A Phase 3, Double-Blind, Placebo-controlled, Randomized, Parallel-Group Study to Evaluate the Efficacy and Safety of Amifampridine Phosphate in Patients With Lambert-Eaton Myasthenic Syndrome
Phase: PHASE3
Conditions: Lambert-Eaton Myasthenic Syndrome
Sponsor: Catalyst Pharmaceuticals, Inc.

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CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 3, Double-blind, Placebo-controlled, Randomized, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Amifampridine Phosphate (3,4-Diaminopyridine Phosphate) in 
Patients with Lambert-Eaton Myasthenic Syndrome (LEMS) 
Protocol Number: 
LMS-003 
Investigational Product: Amifampridine phosphate (3,4-diaminopyridine phosphate) 
IND/EUDRACT 
Number: 
106263 / 2010-021850-20 
Indication: 
Lambert-Eaton Myasthenic Syndrome (LEMS) 
Sponsor: 
Catalyst Pharmaceuticals, Inc. 
Development Phase: 
Phase 3 
Medical Officer: 
Gary Ingenito, MD, PhD 
Study Design: 
Double-blind, Placebo-controlled, Randomized, Parrallel-Group 
Dose: 
30-80 mg total daily dose or placebo equivalent
Patient Population: 
Patients with LEMS
Date of Protocol: 
2 September 2016
Date of Amendment 1: 
18 September 2016 
Date of Amendment 2: 
27 April 2017 
Property of Catalyst Pharmaceuticals, Inc. 
CONFIDENTIAL 
May not be divulged, published, or otherwise disclosed to others without prior written 
approval from Catalyst Pharmaceuticals, Inc. 
This study will be conducted according to the principles of Good Clinical Practice as 
described in the U.S. Code of Federal Regulations and the International Conference on 
Harmonisation Guidelines, including the archiving of essential documents 

 
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1. PROCEDURES IN CASE OF AN EMERGENCY 
 
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 
Adriana Manari 
Clinical Trial Manager 
Catalyst Pharmaceuticals, Inc. 
355 Alhambra Circle, Suite 1250 
Coral Gables, FL 33134 
Tel: +1 305-420-3200, ext. 117 
Email: amanari@catalystpharma.com 
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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2 
SYNOPSIS 
NAME OF COMPANY: 
Catalyst Pharmaceuticals, Inc. 
355 Alhambra Circle, Suite 1250 
Coral Gables, FL  33134 
NAME OF INVESTIGATIONAL PRODUCT:  
Active ingredients: amifampridine phosphate (3,4-diaminopyridine phosphate) 
TITLE OF STUDY: 
A Phase 3, Double-blind, Placebo-controlled, Randomized, Parrallel-Group Study to Evaluate the 
Efficacy and Safety of Amifampridine Phosphate (3,4-Diaminopyridine Phosphate) in Patients with 
Lambert Eaton Myasthenic Syndrome (LEMS). 
PROTOCOL NUMBER: 
LMS-003 
STUDY SITE:  
Up to 3 centers in the United States 
PHASE OF DEVELOPMENT: 
Phase 3 
OBJECTIVES: 
• 
Primary: 
o To assess the clinical efficacy of amifampridine phosphate compared with placebo 
in adults with LEMS, based on change of the co-primary endpoints QMG Score and 
Subject Global Improvement (SGI) 
• 
Secondary: 
o Clinical Global Impression of Improvement (CGI-I) 
• 
Exploratory: 
o Greater than 20% increase in the average time of 3 repetitions for Timed Up and Go 
test (3TUG) 
o Patient rating on change of most bothersome symptom for them 
STUDY DESIGN AND PLAN:  
This randomized (1:1), double-blind, placebo-controlled, parallel-group study is designed to evaluate 
the efficacy and safety of amifampridine phosphate in patients diagnosed with LEMS. Patients will 
have been receiving amifampridine phosphate, after which blinded treatment effect will be assessed 
for continuation or cessation of drug. The study is planned to include approximately 28 male and 
female patients. The planned duration of participation for each patient is 5 days (Day 0 through Day 
4), excluding the screening period, which can last up to 7 days.  

 
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Those patients satisfying all inclusion and exclusion criteria will be randomized to a Treatment 
Group. Amifampridine phosphate (at the patient’s optimal dose) or placebo will be dispensed by the 
site pharmacist, according to the randomization schedule, to begin with the next dose after all Day 0 
assessments are completed and continued for 4 days.  After completion of the study, patients will be 
eligible for expanded access treatment program with open-label amifampridine phosphate.  
 
 
 
 
 
 
 
 
 
 
Screening 
Patients receiving amifampridine phosphate treatment for LEMS, and meeting the inclusion and 
exclusion criteria are eligible to participate in this study. They can be randomized if on a stable dose 
and frequency of amifampridine phosphate for at least 1 week before being randomized.  
Treatment (Days 1-4) (+1 day) 
Patients will be randomized (1:1 ratio) on the last day of the screening period (Day 0) to either 
amifampridine phosphate or placebo. Beginning with the next dose after all Day 0 assessments are 
completed, the patient will take, under double-blind conditions, either amifampridine phosphate 
tablets or placebo tablets through Day 4, with a clinic visit on the last day (Day 4) for assessments 
(Table 3). Any unused portion of dispensed drug will be returned.  
 
During all phases of the study, safety and efficacy assessments will be made as detailed in the 
Schedule of Assessments in Table 3. 
 
NUMBER OF PATIENTS PLANNED: 
Approximately 28 patients to enroll in the study. 
Screening 
(Up to 7 days before 
randomization) 
Subject randomized 
(1:1 ratio) Day 0 
 (Drug) 
Day 1-4 
 (Placebo) 
Day 1-4 

 
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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. Male or female ≥18 years of age with LEMS and currently receiving a stable dose of 
amifampridine phosphate for at least 7 days. 
2. Diagnosis of LEMS by antibody testing or EMG. 
3. Completion of anti-cancer treatment at least 3 months (90 days) prior to Screening. 
4. If receiving peripherally acting cholinesterase inhibitors (e.g. pyridostigmine), a stable dose of 
cholinesterase inhibitors is required for at least 7 days prior to randomization and throughout 
the study. 
5. If receiving permitted oral immunosuppressants (prednisone or other corticosteroid), a stable 
dose is required for at least 30 days prior to randomization and throughout the study. 
6 
Female patients of childbearing potential must practice an effective, reliable contraceptive 
regimen during the study. 
7. Able to perform all study procedures and assessments. 
8.   Willing and able to travel to study site and attend all clinic study visits. 
9. Willing and able to provide written informed consent. 
Individuals who meet any of the following exclusion criteria are not eligible to participate in 
the study: 
1. Clinically significant long QTc interval on ECG in previous 12 months. 
2. Seizure disorder. 
3. Active brain metastases. 
4. Unable to ambulate. 
5. Pregnant or lactating females. 
6. Any other condition which, in the opinion of the Investigator, might interfere with the patient’s 
participation in the study or confound the assessment of the patient. 
7. Patients who cannot discontinue immunomodulatory treatment (e.g. mycophenolate, 
azathioprine, cyclosporine) within 3 weeks before screening. 
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 amifampridine base per tablet. The total daily dose will be individually determined by the 
Investigator, within the bounds of a total daily dose of up to 80 mg, divided into doses taken 3 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. 

 
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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). 
CRITERIA FOR EVALUATION: 
Safety: 
Safety will be assessed by the incidence of treatment-emergent adverse events (TEAEs), including 
serious adverse events (SAEs). Vital signs, physical examination, and concomitant medications will 
also be evaluated. 
Efficacy:  
• Primary: 
o To assess the clinical efficacy of amifampridine phosphate compared with placebo 
in individuals with LEMS, based on change of the co-primary endpoints QMG Score 
and Subject Global Improvement (SGI). 
• 
Secondary: 
o Clinical Global Impression of Improvement (CGI-I) 
• 
Exploratory: 
o Greater than 20% increase in the average time of 3 repetitions for Timed Up and Go 
test (3TUG) 
o Patient rating on change of most bothersome symptom for them. 
 
STATISTICAL METHODS:  
Sample Size Determination 
For Change From Baseline in QMG Scores, a between-treatment difference of -3.5 and a standard 
deviation at most 3, a sample size of  24 patients  will provide power of at least 80% for a 0.05 level 
test. Similarly, for Change From Baseline in SGI Scores, a between-treatment difference of -2.1 and 
a standard deviation at most 2, a sample size of 26 patients will provide power of 80% for a 0.05 
level test. Thus a total sample size of 26 patients, equally randomized to the two treatments, will 
provide power of at least 80% for each of the two co-primary endpoints. 
 
Safety Analysis 
Safety analyses will be conducted on the safety population (i.e. all patients who receive at least 1 
dose of amifampridine or placebo). The safety analysis will be descriptive and will be presented on 
using observed data only. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Only 

 
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treatment-emergent AEs (TEAEs) will be included in the safety analysis. The incidence of TEAEs 
will be summarized by system organ class, preferred term, relationship to treatment, and severity by 
treatment.  
All other safety measures including vital signs, physical examination, and concomitant medications 
data will also be summarized. 
 
Efficacy Analysis 
Efficacy analysis will be conducted on 2 datasets: 
• 
Full Analysis Set (FAS): This population consists of all randomized patients who receive at 
least 1 dose of IP (amifampridine or placebo) and have at least one post-treatment efficacy 
assessment. 
• 
Per Protocol (PP): This population is a subset of the FAS population, excluding patients with 
major protocol deviations. The PP population will include all patients who: 
o Have no major protocol deviations or inclusion/exclusion criteria deviations that 
might potentially affect efficacy, and 
o Patients who took at least 80% of the required treatment doses and remained enrolled 
for at least 4 days. 
Evaluations obtained at the time of discontinuation will be included in the analyses. Patients who 
discontinue with no post-randomization data will be excluded from all efficacy analyses but will be 
included in the safety analyses. 
For each efficacy variable with a corresponding assessment at Baseline, Change From Baseline 
(CFB) will be computed as the post-treatment result minus the Baseline result. The post-treatment 
result will be the result obtained on Day 4, unless the patient discontinued treatment early, in which 
case the post-treatment result may be obtained at an earlier time point. For statistical test, two-sided 
P values <0.05 will be considered as statistically significant. 
Summary statistics for QMG score and the corresponding CFB will be presented by treatment.  The 
analysis of CFB for Total QMG Score is a coprimary efficacy endpoint and analysis will be 
performed by fitting a fixed effects linear model to the data with CFB as the response. The model 
will include terms for treatment and QMG at Baseline. A test comparing the least squares (LS) means 
will be conducted to evaluate the treatment effect.  
The raw scores and CFB for each item of QMG will be summarized by treatment.  Between-treatment 
comparisons with respect to CFB for Right arm outstretched, Left arm outstretched, Right leg 
outstretched, and Left leg outstretched will be performed using a fixed effects linear model with 
terms for treatment and QMG at Baseline.  
Summary statistics for SGI score and the corresponding CFB will be presented by treatment. The 
analysis of CFB for SGI is a coprimary efficacy endpoint and analysis will be performed by fitting a 
fixed effects linear model to the data with CFB as the response. The model will include terms for 
treatment and SGI at Baseline. A test comparing the LS means will be conducted to evaluate the 
treatment effect. 

