Clinical trial NCT02194985
Conditions: Fabry Disease
Keywords: Amicus Therapeutics Galafold Migalastat AT1001
Sponsor: Amicus Therapeutics
Start date: 2015-03-14; Completion date: 2019-10-23
Enrollment: 84 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label extension study intended to provide continued treatment with migalastat hydrochloride (HCl) for participants with Fabry disease who completed treatment of a previous migalastat HCl study. The study assessed the long-term safety and effectiveness of migalastat HCl.

Detailed description:

Arms: arm 1: Migalastat HCl 150 milligram (mg).
Interventions: intervention 1: migalastat HCl 150 mg
Intervention descriptions: intervention 1: Migalastat HCl 150 mg (equivalent to 123 mg migalastat) was provided as capsules in blister packs. One capsule was taken orally every other day.

Protocol documents:
Prot_000.pdf: 
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 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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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 
 
 
 
 
46 
 


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

SAP_001.pdf: 
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 SAP:  
21 August 2019 
 


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STATISTICAL ANALYSIS PLAN 
AT1001-042 
AN OPEN-LABEL EXTENSION STUDY TO EVALUATE THE 
LONG TERM SAFETY AND EFFICACY OF MIGALASTAT 
HYDROCHLORIDE MONOTHERAPY IN SUBJECTS WITH 
FABRY DISEASE 
AUTHOR:
VERSION NUMBER AND DATE: FINAL V1.0, 21AUG2019 
Amicus
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VIA~ 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan Vl.0 (Dated 21Aug2019) for Protocol ATIOOl-042 
Name 
Signature 
Author: 
Position: 
Company: 
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PROTOCOL AT I 001-042 
Page 2 of 42 
Date 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this study. 
Name 
Signature 
Date 
Approved By: 
Position: 
Company: 
IQVIA 
Approved By: 
Position: 
Company: 
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Approved By: 
Position: 
Company: 
Amicus Therapeutics 
Document: 
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Amicus
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MODIFICATION HISTORY 
Unique 
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this Version 
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Previous Authorized Version 
1.0 
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TABLE OF CONTENTS 
1.
LIST OF ABBREVIATIONS ............................................................................................ 7 
2.
INTRODUCTION............................................................................................................... 9
3.
STUDY OBJECTIVES ....................................................................................................... 9 
3.1. 
Primary Objective ........................................................................................................................................... 9 
3.2. 
Secondary Objectives ...................................................................................................................................... 9 
4.
STUDY DESIGN ................................................................................................................. 9 
4.1. 
General Description ......................................................................................................................................... 9 
4.2. 
Schedule of Events ......................................................................................................................................... 10 
5.
PLANNED ANALYSES ................................................................................................... 16 
5.1. 
Data Safety Monitoring Board (DSMB) ...................................................................................................... 16 
5.2. 
Interim Analysis ............................................................................................................................................. 16 
5.3. 
Final Analysis ................................................................................................................................................. 16 
6.
ANALYSIS SETS.............................................................................................................. 16 
6.1. 
All Enrolled (ENR) ........................................................................................................................................ 16 
6.2. 
Intent-to-Treat [ITT] ..................................................................................................................................... 16 
6.3. 
Addendum 1.1.2 ............................................................................................................................................. 17 
7.
GENERAL CONSIDERATIONS ................................................................................... 17 
7.1. 
Reference Start Date and Study Day ........................................................................................................... 17 
7.2. 
Baseline ........................................................................................................................................................... 17 
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7.3. 
Retests, Unscheduled Visits and Early Termination Data ......................................................................... 18 
7.4. 
Windowing Conventions ............................................................................................................................... 18 
7.5. 
Statistical Tests .............................................................................................................................................. 19 
7.6. 
Common Calculations ................................................................................................................................... 19 
7.7. 
Software Version ............................................................................................................................................ 19 
8.
STATISTICAL CONSIDERATIONS ............................................................................ 19 
8.1. 
Adjustments for Covariates and Factors to be Included in Analyses ....................................................... 19 
8.2. 
Multicentre Studies ........................................................................................................................................ 20 
8.3. 
Missing data ................................................................................................................................................... 20 
8.4. 
Multiple Comparisons/ Multiplicity ............................................................................................................. 20 
8.5. 
Examination of Subgroups ............................................................................................................................ 20 
9.
OUTPUT PRESENTATIONS ......................................................................................... 20 
10.
DISPOSITION AND WITHDRAWALS ........................................................................ 21 
11.
PROTOCOL DEVIATIONS ........................................................................................... 21 
12.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 22 
13.
MEDICAL HISTORY ...................................................................................................... 23 
14.
MEDICATIONS ............................................................................................................... 23 
15.
STUDY MEDICATION EXPOSURE AND ACCOUNTABILITY ............................ 23 
16.
STUDY MEDICATION COMPLIANCE ...................................................................... 24 
17.
EFFICACY OUTCOMES................................................................................................ 24 
17.1. 
Efficacy Outcomes and Variables............................................................................................................. 24 
17.1.1. 
Annualized Change in MDRD eGFR ...................................................................................................... 25 
17.1.2. 
