r  q Screening and Day 1 visit may be cominbed into a single visit. 
On Page 40, on Table 3. Schedule of Events, deleted row  
Patient video 
X 
 
X 
On Page 40, on Table 3. Schedule of Events, deleted column  
Follow-Up 
Day 36 c  
(±2 d) 
X 
 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
On Page 41, under 10.2.1 Inclusion Criteria, deleted and added text 
(IRBIRB/IEC/REB) 

 
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On Page 41, under 10.2.1 Inclusion Criteria, added text  
 
5. MFM 20 or 32 score equal or less than 48 or 76, respectively, at Screening. 
 
6. In patients naïve to 3,4-DAP or amifampridine phosphate, improvement of 
>20% in MFM 20 or MFM 32 scores after open label period of uptitration of 
dose 
 
7. In patients previously stabilized on 3,4-DAP or amifampridine phosphate, 
history of meaningful improvement in motor function (in opinion of 
investigator). 
On Page 45, under 10.3.2.1 Product Characteristics and Labeling, deleted text 
(Firdapse® 10 mg Tablets) 
On Page 46, under 10.3.3 Directions for Administration on Table, deleted and added text 
Patient video 
after MFM 
Sitmulated Single fiber EMG^ 
after videoSGI 
 
 
*Administration of medication represents Time 0 (minutes) 
 
 
^Optional test 
 At the end of the MFM testing, the patient’s face will be evaluated for ptosis, extra-
ocular movements, facial strength (i.e. smile, eye closure, puffing cheeks), and speech, 
as age permits. 
If the stimulated single fiber EMG (optional assessment) is not to be performed, then the 
slurp test (also optional), CGI-S and CGI-I assessments should be done following completion 
of the video of the patient’s faceMFM.   
The dose of amifampridine phosphate will be individually determined by the investigator, 
within the bounds of a total daily dose of 10 mg to 80 mg, divided into doses taken 2 to 
4 times per day generally taken with food (e.g. breakfast, lunch, dinner, and snack before 
bed) as prescribed by the investigator, based on optimal neuromuscular benefit (see Table 4). 
On Page 49, on Table 5. Medications Prohibited During Study, deleted rows 

 
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Immunomodulatory treatment (e.g. IVIG) within 3 weeks before Screening 
Plasmapheresis (PE or TPE) within 3 weeks before Screening 
Rituximab within 6 months before Screening 
Any investigational product (other than amifampridine phosphate) or an investigational medical 
device within 30 days before Screening 
 
On Page 52, under 10.7 Efficacy Variables, deleted and added text 
Patient video 
after MFM 
Stimulated Single fiber EMG 
after videoafter MFM 
Slurp test, CGI-S and CGI-I 
At end of assessments 
 
 
*Administration of medication represents Time 0 (minutes) 
At the end of the MFM testing, the patient’s face will be evaluated for ptosis, extra-
ocular movements, facial strength (i.e. smile, eye closure, puffing cheeks), and speech, 
as age permits. 
If the stimulated single fiber EMG (optional assessment) is not to be performed, then the 
slurp test (also optional), CGI-S and CGI-I assessments should be done following completion 
of the video of the patient’s faceMFM.   
On Page 54, under 10.7.5 Slurp Test, deleted section  
10.7.6 Videography 
Videography, using standardized technology and equipment, will be used to evaluate 
patient response. An approximate 20-minute video will be obtained at each protocol 
specified time point and the patient’s head/face area will be evaluated for ptosis, extra-
ocular movements, facial strength (i.e. smile, eye closure, puffing cheeks), and speech, 
as age permits. 
On Page 54, under 11.1 Adverse Events, changed text  
The study period during which all non-serious AEs will be reported begins after informed 
consent is obtained and the first administration of study drug through the last visit (Study 
Day 36 29) or at the early termination visit. 
On Page 61, under 13.1 Screening Visit, deleted and added text  
• Patient video; 
• Stimulated single fiber EMG (optional); 

 
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• CGI-S; 
• Slurp test (optional); 
• Assessment of AEs/SAEs; and 
• Assessment of concomitant medications. 
 