 
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Table of Contents 
1. PROCEDURES IN CASE OF AN EMERGENCY ............................................................2 
2 SYNOPSIS ...........................................................................................................................3 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................12 
4 ETHICS..............................................................................................................................14 
4.1 Institutional Review Board / Independent Ethics Committee ...................................14 
4.2 Ethical Conduct of Study ..........................................................................................15 
4.3 Patient Information and Informed Consent ...............................................................15 
5 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................16 
6 
INTRODUCTION .............................................................................................................17 
6.1 Disease Background ..................................................................................................17 
6.2 Amifampridine ..........................................................................................................19 
6.3 Nonclinical Studies ...................................................................................................20 
6.3.1 
Carcinogenicity Study .................................................................................21 
6.4 Previous Clinical Studies ..........................................................................................22 
6.4.1 
Amifampridine Phosphate in Healthy Subjects ...........................................22 
6.4.2 
Efficacy of Amifampridine in LEMS ..........................................................24 
6.4.3 
Safety of Amifampridine and Amifampridine Phosphate ...........................25 
6.4.4 
Overall Risks and Benefits ..........................................................................27 
6.4.5 
Study Rationale ...........................................................................................27 
7 STUDY OBJECTIVES ......................................................................................................28 
7.1 Primary Objectives ....................................................................................................28 
8 
INVESTIGATIONAL PLAN ............................................................................................28 
8.1 Overall Study Design and Plan .................................................................................28 
8.2 Selection of Study Population ...................................................................................31 
8.2.1 
Inclusion Criteria .........................................................................................31 
8.2.2 
Exclusion Criteria ........................................................................................31 
8.2.3 
Removal of Patients from Treatment or Assessment ..................................32 
8.2.4 
Patient Identification and Randomization ...................................................33 
8.2.5 
Re-screening ................................................................................................33 
8.3 Treatments .................................................................................................................33 
8.3.1 
Treatments Administered ............................................................................33 
8.3.2 
Identity of Investigational Product ..............................................................34 

 
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8.3.3 
Directions for Administration .....................................................................35 
8.3.4 
Method of Assigning Patients to Treatment Groups ...................................36 
8.3.5 
Selection of Doses Used in the Study .........................................................36 
8.3.6 
Blinding .......................................................................................................37 
8.3.7 
Treatment Compliance ................................................................................37 
8.3.8 
Investigational Product Accountability .......................................................37 
8.3.9 
Return and Disposition of Clinical Supplies ...............................................37 
8.4 Prior and Concomitant Medications .........................................................................37 
8.5 Dietary or Other Protocol Restrictions......................................................................38 
8.5.1 
Dietary Restrictions .....................................................................................38 
8.5.2 
Contraception ..............................................................................................38 
8.6 Safety Variables ........................................................................................................38 
8.6.1 
Adverse Events ............................................................................................39 
8.6.2 
Vital Signs ...................................................................................................39 
8.6.3 
Clinical Laboratory Assessments ................................................................39 
8.6.4 
Pregnancy Testing .......................................................................................39 
8.6.5 
Physical Examination ..................................................................................39 
8.7 Efficacy Variables .....................................................................................................40 
8.7.1 
Subject Global Impression ..........................................................................40 
8.7.2 
Quantitative Myasthenia Gravis ..................................................................41 
8.7.3 
Clinical Global Impression of Improvement ...............................................41 
8.7.4 
Triple Timed Up and Go (3TUG) – greater than 20% increase in 
average time, off medication .......................................................................41 
8.7.5 
Patient Evaluation of Most Bothersome Symptom .....................................42 
9 REPORTING ADVERSE EVENTS .................................................................................42 
9.1 Adverse Events .........................................................................................................42 
9.2 Serious Adverse Events ............................................................................................45 
9.3 Safety Blood Collection ............................................................................................47 
9.4 Pregnancy ..................................................................................................................47 
9.5 Urgent Safety Measures ............................................................................................47 
9.6 Medical Monitor Contact Information ......................................................................48 
10 APPROPRIATENESS OF MEASUREMENTS ...............................................................48 
11 STUDY PROCEDURES ...................................................................................................48 
11.1 Screening Visit ..........................................................................................................48 
11.2 Randomization Visit (Study Day 0) ..........................................................................49 

 
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11.3 End of Treatment (Study Day 4) ...............................................................................50 
11.4 Early Discontinuation Visit .......................................................................................51 
12 DATA QUALITY ASSURANCE .....................................................................................51 
13 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................52 
13.1 Determination of Sample Size ..................................................................................52 
13.2 Patient Populations ....................................................................................................52 
13.3 Safety Analysis .........................................................................................................53 
13.4 Efficacy Analysis ......................................................................................................53 
13.5 Changes in the Conduct of the Study or Planned Analyses ......................................54 
14 COMPENSATION, INSURANCE AND INDEMNITY ..................................................55 
15 CASE REPORT FORMS AND SOURCE DOCUMENTS ..............................................55 
16 STUDY MONITORING AND AUDITING .....................................................................56 
17 RETENTION OF RECORDS ...........................................................................................56 
18 USE OF INFORMATION AND PUBLICATION ...........................................................57 
19 REFERENCES ..................................................................................................................58 
20 SIGNATURE PAGE .........................................................................................................63 
Appendix 1    Quantitative Myasthenia Gravis Testing Form ...........................................64 
Appendix 2   Subject Global Impression (SGI) .................................................................65 
Appendix 3 
Clinical Global Impression-Improvement (CGI-I) .....................................66 
Appendix 4   Timed Up and Go (TUG) Test .....................................................................67 
Appendix 5   Most Bothersome Symptom Scale ...............................................................69 
Appendix 6   Protocol Amendment 1 ................................................................................70 
Appendix 7   Protocol Amendment 2 ................................................................................81 
 
 
 
 
 
 
 
 
 
 

 
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List of In-text Tables  
Table 1. 
Emergency Contact Information .....................................................................2 
Table 2. 
Body Surface Area and Exposure-Based Safety Factors ..............................21 
Table 3. 
Schedule of Assessements .............................................................................30 
Table 4. 
Medications Prohibited During Study ...........................................................38 
Table 5. 
Categories of Severity for CTCAE Criteria ..................................................44 
Table 6. 
Description of Relationship to Adverse Event Categories ............................45 
 
 
List of In-text Figures 
 
Figure 1. 
Chemical Structure of Amifampridine Phosphate .........................................34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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3 
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  
ANCOVA 
Analysis of covariance 
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  

 
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EMG 
Electromyogram 
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 

 
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PP 
per protocol 
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. 
4 
 ETHICS 
4.1 
Institutional Review Board / Independent Ethics Committee 
The Investigator will provide the institutional review board (IRB), 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 Form (ICF) 

 
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including compensation procedures, and any other written information provided to the patients, 
including all ICFs 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, and the ICF 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. 
 
4.2 
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. 
4.3 
Patient Information and Informed Consent 
A properly written and executed ICF, in accordance with the Declaration of Helsinki, ICH E6 
(Section 4.8), 21 CFR Part 50 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, or designee, for 
review. The IRB/IEC/REB must approve 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 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 

 
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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 authorization (or similar 
permission form) to each patient and will maintain the original in the record file of the patient. 
 
5 
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 each 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 (or designee) will be responsible for the 
timely reporting of serious adverse events (SAEs) to appropriate regulatory authorities as 
required. 
 
Laboratory evaluations, if required, will be performed at both local laboratories and central 
laboratories. Additional details will be provided in the LMS-003 Study Reference Manual. 
Urine samples for evaluation of dosing compliance and blood specimen for patients who opt 
for ‘liquid biopsy’ cancer screening will be sent to central laboratories. 
 

 
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6 
INTRODUCTION 
A comprehensive review of amifampridine phosphate is contained in the Firdapse® 
Investigator’s Brochure supplied by Catalyst (February, 2015). Investigators are to review the 
document before initiating this study. 
 
6.1 
Disease Background 
Lambert-Eaton Myasthenic Syndrome (LEMS) is a very rare autoimmune disease with the 
primary symptom of proximal muscle weakness. Muscle weakness resulting from LEMS is 
caused by auto-antibodies directed against type P/Q voltage-gated calcium channels (VGCCs) 
located on the pre-synaptic member of the neuromuscular junction (NMJ) (Motomura, 1997). 
Auto-antibodies inhibit the entry of calcium into the nerve, impairing the release of 
acetylcholine from nerve terminals into the synapse, resulting in a loss of neuromuscular 
transmission (Augustine, 1990; Lambert, 1956; Verschuuren, 2006). 
Although the true prevalence of LEMS is uncertain, it has been estimated that this disease 
affects approximately 1 – 9 out of 100,000 of the general population (Sanders, 2003). Available 
literature suggests that approximately 50% to 55% of patients have a paraneoplastic form of 
LEMS, mainly small cell lung cancer (SCLC) (Verschuuren, 2006; Wirtz, 2002a). In a large 
clinical study that included 50 consecutive patients with LEMS, SCLC was present in 84% of 
patients with cancer (O'Neill, 1988). The prevalence of LEMS in patients with SCLC is 
estimated to be approximately 3% (Payne, 2010). In approximately 90% of patients with the 
paraneoplastic form of LEMS, a tumor was detected within 2 years following the diagnosis of 
LEMS (Verschuuren, 2006; Elias, 2010). 
 
Clinically, LEMS is characterized by proximal muscle weakness usually greater in the hip than 
shoulder girdle muscles, fatigability, muscle aches, and autonomic dysfunction 
(e.g. impotence, dry mouth, constipation) (Lambert, 1956; Verschuuren, 2006). Other 
symptoms may include paresthesias, diplopia, and orthostatic hypotension (Wirtz, 2002b). The 
characteristic proximal muscle weakness can compromise the most basic tasks such as walking 
and climbing stairs. The symptoms of impaired neuromuscular transmission typically present 
after age of 40, with a peak incidence between 50 and 70 years (Wirtz, 2002b; O'Neill, 1988). 
The onset of symptoms is usually gradual and insidious, taking place over several weeks to 
many months or even years. In rare cases, weakness of the respiratory muscles can lead to a 
life-threatening respiratory crisis that necessitates artificial ventilation (O'Neill, 1988; 
Maddison, 1999). There have also been isolated reports of patients presenting with acute 

 
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respiratory failure as the primary symptom of LEMS (Verschuuren, 2006; Elias, 2010; 
Vedeler, 2006). In LEMS, the gradual onset of hip girdle weakness is typically an early 
symptom with less dramatic shoulder girdle weakness. Clinical features that present later in 
LEMS include muscle weakness that worsens with prolonged exercise, respiratory muscle 
weakness, diplopia, and dry mouth (Seneviratne, 1999). 
 
The diagnosis of LEMS is typically based on clinical findings and the presence of antibodies 
to VGCC and electrodiagnostic studies. The VGCC radioimmunoassay detects the ability of 
patient’s serum to induce immunoglobulin G (IgG)-calcium complex precipitates after 
exposure to solubilized calcium channels. As discussed above, antibodies against the P/Q-type 
VGCC are present in approximately 85% to 95% of patients with LEMS. 
 
In addition, a characteristic electrophysiologic pattern associated with LEMS may support the 
diagnosis of a presynaptic NMJ disorder. The compound muscle action potential (CMAP) 
amplitude in a resting muscle in patients with LEMS is usually significantly reduced. 
Following high frequency (10-50 Hertz [Hz]) repetitive nerve stimulation (RNS), there is a 
significant increment (> 100%) with a marked increase in the CMAP amplitude 
(Weinberg, 2010). An increase in the CMAP amplitude > 100% after high frequency 
stimulation or exercise is considered diagnostic of a presynaptic NMJ disorder. In addition, the 
muscle action potentials observed in patients with LEMS are often unstable on 
electromyography (EMG) needle examination and the single fiber EMG typically has 
significant jitter and transmission blocking that is characteristically improved at higher firing 
rates (Trontelj, 1991; Chaudhry, 1991). 
 
Management of patients with LEMS can be classified into 3 main categories, each targeting 
different aspects of the pathogenesis of the disease: 1) anti-tumor treatment 
(e.g. chemotherapy, multikinase inhibitors) in paraneoplastic LEMS, 2) immunologic 
treatments (e.g. intravenous immunoglobulin (IVIG), plasma exchange, immunoadsorption, 
prednisone, azathioprine) to suppress anti-VGCC antibodies; and 3) symptomatic treatment 
(e.g. pyridostigmine, amifampridine) acting at the NMJ (Verschuuren, 2006). 
 
The most common cancer accompanying LEMS is SCLC, but lymphoproliferative disorders 
such as Hodgkins Disease, carcinoid or malignant thymoma may also occur. Although there 
are no large clinical studies addressing immunotherapy, standard approaches have been 

 
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developed from small clinical trials, case reports, and clinical experience in the more frequent 
NMJ autoimmune disorder, myasthenia gravis (MG). Intravenous immunoglobulin has been 
demonstrated to increase muscular strength in small clinical trials and can be a maintenance 
therapy if administered approximately monthly. Prednisone is typically started at 
approximately 1 mg/kg/day, maintained at that dosage until there is clinical evidence of 
improvement, and then slowly tapered. The most frequently used steroid-sparing oral 
immunosuppressants are azathioprine or mycophenolate. Although evidence is limited, 
cyclosporine and plasmapheresis are sometimes used in refractory patients. As in other 
autoimmune disorders, immunologic agents are often used in combination. Although most 
experts recommend using similar immunotherapy in paraneoplastic and autoimmune LEMS, 
some physicians are reluctant to immunosuppress patients with malignancy (Weinberg, 2010). 
 