Annualized Change in CKD-EPI eGFR................................................................................................... 25 
17.1.3. 
Plasma Lyso-GB3 ..................................................................................................................................... 26 
17.1.4. 
WBC α-Gal A activity ............................................................................................................................. 26 
17.1.5. 
24-hour urine protein ............................................................................................................................... 26
17.1.6. 
Echocardiography (ECHO) ...................................................................................................................... 27 
17.1.7. 
SF-36 Questionnaire ................................................................................................................................ 27 
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18.
SAFETY OUTCOMES .................................................................................................... 28 
18.1. 
Adverse Events ........................................................................................................................................... 28 
18.1.1. 
All AEs .................................................................................................................................................... 29 
18.1.1.1. 
Severity ............................................................................................................................................ 29 
18.1.1.2. 
Relationship to Study Medication .................................................................................................... 29 
18.1.2. 
AEs Leading to Discontinuation of Study Medication ............................................................................ 30 
18.1.3. 
Serious Adverse Events ........................................................................................................................... 30 
18.1.4. 
Non-Serious Adverse Events ................................................................................................................... 30 
18.1.5. 
Adverse Events Leading to Death ............................................................................................................ 30 
18.1.6. 
Possible Suicidality Related Adverse Event (PSRAE) ............................................................................ 30 
18.2. 
Physical Exams .......................................................................................................................................... 30 
18.3. 
Vital Signs ................................................................................................................................................... 31 
18.4. 
Laboratory Evaluations ............................................................................................................................ 32 
18.4.1. 
Laboratory Reference Ranges and Clinical Significance ......................................................................... 34 
18.5. 
12 Lead ECG (ECG) Evaluations ............................................................................................................. 35 
18.6. 
Echocardiography (ECHO) ...................................................................................................................... 35 
18.7. 
Other Safety Assessments ......................................................................................................................... 39 
19.
DATA NOT SUMMARIZED OR PRESENTED .......................................................... 39 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS .............................. 40 
Dates & Times ............................................................................................................................................................ 40 
Spelling Format ......................................................................................................................................................... 40 
Presentation of Treatment Groups .......................................................................................................................... 40 
Presentation of Visits ................................................................................................................................................. 40 
Schedule of Pharmacokinetic Assessments for Addendum Subject ...................................................................... 41 
Schedule of Baseline Urine Collection for Addendum Subject .............................................................................. 41 
Total Urine Volume Collection Following Dose Regimen Changes ...................................................................... 42 
Listings ....................................................................................................................................................................... 42 
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1. LIST OF ABBREVIATIONS
ACEi 
Angiotensin-converting Enzyme Inhibitors 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
APOINT 
Peak Mitral Inflow Velocity A 
ARB 
Angiotensin II Receptor Blockers 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
Below the Limit of Quatification 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CRF 
Case Report Form 
CS 
Clinically Significant 
CTMS 
Clinical Trial Management System 
DSMB 
Data Safety Monitoring Board 
EARATIO 
Mitral Valve E/A Ratio 
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
eGFR 
Estimated Glomerular Filtration Rate 
ENR 
All Enrolled Population 
EOS 
End of Study 
EPOINT 
Peak Mitral Inflow Velocity E 
ERT 
Enzyme Replacement Therapy 
FS 
Fractional Shortening 
GGT 
Gamma – Glutamyltransferase 
GH 
General Health 
HDL 
High Density Lipoprotein 
HR 
Heart Rate 
IA 
Interim Analysis 
IP 
Investigational Product 
ITT 
Intent-to-Treat 
IVSTD 
Intraventricular Septum Thickness Diastolic 
LDH 
Lactate Dehydrogenase 
LDL 
Low Density Lipoprotein 
LVEF 
Left Ventricular Ejection Fraction 
LVIDd 
Left Ventricular Internal Dimension at End Diastole 
LVIDs 
Left Ventricular Internal Dimension at End Systole 
LVMi 
Left Ventricular Mass Index 
LVPWTD 
Left Ventricular Posterior Wall Thickness Diastole 
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MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MH 
Medical History 
MWFS 
Midwall Fractional Shortening 
NCS 
Not clinically Significant 
PCS 
Potentially Clinically Significant 
PD 
Pharmacodynamic 
PF 
Physical Functioning 
PK 
Pharmacokinetic 
PSRAE 
Possible Suicidality Related Adverse Event 
PT 
Preferred Term 
Q4D 
Every Fourth Day 
QOD 
Every Other Day 
RBC 
Red Blood Cell 
RE 
Role Emotional 
RI 
Renin Inhibitors 
RP 
Role Physical 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SF 
Social Functioning 
SF-36 
Short Form 36 
SOC 
System Organ Class 
ULQ 
Upper Limit of Quantification 
VI 
Vitality 
WBC 
White Blood Cell 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
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2. INTRODUCTION
This statistical analysis plan (SAP) is based on protocol amendment 1.1 with site-specific addendum 1.1.2, dated 
22Jan2018, and it describes the rules and conventions to be used in the presentation and analysis of long-term safety, 
tolerability, pharmacodynamic (PD), and efficacy data for Protocol AT1001-042, and additionally pharmacokinetic 
(PK) data for addendum 1.1.2. It describes the data to be summarized and analyzed, including specifics of the 
statistical analyses to be performed.  
