An Open-Label Extension Study to Evaluate the Long-Term Safety and Efficacy of Migalastat Hydrochloride Monotherapy in Subjects With Fabry Disease
Phase: PHASE3
Conditions: Fabry Disease
Sponsor: Amicus Therapeutics

An Open-Label Extension Study to Evaluate the Long-term 
Safety and Efficacy of Migalastat Hydrochloride 
Monotherapy in Subjects With Fabry Disease 
 
Unique Protocol ID: 
AT1001-042 
NCT Number: 
NCT02194985 
Date of Protocol:  
21 October 2015 
 

 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
AN OPEN-LABEL EXTENSION STUDY TO EVALUATE THE 
LONG TERM SAFETY AND EFFICACY OF MIGALASTAT 
HYDROCHLORIDE MONOTHERAPY IN SUBJECTS WITH 
FABRY DISEASE 
 
Protocol Number: AT1001-042  
Original Protocol: 10 June 2014 
Amendment 1: 30 September 2015 
Amendment 1.1: 21 October 2015 
 
Compound: AT1001 (migalastat hydrochloride)  
Sponsor 
Amicus Therapeutics, Inc. 
1 Cedar Brook Drive 
Cranbury, NJ 08512 
Phone:  609-662-2000 
 
US IND Number: 68,456 
EudraCT Number: 2014-002701-38 
 
 
 
 
The information in this document is the property of Amicus Therapeutics and is strictly 
confidential. Neither the document nor the information contained herein may be 
reproduced or disclosed outside Amicus Therapeutics without the prior written consent of 
the company. 
 
 

Amicus Therapeutics, Inc. 
Study AT1001-042 
Sponsor Information Page 
Clinical Study Identifier: 
AT1001-042 
Sponsor Legal Registered Address: 
Amicus Therapeutics, Inc. 
1 Cedar Brook Drive 
Cranbury, NJ 08512 
USA 
Sponsor Medical Monitor Contact Information: 
1 Cedar Brook Drive 
Cranbury, NJ 08512 
USA 
Safety Fax:  +1 646-963-2056 
Sponsor Serious Adverse Events (SAE) Contact Information: 
Pharmacovigilance Location: 
1 Cedar Brook Drive 
Cranbury, NJ 08512 
USA 
SAE Fax:  +1 646-963-2056 
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Amicus

Amicus Therapeutics, Inc. 
Study ATlO0l-042 
1. 
DECLARATIONS OF SPONSOR AND INVESTIGATOR 
1.1. 
DECLARATION OF SPONSOR 
This clinical study protocol was subject to critical review and has been approved by the 
sponsor. 
The information it contains is consistent with: 
• 
The current benefit-risk evaluation of migalastat HCl 
• 
The moral, ethical, and scientific principles governing clinical research, as set 
out in the Declaration of Helsinki, the principles of Good Clinical Practice 
described in the United States Code of Federal Regulations (CFR; Parts 50, 
54, 56, and 312), and in the ICH Guidelines for Good Clinical Practice (E6) 
The investigator will be supplied with details of any significant or new findings relating 
to treatment ~ith migala~tat HCI. 
Date: .2/ oc;r.2.a/S- Signature: 
Amicus Therapeutics, Inc. 
1.2. 
DECLARATION OF INVESTIGATOR 
I confirm that I have read this clinical study protocol. I understand it, and I will work 
according to the moral, ethical, and scientific principles governing clinical research, as 
set out in the Declaration of Helsinki and the principles of Good Clinical Practice 
described in the United States Code of Federal Regulations (CFR; Parts 50, 54, 56, and 
312) and in the ICH Guidelines for Good Clinical Practice (E6). I will also work in 
accordance with applicable local requirements. 
Investigator 
Date: -----
Signature: _ _______________ _ 
PRINTED NAME: - -------------
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Amicus Therapeutics, Inc. 
Study AT1001-042 
 
TABLE OF CONTENTS 
1. 
DECLARATIONS OF SPONSOR AND INVESTIGATOR.......................................3 
1.1. 
DECLARATION OF SPONSOR .................................................................................3 
1.2. 
DECLARATION OF INVESTIGATOR .....................................................................3 
2. 
LIST OF ABBREVIATIONS.......................................................................................7 
PROTOCOL SUMMARY .............................................................................................................10 
3. 
INTRODUCTION ......................................................................................................12 
3.1. 
Background .................................................................................................................12 
3.2. 
Rationale .....................................................................................................................12 
4. 
OBJECTIVE(S) ..........................................................................................................14 
4.1. 
Primary Objective: ......................................................................................................14 
4.2. 
Secondary Objective: ..................................................................................................14 
5. 
INVESTIGATIONAL PLAN .....................................................................................15 
5.1. 
Study Design ...............................................................................................................15 
5.2. 
Discussion of Design ..................................................................................................15 
6. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA...................................16 
6.1. 
Number of Subjects ....................................................................................................16 
6.2. 
Inclusion Criteria ........................................................................................................16 
6.3. 
Exclusion Criteria .......................................................................................................17 
6.4. 
Withdrawal Criteria ....................................................................................................18 
7. 
STUDY TREATMENTS............................................................................................19 
7.1. 
Investigational Product ...............................................................................................19 
7.2. 
Dosage Schedule .........................................................................................................19 
7.3. 
Packaging and Labeling ..............................................................................................19 
7.4. 
Product Accountability ...............................................................................................19 
7.5. 
Supplies and Accountability .......................................................................................19 
7.6. 
Treatment Compliance ................................................................................................20 
7.7. 
Prohibited Medications and Non-Drug Therapies ......................................................20 
7.8. 
Treatment after the End of the Study ..........................................................................21 
7.9. 
Treatment of Study Treatment Overdose ...................................................................21 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................22 
8.1. 
Critical Baseline Assessments ....................................................................................24 
8.2. 
Safety ..........................................................................................................................25 
 
 
 
 
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8.2.1. 
Safety Assessments .....................................................................................................25 
8.2.2. 
Stopping Criteria .........................................................................................................25 
8.2.3. 
Liver chemistry stopping and follow up criteria .........................................................25 
8.2.4. 
Adverse Events ...........................................................................................................28 
8.2.4.1. 
Definition of an AE ....................................................................................................28 
8.2.4.2. 
Definition of a SAE ....................................................................................................28 
8.2.5. 
Laboratory and Other Safety Assessment Abnormalities Reported as 
AEs and SAEs .............................................................................................................29 
8.2.6. 
Possible Suicidality Related Adverse Event(s) (PSRAE) ..........................................30 
8.2.7. 
Pregnancy ...................................................................................................................30 
8.2.8. 
Reporting of Overdose ................................................................................................30 
8.2.9. 
Reporting of Possible Study Drug Product Quality Complaints ................................30 
8.2.10. 
Time Period and Frequency of Detecting AEs and SAEs ..........................................31 
8.2.11. 
Prompt Reporting of Serious Adverse Events and Other Events to 
Amicus ........................................................................................................................31 
8.2.11.1. 
Regulatory Reporting Requirements for SAEs ...........................................................33 
8.2.12. 
Other Safety Assessments ...........................................................................................33 
8.2.12.1. 
Physical Examination .................................................................................................33 
8.2.12.2. 
Vital Signs, Weight, and Height .................................................................................33 
8.2.12.3. 
ECG ............................................................................................................................34 
8.2.12.4. 
Clinical Laboratory Tests ...........................................................................................34 
8.3. 
Efficacy .......................................................................................................................36 
8.3.1. 
Efficacy/Pharmacodynamic Assessments ..................................................................36 
9. 
DATA MANAGEMENT ...........................................................................................37 
10. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .............................38 
10.1. 
Hypotheses ..................................................................................................................38 
10.2. 
Sample Size Considerations .......................................................................................38 
10.3. 
Data Analysis Considerations .....................................................................................38 
10.3.1. 
Analysis Populations ..................................................................................................38 
10.3.2. 
Analysis Data Sets ......................................................................................................38 
10.3.3. 
Interim Analysis ..........................................................................................................38 
10.3.4. 
Key Elements of Analysis Plan ..................................................................................38 
10.3.4.1. 
Safety Analyses ..........................................................................................................38 
10.3.4.2. 
Efficacy Analyses .......................................................................................................39 
 
 
 
 
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10.3.4.3. 
Pharmacodynamic Analyses .......................................................................................40 
10.3.4.4. 
Health Outcomes Analyses .........................................................................................40 
11. 
STUDY CONDUCT CONSIDERATIONS ...............................................................41 
11.1. 
Posting of Information on Publicly Available Clinical Trial Registers ......................41 
11.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ..........................................................................................................41 
11.3. 
Quality Control (Study Monitoring) ...........................................................................41 
11.3.1. 
Quality Assurance .......................................................................................................42 
11.3.2. 
Study and Site Closure................................................................................................42 
11.3.3. 
Records Retention .......................................................................................................42 
11.3.4. 
Use of Study Findings ................................................................................................43 
11.3.5. 
Liability and Insurance ...............................................................................................44 
11.3.6. 
Data Safety Monitoring Board ....................................................................................44 
12. 
REFERENCES ...........................................................................................................45 
13. 
APPENDICES ............................................................................................................46 
13.1. 
Appendix 1: Contraceptive Requirements ..................................................................46 
13.1.1. 
Female Subjects ..........................................................................................................46 
13.1.2. 
Male Subjects ..............................................................................................................47 
13.2. 
Appendix 2: Liver Chemistry Stopping and Follow-up Criteria ................................48 
 