On Page 62, under 13.2 Open-label Run-in, deleted text 
Improvement of at least 20% in MFM 20 or 32 is not a requirement for these participants. They 
must have not been previously assessed for improvement in subject global impression 
(SGI) and motor function measure (MFM 20 or 32) scores within 3 months prior to 
participating in this study to avoid possible testing bias. 
On Page 62, under 13.2 Open-label Run-in, deleted and added text 
o Patient video; 
o CGI-S;  
o CGI-I; and 
o Slurp test (optional). 
Assessment 
Start Time  
After Dose* 
(± 10 minutes unless 
otherwise specified) 
SGI 
40 minutes 
MFM 20 or 32 
after SGI 
Patient video 
after MFM 
Slurp test, CGI-S and CGI-I 
At end of assessments 
 
 
*Administration of medication represents Time 0 (minutes) 
At the end of the MFM testing, the patient’s face will be evaluated for ptosis, extra-
ocular movements, facial strength (i.e. smile, eye closure, puffing cheeks), and speech, 
as age permits. 
The site pharmacy will dispense bottles containing blinded amifampridine phosphate or 
placebo tablets, depending on the patient’s Treatment Sequence assignment, for daily 
outpatient administration for 7 days (Days 1-7). Administration of blinded study medication 

 
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will begin with the first morning dose on Day 1 of Period 1 the next scheduled dose 
following the Day 0 baseline assessment on open-label medication. (see Section 13.3). 
On Page 63, under 13.3 Period 1, deleted text  
On Day 1, patients will begin administration of randomized study medication 
(amifampridine phosphate or placebo tablets) with the first morning dose. 
Administration will be continued on an outpatient basis for a total of 7 days (Days 1-7).  
On Page 64, under 13.3 Period 1, deleted and added text 
o Patient video; 
o CGI-S;  
o CGI-I; and 
o Slurp test (optional). 
 
Assessment 
Start Time  
After Dose* 
(± 10 minutes unless 
otherwise specified) 
SGI 
40 minutes 
MFM 20 or 32 
after SGI 
Patient video 
after MFM 
Stimulated Single fiber EMG 
after videoMFM 
Slurp test, CGI-S and CGI-I 
At end of assessments 
 
 
*Administration of medication represents Time 0 (minutes) 
At the end of the MFM testing, the patient’s face will be evaluated for ptosis, extra-
ocular movements, facial strength (i.e. smile, eye closure, puffing cheeks), and speech, 
as age permits.If the stimulated single fiber EMG (optional assessment) is not to be 
performed, then the slurp test (also optional), CGI-S and CGI-I assessments should be done 
following completion of the video of the patient’s head areaMFM. 
Open-label amifampridine phosphate will be dispensed at the Day 8 visit for administration 
during the stabilization period, starting on Day 9with the next scheduled dose after Day 8 
assessments  (see Section 13.4). 
On Page 64 and 65, under 13.4 Re-stabilization Period, deleted and added  
o Patient video; 

 
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o CGI-S;  
o CGI-I; and 
o Slurp test (optional). 
Assessment 
Start Time  
After Dose* 
(± 10 minutes unless 
otherwise specified) 
SGI 
40 minutes 
MFM 20 or 32 
after SGI 
Patient video 
after MFM 
Slurp test, CGI-S and CGI-I 
At end of assessments 
 
 
 
*Administration of medication represents Time 0 (minutes) 
At the end of the MFM testing, the patient’s face will be evaluated for ptosis, extra-
ocular movements, facial strength (i.e. smile, eye closure, puffing cheeks), and speech, 
as age permits The slurp test (optional), CGI-S and CGI-I assessments should be done 
following completion of the video of the patient’s faceMFM. 
 