A Data Safety Monitoring Board (DSMB) has been chartered to evaluate accumulating safety data in this clinical 
trial and a DSMB SAP final version 1.1 was effective on 25Oct2015. 
3. STUDY OBJECTIVES
3.1. 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. 
3.2. SECONDARY OBJECTIVES 
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. 
4. STUDY DESIGN
4.1. GENERAL DESCRIPTION 
This study is a multi-center, non-comparative, open-label, long-term extension study of migalastat HCl in subjects 
with Fabry disease who have completed treatment in a previous trial of migalastat HCl given as monotherapy. All 
subjects who were eligible for enrollment and 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 were given the 
option to enroll into this trial.  An alternative dosing regimen will be established per the addendum 1.1.2 for those 
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subjects with renal impairment (glomerular filtration rate (eGFR) < 30 mL/min/1.73m2), confirmed during the 
enrollment of the original protocol and amendment 1 and 1.1. The number of subjects to be enrolled in this study is 
expected to be up to 100, but is dependent on the number of eligible subjects completing migalastat HCl treatment in 
previous studies and who consent to enter this open-label extension study. Therefore, no sample size will be 
calculated. 
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 during the study. For the Addendum 1.1.2 subjects with 
renal impairment, clinical visits are performed approximately every 3 months. The 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). 
Migalastat HCl will be administered 150 mg every other day (QOD) for subjects enrolled under standard protocol 
[AT1001-042], or 150 mg every 4th day (Q4D) or every 7th day (Q7D) for Addendum 1.1.2 subjects as a starting 
point and is subjected to change depending on baseline and follow-up PK and PD assessments for the addendum 
subjects. Within each participating country, subjects will continue to receive treatment with migalastat HCl within 
the protocol until one of the study conclusion conditions is met as specified in the protocol section 5.1, or until one 
of the withdrawal criteria is met as specified in standard protocol section 6.4 or Addendum 1.1.2 section 4.4. 
4.2. SCHEDULE OF EVENTS 
All study visits should be scheduled from the Baseline Visit (Visit 1), and subsequent visits are planned at 
approximately 6-month intervals for Amendment 1.1. Follow-up visits will be scheduled one month later with 
similar window allowances (one week prior and 2 weeks following the designated visit) and will be undertaken only 
if needed based on PK and PD results from the prior visit. As a comparison, study visits will be planned at 
approximately 3-month intervals for Addendum 1.1.2 and similarly, follow-up visits will follow one month later. 
The time and events can be found in Table 1, whereas the time and events of Addendum is described in Table 2. 
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Table 1 Time and Events Table of Amendment 1.1 
1.
Assessments collected for the end of study 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.
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Table 2 Time and Events of Site Addendum 1.1.2 
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α-Gal A = α-galalactosidase A; BP = blood pressure; ECG = electrocardiogram; eGFR = estimated glomerular 
filtration rate; Lyso-Gb3 = globotriaosylsphingosine; HR = heart rate; PK = pharmacokinetics; RR = respiratory rate; 
Temp = temperature; WBC = white blood cell. 
NOTE: Following Month 12 (or 13, if needed), visits will repeat for the duration of the study, occurring every 3 mos 
with follow-up visits one month later, if needed. 
1.
All Baseline safety assessments will be repeated prior to first administration of migalastat at re-entry into
the study.
2.
Follow-up visits will occur only if needed, based on PK/PD assessments performed at the prior visit. If
needed, the subject may be contacted by phone and have assessments done at the study site or drawn by a
home healthcare professional. All samples will be sent to the central Laboratory.
3.
Echocardiograms will be read centrally.
4.
Echocardiogram is to be performed upon withdrawal from the study only if one was not performed within
the previous 6 months.
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.
A diary will be maintained throughout the study to record study drug administration and the occurrence of
any adverse events.
7.
Study Treatment Supply for Study AT1001-042 is intended to occur on Baseline (Visit 1) or on subsequent
days within the allowable window visits.
8.
See Appendix 1 for urine collection intervals.
9.
Additional urine collections for migalastat assessment will be done prior to any change in dose regimen.
Table 2 Time and Events of Site Addendum 1.1.2 (Continued) 
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10. See Appendix 1 for PK assessment times.
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5. PLANNED ANALYSES
The following analyses will be performed for this study: 
•
Analyses for DSMB (described elsewhere in the DSMB Charter)
•
Final Analysis
5.1. DATA SAFETY MONITORING BOARD (DSMB) 
A DSMB SAP describing the methodology and presentation of results and access to results is provided by IQVIA as 
a separate document. The final version (Final V1.1) of DSMB SAP was effective on 25Oct2015. 
5.2. INTERIM ANALYSIS 
There will be no interim analysis (IA) for this study. 
5.3. FINAL ANALYSIS 
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics following Sponsor 
Authorization of this Statistical Analysis Plan and Database Lock. 
6. ANALYSIS SETS
6.1. ALL ENROLLED (ENR) 
The all subjects enrolled (ENR) set will contain all subjects who provide informed consent for this study. 