LIST OF TABLES 
Table 1: 
Time and Events Table ...............................................................................................23 
Table 2: 
SAE and Pregnancy Reporting Time Frames .............................................................32 
Table 3: 
Serum Chemistry Parameters .....................................................................................34 
Table 4: 
Hematology Parameters ..............................................................................................35 
Table 5: 
Urinalysis Parameters .................................................................................................35 
 
 
 
 
 
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2. 
LIST OF ABBREVIATIONS 
α-Gal A 
α-galactosidase A  
ACEIs 
Angiotensin-converting enzyme inhibitors 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ARBs 
Angiotensin II receptor antagonists 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CD 
Compact disc 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration equation 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CS 
Clinically significant 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
ER 
Endoplasmic reticulum 
ERT 
Enzyme replacement therapy 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma –glutamyltransferase 
GL-3 
Globotriaosylceramide 
HCl 
Hydrochloride 
HDL 
High density lipoprotein 
HR 
Heart rate 
 
 
 
 
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ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
IgM 
Immunoglobulin M 
IND 
Investigational new drug 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional Review Board 
ISFN 
Investigator Site File Notebook 
ITT 
Intent to treat 
ITTE 
Intent to treat efficacy  
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LSLV 
Last subject’s last visit 
LVID 
Left ventricular internal dimension 
LVM 
Left ventricular mass 
LVMi 
Left ventricular mass index 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minute 
mL 
Milliliter 
MSDS 
Material Safety Data Sheet 
MWFS 
Midwall fractional shortening 
NCS 
Not clinically significant 
QOD 
Once every other day 
PD 
Pharmacodynamic(s) 
PHI 
Personal Health Information 
PK 
Pharmacokinetic(s) 
PSRAEs 
Possible suicidality related adverse events 
RBC  
Red blood cell 
RNA 
Ribonucleic acid 
RR 
Respiration rate 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan  
 
 
 
 
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SD 
Standard deviation 
SF-36 
Short Form-36 survey 
SOC 
System Organ Class 
SPM 
Study Procedures Manual 
ULN 
Upper limit of normal 
WBC 
White blood cell 
 
 
 
 
 
 
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PROTOCOL SUMMARY 
Rationale 
Fabry disease is a rare X-linked lysosomal storage disease caused by mutations of the 
GLA gene, resulting in reduced or absent levels of the lysosomal enzyme α-galactosidase 
A (α-Gal A).  Reduced enzyme activity results in accumulation of the natural substrate 
globotriaosylceramide (GL-3) in tissues, giving rise to the disease symptoms and 
ultimately premature death due to renal failure, cardiac disease, and stroke.  Current 
treatment for Fabry disease is enzyme replacement therapy (ERT) which is administered 
by intravenous infusion every two weeks.   
Migalastat hydrochloride (HCl) is an orally administered small molecule that has 
widespread tissue distribution and is being developed for the treatment of patients with 
Fabry disease.  Migalastat HCl is a pharmacological chaperone and as such stabilizes 
endogenous α-Gal A allowing it to be properly trafficked to the lysosome where it can 
degrade GL-3. 
The purpose of this study is to investigate the long-term safety and explore the 
efficacy/pharmacodynamics of migalastat HCl administered 150 mg (equivalent to 123 
mg migalastat) every other day (QOD).  Subjects enrolled in this clinical protocol will 
have completed treatment in a previous study of migalastat HCl.  In Japan, subjects 
enrolled in this clinical protocol will have completed AT1001-012.  
Objective(s) 
Primary Objective: 
To assess long-term safety of migalastat HCl in the treatment of subjects with Fabry 
disease who completed treatment in a previous study of migalastat HCl.  
Secondary Objective: 
To explore long-term efficacy/pharmacodynamics of migalastat HCl in subjects with 
Fabry disease who have completed treatment in a previous study of migalastat HCl. 
Study Design 
This is an open-label, non-comparative, long-term extension study for subjects with 
Fabry disease who have completed treatment in a previous trial of migalastat HCl given 
as monotherapy.  Subjects will enter this extension study immediately upon completion 
of their final treatment visit in a previous migalastat HCl study.  The planned duration of 
the treatment will vary among subjects and will continue until the date of regulatory 
approval or marketing authorization and/or commercialization in the participating 
subject’s country, or study termination by the Sponsor, Amicus Therapeutics (Amicus).  
There will be continuous monitoring of safety data and use of specific stopping criteria 
for discontinuation of individual subjects who show evidence of clinical deterioration. 
A data safety monitoring board (DSMB) will be chartered to monitor and evaluate the 
safety of all subjects in this trial by periodically reviewing summaries of safety data, 
evaluating risk/benefit where possible, identifying any clinically relevant trends through 
the study, and assessing whether it is safe for the study to continue.  Predefined stopping 
 
 
 
 
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criteria will be observed for discontinuation of individual subjects who show evidence of 
clinical deterioration. 
Study Assessments 
The safety assessments are: 
• Adverse events (AEs), possible suicidality related AEs (PSRAEs) and serious 
adverse events (SAEs) 
• Withdrawal due to AEs 
• Vital signs (blood pressure, body temperature, respiratory rate, and heart rate) 
and body weight 
• Hematology, chemistry, and urinalysis parameters 
• Electrocardiograms (ECGs) 
• Stopping criteria 
The efficacy/pharmacodynamic assessments are: 
• Estimated glomerular filtration rate (eGFR) based on the Modification of Diet 
in Renal Disease (MDRD) equation and the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation 
• Plasma lyso-Gb3  
• Evaluation of left ventricular mass index (LVMi), as measured by 
echocardiography 
• Ejection fraction, as measured by echocardiography 
• Fractional shortening, as assessed by echocardiography  
• Measurement of LV internal dimension (LVIDd and LVIDs), midwall 
fractional shortening (MWFS), and wall thickness, as assessed by 
echocardiography 
• Evaluation of white blood cell (WBC) α-Gal A activity 
• Evaluation of subject reported Quality of Life as assessed by the Short 
Form-36 Survey (SF-36) 
 
 
 
 
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3. 
INTRODUCTION 
3.1. 
Background 
Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the 
gene (GLA) that encodes the lysosomal enzyme α-galactosidase A (α-Gal A).  Mutations 
in GLA lead to reduced enzyme activity as a result of lowered catalytic activity, improper 
folding, decreased enzyme stability and/or inefficient trafficking into the lysosome 
(Bishop and Desnick 1981; Lemansky 1987; von Scheidt, Eng et al. 1991; Aerts, Groener 
et al. 2008). 
The primary biological role of α-Gal A is to catalyze the first step in the degradation of 
neutral glycosphingolipids, in particular globotriaosylceramide (GL-3, also known as 
Gb3).  Reduced enzyme activity results in the accumulation of GL-3 in cells and organs 
throughout the body (Desnick, Ioannou et al. 2001) leading to the life-threatening 
manifestations of Fabry disease, which include kidney failure, heart disease and stroke.  
Migalastat hydrochloride (HCl) is an orally administered, low molecular weight 
iminosugar, and an analog of the terminal galactose group that is cleaved from the 
substrate GL-3.  Migalastat HCl, which binds at the active site of α-Gal A, is a potent, 
reversible, competitive inhibitor of the enzyme.  The binding of migalastat to both mutant 
and wild-type forms of α-Gal A stabilizes the enzyme.  As a result, the mutant enzyme 
quaternary structure is sufficiently improved for it to pass the endoplasmic reticulum 
(ER) quality control systems and can be properly trafficked to the lysosomes.  At this 
site, the low pH and high concentration of accumulated GL-3 in the lysosomes favor 
dissociation of migalastat from α-Gal A, freeing the enzyme to bind and break down 
GL-3. As such, migalastat acts as a “pharmacological chaperone” to α-Gal A.  
The only specific treatment for Fabry disease is intravenously (IV) administered enzyme 
replacement therapy (ERT).  No oral therapies are currently approved for treating Fabry 
disease. 
3.2. 
Rationale 
Migalastat HCl has been studied in 27 patients with Fabry disease in four completed 
Phase 2 studies [migalastat HCl Investigator’s Brochure].  In these studies, as judged by 
improvements in both α-Gal A activity in different tissues and reduction in the 
pathological substrate (GL-3), treatment with migalastat HCI was associated with 
pharmacodynamic evidence of efficacy.  Migalastat HCl therapy resulted in increases in 
endogenous α-Gal A activity in WBCs, skin, and kidney tissue in the majority of 
subjects.  In those subjects with responsive GLA mutations as determined by in vitro 
assay, GL-3 concentrations tended to decrease in urine and in kidney interstitial 
capillaries.  The decrease in urine GL-3 concentration was greater after administration of 
150 mg migalastat HCl once every other day (QOD) than after either once daily or twice 
daily administration.  Migalastat HCl was well tolerated and there were no treatment 
related serious adverse events SAEs and no treatment limiting toxicities identified. 
After completing one of the four Phase 2 studies subjects were eligible to participate in a 
long-term extension study, FAB-CL-205. In this study, increasing doses up to 500 mg 
 
 
 