Symptomatic treatment is integral to the management of LEMS, and typically is started prior 
to immunotherapy. The first available symptomatic treatment was guanidine, which acts by 
increasing transmitter release from presynaptic terminals. However, a small therapeutic 
window with side effects of marrow suppression and nephrotoxicity limited its use. 
Cholinesterase inhibitors alone (e.g. pyridostigmine) confer little benefit in LEMS 
(Wirtz, 2009), although are sometimes used in combination with guanidine. Aminopyridines, 
such as amifampridine, are first-line symptomatic therapy for patients with LEMS (Skeie, 
2006; Skeie, 2010; Lindquist, 2011). 
 
6.2 
Amifampridine  
Amifampridine (3,4-DAP) is a non-specific voltage-dependent potassium (K+) channel blocker 
used to treat LEMS. 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. 
 
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 

 
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treatment of patients with neurologic disorders, including MG, CMS, 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). 
 
6.3 
Nonclinical Studies 
An extensive nonclinical program assessed the safety and absorption, distribution, metabolism, 
and excretion (ADME) and pharmacokinetic (PK) properties of amifampridine, including: 
• Five safety pharmacology studies in central nervous system (rat), respiratory (rat), 
and cardiovascular (telemeterized dogs, in vitro human Ether-à-go-go Related 
Gene (hERG) and rabbit Purkinje fiber)  
• Pharmacokinetics and mass balance in rat and dog  
• In vitro metabolism in human and animal hepatocytes  
• Human hepatic cytochrome P450 (CYP450) inhibition and induction  
• Human P-glycoprotein (Pgp) interaction  
• Single dose toxicity and toxicokinetic (TK) studies in mouse, rat, and beagle dog 
• 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 
• Carcinogenitcity study (104 weeks) in rats 
 
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 

 
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safety factor based on average Cmax in male and female dog versus human is 1.2 and 1.1, 
respectively. 
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 80 mg in 
this study involving patients with LEMS. 
 
6.3.1 Carcinogenicity Study 
A study of amifampridine phosphate consumption equivalent to 8, 25, or 55 mg/kg/day via 
dietary admixture in male and female Sprague Dawley rats showed no increased early 
mortality.  Survival was increased in male and female rats offered amifampridine phosphate in 
diet compared to control group rats.  Survival at the end of the dosing phase was 47%, 67%, 
73%, and 72% for males, and 48%, 65%, 60%, and 73% for females for dose levels of 0, 8, 25, 
and 55 mg/kg/day, respectively. 

 
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Benign and malignant Schwannomas were only observed in male and female rats given 
amifampridine phosphate.  In male rats, incidence of Schwannoma was comparable between 
rats given 25 and 55 mg/kg/day.  In female rats, incidence was similar to the male rats at 8 and 
25 mg/kg/day with an increased incidence at the highest dose (55 mg/kg/day).   
Endometrial carcinomas were observed with an incidence of 0, 4, 13 and 9 for females offered 
0, 8, 25 and 55 mg/kg/day amifampridine phosphate.  A vast majority (22/26 tumors) of these 
tumors were observed after Study Week 100 and the remaining four were observed in rats 
between Study Weeks 86-99.  The late onset of these tumors parallels the extended survival 
noted in test article-treated rats.  The late appearance of these suggests the tumors arise from 
an epigenetic (non-genotoxic) mechanism, and as the endometrium is responsive to estrogenic 
activity, dose-related changes in pituitary/endocrine axis is the most likely epigenetic factor 
involved with this response. 
The dose levels of 25 and 55 mg/kg/day amifampridine phosphate in males, and the dose levels 
of 8, 25, and 55 mg/kg/day in females were associated with a higher incidence of benign and 
malignant Schwannomas.  Consequently, the no observed adverse effect level (NOAEL) was 
considered 8 mg/kg/day in males and <8 mg/kg/day in females.   
6.4 
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; 
Lindquist, 2011). 
 
6.4.1 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 

 
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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 
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 

 
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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. 
 
6.4.2 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 

 
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total daily dose) versus placebo in patients with LEMS. The 38 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 symptoms. 
Refer to the Firdapse Investigator Brochure (February, 2015) for further details on these 
studies. 
 
6.4.3 Safety of Amifampridine and Amifampridine Phosphate 
Safety data collected from 1,455 patients or healthy volunteers in controlled study LMS-002 
(LEMS), 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 

 
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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 1,455 patients or healthy subjects. Six of 12 deaths 
were associated with accompanying malignancy (1 of 6 with pulmonary embolus as terminal 
event), 1 due to tracheobronchitis, and 2 due to myocardial infarction (MI). Attribution to 
amifampridine for 2 of 3 deaths from the ATU study was specified as unrelated; causality for 
the third death was not reported. No attribution was specified in the academic series, but the 
author singled out the fatal MI as the only serious incident during amifampridine therapy, 
implying that the 2 deaths due to malignancy, the 1 due to malignancy and pulmonary embolus 
and the 1 due to tracheobronchitis were not related in his opinion. The author further states that 
no pathological findings related to amifampridine were found in the patient who died of 
tracheobronchitis. For 1 of the fatal MIs, the author speculates that a “sudden increase of 
physical activity” with amifampridine may have been a contributant (Lundh, 1984; Lundh, 
1993); no causality was reported for the other fatal MI (Bertorini, 2011). Three deaths occurred 
in children with CMS, including 2 with fast-channel CMS (Beeson, 2005). Although no causal 
relationship was established with amifampridine, the authors advise its use cautiously in 
children and in fast-channel patients. The other CMS death was not thought to be related to 
amifampridine (Palace, 1991). Overall 7 of 12 deaths were not considered related to 
amifampridine; neither cause nor causality is known for 4 deaths; and amifampridine may have 
contributed indirectly to 1 of the MI-related deaths. 
The most frequent clinically significant or serious event was seizure. A total of 11 (0.76%) 
patients out of 1,455 patients or healthy subjects experienced seizures or convulsions after 
treatment with amifampridine. Electroencephalogram findings, reported for 4 of the 11 
patients, did not show epileptiform activity. Four of 11 seizures occurred in patients with 
LEMS (4/209; 1.91%), 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).  
Amifampridine was implicated in 5 of these cases of seizure. Three patients experienced 
seizures on a daily dose of ≥90 mg/day (n=3; LEMS or MG). Contributing factors for seizures 
were a daily dose of  ≥90 mg/day, concurrent treatment with theophylline, brain metastases, 

 
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and a case of drug overdose (360 mg/day for 7 days).  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. 
 
6.4.4 Overall Risks and Benefits 
Data on amifampridine treatment in 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. Refer to the Firdapse 
Investigator Brochure (February, 2015) for further discussion on benefit/risk of amifampridine.  
 
6.4.5 Study Rationale 
As discussed previously, a considerable amount of clinical experience is available with 
amifampridine (3,4-diaminopyridine; 3,4-DAP) in patients with LEMS and other neurologic 
disorders and, in December 2009, amifampridine phosphate received marketing approval by 
the European Commission as Firdapse for the symptomatic treatment of patients with LEMS.  
LMS-002 also provided Class 1 evidence that amifampridine phosphate provides statistically 
and clinically significant improvement in LEMS patients. LMS-003 represents a second 
efficacy study. 
 
 

 
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7 
STUDY OBJECTIVES 
 
7.1 
Primary Objectives 
 
The primary objectives of the study are: 
 
• To assess the clinical efficacy of amifampridine phosphate compared to placebo in 
subjects with LEMS, based upon improvement in subject global impression (SGI) and 
quantitative myasthenia gravis (QMG) score; and 
 
• To confirm the safety and tolerability of amifampridine phosphate by adverse event 
reports. 
 
8 
INVESTIGATIONAL PLAN 
 
8.1 
Overall Study Design and Plan 
 
This randomized (1:1), double-blind, placebo-controlled, parallel-group study is designed to 
evaluate the efficacy and safety of amifampridine phosphate in patients diagnosed with LEMS. 
Patients will have been receiving unblinded drug treatment in the expanded access program 
(EAP-001), after which blinded treatment effect will be assessed for continuation or cessation 
of drug. The study is planned to include approximately 28 male and female patients. The 
planned duration of participation for each patient is 5 days, excluding the screening period, 
which can last up to 7 days.  
 
Those patients successfully satisfying all screening criteria will be randomized to a treatment 
group. Amifampridine phosphate (at the patient’s optimal dose) or placebo will be dispensed 
by the site pharmacist, according to the randomization schedule, to begin with the next dose 
after all Day 0 assessments are completed and continued for 4 days.  After completion of the 
study, patients will be eligible for expanded access treatment program with open-label 
amifampridine phosphate. Since patients will have been out of the expanded accesss program 
for less than 30 days, as LMS-003 participants, rescreening to return to expanded access 
program will not be required, per the protocol, and patients may immediately resume their 
participation in the expanded access program (EAP-001). 

 
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Screening 
Patients receiving amifampridine phosphate treatment for LEMS, and meeting the inclusion 
and exclusion criteria are eligible to participate in this study. They can be randomized if on 
stable dose and frequency of amifampridine phosphate for at least 1 week before being 
randomized to a treatment.  Screening and randomization (Day 0) may be combined into a 
single visit. 
 
Treatment (Days 1-4) (+1 day) 
Patients will be randomized (1:1 ratio) on the last day of the screening period (Day 0) to either 
amifampridine phosphate or placebo. Beginning with the next dose after all Day 0 assessments 
are completed, the patient will take, under double-blind conditions, either amifampridine 
phosphate tablets or placebo tablets through Day 4, with a clinic visit on the last day (Day 4) 
for assessments (Table 3). Any unused portion of dispensed drug will be returned to the 
pharmacy.  
 
During the study, safety and efficacy assessments will be made as detailed in the Schedule of 
Assessments in Table 3. 
 
 
Screening 
(Up to 7 days before 
randomization) 
Subject randomized 
(1:1 ratio) Day 0 
 (Drug) 
Day 1-4 
 (Placebo) 
Day 1-4 

 
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Table 3. Schedule of Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Optional test, at patient’s discretion 
2Urine specimen for amifampridine level will be collected on Days 3 and 4 
3Women of child-bearing potential 
 
 
 
 
 
 
 
 
Days 1-4 
 
Screening 
Randomization 
Study Assessment  
or Event  
Days  
-7 to -1 
Day 0 
Day 4  
(+1 d) 
Informed consent  
X 
 
 
Inclusion/exclusion criteria 
X 
 
 
Randomization 
 
X 
 
Medical history 
X 
 
 
Physical exam  
X 
 
 
Vital signs 
X 
 
X 
‘Liquid biopsy’ blood sample1 
X 
 
 
Urine sample for 
amifampridine level2 
 
 
X 
Pregnancy test – urine3 
X 
 
 
 Blinded IP dispense 
 
X 
 
IP accountability 
 
 
X 
CGI-I 
 
 
X 
SGI 
 
X 
X 
QMG  
 
X 
X 
3TUG 
 
X 
X 
Patient most bothersome 
symptom question 
 
X 
X 
Concomitant medications 
X 
X 
X 
Adverse Events 
X 
X 
X 

 
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8.2 
Selection of Study Population 
Criteria for participation in the study are provided in Sections 8.2.1 and 8.2.2. 
 
8.2.1 Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following inclusion 
criteria: 
 
1. Male or female ≥18 years of agewith LEMS and currently receiving a stable dose of 
amifampridine phosphate for at least 7 days. 
2. Diagnosis of LEMS by antibody testing or EMG. 
3. Completion of anti-cancer treatment at least 3 months (90 days) prior to Screening. 
4. If receiving peripherally acting cholinesterase inhibitors (e.g. pyridostigmine), a stable 
dose of cholinesterase inhibitors is required for at least 7 days prior to randomization 
and throughout the study. 
5. If receiving permitted oral immunosuppressants (prednisone or other corticosteroid,), a 
stable dose is required for at least 30 days prior to randomization and throughout the 
study. 
6. Female patients of childbearing potential must practice effective, reliable contraceptive 
regimen during the study. 
7. Able to perform all study procedures and assessments. 
8. Willing and able to travel to study site and attend all clinic study visits. 
9. Willing and able to provide written informed consent. 
 