6.2. INTENT-TO-TREAT [ITT] 
The Intent-to-Treat (ITT) Population will include subjects who take at least one dose of Investigational Product (IP) 
after they have enrolled into this open-label extension study (excluding addendum 1.1.2 subject), and is the primary 
population of interest. All safety, efficacy and demography summaries will be based on the ITT population. Protocol 
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deviations will be reported in a listing. 
6.3. ADDENDUM 1.1.2 
The Addendum 1.1.2 Population will include the only subject whose treatment with migalastat HCl was terminated 
after a confirmed estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2, which met the withdrawal 
criteria, but re-initiated into this ongoing study with the attempt to establish an alternate dosing regimen. This 
subject (original subject ID 20045027) is re-enrolled under the site-specific Addendum 1.1.2 with a different subject 
ID 20045029, and the data about this subject ID will be handled separately and reported in listings only under 
Addendum 1.1.2 Population. All the safety and efficacy assessments planned in Table A-1 of Protocol Addendum 
1.1.2 will be presented in data listings for this population. Demographics, baseline characteristics, drug compliance 
and other historical information will be presented under the ITT population data listings based on subject ID 
20045027 and flagged in a footnote. 
7. GENERAL CONSIDERATIONS
7.1. REFERENCE START DATE AND STUDY DAY 
Study Day (or Start and End Study Day) will be calculated from the reference start date, and will be used to show 
start/ stop day of assessments and events.  
Reference start date is defined as the day of the first dose of study medication in this study, (Day 1 is the day of the 
first dose of study medication), and will appear in every listing where an assessment date or event date appears.  
•
Study Day = (date of event – reference date) +1, (if event date >= reference date)
•
Study Day = date of event – reference date, (if event date is < Day 1)
In the situation where the event date is partial or missing, Study Day, and any corresponding durations will appear 
partial or missing in the listings. 
7.2. BASELINE 
During the subjects transition from their previous study into AT1001-042, the intent is for treatment with migalastat 
HCl to continue without a drug holiday. Assessments collected in the last treatment visit of their previous study 
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(previous studies include AT1001-012 and AT1001-041), are also required for the Baseline Visit in the current 
study, which will serve as the assessment for the Baseline Visit. The visit window for the last treatment visit in the 
previous study will also apply to those Baseline assessments. However, to provide flexibility to investigators and 
subjects, any Baseline Visit assessment that are 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. The 
baseline will then be determined as the last non-missing measurement taken prior to the first migalastat dose date 
(including unscheduled assessments) during this study. Should there be no observations prior to the first dose, the 
baseline will then be assigned to the observation at the nominal baseline visit. 
Blood and urine sampling for plasma migalastat determination will be taken just prior to dosing and at selected time 
points post-dose. 
Use of ACEi/ARB/RI at baseline is defined as having either ACE inhibitor, ARB or RENIN inhibitor within the past 
five years (with start date on or before the baseline visit) and is ongoing through, or the stop day is on or after the 
baseline visit date (informed consent date). 
7.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION 
DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled measurements 
will not be included in by-visit summaries but will be included in tables presenting the clinically significant (CS) 
evaluations at any time of the study. All visits, including nominal, unscheduled, retest, and early termination visits 
will be sorted and presented chronologically. The visit wording to be presented in all outputs can be referred in 
Appendix 1. 
In the case of a retest (same visit number assigned but tested on different dates), the first available measurement for 
that visit will be used for by-visit summaries.  
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
7.4. WINDOWING CONVENTIONS 
No visit windowing will be performed for this study. 
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7.5. STATISTICAL TESTS 
There will be no formal inferential statistics performed in this study and only descriptive statistics will be presented. 
7.6. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
•
Change from Baseline = Test value at Visit X – Baseline Value
•
Continuous variables (e.g., age) are summarized using descriptive statistics (the number of subjects with
available data, mean, standard deviation [SD], median, minimum, and maximum). Categorical variables
(e.g., gender) are summarized using counts and percentages. Percentages are calculated using the total
subjects (per population).
•
For continuous variables, all mean and median values are formatted to one more decimal place than the
measured value. SD values are formatted to two more decimal places than the measured value. The
minimum and maximum values are presented with the same number of decimal places as the measured
value.
•
For categorical variables, the number and percentage of responses are presented in the form XX (XX.X%)
where the percentage is in the parentheses. In case of 0 counts, only “0” with no percentage will be
presented and a percentage of 100 will not include decimals, e.g. 85 (100%).
7.7. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.2 and above. 
8. STATISTICAL CONSIDERATIONS
8.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
Since there are no formal inferential statistics performed, no analysis will be adjusted for covariates or factors. 
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8.2. MULTICENTRE STUDIES 
This study will be conducted by multiple investigators at multiple centers internationally, but no site-specific 
considerations will be included in the analysis, and data from all sites will be pooled in the analysis. 
8.3. MISSING DATA 
No missing data imputation will be carried out in this study.
8.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
No adjustment for multiplicity will be performed. All analyses will be descriptive. 