 
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QOD did not show additional treatment effect relative to 150 mg QOD.  To further 
investigate the efficacy and safety of migalastat HCl treatment, two pivotal Phase 3 
studies were initiated. 
The pivotal Phase 3 studies include AT1001-011, a 24-month randomized double-blind 
placebo-controlled (through month 6) study to evaluate the efficacy and safety of 
migalastat HCl in ERT-naïve male and female patients with amenable mutations, and 
AT1001-012 an 18-month, randomized open-label active comparator trial to evaluate the 
efficacy and safety of migalastat HCl compared to ERT in ERT-experienced male and 
female patients with amenable mutations.  
These pivotal studies have demonstrated efficacy of migalastat in Fabry patients with 
amenable mutations.  Based on the adverse event profile, laboratory evaluations, physical 
examinations, vital signs, and ECGs, these studies have demonstrated that migalastat HCl 
150 mg QOD is a generally safe and well-tolerated treatment for Fabry disease. Long 
term extension studies AT1001-041 and AT1001-042 (the current study) are ongoing at 
this time. 
Since Fabry disease is a chronic condition, typically resulting in declining renal function, 
and usually requiring life-time treatment, the current study (AT1001-042) was designed 
to provide continued migalastat HCl treatment to those subjects who have completed 
treatment in a previous migalastat study, as well as to enable collection of longer term 
safety and efficacy data. However, previous Phase 1 studies with migalastat HCl have 
shown migalastat HCl to be primarily excreted (77% of the dose) via the kidneys. 
Therefore, it is not unexpected that migalastat HCl would demonstrate increased systemic 
exposure with declining renal function. A Phase 1 renal impairment study, AT1001-015, 
conducted in non-Fabry patients with varying stages of renal impairment and normal 
renal function demonstrated significant accumulation of plasma migalastat in subjects 
with eGFR < 30 mL/min/1.73m2.  
Eleven subjects had > 2-fold increase in AUC relative to the mean (12400 ng∙hr/mL) of 
normal renal function (> 90 mL/min/1.73m2) in study AT1001-015. Eight of the 11 
subjects had severe renal impairment (< 30 mL/min/1.73m2) with 2.9- to 6.7-fold 
increased area under the concentration-time curve (AUC), and all 8 had elevated (> 100 
ng/mL) trough concentrations of plasma migalastat from 238 to 582 ng/mL. Based on 
AT1001-015 results, an eGFR of < 30 mL/min/1.73 m2 in non-Fabry subjects is 
associated with plasma migalastat accumulation.  
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4. 
OBJECTIVE(S) 
4.1. 
Primary Objective: 
To assess the long-term safety of migalastat HCl in the treatment of subjects with Fabry 
disease who completed treatment in a previous study of migalastat HCl. 
4.2. 
Secondary Objective: 
To explore the long-term efficacy/pharmacodynamics of migalastat HCl in subjects with 
Fabry disease who completed treatment in a previous study of migalastat HCl. 
 
 
 
 
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5. 
INVESTIGATIONAL PLAN 
5.1. 
Study Design 
This will be a multi-centre open-label extension study of migalastat HCl in subjects with 
Fabry disease.  All subjects who completed migalastat HCl monotherapy treatment in a 
previous study, and who in the opinion of the investigator could benefit from remaining 
on migalastat HCl treatment, may be considered for enrollment in this study. 
The study will consist of a Baseline Visit (Visit 1) which will be performed at the time of 
the final visit of the previous study, followed by clinic visits every 6 months for each year 
of the study.  The duration of the treatment will vary among subjects. 
Within each participating country, subjects will continue to receive treatment with 
migalastat HCl within this protocol until one of the following study conclusion conditions 
apply:  
1. Regulatory approval and/or commercialization of migalastat HCl in the local 
country or 
2. Migalastat HCl is rejected by the regulatory authority in the local country or 
3. The study is terminated by the sponsor for reasons including, but not limited to 
safety issues or 
• If the sponsor decides to continue to provide AT1001, it may occur via a 
separate open-label extension protocol, early access, or other program 
depending on local regulations. 
4. The subject is withdrawn or withdraws consent. 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns.  Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.  
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual/Investigator Site File Notebook 
(SPM/ISFN).  The SPM/ISFN will provide the site personnel with administrative and 
detailed technical information that does not impact subject safety. 
5.2. 
Discussion of Design 
This is an open-label extension study intended to provide continued treatment with 
migalastat HCl for subjects with Fabry disease who completed treatment of a previous 
migalastat HCl monotherapy study as outlined in Section 5.1. 
The study will be used to assess the long-term safety and explore the 
efficacy/pharmacodynamics of migalastat HCl in subjects with Fabry disease who 
completed migalastat HCl treatment in a previous study.  
 
 
 
 
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6. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA. 
6.1. 
Number of Subjects 
The number of subjects to be enrolled will be dependent on the number of eligible 
subjects completing migalastat HCl treatment in previous studies and who consent to 
enter this open-label extension study.  It is expected that up to 100 subjects will be 
eligible to enter into this study based on current enrollment in existing studies and 
potential enrollment in future studies. 
6.2. 
Inclusion Criteria 
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the Amicus investigational product (IP) or other study 
treatment that may impact subject eligibility is provided in the Investigator Brochure. 
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability, or subject safety.  Therefore, 
adherence to the criteria as specified in the protocol is essential.  
Subjects eligible for enrollment in the study must meet all of the following criteria: 
1. Subject with Fabry disease who completed treatment in a previous study of 
migalastat HCl given as monotherapy.  
2. Male or female subjects 18 years of age or older. 
Note:  Subjects under the age of 18 will be enrolled only at sites with all required 
regulatory and ethics approvals to do so.  
3. A female subject is eligible to participate if she is: 
a. Of non-childbearing potential, or 
b. Of childbearing potential and NOT pregnant or nursing, has a negative urine 
pregnancy test at the Baseline Visit (Visit 1), and agrees to one of the methods 
of avoiding pregnancy listed in Appendix 1 from the time of first dose of 
study medication until 30 days after study completion. 
A female is considered “Non-childbearing potential” if she is status-post 
hysterectomy, status-post surgical removal of both ovaries, has current, 
documented tubal ligation, or is postmenopausal and >2 years without 
menses.  Female subjects who are post-menopausal <2 years must be 
confirmed menopausal by Follicle Stimulating Hormone (FSH) and estradiol 
levels. 
A female is considered “childbearing potential” if she has functional ovaries, 
ducts, and uterus with no impairment that would cause sterility.  This includes 
women with oligomenorrhea (even severe), and women who are 
perimenopausal or who have just begun to menstruate. 
4. Male subjects must agree to use one of the contraception methods listed in 
Appendix 1.  This criterion must be followed from the time of the first dose of 
study medication until 30 days after study completion.  
 
 
 
 
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5. Subject is willing and able to provide written informed consent and authorization 
for use and disclosure of Personal Health Information (PHI) or research related 
health information or has a legally authorized representative who has given 
written informed consent. 
Note: In Japan, subjects under 20 years of age will provide written informed 
assent, and written informed consent will be provided by their parent or legal 
guardian. 
6.3. 
Exclusion Criteria 
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.  
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. The last available estimated glomerular filtration rate (eGFR) in the previous 
study was <30 mL/min/1.73m2; unless there is measured GFR available within 3 
months of Baseline Visit (Visit 1), which is >30 mL/min/1.73m2. 
2. The subject has undergone, or is scheduled to undergo kidney transplantation or is 
currently on dialysis. 
3. The subject is treated or has been treated with another investigational drug (except 
migalastat HCl) within 30 days of study start.  
4. Subject is unable to comply with study requirements, or deemed otherwise 
unsuitable for study entry, in the opinion of the investigator.  
5. Had a documented transient ischemic attack, stroke, unstable angina, or 
myocardial infarction within the 3 months before Visit 1.  
6. Has clinically significant unstable cardiac disease in the opinion of the 
investigator (e.g., cardiac disease requiring active management, such as 
symptomatic arrhythmia, unstable angina, or NYHA class III or IV congestive 
heart failure).  
7. Has a history of allergy or sensitivity to AT1001 (including excipients) or other 
iminosugars (e.g., miglustat, miglitol).  
8. Requires treatment with Glyset® (miglitol) or Zavesca® (miglustat).  
9. Has any intercurrent illness or condition that may preclude the subject from 
fulfilling the protocol requirements or suggests to the investigator that the 
potential subject may have an unacceptable risk by participating in this study. 
10. Patients with severe or unsuitable concomitant medical condition (cardiovascular, 
neurological, hepatic, renal, metabolic, hematological, immunological, 
pulmonary, or gastrointestinal disorder). The medical monitor or designee must be 
contacted to discuss the stability of a subject’s medical condition(s) and the 
potential impact of the condition(s) on trial participation. 
11. Patients with clinically significant abnormal laboratory value(s) and clinically 
significant electrocardiogram (ECG) findings. The medical monitor or designee 
 
 
 
 
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Amicus Therapeutics, Inc. 
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must be contacted to discuss the subject’s medical condition(s) and the potential 
impact of the condition(s) on continued trial participation. 
6.4. 
Withdrawal Criteria 
Subjects may discontinue migalastat HCl and withdraw from the study for any reason 
including, but not limited to, the following:  
• At their own request or at the request of their parent or guardian (if the subject 
is a minor) or legally authorized representative∗. 
• If, in the investigator’s opinion, continuation in the study would be 
detrimental to the subject's well-being. 
• Occurrence of an intolerable adverse event (AE) as determined by the 
investigator and/or the subject.  
• Subject initiates or plans to initiate regular ERT for Fabry disease. 
• Suspected hepatotoxicity, as defined by increase of ALT or AST ≥3X upper 
limit of normal (ULN) and total bilirubin >2X ULN when no other reason can 
be found to explain the increase in liver enzymes. 
• Persistent noncompliance with study requirements, such as failure to return to 
the study site for scheduled visits. 
• Pregnancy and/or breast feeding. 
• Documented eGFRMDRD value meeting the criteria defined below: 
− An eGFR value (calculated centrally) that is < 30 mL/min/1.73m2  
In all cases, the reason for withdrawal and the date of withdrawal must be recorded in the 
electronic case report form (eCRF) and in the subject’s medical records.   
∗ 
“Legally authorized representative” means an individual or judicial or other body 
authorized under applicable law to consent on behalf of a prospective subject to the 
subject’s participation in the procedure(s) involved in the research. 
 