8.2.2 Exclusion Criteria 
Individuals who meet any of the following exclusion criteria are not eligible to participate in 
the study: 
 
1. Clinically significant long QTc interval on ECG in previous 12 months. 
2. Seizure disorder. 
3. Active brain metastases. 
4. Unable to ambulate 
5. Pregnant or lactating females. 
6. Any other condition which, in the opinion of the investigator, might interfere with the 
patient’s participation in the study or confound the assessment of the patient. 
7.  Patients who cannot discontinue immunomodulatory treatment (e.g. mycophenolate, 
azathioprine, cyclosporine) within 3 weeks before screening. 

 
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8.2.3 Removal of Patients from Treatment or Assessment 
Patients may withdraw their consent to participate in the study or refuse 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. In the event that the patient’s LEMS 
symptoms worsen to a clinically significant level, in the opinion of the Investigator, the patient 
may be placed on open-label amifampridine phosphate, and Early Discontinuation assessments 
should be performed as described for Day 4 (Table 3). 
 
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; and 
• Patient becomes pregnant. 
 
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; and 
• 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. 

 
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The Investigator or designee must explain to each patient, before enrollment into the study, 
that for evaluation of study results, the patient’s protected health information obtained during 
the study may be shared with Catalyst, regulatory agencies, and IRB/IEC/REB. It is the 
Investigator’s (or designee’s) responsibility to obtain written permission to use protected health 
information, per country-specific regulations, from each patient. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written 
request, to ensure that no further data will be collected from the patient and the patient will be 
removed from the study. 
 
8.2.4 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 2 digit site number and a 3 or 4 digit subject 
number. Screen failures that are allowed to repeat screening (Section 8.2.5) will be assigned a 
new ID and the previous ID will be kept as part of the record. Randomized subjects that drop 
out of the study may be replaced.  
 
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. Study site Pharmacy will obtain the treatment group for the 
subject to be enrolled at the time of randomization (Day 0). 
 
8.2.5 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.  
 
8.3 
Treatments 
 
8.3.1 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, 

 
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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 site pharmacy 
department, who will dispense the necessary amount for each part of the study. 
The product will be blinded, neither the invesigator nor the patient will know what product 
they are assigned. 
 
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. The product will be blinded, neither the Investigator nor 
the patient will know what product they are assigned. 
  
8.3.2 Identity of Investigational Product 
The chemical name of amifampridine phosphate is: 
3,4-pyridinediamine, phosphate (1:1) diamino-3,4-pyridine, phosphate salt 
3,4-diaminopyridine phosphate 
The chemical structure is provided in Figure 1. 
Figure 1. Chemical Structure of Amifampridine Phosphate 
 
8.3.2.1 
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 containers of tablets are labeled “Amifampridine phosphate Tablets, 
10 mg.” 
 
The tablets are to be dispensed by the site pharmacy department into suitably sized pharmacy 
containers for patient use. Placebo will be provided as tablets indistinguishable from 
amifampridine phosphate. The amifampridine phosphate tablets and placebo tablets will be 
H3PO4
N
NH2
NH2
4
1
2
3

 
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clearly labeled and the pharmacist is responsible for dispensing the amifampridine phosphate 
tablets or placebo tablets, in a blinded fashion, for each patient, according to the randomization 
schedule provided. 
 
Each contianer will be labeled to include the study number, 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.  
 
8.3.2.2 
 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. 
 
8.3.3 Directions for Administration  
The dose of amifampridine phosphate will be individually determined by the Investigator, 
within the bounds of a total daily dose of 30 mg to 80 mg, divided into doses taken 3 to 4 times 
per day as prescribed by the Investigator, based on optimal neuromuscular benefit. 
All doses of study medication will be taken orally by mouth. 
Generally, doses of study treatment will be taken outside the clinic, except during the in-clinic 
study visit. If the patient takes the dose three or four times a day, the patient should be given 
specific instructions on dosing relative to the time of their visit to assure a dose will be given 
during the in-clinic visit, corresponding to the second, third, or fourth dose. A dose must be 
administered in the clinic in order to perform efficacy assessments at the correct time in 
relation to dosing. Safety assessments are to be performed before the dose administered to 
the patient during the scheduled in-clinic visit. All efficacy assessments will be performed at 
times relative to the dose administered in the clinic. In this case, the dose will be 40 minutes 
before the first efficacy assessment. 

 
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Assessment 
Start Time  
After Dose* 
(+ 10 minutes unless 
otherwise specified) 
SGI 
40 minutes 
Patient most bothersome 
symptom 
Following SGI 
QMG 
Following patient symptom 
evaluation 
CGI-I˚ 
Following QMG 
3TUG 
Following CGI-I 
 
 
*Administration of medication represents Time 0 (minutes) 
 
 
˚Except on Day 0 
 
If the patient is taking pyridostigmine, the dosing schedule must be fixed in relation to when 
they take the IP, such that on the days of clinic assessments the timing between pyridostigmine 
dose and IP do not vary.   
 
Assessments for each clinic visit must be performed relative to the same dose as occurred 
on Day 0.   
 
8.3.4 Method of Assigning Patients to Treatment Groups 
Patients will be randomized Day 0 to either  treatment group in a 1:1 ratio. IP will be 
administered under double-blind conditions such that neither the Investigator nor patient 
knows if they are taking placebo or amifampridine phosphate.  
The randomization code will be provided by Catalyst or designee to the site Pharmacist. Details 
will be included in the Pharmacy Manual.  
 
8.3.5 Selection of Doses Used in the Study 
The amifampridine phosphate dose is 30 mg to 80 mg total daily dose, given in 3 to 4 divided 
doses, with no single dose >20 mg. Safety of a single maximum dose of 20 mg is based on 
completed animal and in vitro pharmacology, PK, and toxicology studies. 
 

 
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8.3.6 Blinding 
This is a double-blind study where both the patients and Investigator will be blinded to 
treatment assignment. 
 
8.3.7 Treatment Compliance 
Patients will be instructed to return all IP containers and remaining study medication at the 
study clinic 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. Urine specimens 
will be collected to further assess treatment compliance. 
 
8.3.8 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 (CRA) has 
confirmed the accountability data. 
 
8.3.9 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. 
 
The monitor must account for all IP in a formal reconciliation process prior to IP destruction. 
Unused IP will be returned to Catalyst. 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 returned according 
to applicable study procedures. 
 
8.4 
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).  

 
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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 4. 
Table 4. Medications Prohibited Before and During Study 
Immunomodulatory treatment (e.g. azothiaprine, mycophenolate, cyclosporine) within 3 weeks 
before Screening 
IVIG within 2 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 
Products with atropinic effects 
 
8.5 
Dietary or Other Protocol Restrictions 
 
8.5.1 Dietary Restrictions 
There are no dietary restrictions for patients during any part of this study. 
 
8.5.2 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. 
 
8.6 
Safety Variables 
Safety in this study will be determined from evaluation of AEs/SAEs, vital signs assessments, 
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. 
 

 
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8.6.1 Adverse Events 
The determination, evaluation and reporting of AEs will be performed as outlined in Adverse 
Events. 
 
8.6.2 Vital Signs 
Specific visits for obtaining vital signs are provided in Table 3 and in Section 11. 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. Weight (kg) 
and temperature in degrees Celsius (°C) will also be measured. Clinically significant changes 
from baseline will be recorded as AEs. 
 
8.6.3 Clinical Laboratory Assessments 
Since LEMS can be associated with neoplastic disease, all patients who enter the trial will have 
the option to participate in cancer screening using the ‘liquid biopsy’ technique, every 6 months 
for 2 years.  
 
The procedure involves collecting tubes of blood which is then incubated with a variety of 
antibodies directed towards circulating tumor cells.  Additional analysis of identified cells may 
then be performed. Follow-up screening will be performed by expanded access clinical sites. 
 
8.6.4 Pregnancy Testing 
Female patients of childbearing potential will have a urine pregnancy test at Screening. If the 
test is equivacol or there is another conern about pregnancy, a serum pregnancy test may be 
performed. Female patients with a positive pregnancy test at Screening do not meet eligibility 
criteria for enrollment.  
 
Refer to Section 9.4 for details on the reporting procedures to follow in the event of pregnancy. 
 
8.6.5 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 11. Complete physical examination will include 
assessments of general appearance as well as the following: 
• 
Head 

 
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• 
Eyes 
• 
Ears 
• 
Nose 
• 
Throat 
• 
Cardiovascular 
• 
Dermatologic 
• 
Lymphatic 
• 
Respiratory 
• 
Gastrointestinal 
Other body systems may be examined. Clinically significant changes from baseline will be 
recorded as AEs. 
 
8.7 
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 
Patient most bothersome 
symptom 
Following SGI 
QMG 
Following patient symptom 
evaluation 
CGI-I˚ 
Following QMG 
3TUG 
Following CGI-I 
 
*Administration of medication represents Time 0 (minutes) 
 
˚Except on Day 0 
 
Primary Efficacy Variables 
 
8.7.1 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. 

 
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The SGI has demonstrated concordance with the physician’s assessment of improvement 
(Dodick, 2007). Instructions for the SGI are provided in Appendix 2 and the LMS-003 Study 
Reference Manual. 
 
8.7.2 Quantitative Myasthenia Gravis 
The QMG is a physician-rated test including 13 assessments such as facial 
strength, swallowing, grip strength, and duration of time that limbs can be maintained 
in outstretched positions. The QMG was first developed by Besinger (Besinger, 1983), 
expanded by Tindall (Tindall, 1993; Tindall, 1987); and subsequently further modified by 
Barohn (Appendix 1) (Barohn, 1998). His modified QMG has been assessed for inter-rater 
reliability and was used as the outcome measure in a prospective study of IVIG for MG (Wolfe, 
2002) and two studies of amifampridine for LEMS (Sanders, 2000; Oh, 2009). Instructions for 
conducting the QMG are provided in Appendix 1 and the LMS-003 Study Reference Manual. 
 
Secondary Efficacy Variable 
 
8.7.3 Clinical Global Impression of Improvement 
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 3 and the LMS-003 Study Reference Manual. 
 
Exploratory Efficacy Variables 
 
8.7.4 Triple Timed Up and Go (3TUG) – greater than 20% increase in average time, 
off medication 
The Timed Up and Go (TUG) is a functional mobility test that requires a subject to stand up 
from a straight-backed armchair, walk 3 meters, turn around, walk back, and sit down in the 
chair. A modification of this is where the individual performs the test three times without 
pause, and the measurement is the average time required to complete each of the 3 repetitions.  
Based upon literature reports that a significant change in gait for a similar walk-test is an 
increase in time of more than 20%, this has been incorporated into the endpoint. 
Instructions for the 3TUG are contained in Appendix 4 and the LMS-003 Study Reference 
Manual. 

 
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8.7.5 Patient Evaluation of Most Bothersome Symptom 
Patients identify their most bothersome LEMS-associated symptom as a measure of patient 
satisfaction with the treatment. The evaluation consists of 2 questions, the first is to identify 
before treatment or while off medication, what the patient perceived as their most bothersome 
symptom and the level to which it bothered them, on a 4 point scale. Following blinded 
treatment with study medication, the patient is asked to evaluate how much the previously 
identified symptom bothered them during the prior 24 hours, on the same 4 point scale. 
 
The Symptom Scale is contained in Appendix 5 and the LMS-003 Study Reference Manual. 
 
9 
REPORTING ADVERSE EVENTS 
 
9.1 
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 serious and non-serious AEs will be reported begins after 
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discontinuation. The criteria for determining, and the reporting of SAEs is provided in Section 
9.2. 
 
The Investigator should follow all unresolved AEs until the events are resolved or stabilized, 
the patient is lost to follow-up, or it has been determined that the study treatment or 
participation is not the cause of the AE. Resolution of AEs (with dates) should be documented 
on the appropriate CRF page(s) and in the patient’s medical record. 
 
The Investigator responsible for the care of the patient or qualified designee will assess AEs 
for severity, relationship to IP, and seriousness (refer to Section 9.2 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 v4) grades defined in Table 5 (the event 
will be recorded on the source documents and AE CRF). 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 as stated below. 

 
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Table 5. 
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. 
 
The Investigator will suggest the relationship of an AE to the IP and will record it on the source 
documents and AE CRF, using the relationship categories defined in Table 6. 
The Investigator should review the AE Log for the patient, from the EAP-001 expanded access 
program. Any ongoing/open/unresolved AEs will be transcribed to the LMS-003 study AE 
Log. At the end of patient’s participation in the LMS-003 study, the AE Log should be provided 
to the expanded access program site, so that the expanded access site can update their AE Log 
with any changes. 