8.5. EXAMINATION OF SUBGROUPS 
Descriptive analyses of the efficacy endpoints (annualized change in MDRD eGFR and CKD-EPI eGFR) will be 
performed on the following subgroups: 
•
Males, 24-hr urine protein < 100 mg/24h
•
Males, 24-hr urine protein ≥100, <1000 mg/24h
•
Males, 24-hr urine protein ≥ 1000 mg/24h
•
Females, 24-hr urine protein < 100 mg/24h
•
Females, 24-hr urine protein ≥100, <1000 mg/24h
•
Females, 24-hr urine protein ≥ 1000 mg/24h
9. OUTPUT PRESENTATIONS
Appendix 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describes the presentations for this study as well as format and content of the 
summary tables, figures, and listings to be provided by IQVIA Biostatistics. 
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10.
DISPOSITION AND WITHDRAWALS
All subjects who provide informed consent will be accounted for in this study. Number of subjects, subject 
discontinuation, and primary reason for discontinuation will be presented for the ITT and Addendum 1.1.2 
population. 
The list of primary reasons for discontinuation (as per CRF) can be referred to as below: 
•
Screen Failure
•
Adverse Event
•
Subject Met Protocol Defined Stopping Criteria
•
Physician Decision
•
Lost to Follow-up
•
Non-Compliance with Study Requirements
•
Pregnancy and/or Breast feeding
•
Protocol Violation
•
Withdrawal by Subject
•
Study Terminated by Sponsor
•
Death
•
Other
11.
PROTOCOL DEVIATIONS
Protocol Deviations as classified in the clinical trial management system (CTMS) will be summarized in a table 
according to the following categories and presented overall based on the ITT population: 
•
Administrative Criteria
•
Concomitant Medications Criteria
•
Efficacy Criteria
•
Eligibility and Entry Criteria
•
Investigational Product Compliance
•
Informed Consent Criteria
•
Laboratory Assessment Criteria
•
Randomization Criteria
•
Regulatory or Ethics Approvals Criteria
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•
Serious adverse event (SAE) Criteria
•
Source Document Criteria
•
Study Procedures Criteria
•
Visit Scheduled Criteria
•
Other Criteria
All protocol deviations will be listed. 
12.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Demographic data and other baseline characteristics will be presented for the ITT population. The following 
demographic and other baseline characteristics will be summarized using descriptive statistics under AT1001 
(Migalastat HC1) column: 
•
Age (years) (calculated relative to date of consent)
•
Sex
•
Race
•
Ethnicity (USA and Japan Sites only)
•
Country
•
Protocol Version
•
Weight (kg)
•
Height (cm)
•
BMI (kg/m2)
•
Use of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin II receptor blockers (ARB)/renin
inhibitors (RI)
•
24-hour urine protein (mg/24h)
•
Estimated Glomerular Filtration Rate based on Chronic Kidney Disease Epidemiology Collaboration
(eGFRCKD-EPI) (mL/min/1.73m2)
•
Estimated Glomerular Filtration Rate based on Modification of Diet in Renal Disease (eGFRMDRD)
(mL/min/1.73m2)
•
Previous Studies (subjects can be in more than one previous study)
It will be considered use of ACEi/ARB/RI if the reported medication is taken on the date of consent, regardless of 
the start or end date.  
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eGFRMDRD data will be calculated by the central lab and included in the data transfer, whereas eGFRCKD-EPI data will 
be derived from serum creatinine based on the formula in Section 17.1.2. 
Some of the baseline characteristics will not be collected directly in the eCRF and will be derived as follows: 
•
Age = (date of consent – date of birth) / 365.25. If date of birth contains only partial date, use the first day
of the month in the calculation if day part is missing, or first day of the year if both day and month parts are
missing.
•
BMI (kg/m2) = weight (kg)/ height (m)2 at the baseline visit
Demographic and baseline characteristics will be provided in two separate data listings. 
13.
MEDICAL HISTORY
Medical History information including the concomitant illness (Ongoing at Study Entry, or start on or after the 
Study Entry) for this study is not complete entry for most subjects and is collected only for a small portion of the 
subjects whose information is collected from the eCR. This information will be presented in a set of summary tables 
and listing. Medical History for other subjects whose information are not collected in this study will be integrated 
from their feeder study (AT1001-041 and AT1001-012) as Medical History, and this information will not be 
included in SDTM or ADaM dataset, and will only be presented in a separate set of summary table and listing. All 
Medical History will be coded using version 16.1 of MedDRA and presented by SOC and PT for the ITT 
population.  
14.
MEDICATIONS
Medications will be coded using September 2013 version of the World Health Organization Drug Dictionary 
Enhanced (WHO-DDE) and presented for the ITT population, and a table will be provided to summarize the 
medications by ATC Level 3 and PT. Medications will similarly be summarized for subjects taking ACEi/ARB/RI. 
A listing of all medications will be provided for ATC Level 3 and PT. In addition, a listing presenting the enzyme 
replacement therapy (ERT) history will be provided.  
15.
STUDY MEDICATION EXPOSURE AND ACCOUNTABILITY
Migalastat HCl, 150 mg per capsule, and reminder capsules in blister packs will be administered at the baseline visit 
and subsequent visits in 6-month intervals. Subjects are expected to take one 150 mg capsule every other day (QOD) 
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except for the Addendum 1.1.2 subjects, who are expected to take one 150 mg capsule on every 4th (Q4D) or 7th 
day (Q7D)..  