 
 
 
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7. 
STUDY TREATMENTS 
7.1. 
Investigational Product  
Migalastat HCl, 150 mg (equivalent to 123 mg migalastat) per capsule, and reminder 
capsules are formulated with magnesium stearate (vegetable) and pregelatinized starch in 
a hard gelatin capsule and will be supplied in blister packs.  Reminder capsules will not 
be identical in appearance to migalastat HCl capsules. 
7.2. 
Dosage Schedule 
Blister packs contain either 1) alternating 150 mg migalastat HCl capsules and inactive 
reminder capsules or 2) 150 mg migalastat HCl capsules only.  Subjects will take one 150 
mg capsule of migalastat HCl every other day (QOD) at approximately the same time of 
day.  On alternate days when migalastat HCl is not administered, a reminder capsule will 
be provided which should be taken at approximately the same time of day or punch-out 
foil in the blister pack to keep track of QOD dosing regimen instead.  Subjects are 
required to fast (no food or beverages, except water) 2 hours before and 2 hours after 
taking migalastat HCl.  In order to ensure continuous treatment with migalastat HCl as 
subjects transition from the previous study; the first dose of study medication (either a 
reminder or active capsule, as appropriate to maintain the migalastat 150 QOD dosing 
regimen) should be taken within the window of the Baseline Visit. 
7.3. 
Packaging and Labeling 
Migalastat HCl will be supplied by the sponsor to the study sites as capsules packaged in 
blister packs.  The blister pack contains migalastat HCl capsules and may include non-
identical reminder capsules. 
The contents of the label will be in accordance with all applicable regulatory 
requirements. 
Each blister pack will have a label that will contain the drug name, strength, quantity, lot 
number, sponsor name, and applicable local law statements.  
7.4. 
Product Accountability 
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to Amicus (or 
designee), when applicable.  Product accountability records must be maintained 
throughout the course of the study. 
7.5. 
Supplies and Accountability 
Sites will be instructed to store the study medication at room/ordinary temperature (15°C 
to 25°C / 59°F to 77°F) in a secure area, free from environmental extremes, and with 
 
 
 
 
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restricted access.  The capsules must be dispensed to subjects in the original study 
medication container provided by the sponsor. 
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and administration of the investigational product 
will be limited to the investigator and authorized site staff.  Investigational product must 
be dispensed or administered only to subjects enrolled in the study and in accordance 
with the protocol. 
The investigator, or appropriately assigned designee, will inventory and acknowledge 
receipt of all shipments of the study medication.  The investigator agrees to keep accurate 
records of the quantities of study medication dispensed, used, and returned by each 
subject.  Subjects will be instructed to return all unused, partially used, or empty study 
medication containers at the specified visits.  The study monitor will periodically check 
the supplies of study medication held at the site to verify accountability of all study 
medication used and to verify that a final report of drug accountability to the unit dose 
level is prepared and maintained in the investigator study file.  When instructed by the 
monitor, the investigator agrees to return all original containers of study medication, 
whether empty, or containing used or unused study medication to the sponsor or their 
designee. 
7.6. 
Treatment Compliance 
Dosing compliance will be assessed at each clinic visit through subject interview and 
comparison of the amount of study medication the subject was scheduled to take over the 
number of days during the study with the amount returned.   
The investigator may choose to interrupt or discontinue the study medication in case of 
an AE.  Any interruption in dosing for this, or other reasons, must be documented. 
The investigator should discontinue the study medication if continued administration of 
the study medication is believed to be contrary to the best interest of the subject.  The 
reasons for discontinuation must be documented. 
If the reason for the interruption or discontinuation of the study medication is an AE, an 
abnormal assessment (e.g., ECG finding), or a laboratory test abnormality, this 
information will be recorded as an AE. 
If the subject is not compliant with the study medication administration, the investigator 
may need to evaluate whether the noncompliance should warrant subject withdrawal 
from the study.   
7.7. 
Prohibited Medications and Non-Drug Therapies 
Use of investigational/experimental therapy is not allowed at any time during the study. 
Routine use of the following medications during this trial is prohibited: 
• Glyset (miglitol) 
• Zavesca (miglustat) 
• Fabrazyme (agalsidase beta) 
 
 
 
 
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• Replagal (agalsidase alfa) 
If the subject receives investigational therapy, or if routine use of prohibited medications 
is initiated, the subject must be prematurely discontinued from the trial and final 
assessments performed at the last treatment visit. 
Drugs that affect lysosomal pH (e.g., chloroquine) and drugs that result in accumulation 
of phospholipids in lysosomes (e.g., gentamicin, amiodarone) should be avoided due to 
the theoretical potential for interactions with migalastat.  If alternative therapies exist 
these should be used. 
7.8. 
Treatment after the End of the Study 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition whether or not Amicus is providing specific 
post study treatment. 
7.9. 
Treatment of Study Treatment Overdose 
An overdose of migalastat HCl is defined as an ingestion of a dose greater than the 
prescribed dose of 150 mg migalastat HCl QOD.  There are no known antidotes and 
Amicus does not recommend a specific treatment in the event of a suspected overdose.  
The investigators will use clinical judgment in treating the symptoms of a suspected 
overdose. 
 
 
 
 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
The Time and Events Table displays each study assessment and procedure along with the 
scheduled time of occurrence (Table 1).  All study assessments should be conducted by 
the investigator, and/or a suitably qualified designee.  Information will be recorded in the 
source documents and, where appropriate, the eCRF. 
All study visits should be scheduled from the Baseline Visit (Visit 1) as specified.  
Further information can be found in the SPM/ISFN. 
 
 
 
 
 
 
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Table 1: 
Time and Events Table 
Study Month # 
Baseline  
 (Month 0)
1 
6 
Months 
(±30 
days) 
 
12 
Months 
(±30 
days) 
  
Repeat 6 & 
12 Month 
visits in the 
subsequent 
years 
End of Study 
(Approximately 
30 days after 
last treatment) 
Visit Number 
V1 
V2 
V3 
V4, V5, etc 
 
Assessments 
 
 
 
 
 
Review Informed Consent 
X 
 
 
 
 
Review Inclusion/Exclusion 
Criteria 
X 
X 
X 
 
 
Physical Examination 
X 
X 
X 
 
X 
Concomitant Medications 
X 
X 
X 
 
X 
Vital Signs (BP, HR, RR, 
Temp)   
X 
X 
X 
 
X 
Weight 
X 
X 
X 
 
X 
Height 
X 
 
 
 
X 
12 Lead ECG 
X 
X 
X 
 
X 
Echocardiography
2 
X 
 
X 
 
X
3 
Chemistry
4 
5 
X 
X 
X 
 
X 
Hematology5 
X 
X 
X 
 
X 
Urinalysis5 
X 
X 
X 
 
X 
24-Hour Urine5 
X 
X 
X 
 
X 
eGFR calculation5 
X 
X 
X 
 
X 
WBC α-Gal A Activity5 
X 
X 
X 
 
X 
Pregnancy Test
6 
X 
X 
X 
 
X 
Plasma Lyso-GB3 
X 
X 
X 
 
X 
Adverse Events 
X 
X 
X 
 
X 
SF-36 Survey 
X 
X 
X 
 
X 
Study Treatment 
Supply/Resupply/Return
7 
X 
X 
X 
 
X 
Intermediate Subject Contact
8 
X 
X 
X 
 
X 
  
1 Assessments collected for the last treatment visit in the previous study, which are also required at 
Baseline for the current study, will serve as Baseline Visit 1 assessments for this study.  The visit window 
for the last treatment visit will apply for the completion of such assessments.  Assessments required at 
Baseline (Visit 1) that are not performed as part of the last treatment visit in the previous study will have 
a visit window of +30 days. 
2 ECHOs will be read centrally. 
 
 
 
 
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3 ECHO is to be performed for subjects who withdraw from the study and did not have an ECHO 
performed within the previous 6 months. 
4 Subjects must fast for approximately 8 or more hours before serum chemistry is performed. 
5 In the event of an abnormal lab result, at the investigator’s discretion, the test can be repeated in an 
unscheduled visit and sent to the central laboratory for analysis. 
6 Urine pregnancy test to be performed at Baseline Visit 1 according to previous protocol; thereafter the 
urine pregnancy test will be performed locally using dipstick. 
7 Study Treatment Supply for Study AT1001-042 is intended to occur on Baseline (Visit 1) or in 
subsequent days within the allowable window for this visit. 
8 Subjects will receive a telephone contact, or contact using another acceptable method, approximately 
midway between visits to assess Adverse Events and dosing compliance. It is better to have the phone 
contact performed earlier or later than scheduled, rather than not at all. 
Baseline 
During transition from the previous study into the current study, the intent is for 
treatment with migalastat HCl to continue without a break.  
Assessments collected as a part of the last treatment visit in the previous study, that are 
also required for the Baseline Visit in the current study, will serve as the assessment for 
the Baseline Visit.  The visit window for the last treatment visit in the previous study will 
apply to those Baseline Visit assessments.  However, to provide flexibility to 
investigators and subjects, any Baseline Visit assessment that is required for the current 
study and not a required assessment for the last treatment visit in the previous study, may 
be performed up to 30 days after entry into the current study.   
Unscheduled visits  
Unscheduled visits can be performed at any time point at the investigator’s discretion for 
medical reasons, such as evaluation of AEs and/or repeat laboratory tests. 
Early Withdrawal 
Subjects who meet any of the withdrawal criteria in Section 6.4 and withdraw from the 
study will be asked to return for a visit approximately 30 days after last treatment and 
have end of study assessments performed as shown in Table 1.  An echocardiogram 
(ECHO) will be performed for subjects who have not had an ECHO within the previous 6 
months.   
End of Study 
An End of Study visit will occur within approximately 30 days of the subject’s last 
treatment dose. 
8.1. 
Critical Baseline Assessments 
Fabry disease may result in end stage cardiovascular and renal disease and organ damage. 
Cardiovascular and other medical history and risk factors will be assessed at the Baseline 
Visit (Visit 1). The medical monitor or designee must be contacted to discuss the stability 
of a subject’s medical condition(s) and the potential impact of the condition(s) on trial 
participation.  
 