The site will dispense bottles containing amifampridine phosphate or placebo tablets, 
depending on the patient’s Treatment Sequence assignment, for Period 2 (Days 22-28). 
Administration of blinded study medication will begin with the next scheduled dose after 
Day 21 assessments are completedfirst morning dose on Day 22 of Period 2 (see 
Section 13.5). 
On Page 65, under 13.5 Period 2, deleted and added text 
On Day 22, pPatients will begin administration with the first morning dose of the 
randomizedthe blinded study medication they did not receive in Period 1. Administration 
will be continued on an outpatient basis for a total of 7 days (Days 22-28). 
Patients will report to the study site on Day 29 (+1 day) and receive a dose of the same study 
medication they received for the previous 7 days, under the supervision of the study 
personnel, in order to time the following assessments/procedures in relation to the medication 
dose. 
• 
Assessment of AEs/SAEs; 
• 
Abbreviated Complete physical exam with weight; 

 
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• 
Vital signs (seated position), including SBP, DBP, heart rate, respiration, and body 
temperature; 
• 
Standard resting 12-lead ECG; 
• 
Clinical laboratory tests; 
• 
Urine pregnancy test in females of childbearing potential only; 
• 
Concomitant medications; 
• 
IP accountability; 
• 
Efficacy assessments, including: 
o 
MFM 20 or 32; 
o 
SGI (patient/parent/guardian/caregiver); 
o 
Stimulated single fiber EMG (optional); 
o 
Patient video; 
o 
CGI-S; 
o 
CGI-I; and 
o 
Slurp test (optional). 
Assessment 
Start Time  
After Dose* 
(± 10 minutes unless 
otherwise specified) 
SGI 
40 minutes 
MFM 20 or 32 
after SGI 
Patient video 
after MFM 
Stimulated Single fiber EMG 
after videoMFM 
Slurp test, CGI-S and CGI-I 
At end of assessments 
*Administration of medication represents Time 0 (minutes) 
At the end of the MFM testing, the patient’s face will be evaluated for ptosis, extra-
ocular movements, facial strength (i.e. smile, eye closure, puffing cheeks), and speech, 
as age permits If the stimulated single fiber EMG (optional assessment) is not to be 
performed, then the slurp test (also optional), CGI-S and CGI-I assessments should be done 
following completion of the video MFMof the patient’s head area. 

 
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After completion of the above procedures/assessments, patients will be restored to open-
label amifampridine phosphate at the same dose and frequency as established in the 
run in phase of the study and they will be eligible for an expanded access program. 
On Page 66, under 13.5 Period 2, deleted section  
13.6 Safety Follow Up 
Patients taking open-label amifampridine phosphate, following Study Day 29 visit, will 
return to the study site on Day 36 (±2 days) for a final safety assessment, including: 
• Assessment of AEs/SAEs; 
• Complete physical exam with weight; 
• Vital signs (seated position), including SBP, DBP, heart rate, respiration, and 
body temperature; 
• Standard resting 12-lead ECG; 
• Urine pregnancy test in females of childbearing potential only; and 
• Concomitant medications; 
• IP accountability. 
On Page 66, under 13.6 Early Discontinuation Visit, changed text  
13.7 13.6 Early Discontinuation Visit 
On Page 66 and 67 under 13.6 Early Discontinuation Visit, deleted and added text  
o 
Stimulated Single fiber EMG (optional); 
o 
Patient video; 
o 
CGI-S; 
o 
CGI-I; and 
o 
Slurp test (optional). 
 
 
 
 

 
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Appendix 10: Protocol Amendment 5 
PURPOSE:  The purpose of this amendment is as follows: 
To formally remove the videotaping of patients from the protocol, clarify the start and stop 
times of Periods 1 and 2, blinded medication dosing, and remove the Day 36 visit.  The 
patient is either on a stable dose of amifampridine phosphate or has been titrated over a 
period of 4 weeks. Also, the patient is observed on open label medication for 2 weeks during 
the restabilization period.  Therefore, the Day 36 visit on open label medication adds no new 
information to the efficacy or safety profile of amifampridine phosphate and the patient may 
go directly into the expanded access program. 
Risk: these administrative changes provide clarity, adding no additional risk to the patient. 
 