Exposure to study medication will be presented for the ITT population by descriptive statistics. The date of first and 
last study medication administration will be taken from the eCRF Study Drug Administration form for duration of 
exposure as follows, and interruptions, compliance, and dose changes are not taken into account for duration of 
exposure.  
Duration of exposure (days) = date of last study medication administration – date of first study medication 
administration + 1.  
Duration of exposure (months) = Duration of exposure (days) / (365.25/12) rounded to one decimal place. 
Duration of exposure [months] categorized by 6-month interval up to 48 months will also be included in the table. 
Listings presenting the study drug administration information including duration of exposure and drug 
accountability will be provided. In addition, a listing is provided to present dosing regimen for Addendum 1.1.2. 
16.
STUDY MEDICATION COMPLIANCE
Compliance to study medication will be presented for the ITT population. Since no patient diary will be filled for 
ITT population and only a study drug administration eCRF page will be completed to capture the first and last dose 
date, an estimate of the compliance will be calculated as follows: 
Compliance = [(Last dose date –  first dose date) +  1]/2 −missed doses +  extra doses
[(Last dose date –  first dose date) +  1]/2
× 100% 
Descriptive statistics for the compliance (n, mean, median, standard deviation, minimum, maximum values) will 
be presented and a frequency distribution will be computed for the following categories: < 80%, >= 80 - <120%, 
and >= 120%.  
A listing presenting the overall study medication compliance will be provided.
17.
EFFICACY OUTCOMES
17.1. EFFICACY OUTCOMES AND VARIABLES 
All efficacy outcomes will include all subjects (excluding the renal impairment subject) and will be summarized 
using nominal visits (not including unscheduled visit or early termination) and descriptive statistics. Efficacy 
assessments will be performed at the Baseline Visit, followed by subsequent clinic visits in every 6 months until the 
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End of Study visit. All efficacy outcomes will follow the same visit pattern unless otherwise specified. Descriptive 
statistics will be calculated for baseline and each post-baseline visit (as well as time point if applicable), followed by 
change from baseline at that visit. Baseline is defined in section 7.2, whereas change from baseline is defined in 
section 7.6. 
The efficacy endpoints to be presented are
•
eGFRMDRD and eGFRCKD-EPI
•
Plasma lyso-Gb3 (Plasma globotriaosylsphingosine)
•
Measurement of white blood cell (WBC) α-Gal A activity
•
Measurement of 24-hour urine protein
•
Measurement of left ventricular mass (LVM) and LVM index (LVMi), as assessed by echocardiography
•
Measurement in ejection fraction, as assessed by echocardiography
•
Measurement of fractional shortening, as assessed by echocardiography
•
Measurement of left ventricular internal dimension (LVIDd and LVIDs), midwall fractional shortening
(MWFS), and wall thicknesses, as assessed by echocardiography
•
Measurement of patient reported Quality of Life as assessed by the Short Form 36 (SF-36)
Each endpoint (consisting of one or more variables) will be summarized in a table. Listings will be provided by 
domain or sub-domain categories, e.g. Laboratory categories - Chemistry, Hematology, Urinalysis, 
Echocardiography, and Questionnaire. 
17.1.1. 
ANNUALIZED CHANGE IN MDRD EGFR 
The MDRD eGFR values at every visit will be provided by the central laboratory. 
The annualized change (the slope) in MDRD eGFR will be computed over the available visits of each patient 
between baseline and End of Study (EOS). A simple linear regression between the observed values and the 
assessment times (study day of the visits as the dependent variable) will be applied to estimate the annualized 
change. 
The duration between baseline and the last post-baseline visit in years (study days of the visit/365.25 days per year) 
will be presented along with the annualized rate of change for MDRD eGFR. 
17.1.2. 
ANNUALIZED CHANGE IN CKD-EPI EGFR 
 The CKD-EPI values will be computed for every visit using the following equation: (Levey et.al.,2009): 
CKD-EPI eGFR = 141 x min(SCR/k, 1)α x max(SCR/k, 1)-1.209 x 0.993Age x 1.018(if female) x 1.159(if black) where 
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k is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of 
SCR/k or 1, and max indicates the maximum of SCR/k or 1, SCR is the serum creatinine (mg/dL). 
The annualized change (the slope) in CKD-EPI eGFR will be computed over the available visits of each patient 
between baseline and EOS. A simple linear regression between the observed values and the assessment times (study 
day of the visits as the dependent variable) will be applied to estimate the annualized change. 
The duration between baseline and the last post-baseline visit in years (study days of the visit/365.25 days per year) 
will be presented along with the annualized rate of change for CKD-EPI eGFR. 
17.1.3. 
PLASMA LYSO-GB3 
A blood draw will be collected for testing of plasma lyso-GB3, a biomarker that 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 in triplicates. The mean of each time 
point within the same visit is calculated (regardless of possible missing data for one or two of the triplicates). The 
derived parameter based on the average of the triplicates is summarized in a table. However, all the originally 
collected data as well as the derived lyso-GB3 parameter will be included in a listing. 
17.1.4. 