 
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Table 6. Description of Relationship to Adverse Event Categories 
Relationship 
Category 
Description 
Not Related 
Exposure to the IP has not occurred 
OR 
The administration of the IP and the occurrence of the AE 
are not reasonably related in time  
OR 
The AE is considered likely to be related to an etiology other 
than the use of the IP; that is, there are no facts [evidence] or 
arguments to suggest a causal relationship to the IP. 
Possibly 
Related 
The administration of the IP and the occurrence of the AE 
are reasonably related in time 
AND 
The AE could be explained equally well by factors or causes 
other than exposure to the IP. 
Probably 
Related 
The administration of IP and the occurrence of the AE are 
reasonably related in time  
AND 
The AE is more likely explained by exposure to the IP than 
by other factors or causes. 
 
In order to classify AEs and diseases, preferred terms will be assigned by the sponsor to the 
original terms entered in the eCRF, using Medical Dictionary for Regulatory Activities 
(MedDRA) terminology. 
 
9.2 
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 
o Note: Life-threatening refers to an event that places the patient at immediate 
risk of death. This definition does not include a reaction that, had it occurred 
in a more severe form, might have caused death 
• Requires or prolongs in-patient hospitalization 
• Results in persistent or significant disability or incapacity 

 
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• 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. 
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. The Investigator should not wait to collect information that fully documents the SAE 
before notifying Catalyst. As additional information becomes available, including but not 
limited to the outcome of the SAE and any medication or other therapeutic measures used to 
treat the event, it must be reported within 24 hours in a follow-up report 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 will be done in compliance with the standard operating 
procedures and policies of the IRB and with applicable regulatory requirements. Adequate 
documentation must be provided showing that the IRB was properly and promptly notified as 
required. 

 
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9.3 
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. 
 
9.4 
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 Report 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 Report 
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. 
 
9.5 
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 (and consistent with the US FDA regulations at 21 CFR 56.108(a)), 
“…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 with 24 hours. 

 
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Examples of situations that may require urgent safety measures include discovery of the 
following: 
• An immediate need to revise IP administration (i.e. modified dose amount or frequency 
not defined in protocol). 
• Lack of study scientific value, or detrimental study conduct or management. 
• Discovery that the quality or safety of IP does not meet established safety requirements. 
 
9.6 
Medical Monitor Contact Information 
Contact information and additional requirements will be provided in the LMS-003 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 
 
10 
APPROPRIATENESS OF MEASUREMENTS 
The measures of safety used in this study are routine clinical 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 LEMS. 
11 
STUDY PROCEDURES 
11.1 
Screening Visit 
An ICF must be signed and dated by the patient, the Investigator or designee, and witness (if 
required) before any study-related procedures are performed.  
After patient has signed an ICF, they will be screened for enrollment into the study. The study 
activities listed below will be performed during the 7 days that constitute the Screening Visit. 
• Informed Consent 

 
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• 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,  
• History of orthopedic procedures that may affect walking or getting up out of a chair 
• Method of LEMS diagnosis 
• Complete physical examination including weight and height  
• Vital signs (seated position), including systolic blood pressure (SBP), diastolic blood 
pressure (DBP), heart rate, and body temperature  
• Liquid biopsy specimen (if patient opts for cancer screening) 
• Urine pregnancy test in females of childbearing potential only 
• Assessment of AEs/SAEs 
• Assessment of concomitant medications 
11.2 
Randomization Visit (Study Day 0) 
The study activities listed below will be performed on Study Day 0, while the patient has been 
on open-label amifampridine phosphate and in relationship to the usual dosing schedule. 
Assessment 
Start 
Time  
After Dose* 
(+ 
10 
minutes 
unless 
otherwise specified) 
SGI 
40 minutes 
Patient 
most 
bothersome 
symptom, Question 1 
Following SGI 
QMG 
Following patient symptom 
evaluation 
3TUG 
Following QMG 
*Administration of medication represents Time 0 (minutes) 
• Assessmentof AEs/SAEs 
• Assessment of concomitant medications 
Patients who are deemed eligible will be dispensed double-blind study medication 
(amifampridine phosphate or placebo tablets) on Study Day 0, according to the treatment group 
to which they are randomized. The patient’s open-label amifampridine must be collected. 
Patients must stop their open-label amifampridine and will start to take the blinded study 

 
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medication beginning with the next scheduled dose after all assessments on open-label 
medication have been completed. 
 
Patients must be instructed that they are not to take any doses of their prior, open-label 
amifampridine during the study and not to change pyridostigmine dose or schedule. 
 
11.3 
End of Treatment (Study Day 4)  
Patients will take their blinded study medication on Days 1-3.  On Day 4, a dose of blinded 
study medication must be administered by the site study personnel.  This is the same 
medication that the patient has been taking on Days 1-3. The assessments listed below will be 
performed following either the second, third, or fourth dose of medication to be taken on 
Day 4, and this should be the same dose that assessments on Day 0 were subsequently 
performed. For example, if the patient took their second dose of amifampridine in the clinic 
on Day 0 and had assessments started 40 minutes later, then on Day 4, that patient should be 
assessed after taking their second dose of medication in the clinic, starting 40 minutes after the 
dose. 
 
Safety assessments (vital signs and AEs/SAEs) should be performed before study personnel 
give the dose of blinded medication. Concomitant medications should be reviewed for any 
changes. A urine sample, to determine amifampridine level, should be collected on Day 3 (after 
patient has taken a dose of blinded medication), and on Day 4, before study personnel give the 
dose of blinded medication. 
Assessment 
Start Time  
After Dose* 
(+ 10 minutes unless 
otherwise specified) 
SGI 
40 minutes 
Patient most bothersome 
symptom, Question 2 
Following SGI 
QMG 
Following patient symptom 
evaluation 
CGI-I (compared to Day 0) 
Following QMG 
3TUG 
Following CGI-I 
 
 
*Administration of medication represents Time 0 (minutes) 

 
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The container of blinded study medication dispensed on Study Day 0 must be returned to study 
personnel and the IP Accountability form completed to determine if the blinded study 
medication doses were taken.   
 
This represents the end of the study. 
 
11.4 
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 study medication.  Every reasonable effort should be made to contact any patient who 
is lost to follow-up. 
In cases of Early Discontinuation, medication will have been stopped some time prior to seeing 
the patient for the below assessments.  The date and time of the last dose of medication should 
be recorded in relation to when the assessments are performed. 
• Assessment of AEs/SAEs 
• Vital signs 
• Concomitant medications 
• IP accountability 
• SGI 
• CGI-I (compared to Day 0) 
• Patient most bothersome symptom, Question 2 
• QMG 
• 3TUG 
 
12 
DATA QUALITY ASSURANCE  
Catalyst personnel or designee(s) will visit the study site before inititation of the study to 
preview with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization preocedures, source document 
requirements, CRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs. 
 

 
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At visits during and after the study, a CRA will monitor the site for compliance with regulatory 
documentation. Data quality control and analysis will be performed by Catalyst, or designee, 
based on a predefined plan. 
 
13 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE  
13.1 
Determination of Sample Size  
For Change From Baseline in QMG Scores, a between-treatment difference of -3.5 and a 
standard deviation at most 3, a sample size of at least 24 patients will provide power of  at least 
80% for a 0.05 level test. Similarly, for Change From Baseline in SGI Scores, a between-
treatment difference of -2.1 and a standard deviation at most 2, a sample size of at least 26 
patients will provide power of 80% for a 0.05 level test. Thus a total sample size of 26 patients, 
equally randomized to two treatment sequences, will provide power of at least 80% for each 
of the two co-primary endpoints. 
 
13.2 
Patient Populations 
Analyses will be presented for  
• Safety Population: This population consists of all randomized patients who receive at 
least 1 dose of IP (amifampridine or placebo) 
• Full Analysis Set (FAS): This population consists of all randomized patients who 
receive at least 1 dose of IP (amifampridine or placebo) and have at least one post-
treatment efficacy assessment. 
• Per Protocol (PP): This population is a subset of the FAS population, excluding patients 
with major protocol deviations. The PP population will include all patients who: 
o Have no major protocol deviations or inclusion/exclusion criteria deviations 
that might potentially affect efficacy, and 
o Patients who took at least 80% of the required treatment doses and remained 
enrolled for at least 4 days. 
 
Evaluations obtained at the time of discontinuation will be included in the analyses. Patients 
who discontinue with no post-randomization data will be excluded from all efficacy analyses 
but will be included in the safety analyses. 
 

 
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13.3 
Safety Analysis  
Safety analyses will be conducted on the Safety Population. The safety analysis will be 
descriptive and will be presented using observed data only.  
 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Only TEAEs will be included in the safety analysis. The incidence of TEAEs will be 
summarized by system organ class, preferred term, relationship to IP, and severity by 
treatment. Deaths, SAEs, and AEs leading to premature discontinuation will be listed. Vital 
signs, ECGs, physical examination data, and concomitant medications will also be 
summarized.  Routine laboratory assessments will not be performed. Laboratory evaluations, 
if performed, will be listed. 
 
13.4 
Efficacy Analysis  
Efficacy analyses will be conducted on the FAS and PP populations, with the FAS population 
serving as the primary analysis set.  For each efficacy variable with a corresponding assessment 
at Baseline, Change From Baseline (CFB) will be computed as the post-treatment result minus 
the Baseline result.  The post-treatment result will be the result obtained on Day 4, unless the 
subject discontinued treatment early, in which case the post-treatment result may be obtained 
at an earlier time point.  For statistical tests, two-sided P values <0.05 will be considered as 
statistically significant. 
Summary statistics for QMG score and the corresponding CFB will be presented by treatment.  
The analysis of CFB for Total QMG Score is a coprimary efficacy endpoint and analysis will 
be performed by fitting a fixed effects linear model to the data with CFB as the response.  The 
model will include terms for treatment and QMG at Baseline.  The following test comparing 
the least squares (LS) means will be conducted to evaluate the treatment effect: 
HA,0: LSMeanQMG(A)  = LSMeanQMG(P)  vs.  HA,1: LSMeanQMG(A) ≠ 
LSMeanQMG(P), 
where LSMeanQMG(A) is the QMG LS mean of the amifampridine treatment group and 
LSMeanQMG(P) is the QMG LS mean of the placebo treatment group.  
The raw scores and CFB for each item of QMG will be summarized by treatment.  Between-
treatment comparisons with respect to CFB for Right arm outstretched, Left arm outstretched, 
Right leg outstretched, and Left leg outstretched will be performed using a GLM with terms 
for treatment, QMG at Baseline and treatment duration (in days).  

 
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Summary statistics for SGI score and the corresponding CFB will be presented by treatment. 
The analysis of CFB for SGI is a coprimary efficacy endpoint and analysis will be performed 
by fitting a fixed effects linear model to the data with CFB as the response.  The model will 
include terms for treatment and SGI at Baseline.  The following test comparing the LS means 
will be conducted to evaluate the treatment effect: 
HB,0: LSMeanSGI(A)  = LSMeanSGI(P)  vs.  HB,1: LSMeanSGI(A) ≠ LSMeanSGI(P), 
where LSMeanSGI(A) is the SGI LS mean of the amifampridine treatment group and 
LSMeanSGI(P) is the SGI LS mean of the placebo treatment group.  
A sensitivity analysis of the coprimary endpoints will be conducted to evaluate the patterns of 
early treatment discontinuation.  For each coprimary endpoint, a randomization test will be 
conducted to determine if the results from the primary analysis are supported.  The 
randomization test is an alternative to a full permutation, and will evaluate the fixed effects 
model specified above using permutations of the treatment group assignments.  If early 
discontinuations are not associated with treatment, then it is expected that the p-value resulting 
from the randomization test will yield the same statistical interpretation as the p-value resulting 
from the primary analysis.    
 
The proportion of patients with at least 20% increase in average time for 3TUG will be 
summarized by treatment and analyzed using Fisher’s Exact Test. The assessment of the 
Patient’s Most Bothersome Symptom will be summarized by treatment and analyzed using a 
Wilcoxon Rank Sum Test. 
 
13.5 
Changes in the Conduct of the Study or Planned Analyses 
Any change in study conduct considered necessary by the Investigator will be made only after 
consultation with Catalyst, who will then issue a formal protocol amendment to implement the 
change. The only exception is when an Invesigator considers that a patient’s safety is 
compromised without immediate action.  In these circumstances, immediate approval of the 
IRB/IEC/REB must be sought, and the Investigator should inform Catalyst within 2 working 
days after the emergency occurs. 
 