MODIFICATIONS TO PROTOCOL: 
• Bold and underlined text:   
Changed Text 
• Bold and strike through text:  
Deleted Text 
• Bold and italicized text:  
 
Added Text 
 
On Page 1, under Clinical Study Protocol, added text 
Date of Amendment 5: 
26 June 2017 
On Page 32, under 8.4.4 Safety of Amifampridine and Amifampridine Phosphate, added text 
Based upon the previous clinical studies involving the use of amifampridine in the 
treatment of Lambert-Eaton myasthenic syndrome (LEMS), there have been reports of 
provocation of bronchial asthma, respiratory failure, or respiratory disorder.  These events 
are also part of CMS symptoms; however, the risk may be more likely when the patient has 
asthma or respiratory disorder as a comorbidity with CMS. 
On Page 33, under 8.5 Overall Risks and Benefits, added and deleted text  
Risks of of study involvement have been minimized by: 
1. Patients entering the study may already be on some formulation of 3,4-diaminopyridine 
and have demonstrated tolerability or; 
2. Patients naïve to the medication are titrated to a tolerable and effective dose with open-
label medication, under the observation of the Investigator.  Thus, the development of 
adverse events or lack of efficacy is monitored by the Investigator during the step-wise 

 
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titration and study medication dose can be reduced or discontinued at any point in the 
titration for either safety or lack of efficacy.   
The pharmacokinetic half-life of amifampridine phosphate is short (1.8 hours), therefore 
discontinuation of medication will qickly terminate the effects, and mitigate adverse 
reactions.  
This is a withdrawal study design looking at patient worsening on placebo; which is 
possible due to the short half-life of amifampridine phosphate. Therefore, patients must 
demonstrate a level of efficacy during the open-label titration period.  This further reduces 
patient risk, by not continuing an experimental medication in patients who fail to 
demonstrate a benefit.  
During the placebo withdrawal period, patients who deteriorate to a point that the 
Investigator assess to be lower than their baseline, open-label amifampridine phosphate is 
provided as to rescue the patient.  
Refer to the Firdapse Investigator Brochure (February, 2015) for further discussion 
information on benefit/risk of amifampridine. 
 On Page 51, under Table 5. Medications Prohibited During Study added and deleted text  
The following medicinal products should be use with caution in patients taking 
amifampridine phosphate: 
Medicinal products known to cause cardiac QT prolongation 
Medicinal products known to lower epileptic threshold 
Medicinal products with atropinic effects  
The concomitant use of amifampridine phosphate and medicinal products with atropinic 
effects may reduce the effect of both active substances and should be taken into 
consideration. Medicinal products with atropinic effects include tricyclic anti-depressants, 
most H1 atropinic anti-histamines, anticholinergic, anti-Parkinson medicinal products, 
atropinic antispasmodics, disopyramide, phenothiazine neuroleptics and clozapine.  
Medicinal products with cholinergic effects  
The concomitant use of amifampridine phosphate and medicinal products with cholinergic 
effects (e.g. direct or indirect cholinesterase inhibitors) may lead to an increased effect of 
both products and should be taken into consideration.  
Non-depolarizing muscle relaxant acting medicinal products  

 
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The concomitant use of amifampridine phosphate and medicinal products with non-
depolarizing muscle relaxant effects (e.g. mivacurium, pipercurium) may lead to a 
decreased effect of both products and should be taken into consideration.  
Depolarizing muscle relaxant acting medicinal products  
The concomitant use of amifampridine phosphate and medicinal products with 
depolarizing muscle relaxant effects (e.g. suxamethonium) may lead to a decreased effect 
of both products and should be taken into consideration. 
Concomitant use of amifampridine phosphate with medicinal products with atropinic 
effects may reduce the effect of amifampridine phosphate, which should be taken into 
consideration.