 
 
 
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8.2. 
Safety 
8.2.1. 
Safety Assessments 
Safety assessments include the following: 
• Adverse events (AEs), possible suicidality related adverse events (PSRAEs), 
and serious adverse events (SAEs) 
• Withdrawal due to AEs 
• Vital signs (blood pressure, body temperature, respiration rate, and heart rate) 
and weight 
• Hematology, chemistry, and urinalysis parameters 
• Echocardiography (ECHO) 
• Electrocardiograms (ECGs) 
• Stopping criteria 
8.2.2. 
Stopping Criteria 
Subjects must discontinue study medication and be withdrawn from the study if they 
meet any of the following stopping criteria: 
• 30% increase in serum creatinine from Baseline (Visit 1) confirmed by repeat 
analysis in fully hydrated subject 
• 25% decrease from Baseline in cardiac ejection fraction as determined by 
echocardiogram 
• Cerebrovascular event with significant sequelae, including stroke 
• An eGFR value of < 30 mL/min/1.73m2 
8.2.3. 
Liver chemistry stopping and follow up criteria 
Liver chemistry stopping and follow up criteria have been designed to assure subject 
safety and evaluate liver event etiology (in alignment with the FDA premarketing clinical 
liver safety guidance). Phase 3 criteria will be used for this study. 
Phase III-IV liver chemistry stopping criteria 1-5 are defined below and in Appendix 2. 
1. ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) (or ALT ≥3xULN 
and INR>1.5, if INR measured) 
NOTE: if serum bilirubin fractionation is not immediately available, withdraw 
study drug if ALT ≥3xULN and bilirubin ≥2xULN.  Serum bilirubin fractionation 
should be performed if testing is available.  If testing is unavailable, record 
presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury. 
2. ALT ≥8xULN. 
3. ALT ≥5xULN but <8xULN persists for ≥2 weeks. 
 
 
 
 
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4. ALT ≥3xULN if associated with symptoms (new or worsening) believed to be 
related to  hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, or jaundice) or believed to be related to hypersensitivity (such as 
fever, rash or eosinophilia). 
5. ALT ≥5xULN but <8xULN and cannot be monitored weekly for ≥2 weeks. 
When any of the liver chemistry stopping criteria 1-5 is met, do the following: 
• Immediately withdraw investigational product.  
• Report the event to Amicus within 24 hours of learning its occurrence. 
• Complete the liver event CRF and SAE data collection tool if the event also 
meets the criteria for an SAE. All events of ALT ≥3xULN and bilirubin 
≥2xULN (>35% direct) (or ALT ≥3xULN and INR >1.5, if INR measured); 
INR measurement is not required and the threshold value stated will not apply 
to patients receiving anticoagulants), termed ‘Hy’s Law’, must be reported 
as an SAE (excluding studies of hepatic impairment or cirrhosis).  
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug 
if ALT ≥3xULN and bilirubin ≥2xULN. Serum bilirubin fractionation should be 
performed if testing is available.  If testing is unavailable, record presence of detectable 
urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver 
injury. 
• Complete the liver imaging and/or liver biopsy CRFs if these tests are 
performed. 
• Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below.  
• Withdraw the subject from the study (unless further safety follow up is 
required) after completion of the liver chemistry monitoring as described 
below. 
• Do not re-challenge with investigational product.   
In addition, for criterion 1:  
• Make every reasonable attempt to have subjects return to the clinic within 24 
hours for repeat liver chemistries, liver event follow up assessments (see 
below), and close monitoring. 
• A specialist or hepatology consultation is recommended. 
• Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values. 
For criteria 2, 3, 4 and 5: 
• Make every reasonable attempt to have subjects return to clinic within 24-72 
hrs for repeat liver chemistries and liver event follow up assessments (see 
below). 
 
 
 
 
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• Monitor subjects weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values; 
criterion 5 subjects should be monitored as frequently as possible. 
Subjects with ALT ≥5xULN and <8xULN which exhibit a decrease to ALT x≥3xULN, 
but <5xULN and bilirubin <2xULN without hepatitis symptoms or rash, and who can be 
monitored weekly for 4 weeks: 
• Notify the Quintiles and Amicus medical monitor within 24 hours of learning 
of the abnormality to discuss subject safety. 
• Can continue investigational product.  
• Must return weekly for repeat liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) until they resolve, stabilize or return to within 
baseline.  
• If at any time these subjects meet the liver chemistry stopping criteria, 
proceed as described above. 
• If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, 
monitor subjects twice monthly until liver chemistries normalize or return to 
within baseline values.  
For criteria 1-5, make every attempt to carry out the liver event follow up assessments 
described below: 
• Viral hepatitis serology including: 
− Hepatitis A IgM antibody; 
− Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
− Hepatitis C ribonucleic acid (RNA); 
− Cytomegalovirus IgM antibody; 
− Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  
− Hepatitis E IgM antibody 
• Blood sample for pharmacokinetic (PK) analysis, obtained within 72 hours of 
last dose.  Record the date/time of the PK blood sample draw and the 
date/time of the last dose of investigational product prior to blood sample 
draw on the CRF.  If the date or time of the last dose is unclear, provide the 
subject’s best approximation.  If the date/time of the last dose cannot be 
approximated or a PK sample cannot be collected in the time period indicated 
above, do not obtain a PK sample.  Instructions for sample handling and 
shipping are in the SPM/ISFN.  
• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total bilirubin ≥2xULN. 
• Obtain complete blood count with differential to assess eosinophilia. 
 
 
 
 
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• Record the appearance or worsening of clinical symptoms of hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever rash, or eosinophilia as relevant on the AE report form. 
• Record use of concomitant medications, acetaminophen, herbal remedies, 
other over the counter medications, or putative hepatotoxins, on the 
concomitant medications report form. 
• Record alcohol use on the liver event alcohol intake case report form. 
The following are required for subjects with ALT ≥3xULN and bilirubin ≥2xULN (>35% 
direct) but are optional for other abnormal liver chemistries: 
• Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver 
kidney microsomal antibodies. 
• Serum acetaminophen adduct assay (quantifies potential acetaminophen 
contribution to liver injury, detectable by HPLC assay more than 1 week 
following acetaminophen use)(James, Letzig et al. 2009).   
• Only in those with underlying chronic hepatitis B at study entry (identified by 
positive hepatitis B surface antigen):  quantitative hepatitis B DNA and 
hepatitis delta antibody. 
• Liver imaging (ultrasound, magnetic resonance, or computerized tomography) 
to evaluate liver disease. 
8.2.4. 
Adverse Events 
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
8.2.4.1. 
Definition of an AE 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical 
product, biologic (at any dose), or medical device, which does not necessarily have a 
causal relationship with the treatment.  Therefore, an AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medical product, whether or not considered 
related to the medical product.  AEs may include the onset of new illness and the 
exacerbation of pre-existing conditions. 
The routine evolution of the disease condition under treatment according to the protocol 
will be evaluated as part of the disease symptoms assessments.  Changes in the disease 
condition may not qualify as AEs.  However, if there is a clinically relevant worsening of 
a sign or symptom of the condition under treatment and the outcome fulfills the definition 
of an AE, it must be reported as directed in the protocol. 
8.2.4.2. 
Definition of a SAE 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
 
 
 
 
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NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
c. Requires hospitalization or prolongation of existing hospitalization 
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are AEs.  
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in disability/incapacity, or 
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
e. Is a congenital anomaly/birth defect. 
f. Medical or scientific judgment should be exercised in deciding whether 
reporting is appropriate in other situations, such as important medical events 
that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition.  These should also be considered serious.  Examples of such events 
are invasive or malignant cancers, intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug 
abuse. 
8.2.5. 
Laboratory and Other Safety Assessment Abnormalities Reported as AEs 
and SAEs 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, vital signs measurements), including those that 
worsen from baseline, and felt to be clinically significant in the medical and scientific 
judgment of the investigator are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs. 
 