WBC α-GAL A ACTIVITY 
The α-Gal A enzyme activity in leukocytes data will be collected after repeated oral doses at each visit, and will be 
analyzed for PD analyses by descriptive statistics. The WBC α-Gal A activity will also be reported in a listing. 
17.1.5. 
24-HOUR URINE PROTEIN 
A 24-hour urine sample will be collected per the eCRF at every study visit in a 6-month interval until the End of 
Study visit with information of starting date and time, and stopping date and time. The urine volume will also be 
collected. These samples will be used to measure 24-hour urine protein, albumin and creatinine levels, and in case of 
duration of collection not being compliant with the exact 24 hours, the corrected values with respects to 24 hours 
will be used in the summary tables. 
The 24-hour urine protein samples will be summarized in a table. A shift table and another table presenting 
clinically significant (CS) result are included. Similarly, other 24-hour urine parameters will be presented in a 
summary table as well as a shift table and a CS table. All 24-hour urine sample related parameters including the 24-
hour urine protein will be presented in a listing. 
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17.1.6. 
ECHOCARDIOGRAPHY (ECHO) 
An ECHO will be performed at baseline, and every 12 months subsequently until the end of study visit, and the 
ECHO data will be collected in the EC domain. The following parameters will be summarized separately in tables 
•
LVM and LVMi
•
Ejection Fraction
•
Fractional Shortening
•
LVIDd, LVIDs, MWFS, Wall Thickness.
These parameters will be presented to summarize the data by each visit for baseline, post-baseline and change from 
baseline. Supportive listings to these parameters will also be provided. ECHO parameters for safety evaluation is 
provided in the Safety Outcomes section. 
17.1.7. 
SF-36 QUESTIONNAIRE 
SF-36 is an indicator of overall health status which consists of eight sub-scaled scores. The scores are weighted 
sums of the questions in each sub-scale. The SF-36 will be collected at Baseline, and every 6 months subsequently 
until the End of Study visit. The SF-36 consists of the following subscales: 
•
Physical Functioning (PF)
•
Role Physical (RP)
•
Bodily Pain (BP)
•
General Health (GH)
•
Vitality (VI)
•
Social Functioning (SF)
•
Role Emotional (RE)
•
Mental Health (MH)
And can be further summarized into physical and mental components: 
•
Physical Component Summary
•
Mental Component Summary
Norm based scoring of the SF-36v2 will be performed by OPTUM Insight Life Sciences and the above mentioned 
sub-scales and component summaries will be provided. Each sub-scale and component summary scores will be 
summarized at baseline and every post-baseline visit, as well as change from baseline, in a summary table.  
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Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
Three listings presenting SF-36 individual questions, norm based scores, and physical and mental component 
summary scores will be provided. 
18.
SAFETY OUTCOMES
The safety parameters include Adverse Events, Physical Examination, Vital Signs, Laboratory Tests, 12 Lead ECG, 
use of Concomitant Medications. All outputs for safety outcomes will be based on the ITT population using nominal 
visits (not including unscheduled visits and early termination) except tables presenting clinically significant results. 
These tables presenting clinically significant results will include unscheduled visits and early termination alongside 
the scheduled visits. Each continuous variable will be summarized for quantitative analysis using descriptive 
statistics by each visit including baseline, and change from baseline for that visit. Categorical variables will be 
summarized for qualitative analysis using incidence counts and percentages. The summary will be performed by 
each visit including baseline for each categorical parameter (e.g. Urinalysis parameters except pH and specific 
gravity).  
18.1. ADVERSE EVENTS 
Adverse Events (AEs) will be coded using Medical Dictionary for Regulatory Activities (MedDRA) central coding 
dictionary, Version 16.1 and will be summarized. The AE will be presented in summary tables for each of the 
following items, by the counts and percentages of subjects and events: 
•
The counts and percentages of subjects and events with each adverse event by SOC and preferred term
•
The counts and percentages of subjects and events with each (investigator determined) treatment related
adverse event by SOC and preferred term
•
The counts and percentages of subjects and events with each adverse event leading to discontinuation of
study medication by SOC and preferred term
•
The counts and percentage of subjects and events with each serious adverse event by SOC and preferred
term
•
The counts and percentage of subjects and events with each adverse event leading to death
•
Possible Suicidality Related Adverse Event (PSRAE)
Adverse events will also be summarized by the following categories: 
•
Severity
•
Relationship to Study Drug
An overall summary of number of subjects and the events within each of the categories described in the sub-section 
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Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
below, will be provided as specified in the templates.  
A listing including all AEs will be provided. Separate listings for AEs Leading to Discontinuation of Study 
Medication, Serious AEs, AEs Leading to Death, and PSRAE will also be provided. 
18.1.1. 
ALL AES
Incidence of AEs will be presented by System Organ Class (SOC) and Preferred Term (PT) and also broken down 
further by maximum severity and relationship to study medication. The following summary tables will be provided 
using counts and percentages of subjects and events: 
•
Overall summary of AEs
•
Summary of AEs by SOC and PT
•
Summary of AEs by PT
•
Summary of AEs by SOC, PT and Severity
•
Summary of AEs by SOC, PT and Relationship
•
Summary of Serious AEs (SAE) by SOC and PT
•
Summary of Non-serious AEs by SOC and PT
•
Summary of Non-serious AEs by PT
•
Summary of Non-serious AEs occurred in 5% or more of Subjects by SOC and PT
•
Summary of AEs occurred in 5% or more of Subjects by SOC and PT
18.1.1.1. 