 
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14 
COMPENSATION, INSURANCE AND INDEMNITY 
There will be no charge to study patients to be in this study.  Catalyst will pay all costs of test, 
procedures, and treatment that are part of this study (as included in the site budget).  In addition, 
after IRB/IEC/REB approval, Catalyst will pay the cost of travel, lodging and meals for study 
duration. Catalyst will not pay for any hospitalizations, tests, or treatment 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, test, 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 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. To the extent a patient 
has reasonably followed the Investigator’s instructions and attempted to comply with study 
procedures, 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. 
 
15 
CASE REPORT FORMS AND SOURCE DOCUMENTS 
The CRO data management vendor, 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 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 

 
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consent. The Investigator must review and sign the completed CRF casebook to verify its 
accuracy.  
 
16 
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 Compliance 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. 
 
17 
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 

 
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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 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. 
 
18 
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 any Clinical Trial 
Agreement. 
 
 
 
 
 

 
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firing rates. Muscle Nerve 14[3], 226-232. 1991. 
 
Vedeler CA, Antoine JC, Giometto B, Graus F, et al. Management of paraneoplastic 
neurological syndromes: report of an EFNS Task Force. Eur J Neurol 13[7], 682-690. 2006. 
 
Verschuuren JJ, Wirtz PW, Titulaer MJ, Willems LN, et al. Available treatment options for 
the management of Lambert-Eaton myasthenic syndrome. Expert Opin Pharmacother 7[10], 
1323-1336. 2006. 
 
Weinberg DH. Clinical features and diagnosis of Lambert-Eaton myasthenic syndrome. 
UpToDate. 1-11. 2010. 
 
Wirtz PW, Verschuuren JJ, van Dijk JG, de Kam ML, et al. Efficacy of 3,4-diaminopyridine 
and pyridostigmine in the treatment of Lambert-Eaton myasthenic syndrome: a randomized, 
double-blind, placebo-controlled, crossover study. Clin Pharmacol Ther 86[1], 44-48. 2009. 
 

 
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Wirtz P, van Gerven JMA, van Dijk JGl. The effects of 3,4-DAP (DAP) and pyridostigmine 
(PS) on muscle function in the Lambert-Eaton myasthenic syndrome (LEMS): a double-blind 
placebo-controlled cross-over study. Neuromuscul Disord , 12-760. 2002a. 
 
Wirtz PW, Smallegange TM, Wintzen AR, Verschuuren JJ. Differences in clinical features 
between the Lambert-Eaton myasthenic syndrome with and without cancer: an analysis of 
227 published cases. Clin Neurol Neurosurg 104[4], 359-363. 2002b. 
 
Wolfe GI, Barohn RJ, Foster BM, Jackson CE, et al. Randomized, controlled trial of 
intravenous immunoglobulin in myasthenia gravis. Muscle Nerve 26[4], 549-552. 2002. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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20 
SIGNATURE PAGE 
Protocol Title: A Phase 3, Double-blind, Placebo-controlled, Randomized, Parallel-Group 
Study to Evaluate the Efficacy and Safety of Amifampridine Phosphate (3,4-Diaminopyridine 
Phosphate) in Patients with Lambert-Eaton Myasthenic Syndrome (LEMS) 
Protocol Number: LMS-003 
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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 Appendix 1    Quantitative Myasthenia Gravis Testing Form  
 
TEST ITEMS WEAKNESS 
NONE 
MILD 
MODERATE 
SEVERE 
SCORE 
GRADE 
0 
1 
2 
3 
Double vision 
(lateral gaze) Sec. 
60 
11-59 
1-10 
Spontaneous 
Ptosis (upward gaze) Sec. 
60 
11-59 
1-10 
Spontaneous 
Facial Muscles 
Norma
l lid 
closure 
Complete, 
weak, 
some 
i
Complete, 
without 
resistance 
Incomplete 
Swallowing 
4 oz. Water (1/2 cup) 
Normal 
Minimal 
coughing 
or throat 
clearing 
Severe coughing 
Choking or 
nasal 
regurgitation 
Cannot 
swallow 
(test not 
attempted) 
Speech following counting 
aloud from 1-50 
(onset of dysarthria) 
None 
at #50 
Dysarthria at 
#30-49 
Dysarthria at 
#10-29 
Dysarthria at 
#9 
Right arm outstretched 
(90˚, sitting) Sec. 
240 
90-239 
10-89 
0-9 
Left arm outstretched 
(90˚, sitting) Sec. 
240 
90-239 
10-89 
0-9 
Forced vital capacity 
>80% 
65-79% 
50-64% 
<50% 
Rt hand grip: male 
(Kg)         : 
f
l
>45 
>30 
15-44 
10-29 
5-14 
5-9 
0-4 
0-4 
Left hand grip: male 
(Kg)           : 
f
l
>35 
>25 
15-34 
10-24 
5-14 
5-9 
0-4 
0-4 
Head, lifted 
(45%, supine) Sec. 
120 
30-119 
1-29 
0 
Right leg outstretched 
(45-50%, supine) Sec. 
100 
31-99 
1-30 
0 
Left leg outstretched 
(45-50%, supine) Sec. 
100 
31-99 
1-30 
0 

 
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Appendix 2   Subject Global Impression (SGI) 
The SGI will be assessed at the protocol-specified time points (see Table 3) by the patient.  
 
Using the 7-point scale below, rate your impression of the effects of the study medication 
during the preceding 3 days on your physical well being.  
 
1=Terrible 
2= Mostly dissatisfied 
3= Mixed 
4=Partially satisfied 
5= Mostly satisfied  
6= Pleased 
7= Delighted  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 3 
Clinical Global Impression-Improvement (CGI-I) 
The CGI-I will be used to capture the Investigator’s global impression of the patient’s 
improvement at the end of treatment (Day 4), compared to their condition at the time of 
randomization (Day 0). 
 The Investigator will complete the 7-point CGI-I, based on changes in symptoms, behavior, 
and functional abilities, at the protocol-specified time points. 
 
Rate total improvement whether or not, in your judgment, it is due entirely to drug treatment. 
Compared to the patient’s condition at Day 0, 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 
 
 

 
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Appendix 4   Timed Up and Go (TUG) Test 
Equipment: Stopwatch, Standard Chair with armrests and seat height approximately 44 cm (17 
inches) and arm rest height approximately 65 cm (26 inches), Measured distance of of 3 meters 
(9 feet 10 inches).  
 
Patient Instructions given by the evaluator: 
 
“Sit in the chair with your back resting on the back of the chair and hands on the armrests.  At 
the end of the test mat in front of you is a green light.  When you see the green light turn on , 
I want you to get up from the chair.  You should use the arms of the chair to assist in standing 
up or sitting down from the chair.  Walk forward as quickly as you feel comfortable until you 
reach the orange area on the floor marking the end of the course.  You need to be in the orange 
area with both feet, turn around, walk back to the chair, turn around and sit down completely 
in the chair, touching your back to the back of the chair.  Immediately repeat the course I have 
just explained to you two more times.  Therefore, you will complete the course a total of three 
times without resting between each time that you do the course.” 
 
“I will record the time it takes you to complete the course three times, with the ending time 
occurring when you sit down in the chair for the third time.  You may not use the wall for 
support. Please try to complete the course three times without resting between each time, if 
possible.” 
 
“We will begin in a moment.  Please focus on the light at the end of the course and listen for 
the beep.  Begin immediately upon hearing the beep and seeing the light.  Thank you.” 
 
Evaluator instructions: 
 
The timing, gait, and progress in this test will be recorded automatically by the Prokinetics 
software, both electronically by the sensor mat and by video camera.  Ensure that the subject’s 
back is touching the back of the chair at the beginning and end of each cycle of the course.  
Ensure that the subject’s wear their regular footwear for the test and that they wear the same 
footwear each time the test is conducted.  Refer to past records to ensure the subject’s footwear 
has not changed between days.  The subject may use a walking assistive device (cane or 
walker) if that this their usual and normal practice for walking.  If a walking assistive device 

 
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is used, record the type of device in the source documents.  This device should be used for each 
evaluation.  Subject’s may not be assisted by another person during this test.  If the subject’s 
become fatigued while walking, they may stop and rest, but should not sit down.  Any 
comments or question directed to the subject during the test should be for safety reasons only 
and be non-directive.  For example, “Are you ok?”.  Remember that the entire test is recorded 
by video. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 5   Most Bothersome Symptom Scale 
 
Question 1: 
 
Before treatment for LEMS or while off of medication, what was your most bothersome 
symptom and how would you rate it? 
 
0 = Not at all bothersome 
1 = Bothered me a little 
2 = Bothered me some 
3 = Bothered me a lot 
Question 2: 
After treatment with the study medication, how would you rate the most bothersome symptom 
that you previously identified, during the last 24 hours? 
0 = Not at all bothersome 
1 = Bothers me a little 
2 = Bothers me some 
3 = Bothers me a lot 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 6   Protocol Amendment 1 
 
PURPOSE:  The purpose of this amendment is as follows: 
 
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, on the header changed text. 
Amendment 1 
On Page 1, under Study Title, deleted and added text. 
Two period Two treatment Crossover 
Parrallel- Group 
On Page 1, under Study Design, deleted and added text. 
Two period Two treatment Crossover 
Parrallel- Group 
On Page 1, under Date of Protocol added text. 
Date of Amendment 1:     18 September 2016 
On Page 3, under Title of Study, deleted text and added text. 
Two period Two treatment Crossover 
Parrallel- Group 
On Page 3, under Study Design and Plan, deleted and added text. 
Two period Two treatment Crossover 
Parrallel- Group 
On Page 3, under Study Design and Plan, deleted up to 24 males and added added 28. 
The study is planned to include up to 24 approximately 28 male and female patients. 
On Page 3, under Study Design and Plan, deleted 8 days and added 5 days (Day 0 through 
Day 4). 

 
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The planned duration of participation for each patient is 8 5 days (Day 0 through Day 
4), excluding the screening period, which can last up to 7 days.  
On Page 4, under Study Design and Plan, deleted and added text. 
Treatment Sequence Group. 
On Page 4, under Study Design and Plan, deleted and added text. 
Amifampridine phosphate (at the patient’s optimal dose) or placebo will be dispensed 
by the site pharmacist, according to the randomization schedule, to begin with the next 
dose after all Day 0 assessments are completed and continued for  the 4 days of Period 1.  
Following Period 1, patients will receive the treatment not received during Period 1, 
during double-blind Period 2, for 4 days (Days 5-8). After completion of Period 2 the 
study, patients will be eligible for expanded access treatment program with open-label 
amifampridine phosphate.  
On Page 4, on figure, deleted text boxes. 
 
 
On Page 4, on figure, changed text boxes. 
 