 
 
 
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8.2.6. 
Possible Suicidality Related Adverse Event(s) (PSRAE) 
The PSRAE eCRF form should be completed (in addition to the AE or SAE pages, as 
appropriate) if there is an occurrence of an adverse event which, in the investigator’s 
opinion, is possibly related to suicidality.  This may include, but is not limited to, an 
event that involves suicidal ideation, a preparatory act toward imminent suicidal 
behavior, a suicide attempt, or a completed suicide.  The investigator will exercise his or 
her medical and scientific judgment in deciding whether an event is possibly related to 
suicidality.  The investigator will record this information in the source document and the 
PSRAE eCRF.  The PSRAE form should be completed in its entirety as soon as the 
information is available and updated with any additional follow-up information received. 
If the adverse event meets the definition of an SAE, the investigator must ensure that 
there are no discrepancies between the PSRAE and SAE forms.  Both forms (PSRAE and 
SAE) should be updated with any follow-up information. 
8.2.7. 
Pregnancy 
Any pregnancy that occurs during study participation must be reported using a 
notification of pregnancy form.  To ensure subject safety, each pregnancy must be 
reported to Amicus within 5 days of learning of its occurrence.  The pregnancy must be 
followed up to determine outcome (including premature termination) and status of 
mother and child.  Pregnancy complications and elective terminations for medical reasons 
must be reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE. 
Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to Amicus. 
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the 
study.  Pregnancy information must be reported to Amicus as described above. 
8.2.8. 
Reporting of Overdose 
Any event associated with or observed in conjunction with a product overdose (whether 
accidental or intentional) is considered by the sponsor to be an AE and must be reported 
as such. If a subject experiences an overdose (defined as higher than the dose of study 
medication prescribed in the protocol) during the course of the study (whether 
symptomatic or not), the sponsor must be informed within 5 working days of the 
investigator or study staff first becoming aware of the overdose.  Follow-up information 
must be forwarded on the outcome as applicable. If an SAE occurs in conjunction with 
the overdose, then the reporting time frame for an SAE as described below must be met. 
8.2.9. 
Reporting of Possible Study Drug Product Quality Complaints 
Any defect or possible defect associated with the study medication provided by the 
sponsor must be reported by the investigator or study staff to the sponsor within 1 
working day of first becoming aware of the possible defect.  The study medication and 
packaging components in question, if available, must be stored in a secure area under the 
specified storage conditions until it is determined whether the study medication and/or 
 
 
 
 
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packaging is required for investigation of the possible defect.  If the possible defect is 
associated with an SAE, the SAE must be reported as described below. The SAE report 
form must mention the possible study medication defect complaint. 
8.2.10. 
Time Period and Frequency of Detecting AEs and SAEs 
The investigator or site staff is responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE. 
AEs will be collected from the start of the subject’s first dose of study medication in the 
current study and until the follow up contact or 30 days after last dose, whichever comes 
first.   
SAEs will be collected over the same time period as stated above for AEs.  However, any 
SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy), will be recorded from the time 
a subject consents to participate in the study up to and including any follow up contact.  
All SAEs will be reported to Amicus within 24 hours, as indicated in Section 8.2.11.  
8.2.11. 
Prompt Reporting of Serious Adverse Events and Other Events to 
Amicus 
SAEs, pregnancies, medical device incidents and liver function abnormalities meeting 
pre-defined criteria will be reported promptly by the investigator to Amicus as described 
in the following table once the investigator determines that the event meets the protocol 
definition for that event. 
 
 
 
 
 
 
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Table 2: 
SAE and Pregnancy Reporting Time Frames 
 
Initial Reports 
Follow-up Information on a Previous 
Report 
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours 
“SAE” data 
collection tool 
 
24 hours 
Updated “SAE” 
data collection tool 
Pregnancy 
5 days 
“Pregnancy 
Notification 
Form” 
5 days 
“Pregnancy Follow-
up Form” 
Liver chemistry abnormalities for Phase III to IV: 
ALT≥3xULN and 
Bilirubin≥2xULN 
(>35% direct) (or 
ALT≥3xULN and 
INR>1.5, if INR 
measured)
1 
24 hours
2 
“SAE” data 
collection tool.  
“Liver Event 
eCRF” and “Liver 
Imaging” and/or 
“Liver Biopsy” 
eCRFs, if 
applicable
3 
24 hours 
Updated “SAE” 
data collection 
tool/“Liver Event” 
Documents3 
ALT≥8xULN; 
ALT≥3xULN with 
hepatitis or rash or 
≥3xULN and 
<5xULN that 
persists≥4 weeks 
24 hours2 
“Liver Event” 
eCRF 3 
24 hours 
Updated “Liver 
Event” eCRF3 
ALT≥5xULN plus 
bilirubin <2xULN 
24 hours2 
“Liver Event” 
eCRF do not need 
completing unless 
elevations persist 
for 2 weeks or 
subject cannot be 
monitored weekly 
for 2 weeks3 
24 hours 
Updated “Liver 
Event” eCRF if 
applicable3 
ALT≥5xULN and 
bilirubin <2xULN that 
persists ≥2 weeks 
24 hours2 
“Liver Event” 
Documents 
(defined above)3 
24 hours 
Updated “Liver 
Event” eCRF3 
ALT≥3xULN and <5x 
ULN and bilirubin 
<2xULN 
24 hours2 
“Liver Event” 
eCRF do not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks3 
24 hours 
Updated “Liver 
Event” eCRF, if 
applicable3 
1 INR measurement is not required; if measured, the threshold value stated will not apply to patients 
receiving anticoagulants. 
 
 
 
 
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2 Amicus must be contacted at onset of liver chemistry elevations to discuss subject safety. 
3 Liver Event Documents should be completed as soon as possible. 
ALT = alanine aminotransferase, eCRF = electronic case report form, INR = international normalized ratio, 
SAE = serious adverse event, ULN = upper limit of normal 
The method of detecting, recording, evaluating, and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to Amicus are provided in the 
SPM/ISFN.  Procedures for post-study AEs/SAEs are provided in the SPM/ISFN. 
Procedures for documenting, transmitting, and follow-up of medical device incidents 
along with the regulatory reporting requirements for medical devices are provided in the 
SPM/ISFN. 
8.2.11.1. Regulatory Reporting Requirements for SAEs 
Prompt notification of SAEs by the investigator to Amicus is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met. 
Amicus has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  Amicus 
will comply with country specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) and investigators. 
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Amicus policy, and are 
forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from Amicus will file it 
with the Investigator Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.2.12. 
Other Safety Assessments 
Planned time points for all safety assessments are listed in the Time and Events (Table 1). 
8.2.12.1. Physical Examination 
All subjects will undergo a complete physical examination at Baseline (Visit 1) and each 
subsequent scheduled visit.  Any clinically significant abnormal observation, newly 
emerged or worsened after the start of the subject’s first dose of study medication in the 
current study, should be reported as an AE. 
8.2.12.2. Vital Signs, Weight, and Height 
At all visits, blood pressure (systolic and diastolic) measurement should be obtained 
using the same arm, and the respiration and heart rate values, and body temperature will 
be assessed.  The measurements will be taken with the subject in sitting or supine 
position after having rested for a 5-minute period.  The same position should be used at 
all visits. 
 
 
 
 
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Body weight will be recorded at all scheduled visits.  Height will be recorded at the 
Baseline (Visit 1) and at the Follow-up Visit.   
8.2.12.3. ECG 
A standard 12-lead ECG will be performed at every scheduled visit.  Subjects will rest for 
approximately 5 minutes before the ECG recording begins and will be supine throughout 
the ECG evaluation.  Significant findings not present prior to start of treatment, which 
meet the definition of an AE, must be recorded in the CRF. 
8.2.12.4. Clinical Laboratory Tests 
If any results from the Baseline Visit (Visit 1) demonstrate, in the investigator’s opinion, 
a clinically significant abnormality that the subject has not previously experienced, then 
the subject should be asked to return as soon as possible but no later than 3 months of the 
Baseline Visit for an unscheduled visit so that repeat specimens can be obtained. 
The collection, processing and shipment of clinical laboratory samples will be fully 
described in the study laboratory manual.  The parameters measured in these samples are 
described below. 
The investigator (or his/her designee) will review each laboratory report from the central 
laboratory and assess any out of range lab results as “not clinically significant” (NCS) or 
“clinically significant” (CS).  Any results which are considered clinically significant 
should be confirmed in a repeat test at the investigator’s discretion.  The investigator 
should consider repeat testing of persistent clinically significant results until the analyte 
returns to normal, or until an etiology is determined.  The investigator (or his/her 
designee) will sign and date all laboratory reports.  
Clinically significant laboratory abnormalities must be reported as an AE or SAE as 
appropriate. 
Serum Chemistry  
The serum chemistry parameters in Table 3 will be assessed at every visit. Subjects are 
required to fast for approximately 8 or more hours prior to the serum chemistry being 
performed. 
Table 3: 
Serum Chemistry Parameters 
 
Alanine aminotransferase (ALT) 
Creatinine, serum 
Alkaline phosphatase 
Gamma –glutamyltransferase (GGT) 
Aspartate aminotransferase (AST) 
Glucose 
Albumin 
Lactate dehydrogenase (LDH) 
Bilirubin, total  
Magnesium 
Blood urea nitrogen (BUN) 
Phosphorous 
Calcium, total 
Potassium 
Carbon dioxide, total (bicarbonate) 
Protein, total 
Chloride 
Sodium 
 
 
 
 
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Alanine aminotransferase (ALT) 
Creatinine, serum 
Creatine phosphokinase 
Low density lipoprotein (LDL) cholesterol 
Uric acid 
High density lipoprotein (HDL) cholesterol 
Cystatin C 
triglycerides 
Hematology 
The hematology parameters in Table 4 will be assessed at every visit. 
Table 4: 
Hematology Parameters 
 
Platelet count 
Automated WBC Differential: 
RBC count 
Neutrophils 
WBC count (absolute) 
Lymphocytes 
Hematocrit 
 
Monocytes 
Hemoglobin 
Eosinophils 
 
Basophils 
Urinalysis 
Safety urinalysis parameters in Table 5 will be assessed at every visit, using the urine 
sample collected during the visit (not the 24-hour urine sample).   
Table 5: 
Urinalysis Parameters 
 
Color 
Ketones  
Appearance 
Blood  
Specific gravity 
WBC 
pH 
Nitrite  
Protein 
Bilirubin 
Glucose 
Microscopy of sediment 
24-hour Urine Collection 
A 24-hour urine sample will be collected at every study visit.  These samples will be used 
to measure 24-hour urine protein, albumin, and creatinine levels.   
Investigators are asked to minimize factors that may affect variability of results from 24-
hour urine samples, which could confound interpretation of the efficacy of treatment with 
migalastat HCl.  Refer to the SPM/ISFN for guidance on educating subjects and 
reminding them of proper methods for collection of 24-hour urine. Refer to the laboratory 
manual for following correct techniques for measuring and processing 24-hour urine 
samples.   
Since angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor 
blockers (ARBs) can reduce proteinuria, please ensure that clinically indicated initiation 
 
 
 
 
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Amicus Therapeutics, Inc. 
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of treatment with, or dose modification of, any of these medications is correctly recorded 
in the eCRF. 
Retained Biological Samples 
Any biological specimens remaining at the end of the study may be used for future 
exploratory analyses to improve the understanding of Fabry disease and its management. 
The retention of samples is optional; subjects will have the option to agree or refuse to 
have their samples retained. In Japan, no genetic testing will be done on retained 
biological samples.  
Plasma Lyso-GB3 (Plasma globotriaosylsphingosine) 
A blood draw will be collected for testing of plasma lyso-GB3. Plasma lyso-GB3, a 
biomarker, has been shown to be elevated in Fabry subjects and appears to be related to 
the clinical condition and disease progression in Fabry disease.   Concentrations of 
lyso-GB3 will be measured in plasma using a qualified assay.    
Pregnancy Tests 
All female subjects of childbearing potential, as defined in Section 6.2, will have a urine 
pregnancy test performed at every study visit. 
For any positive urine pregnancy test, a serum pregnancy test should be completed as 
soon as possible.  The procedures for pregnancy reporting are described in Section 8.2.7. 
8.3. 
Efficacy 
8.3.1. 
Efficacy/Pharmacodynamic Assessments 
• Estimated GFR (eGFR) based on the MDRD equation and CKD-EPI equation 
• Plasma lyso-Gb3 
• Measurement of 24-hour urine protein 
• Measurement of left ventricular mass (LVM) and LVM index (LVMi), as 
measured by echocardiography  
• Measurement in ejection fraction, as measured by echocardiography 
• Measurement of fractional shortening, as assessed by echocardiography  
• Measurement of LV internal dimension (LVIDd and LVIDs), MWFS, and 
wall thicknesses,  as assessed by echocardiography 
• Measurement of WBC α-Gal A activity  
• Measurement of patient reported Quality of Life as assessed by the SF-36.  
Change from baseline will be evaluated for each efficacy endpoint, where baseline is 
defined (as in Table 1) as the value from the last treatment visit of the previous migalastat 
HCl study. 
 
 
 
 
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9. 
DATA MANAGEMENT 
For this study, subject data will be entered into InForm Remote Data Capture system 
managed by Amicus therapeutics (or designee).  The data will be transmitted 
electronically to the sponsor and combined with data from other sources in a validated 
data system (e.g. laboratory and ECHO data).  
Management of clinical data will be performed in accordance with applicable Amicus 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events, and concomitant medications 
terms will be coded using Medical Dictionary for Regulatory Activities (MedDRA and 
WHOMD).   
After database lock, each study center will receive a compact disc (CD) containing all of 
their site-specific eCRF data as entered into the InForm Remote Data Capture for the 
study, including full discrepancy and audit history.  Additionally, a CD copy of all of the 
study center’s data from the study will be retained by the Amicus Therapeutics and 
designee for storage.    
 
 
 
 
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10. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
10.1. 
Hypotheses 
No formal hypothesis testing will be performed for this study since the primary goal is to 
evaluate long-term safety and tolerability and the study population consists of (non-
randomized) subjects taking the same open-label active treatment. 
10.2. 
Sample Size Considerations 
Since any subject with Fabry disease completing a treatment in a preceding migalastat 
HCl trial, or participating in a preceding open-label extension of migalastat HCl, can be 
enrolled into the this extension study, no sample size calculation will be performed for 
this study. 
10.3. 
Data Analysis Considerations 
Full details of the analysis plan will be provided in the Statistical Analysis Plan (SAP). 
Continuous variables will be summarized by n, mean, standard deviation (SD), median, 
minimum, and maximum values.  Discrete variables will be summarized by counts and 
percentages. 
10.3.1. 
Analysis Populations 
The Intent-to-Treat (ITT) Population is the primary population of interest and will 
include subjects who take at least one dose of IP after they have enrolled into this open-
label extension study.   
10.3.2. 
Analysis Data Sets 
All safety and demography summaries will be based on the ITT population.   
10.3.3. 
Interim Analysis 
Full details of the analysis plan will be provided in the Statistical Analysis Plan (SAP). 
10.3.4. 
Key Elements of Analysis Plan 
10.3.4.1. Safety Analyses 
Exposure 
The number of subjects exposed to IP will be summarized.  Duration of exposure will 
also be summarized.  Subject exposure will be categorized and the number and 
percentage of subjects in each category will be presented.   
Adverse events  
Adverse events will be coded using the MedDRA coding dictionary to collapse similar 
investigator terms for the adverse events.  The various coded (preferred) terms will then 
be grouped into system organ class (SOC) categories. 
 
 
 
 
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The following will be summarized separately for the Treatment Phase and Follow-up 
Phase, as well as across all study phases combined: 
• The percentage of subjects with each adverse event by SOC and preferred 
term. 
• The percentage of subjects with each (investigator determined) treatment-
related adverse event by SOC and preferred term. 
• The percentage of subjects with each adverse event leading to study 
withdrawal by SOC and preferred term. 
• The percentage of subjects with each serious adverse event by SOC and 
preferred term. 
Other Safety Assessments 
For all other safety variables (as listed below), continuous variables will be summarized 
with descriptive statistics (n, mean, median, standard deviation, minimum, and 
maximum) and categorical variables will be summarized with frequency distributions. 
Vital Signs and Weight 
Vital signs (blood pressure and heart rate) and weight data will be summarized by visit. 
This will include a summary of changes from the Baseline Visit (Visit 1) of this study.  
Baseline refers to values from the last treatment visit of the previous migalastat HCl 
study.  
Labs 
Laboratory data will be summarized by visit.  This will include a summary of changes 
from the Baseline Visit (Visit1). 
ECG 
Electrocardiogram results will be assessed at each study visit and will be summarized 
descriptively over time in box-plots, where relevant, and in tables summarizing the 
distributions in each group, by study visit.  
Further details will be provided in the Statistical Analysis Plan (SAP). 
Protocol Deviations 
A table will summarize the number and percent of subjects who experienced any protocol 
deviation.  A by-subject listing will also be presented. 
10.3.4.2. Efficacy Analyses 
Since no hypothesis testing is planned for this study, all efficacy parameters will be 
summarized using descriptive statistics for subjects in the ITT population.  Summaries of 
the efficacy variables will be provided for the value at baseline and at each post-baseline 
time point and the change from baseline at each post-baseline time point. 
 
 
 
 
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10.3.4.3. Pharmacodynamic Analyses 
Pharmacodynamic (PD) assessment will include the evaluation of the effect of migalastat 
on WBC α-Gal A enzyme levels after repeated oral doses.  Pharmacodynamic parameters 
will be summarized for the data from all subjects in the ITT population.  The following 
data will be summarized for α-Gal A levels in WBCs and plasma lyso-Gb3: the value at 
baseline and at each post-baseline time point and the change from baseline at each post-
baseline time point. 
10.3.4.4. Health Outcomes Analyses 
Subjects will receive a translated SF-36 questionnaire in their local language.  Subjects 
will complete the questionnaires during appropriate site visits.  Site personnel will collect 
the completed questionnaires and enter them into the electronic data capture (EDC) 
system. 
SF-36 data will be handled in a similar fashion as the PD assessments, with the additional 
steps that domain scores for each completed questionnaire will be calculated so that the 
results at each study time point and change from baseline at each post-baseline time 
point can be reported for each of the SF-36 domains (Physical function, Role Physical, 
Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental 
Health).  Data collected on the SF-36 will not be reconciled with AE data. 
 
 
 
 
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11. 
STUDY CONDUCT CONSIDERATIONS 
Amicus is contracting with Quintiles to perform study monitoring (Ex-US) and data 
management services for this study. 
11.1. 
Posting of Information on Publicly Available Clinical Trial 
Registers 
Amicus will be responsible for registering this clinical trial in a public registry that meets 
the requirements specified by the International Council of Medical Journal Editors 
(ICMJE), such as www.clinicaltrials.gov, and for publication of study results. 
Investigators will provide contact information to Amicus for the study listing. 
11.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Prior to initiation of a study site, Amicus will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements. 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to: 
• Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
review and favorable opinion/approval of study protocol and any subsequent 
amendments. 
• Subject informed consent. 
• Investigator reporting requirements. 
Written informed consent must be obtained from each subject prior to participation in the 
study. 
11.3. 
Quality Control (Study Monitoring) 
In accordance with applicable regulations, GCP, and Amicus procedures, Amicus 
monitors, or its designee will contact the site prior to the start of the study to review with 
the site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and Amicus, or its designees, requirements.  When reviewing data 
collection procedures, the discussion will include identification, agreement and 
documentation of data items for which the CRF will serve as the source document. 
Amicus or its designee will monitor the study to ensure that the: 
• Data are authentic, accurate, and complete. 
• Safety and rights of subjects are being protected. 
 