 
 
On Page 4, under Screening, deleted text. 
They can be randomized if on a stable dose and frequency of amifampridine phosphate 
for at least 1 week before being randomize 
ed. to a Treatment Sequence.   
On Page 4, under Screening, deleted and added text. 
Period 1 Treatment (Days 1-4) (+1 day) 
On Page 4, under Treatment (Days 1-4) (+1 day), deleted and added text. 
Patients will be randomized (1:1 ratio) on the last day of the screening period (Day 0) to 
either Treatment Sequence I or II and commence Period 1 for the respective Treatment 
Sequence amifampridine phosphate or placebo. Beginning with the next dose after all Day 
0 assessments are completed on Day 1 of Period 1, the patient will take, under double-
blind conditions, either amifampridine phosphate tablets or placebo tablets for through 
Treatment 
Sequence I 
Period I 
(Drug) 
Period I 
(Placebo) 
Treatment 
Sequence II 

 
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Day 4 days, with a clinic visit on the last day of Period 1(Day 4) for assessments (Table 
3). Any unused portion of dispensed drug will be returned before dispensing drug for 
Period 2.  
On Page 4, under Treatment (Days 1-4) (+1 day), deleted paragragh. 
Period 2 (Days 5-8) (+1 day) 
After completion of Period 1, patients will receive the blinded study appropriate 
medication/placebo for Period 2 during Study Days 5-8 as per their randomized 
Treatment Sequence. A clinic visit will occur at the end of Period 2 (Day 8) for final study 
assessments (Table 3). 
On Page 4, under Number of Patients Planned deleted and added text.  
Up to 24Approximately 28 patients to enroll in the study. 
On Page 5, under Investigational Product(s), Dose Route and Regimen, deleted text. 
Amifampridine phosphate tablets are to be taken orally by mouth with food. 
On Page 6, under Sample Size Determination deleted and added text. 
For Change From Baseline in QMG Scores, a between-treatment difference of -2.83.5 
and a standard deviation at most 3.07, as observed in LSM-002, a sample size of at least 
11 24 patients per sequence will provide power of at least 80% for a 0.05 level test using 
the two-period, two-treatment crossover design. Similarly, for Change From Baseline in 
SGI Scores, a between-treatment difference of -2.1 and a standard deviation at most 
2.42, as observed in LSM-002, a sample size of at least 1226 patients per sequence will 
provide power of 80% for a 0.05 level test using the two-period, two-treatment 
crossover design. Thus a total sample size of 24 26 patients, equally randomized to the 
two treatments sequences, will provide power of at least 80% for each of the two co-
primary endpoints. 
On Page 7, under Efficacy Analysis deleted text.  
Each of the efficacy variables, as well as Change From Baseline (CFB) if appropriate, 
will be summarized by treatment and period. P values <0.05 will be considered as 
statistically significant. 
On Page 7, under Efficacy Analysis deleted and added text. 
The between-treatment comparisons with respect to the CFB in QMG total scores, and 
SGI will be performed using a two-period, two-treatment crossover design. The 95% 

 
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confidence interval (CI) based on this model will be presented for the difference in the 
Least Squares (LS) means for each of these analyses.Summary statistics for QMG score 
and the corresponding CFB will be presented by treatment.  The analysis of CFB for Total 
QMG Score is a coprimary efficacy endpoint and analysis will be performed using analysis 
of covariance (ANCOVA) with QMG at Baseline as the only covariate.  
On Page 7, under Efficacy Analysis deleted and added text. 
The scores for each item of QMG will be summarized by treatment. and period and 
between-treatment comparisons with respect to scores for Right arm outstretched, Left 
arm outstretched, Right leg outstretched, and Left leg outstretched will be performed 
using a two-period, two-treatment crossover design with a multinomial logistic regression 
modelANCOVA with the corresponding assessment at Baseline as the only covariate.  
On Page 7, under Efficacy Analysis deleted and added text. 
Summary statistics for SGI and the corresponding CFB will be presented by treatment. 
The analysis of CFB for SGI is a coprimary efficacy endpoint and analysis will be 
performed using ANCOVA with SGI at Baseline as the only covariate. 
The proportion of patients with at least 20% increase in average time for 3TUG and 
assessment of the Patient’s Most Bothersome Symptom will be summarized by 
treatment and period and analyzed using a nonparametric approach. 
On Page 10, in table of contents, added text. 
20. Protocol signature page 
On Page 28, under Overall Study Design and Plan, deleted and added text. 
This randomized (1:1), double-blind, placebo-controlled, two-period, two-treatment 
crossover parallel-group study is designed to evaluate the efficacy and safety of 
amifampridine phosphate in patients diagnosed with LEMS. 
On Page 28, under Overall Study Design and Plan, deleted and added text. 
The study is planned to include up to 24approximately 28 male and female patients. The 
planned duration of participation for each patient is 8 5 days, excluding the screening 
period, which can last up to 7 days.  
On Page 28, under Overall Study Design and Plan, deleted and added text. 

 
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Those patients successfully satisfying all screening criteria will be randomized to a 
Treatment Sequencetreatment group. Amifampridine phosphate (at the patient’s 
optimal dose) or placebo will be dispensed by the site pharmacist, according to the 
randomization schedule, to begin with the next dose after all Day 0 assessments are 
completed and continued for  the 4 days of Period 1.   Following Period 1, patients will 
receive the treatment not received during Period 1, during double-blind Period 2, for 4 
days (Days 5-8). After completion of Period 2the study, patients will be eligible for 
expanded access treatment program with open-label amifampridine phosphate. 
On Page 29, on figure, deleted text boxes. 
 
 
On Page 29, on figure, changed text boxes. 
 
 
 
On Page 29, under screening deleted and added text. 
Patients receiving amifampridine phosphate treatment for LEMS, and 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 of amifampridine phosphate 
for at least 1 week before being randomized to a Treatment Sequencetreatment.   
On Page 29, under Treatment (Days 1-4) (+1 day), deleted and added text. 
Patients will be randomized (1:1 ratio) on the last day of the screening period (Day 0) to 
either Treatment Sequence I or II and commence Period 1 for the respective Treatment 
Sequence amifampridine phosphate or placebo. Beginning with the next dose after all Day 
0 assessments are completed on Day 1 of Period 1, the patient will take, under double-
blind conditions, either amifampridine phosphate tablets or placebo tablets for through 
Day 4 days, with a clinic visit on the last day of Period 1(Day 4) for assessments (Table 
3). Any unused portion of dispensed drug will be returned before dispensing drug for 
Period 2.  
  
On Page 29, under Treatment (Days 1-4) (+1 day), deleted and added text. 
Treatment 
Sequence I 
Period I 
(Drug) 
Day 1-4 
Period I 
(Placebo) 
Day 1-4 
Treatment 
Sequence II 

 
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Period 2 (Days 5-8) (+1 day) 
After completion of Period 1, according to the randomization schedule, patients will 
receive the blinded study appropriate medication/placebo for Period 2 for 4 days (Day 
5-8). Patients begin taking investigational material for Period 2 on the morning of Day 
5. A clinic visit will occur at the end of Period 2 (Day 8) for final study assessments 
(Table 3). 
 
During all phases of the study, safety and efficacy assessments will be made as detailed 
in the Schedule of Assessments in Table 3. 
On Page 30, on Table 3, deleted text 
Period 1 
On Page 30, on Table 3, added text. 
Blinded IP dispense 
On Page 30, on Table 3, deleted row. 
IP administration 
On Page 30, on Table 3, deleted column 5.  
Period 2 
Days 5-8 
Day 8 
(+1 d) 
On Page 30, on Table 3, added text. 
Urine sample for amifampridine level2 
On Page 30, on Table 3, deleted and added text. 
Pregnancy test – urine23 
On Page 30, on Table 3 between Urine sample for amifampridine level2 and Day 4(+1d) 
deleted text. 
X4 
On Page 30, under Table 3 deleted text. 
3Drug dispensed for Period 2, at end of Period 1 
On Page 30, under Table 3 deleted and added text. 
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On Page 30, under Table 3, deleted text. 
2Women of child-bearing potential32Urine specimen for amifampridine level will be 
collected on Days 3 and 4 
On Page 30, under Table added text. 
3Women of child-bearing potential 
On Page 32, under Removal of Patients from Treatment or Assessment, deleted and added 
text. 
In the event that the patient’s LEMS symptoms worsen to a clinically significant level, 
in the opinion of the Investigator, the patient may be placed on open-label 
amifampridine phosphate, and Early Termination Discontinuation assessments should 
be performed as described for Period 2, Day 8 4 (Table 3). 
On Page 33, under Patient Identification and Randomization, deleted and added text. 
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. Study site Pharmacy will obtain 
the Treatment Sequencetreatment group for the subject to be enrolled in Period 1 at the 
time of randomization (Day 0). 
On Page 35, under Directions for Administration, deleted text.  
30 mg to 80 mg, divided into doses taken 3 to 4 times per day taken with food (e.g. 
breakfast, lnch, dinner, and snack before bed) 
On Page 36, under Method of Assigning Patients to Treatment Groups, deleted and added 
text.  
Patients will be randomized Day 0 to either Treatment Sequence I or II, treatment group 
in a 1:1 ratio. IP will be administered within Period 1 and Period 2 under double-blind 
conditions for each Treatment Sequence such that neither the Investigator nor patient 
knows if they are taking placebo or amifampridine phosphate.  
On Page 37, Treatment Compliance, deleted text.  
Patients will be instructed to return all IP containers and remaining study medication 
at each the study clinic visit. 
On Page 41, under Efficacy Variables, added text. 
Exploratory Efficacy Variables 
On Page 41, section 8.7.4, deleted text. 

 
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The Timed Up and Go (TUG) is a functional mobility test that requires a subject to stand up 
from an 18 inch straight-backed armchair, walk 3 meters, turn around, walk back, and sit 
down in the chair. 
On Page 42, under 8.7.5, deleted and added text. 
The evaluation consists of 2 questions, the first is to identify before treatment or while off 
medication, what the patient perceived as their most bothersome symptom and the level to 
which it bothered them, on a 4 point scale.  The second question is the evaluation of that 
symptom during each of the double-blind treatment periods. Following blinded 
treatment with study medication, the patient is asked to evaluate how much the previously 
identified symptom bothered them during the prior 24 hours, on the same 4 point scale. 
On Page 43, under Adverse Events, deleted and added text.  
The study period during which all serious and non-serious AEs will be reported begins 
after informed consent is obtained and through the last visit of Period 2 on Study Day 8 
4 
On Page 43, under Adverse Events, deleted and changed text. 
(refer to Section 11.2 9.2 for SAE definition). 
On Page 50, under Randomization Visit (Study Da 0) deleted and added word. 
Patients who are deemed eligible will be dispensed double-blind study medication 
(amifampridine phosphate or placebo tablets) on Study Day 0, according to the 
treatment sequence group to which they are randomized. The patient’s open-label 
amifampridine must be collected and only enough pills to complete usual dosing on Day 
0 provided. Patients must stop their open-label amifampridine and will start to take the 
blinded study medication the next morning (Study Day 1) beginning with the next 
scheduled dose after all assessments on open-label medication have been completed. 
On Page 50, under Table, deleted and added text. 
Patients must be instructed that they are not to take any doses of their prior, open-label 
amifampridine during either Period 1 or Period 2the study and not to change 
pyridostigmine dose or schedule. 
On Page 50, under End of Treatment (Study Day 4), titled changed  
End of Period 1Treatment (Study Day 4) 
On Page 50, under End of Treatment (Study Day 4), deleted and added text. 
Patients will take their blinded study medication on Days 1-3 of Period 1.  On Day 4, a 
dose of blinded study medication must be administered by the site study personnel.  
This is the same medication that the patient has been taking on Days 1-3 of Period 1. 

 
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On Page 50, under End of Treatment (Study Day 4), deleted and added text. 
For example, If the patient took their second dose of amifampridine in the clinic on Day 
0 and had assessments started 40 minutes later, then on Day 4 and 8, that patient 
should be assessed after taking their second dose of medication in the clinic, starting 40 
minutes after the dose. 
On Page 51, under End of Treatment (Study Day 4), deleted and added text. 
A urine sample, to determine amifampridine level, should be collected on Day 2 3 or 
Period 1, and on Day 4, before study personnel give the dose of blinded medication. 
On Page 51, under Table deleted text. 
The patient should be given back only enough of the Period 1 study medication to 
complete dosing for that day (Day 4). 
On Page 51, deleted paragraph and section 11.4. 
A new container of blinded study medication for Period 2 will be given to the patient at 
the end of the assessments.  Blinded study medication for Period 2 is to be taken 
beginning the next morning, Study Day 5, after completing all Day 4 medication. 
 
11.4 End of Period 2 (Study Day 8) 
Patients will take their blinded study medication on Days 5-7 of Period 2.  On Day 8, 
blinded study medication will be administered by the site study personnel.  This is the 
same medication that the patient has been taking on Days 5-7 of Period 2. The 
assessments listed below will be performed following either the second, third, or fourth 
dose of medication to be taken on Day 4, and this should be the same specific dose after 
which assessments on Day 0 were subsequently performed.   
 
Safety assessments (vital signs and AEs/SAEs) should be performed before study 
personnel give the dose of blinded medication. Concomitant medications should be 
reviewed for any changes. 