 
 
 
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• Study is conducted in accordance with the currently approved protocol and 
any other study agreements, GCP, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
11.3.1. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, Amicus may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study.  In the event of an assessment, audit or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to 
all relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified. 
11.3.2. 
Study and Site Closure 
Upon completion or termination of the study, the Amicus monitor or its designee will 
conduct site closure activities with the investigator or site staff (as appropriate), in 
accordance with applicable regulations, GCP, and Amicus or its designee Standard 
Operating Procedures. 
Amicus reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe non-
compliance.  If Amicus determines that such action is required, Amicus will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, Amicus will provide advance notice to the 
investigator or head of the medical institution of the impending action. 
If a study is suspended or terminated for safety reasons, Amicus will promptly inform all 
investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study.  Amicus or its designee will also promptly inform the relevant 
regulatory authorities of the suspension/termination along with the reasons for such 
action.  Where required by applicable regulations, the investigator or head of the medical 
institution must inform the IRB/IEC promptly and provide the reason(s) for the 
suspension/termination. 
11.3.3. 
Records Retention 
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a Amicus audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff. 
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
 
 
 
 
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investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions. 
Amicus will inform the investigator of the time period for retaining the site records in 
order to comply with all applicable regulatory requirements.  The minimum retention 
time will meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, Amicus standard operating procedures, and/or institutional 
requirements. 
The investigator must notify Amicus of any changes in the archival arrangements, 
including, but not limited to archival of records at an off-site facility or transfer of 
ownership of the records in the event that the investigator is no longer associated with the 
site. 
11.3.4. 
Use of Study Findings 
All information concerning the product as well as any matter concerning the operation of 
the sponsor, such as clinical indications for the drug, its formula, methods of manufacture 
and other scientific data relating to it, that have been provided by the sponsor and are 
unpublished, are confidential and must remain the sole property of the sponsor.  The 
investigator will agree to use the information only for the purposes of carrying out this 
study and for no other purpose unless prior written permission from the sponsor is 
obtained. 
The sponsor has full ownership of the data collected as part of the study. 
By signing the clinical study protocol and the confidentiality agreement, the investigator 
agrees that the results of the study may be used for the purposes of national and 
international registration, publication, and information for medical and pharmaceutical 
professionals.  The authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement. 
The sponsor will ensure that a final report on the study is prepared.  The sponsor will 
ensure that the study findings are reported in a manner that complies with applicable 
requirements for reporting clinical trial results. 
As required by local regulation or by the IEC/IRB, a summary of the clinical study will 
be submitted by the sponsor to the regulatory authorities and by the investigator to the 
IEC/IRB. 
All materials, documents and information supplied by the sponsor to the investigator, and 
all materials, documents and information prepared or developed in the course of the study 
to be performed under this protocol, shall be the sole and exclusive property of the 
sponsor.  Subject to obligations of confidentiality, the investigator reserves the right to 
publish only the results of the work performed pursuant to this protocol, provided, 
however, that the investigator provides an authorized representative of the sponsor with a 
copy of any proposed publication for review and comment at least 45 days in advance of 
its submission for publication.  In addition, if requested and prior to publication, the 
 
 
 
 
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investigator will remove any information determined by the sponsor to be confidential or 
proprietary information of the sponsor or its collaboration partner and will withhold 
publication an additional 90 days to allow for filing a patent application or taking such 
other measures as the sponsor deems appropriate to establish and preserve its proprietary 
rights. 
It is agreed that, consistent with scientific standards, publication of the results of the 
study shall be made only as part of a publication of the results obtained by all sites 
performing the protocol. 
Authorship for publications derived from this study will be based on all of the following: 
(1) substantial contributions to conception and design, or acquisition of data, or analysis 
and interpretation of data, (2) drafting the article or revising it critically for important 
intellectual content, and (3) final approval of the version to be published. 
11.3.5. 
Liability and Insurance 
Liability and insurance provisions for this study are given in separate agreements. 
11.3.6. 
Data Safety Monitoring Board 
A data safety monitoring board (DSMB) will be chartered to monitor and evaluate the 
safety of all subjects in this trial by periodically reviewing summaries of safety data, 
evaluating risk/benefit where possible, identifying any clinically relevant trends, and 
assessing whether it is safe for the study to continue.  A DSMB Charter will include 
operational and logistical procedures for the DSMB. The following stopping criteria will 
be observed for discontinuation of individual subjects:   
• 30% increase in serum creatinine from baseline (confirmed by repeat 
measurement in fully hydrated subject) 
• 25% decrease from baseline in cardiac ejection fraction by echocardiogram  
• Cerebrovascular event with significant sequelae, including stroke 
• An eGFR value of < 30 mL/min/1.73m2 
 
 
 
 
 
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12. 
REFERENCES 
 
Aerts, J. M., J. E. Groener, et al. (2008). "Elevated globotriaosylsphingosine is a hallmark 
of Fabry disease." Proceedings of the National Academy of Sciences of the 
United States of America 105(8): 2812-2817. 
Bishop, D. F. and R. J. Desnick (1981). "Affinity purification of α-galactosidase A from 
human spleen, placenta, and plasma with elimination of pyrogen contamination. 
Properties of the purified splenic enzyme compared to other forms." J Biol Chem 
256(3): 1307-1316. 
Desnick, R., Y. Ioannou, et al. (2001). α-Galactosidase A deficiency: Fabry disease. The 
Metabolic and Molecular Bases of Inherited Disease. C. Scriver, A. Beaudet, W. 
Sly and D. Valle. New York, McGraw-Hill: 3733-3774. 
James, L. P., L. Letzig, et al. (2009). "Pharmacokinetics of Acetaminophen-Protein 
Adducts in Adults with Acetaminophen Overdose and Acute Liver Failure." Drug 
Metabolism and Disposition 37(8): 1779-1784. 
Lemansky, P., Bishop, D. F., Desnick, R. J., Hasilik, A., and von Figura, K. (1987). 
"Synthesis and processing of α-galactosidase A in human fibroblasts. Evidence 
for different mutations in Fabry disease." J Biol Chem 262: 2062-2065. 
Togawa, T., I. Kawashima, et al. (2010). "Tissue and plasma globotriaosylsphingosine 
could be a biomarker for assessing enzyme replacement therapy for Fabry 
disease." Biochemical and Biophysical Research Communications 399(4): 716-
720. 
Togawa, T., T. Kodama, et al. (2010). "Plasma globotriaosylsphingosine as a biomarker 
of Fabry disease." Molecular Genetics and Metabolism 100(3): 257-261  
von Scheidt, W., C. M. Eng, et al. (1991). "An atypical variant of Fabry's disease with 
manifestations confined to the myocardium." New England Journal of Medicine 
324(6): 395-399. 
 
 
 
 
 
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13. 
APPENDICES 
13.1. 
Appendix 1: Contraceptive Requirements 
The allowed methods of contraception described in the following sections are only 
effective when used consistently, correctly, and in accordance with the product label. The 
investigator is responsible for ensuring subjects understand how to properly use these 
methods of contraception. 
13.1.1. 
Female Subjects 
Female subjects of childbearing potential must not become pregnant and must use 
medically accepted methods of contraception with a failure rate of <1% per year 
throughout the duration of the study and for up to 30 days after last dose of protocol 
defined study medication. 
A female subject is considered of childbearing potential if she has functional ovaries, 
ducts, and uterus with no impairment that would cause sterility. This includes women 
with oligomenorrhea (even severe), and women who are peri-menopausal or who have 
just begun to menstruate. 
A female is considered of non-childbearing potential if she is status-post hysterectomy, 
status-post surgical removal of both ovaries, has current, documented tubal ligation, or is 
postmenopausal and >2 years without menses. Female subjects who are post-menopausal 
<2 years must be confirmed menopausal by Follicle Stimulating Hormone (FSH) and 
estradiol levels. 
For sites in Italy: If of reproductive potential, agree to plan and document (or have their 
partner plan) a birth control strategy (or method) with his/her physician in order to avoid 
pregnancy throughout the duration of the study and for up to 30 days after last dose of 
protocol defined study medication. 
Contraceptive Methods with a Failure Rate of < 1% per year 
• Oral contraceptive, either combined or progestogen alone 
• Injectable progestogen  
• Implants of etonogestrel or levonorgestrel  
• Estrogenic vaginal ring  
• Percutaneous contraceptive patches  
• Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% 
failure per year rate as stated in the product label 
• Male partner sterilization (vasectomy with documentation of azoospermia) 
prior to the female subject's entry into the study, and this male is the sole 
partner for that subject.  For this definition, “documented” refers to the 
outcome of the investigator's/designee’s medical examination of the subject or 
 
 
 
 
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review of the subject's medical history for study eligibility, as obtained via a 
verbal interview with the subject or from the subject’s medical records. 
• Double barrier method: condom and occlusive cap (diaphragm or 
cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) 
13.1.2. 
Male Subjects 
To prevent pregnancy in a female partner, male subjects must use one of the following 
contraceptive methods: 
• Condom and occlusive cap (diaphragm or cervical/vault caps) plus 
spermicidal agent. 
• Male sterilization (e.g., vasectomy with documentation of azoospermia) prior 
to the subject's entry into the study. For this definition, “documented” refers to 
the outcome of the investigator's/designee’s medical examination of the 
subject or review of the subject's medical history for study eligibility, as 
obtained via a verbal interview with the subject or from the subject’s medical 
records. 
 
 
 
 
47 
 

Amicus Therapeutics, Inc. 
Study AT1001-042 
 
13.2. 
Appendix 2: Liver Chemistry Stopping and Follow-up Criteria 
 
 
 
 
 
48