 
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Assessment 
Start Time  
After Dose* 
(+ 10 minutes unless 
otherwise specified) 
SGI 
40 minutes 
Patient most bothersome 
symptom, Question 2 
Following SGI 
QMG 
Following patient 
symptom evaluation 
CGI-I (compared to Day 0 and 
Day 4) 
Following QMG 
3TUG 
Following CGI-I 
 
 
*Administration of medication represents Time 0 (minutes) 
 
The container of blinded study medication dispensed on Study Day 4 must be returned 
to study personnel and the IP Accountability form completed to determine if the 
blinded study medication doses were taken.  Sufficient tablets should be returned to the 
patient to complete any remaining doses for Day 8.  
On Page 52, under Early Discontinuation Visit, deleted text.  
• CGI-I (compared to Day 0 and Day 4, based upon the time of discontinuation) 
On Page 52, under Determination of Sample Size, deleted and added text. 
For Change From Baseline in QMG Scores, a between-treatment difference of -2.83.5 
and a standard deviation at most 3.07, as observed in LSM-002, a sample size of at least 
11 24 patients per sequence will provide power of  at least 80% for a 0.05 level test using 
the two-period, two-treatment crossover design. Similarly, for Change From Baseline in 
SGI Scores, a between-treatment difference of -2.1 and a standard deviation at most 
2.42, as observed in LSM-002, a sample size of at least 12 26 patients per sequence will 
provide power of 80% for a 0.05 level test using the two-period, two-treatment 
crossover design. Thus a total sample size of 24 26 patients, equally randomized to two 
treatment sequences, will provide power of at least 80% for each of the two co-primary 
endpoints. 
On Page 53, under Efficacy Analysis, deleted and added text. 
Each of the efficacy variables, as well as Change From Baseline (CFB) if appropriate, will be 
summarized by treatment and period. 

 
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QMG total scores and SGI are co-primary endpoints. The between-treatment 
comparisons with respect to the CFB in QMG total scores and SGI, will be performed 
using a two-period, two-treatment crossover design. The 95% confidence interval (CI) 
based on this model will be presented for the difference in the Least Squares (LS) 
means for each of these analyses. Summary statistics for QMG score and SGI, and the 
corresponding CFB, will be presented by treatment.  The analysis of CFB for Total QMG 
Score and SGI are coprimary efficacy endpoints and analysis will be performed using 
ANCOVA with QMG or SGI at Baseline as the only covariate, respectively. 
 
The scores for each item of QMG will be summarized by treatment. and period and 
bBetween-treatment comparisons with respect to scores for Right arm outstretched, 
Left arm outstretched, Right leg outstretched, and Left leg outstretched will be 
performed using a two-period, two-treatment crossover design with a multinomial 
logistic regression modelANCOVA with the corresponding assessment at Baseline as the 
only covariate.  
 
The proportion of patients with at least 20% increase in average time for 3TUG will be 
summarized by treatment and period and analyzed using a nonparametric 
approachFisher’s Exact Test. The assessment of the Patient’s Most Bothersome 
Symptom will be summarized by treatment and period and analyzed using a 
nonparametric approacha Wilcoxon Rank Sum Test. 
On Page 62, Signature page added. 
On Page 65, under Appendix 3, deleted and added text. 
The CGI-I will be used to capture the Investigator’s global impression of the patient’s 
improvement at the end of each double-blind treatment (Day 4) period, compared to their 
condition at the time of randomization (Day 0). 
On Page 66, Appendix 4, deleted  and added text. 
I will record the time it takes you to complete the course three times, with the ending time 
occurring when your back touches the back of sit down in the chair for the third time. 
 
 
 
 
 

 
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Appendix 7   Protocol Amendment 2 
 
PURPOSE:  The purpose of this amendment is as follows: 
 
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, on the header added text. 
Amendment 2 
On Page 2, under Emerency Contact Information deleted and added text. 
Richard Erwin Adriana Manari 
Executive Director Clinical Trial Manager 
Ext. 130 117 
rerwin@catalystpharma.com amanari@catalystpharma.com 
On Page 5, under Criteria for Inclusion and Exclusion, deleted and added text. 
1. Male or female ≥18 years of age with LEMS and currently receiving  a stable dose of 
amifampridine phosphate for LEMSat least 7 days. 
On Page 5, under Criteria for Inclusion and Exclusion, added text. 
8. Patients who cannot discontinue immunomodulatory treatment (e.g. mycophenolate, 
azathioprine, cyclosporine) within 3 weeks before screening. 
On Page 7, under Efficacy Analysis deleted and added text. 
Each of the efficacy variables, as well as Change From Baseline (CFB) if appropriate, 
will be summarized by treatmentFor each efficacy variable with a corresponding 
assessment at Baseline, Change From Baseline (CFB) will be computed as the post-
treatment result minus the Baseline result. The post-treatment result will be the result 
obtained on Day 4, unless the subject discontinued treatment early, in which case the post-
treatment result may be obtained at an earlier time point. For statistical tests, two-sided  P 
values <0.05 will be considered as statistically significant. 
 
 

 
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Summary statistics for QMG score and the corresponding CFB will be presented by treatment.  
The analysis of CFB for Total QMG Score is a coprimary efficacy endpoint and analysis will 
be performed using analysis of covariance (ANCOVA) by fitting a general linear fixed effects 
linear model (GLM) to the data with CFB as the response. The model will include terms for 
treatment, with and; QMG at Baseline and treatment duration (in days) as the only 
covariate. A test comparing least squares (LS) means will be conducted to evaluate the 
treatment effect. 
 
The raw scores, and CFB for each item of QMG will be summarized by treatment.  Between-
treatment comparisons with respect to CFB for Right arm outstretched, Left arm outstretched, 
Right leg outstretched, and Left leg outstretched will be performed using ANCOVA a fixed 
effects linear model with terms for treatment and QMG at Baseline. with the corresponding 
assessment at Baseline as the only covariate.  
 
Summary statistics for SGI score and the corresponding CFB will be presented by treatment. 
The analysis of CFB for SGI is a coprimary efficacy endpoint and analysis will be performed 
by fitting a GLM fixed effects linear model to the data with CFB as the response. The model 
will include terms for treatment and; SGI at Baseline and treatment duration (in 
days)using ANCOVA with SGI at Baseline as the only covariate. 
 
On Page 29, under 8.1 Overall Study Design and Plan added text.  
Patients will have been receiving unblinded drug treatment in the expanded access program 
(EAP-001), after which blinded treatment effect will be assessed for continuation or 
cessation of drug. 
On Page 30, under Screening added text. 
They can be randomized if on stable dose and frequency of amifampridine phosphate for at 
least 1 week before being randomized to a treatment.  Screening and randomization (Day 0) 
may be combined into a single visit. 
On Page 33, under 8.2.1 Inclusion Criteria deleted and added text.  
1. Male or female ≥18 years of agewith LEMS and currently receiving a stable dose 
of amifampridine phosphate for LEMSat least 7 days. 
On Page 33, under 8.2.1 Inclusion Criteria deleted and added text. 
5.  If receiving permitted oral immunosuppressants (prednisone or other 
corticosteroid, azathioprine, mycophenolate), a stable dose is required for at least 30 
days prior to randomization and throughout the study. 

 
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On Page 33, under 8.2.2 Exclusion Criteria deleted and added text.  
3.         Active brain metastases. 
3.4. 
Unable to ambulate 
4.5. 
Pregnant or lactating females. 
6. 
Any other condition which, in the opinion of the investigator, might interfere with the 
patient’s participation in the study or confound the assessment of the patient. 
5.7. 
 Patients who cannot discontinue immunomodulatory treatment (e.g. 
mycophenolate, azathioprine, cyclosporine) within 3 weeks before screening. 
 
On Page 35, under 8.2.4 Patient Identification and Randomization deleted and added text. 
Upon signing of the ICF, subjects will be assigned an ID composed of a 2 digit site number 
and a 3 or 4 2 digit subject number. 
On Page 40, on title Table 4. Medications Prohibited Before and During Study, added text. 
Table 5. Medications Prohibited Before and During Study 
On Page 40, under Table 4. Medications Prohibited Before and During Study, added text. 
Immunomodulatory treatment (e.g. azothiaprine, mycophenolate, cyclosporine) within 3 
weeks before Screening 
On Page 41, under 8.6.3 Clinical Laboratory Assessments added text. 
The procedure involves collecting tubes of blood which is then incubated with a variety of 
antibodies directed towards circulating tumor cells.  Additional analysis of identified cells 
may then be performed. Follow-up screening will be performed by expanded access clinical 
sites. 
On Page 46, under Table 5 added text. 
The Investigator should review the AE Log for the patient, from the EAP-001 expanded 
access program. Any ongoing/open/unresolved AEs will be transcribed to the LMS-003 
study AE Log. At the end of patient’s participation in the LMS-003 study, the AE Log 
should be provided to the expanded access program site, so that the expanded access site 
can update their AE Log with any changes. 
On Page 52, under 11.3 End of Treatment (Study Day 4) added text.   
A urine sample, to determine amifampridine level, should be collected on Day 3 (after 
patient has taken a dose of blinded medication), and on Day 4, before study personnel give 
the dose of blinded medication. 

 
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On Page 53, under table deleted text.    
The patient should be given back only enough of the study medication to complete 
dosing for that day (Day 4). 
On Pages 55 and 56, under 13.4 Efficacy Analysis deleted and added text.  
Each of the efficacy variables, as well as Change From Baseline (CFB) if appropriate, 
will be summarized by treatment. P values <0.05 will be considered as statistically 
significant. 
Summary statistics for QMG score and SGI, and the corresponding CFB, will be 
presented by treatment.  The analysis of CFB for Total QMG Score and SGI are 
coprimary efficacy endpoints and analysis will be performed using ANCOVA with 
QMG or SGI at Baseline as the only covariate, respectively. 
The scores for each item of QMG will be summarized by treatment. Between-treatment 
comparisons with respect to scores for Right arm outstretched, Left arm outstretched, 
Right leg outstretched, and Left leg outstretched will be performed using ANCOVA 
with the corresponding assessment at Baseline as the only covariate.  
Efficacy analyses will be conducted on the FAS and PP populations, with the FAS 
population serving as the primary analysis set.  For each efficacy variable with a 
corresponding assessment at Baseline, Change From Baseline (CFB) will be computed as 
the post-treatment result minus the Baseline result.  The post-treatment result will be the 
result obtained on Day 4, unless the subject discontinued treatment early, in which case 
the post-treatment result may be obtained at an earlier time point.  For statistical tests, two-
sided P values <0.05 will be considered as statistically significant. 
Summary statistics for QMG score and the corresponding CFB will be presented by 
treatment.  The analysis of CFB for Total QMG Score is a coprimary efficacy endpoint 
and analysis will be performed by fitting a general linear model (GLM) fixed effects 
linear model to the data with CFB as the response.  The model will include terms for 
treatment, QMG at Baseline and treatment duration (in days).  The following test 
comparing the least squares (LS) means will be conducted to evaluate the treatment effect: 
HA,0: LSMeanQMG(A)  = LSMeanQMG(P)  vs.  HA,1: LSMeanQMG(A) ≠ LSMeanQMG(P), 
where LSMeanQMG(A) is the QMG LS mean of the amifampridine treatment group and 
LSMeanQMG(P) is the QMG LS mean of the placebo treatment group.  
The raw scores and CFB for each item of QMG will be summarized by treatment.  
Between-treatment comparisons with respect to CFB for Right arm outstretched, Left arm 

 
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outstretched, Right leg outstretched, and Left leg outstretched will be performed using a 
GLM with terms for treatment, QMG at Baseline and treatment duration (in days).  
Summary statistics for SGI score and the corresponding CFB will be presented by 
treatment. The analysis of CFB for SGI is a coprimary efficacy endpoint and analysis will 
be performed by fitting a GLM fixed effects linear model to the data with CFB as the 
response.  The model will include terms for treatment and; SGI at Baseline and treatment 
duration (in days).  The following test comparing the LS means will be conducted to 
evaluate the treatment effect: 
HB,0: LSMeanSGI(A)  = LSMeanSGI(P)  vs.  HB,1: LSMeanSGI(A) ≠ LSMeanSGI(P), 
where LSMeanSGI(A) is the SGI LS mean of the amifampridine treatment group and 
LSMeanSGI(P) is the SGI LS mean of the placebo treatment group.  
A sensitivity analysis of the coprimary endpoints will be conducted to evaluate the patterns 
of early treatment discontinuation.  For each coprimary endpoint, a randomization test 
will be conducted to determine if the results from the primary analysis are supported.  The 
randomization test is an alternative to a full permutation, and will evaluate the fixed 
effects model specified above using permutations of the treatment group assignments.  If 
early discontinuations are not associated with treatment, then it is expected that the p-
value resulting from the randomization test will yield the same statistical interpretation as 
the p-value resulting from the primary analysis.    
On Page 69, under Appendix 4  Timed Up and Go (TUG) Test deleted and added text. 
Walk forward as quickly as you feel comfortable until you pass the piece of tapereach the 
orange area on the floor marking the end of the course.  Cross the tapeYou need to be in 
the orange area with both feet, turn around, walk back to the chair, turn around and sit down 
completely in the chair, touching your back to the back of the chair.