Severity 
Severity is classified as mild/ moderate/ severe (increasing severity). AEs with a missing severity will be classified 
as severe. If a subject reports an AE more than once within that SOC/ PT, the AE with the worst-case severity will 
be used in the corresponding severity summaries. 
18.1.1.2. 
Relationship to Study Medication 
Relationship, as indicated by the Investigator, is classified as “Unrelated”, “Unlikely”, “Possible”, “Probable”, 
and “Definite” (increasing level of relationship). A “Potentially Related” AE is defined as an AE with a relationship 
to study medication as “Possible”, “Probable” or “Definite” to study medication. AEs with a missing relationship 
to study medication will be regarded as “Potentially related” to study medication. If a subject reports the same AE 
more than once within that SOC/PT, the AE with the worst-case relationship to study medication will be used in the 
corresponding relationship summaries.  
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18.1.2. 
AES LEADING TO DISCONTINUATION OF STUDY MEDICATION 
AEs leading to permanent discontinuation of study medication will be identified by using the eCRF AE form with 
“Stopped Permanently” recorded for question “Action Taken with Study Drug”. For AEs leading to discontinuation 
of study medication, a summary on the number of subjects and events by SOC and PT will be prepared. 
18.1.3. 
SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as “Yes” to the question “Serious” on the Adverse Events 
page of the eCRF. A summary of serious AEs on the number of subjects and events by SOC and PT will be 
prepared. 
18.1.4. 
NON-SERIOUS ADVERSE EVENTS 
A summary of non-serious AEs (excluding SAEs) by SOC and PT will be prepared. A supporting listing will also be 
provided for non-serious AEs. 
18.1.5. 
ADVERSE EVENTS LEADING TO DEATH 
AEs leading to Death are those events which are recorded as having “Fatal Outcomes” on the Adverse Events page 
of the eCRF.  
18.1.6. 
POSSIBLE SUICIDALITY RELATED ADVERSE EVENT (PSRAE) 
If an occurrence of an adverse event which, in the investigator’s opinion, is possibly related to suicidality, it will be 
recorded on the PSRAE eCRF form and reported under this category. The AE number of PSRAE will be collected 
in the PSRAE eCRF, which will be linked to the particular AEs in the AE eCRF pages in EDC. A summary of 
PSRAE by SOC and PT will be prepared. 
A listing with SOC and PT for PSRAE will be presented. In addition, all other information captured in the PSRAE 
eCRF will be presented in another listing. 
18.2. PHYSICAL EXAMS 
A data listing will be provided to present physical examination findings. 
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18.3. VITAL SIGNS 
Vital Signs will be assessed at each study visit and results will be summarized descriptively by study visit for 
baseline, post-baseline visit and change from baseline.  
The following Vital Signs measurements will be reported for this study: 
•
Sitting / Supine Systolic Blood Pressure (mmHg)
•
Sitting / Supine Diastolic Blood Pressure (mmHg)
•
Heart Rate (bpm)
•
Respiratory Rate (breaths/min)
•
Temperature (⁰C)
•
Weight (kg)
•
Height (cm)
•
BMI (kg/m2)
Body Mass Index (BMI) will be calculated using the same formula as baseline: BMI (kg/m2) = weight (kg)/ height 
(m)2 of the same visit. It will be reported only for Baseline and Study Completion Visits.
Each measurement of the following parameters will be evaluated against the criteria of abnormality detailed below
for potentially clinically significant vital signs. Potentially clinically significant vital signs are derived and
categorized into PCS Low and PCS High, as well as Normal. In addition, a table summarizing the counts and
percentages of each PCS category at any time including unscheduled visits will be presented.
Vital Signs 
Criteria 
Abnormality Categories 
Pulse 
≥ 120 bpm at any post-baseline time point and ≥ 15 
bpm increase from baseline at any post-baseline time 
point 
PCS High 
≤ 50 bpm at any post-baseline time point and ≥ 15 
bpm decrease from baseline at any post-baseline time 
point 
PCS Low 
Systolic blood 
pressure 
≥ 180 mm Hg at any post-baseline time point and ≥ 
20 mm Hg increase from baseline at any post-baseline 
time point 
PCS High 
≤ 90 mm Hg at any post-baseline time point and ≥ 20 PCS Low 
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Vital Signs 
Criteria 
Abnormality Categories 
mm Hg decrease from baseline at any post-baseline 
time point 
Diastolic blood 
pressure 
≥ 105 mm Hg at any post-baseline time point and ≥ 
15 mm Hg increase from baseline at any post-baseline 
time point 
PCS High 
< 40 mm Hg at any post-baseline time point and ≥ 15 
mm Hg decrease from baseline at any post-baseline 
time point 
PCS Low 
Weight 
≥ 7% change from baseline at any post-baseline time 
point 
PCS High 
A listing presenting all available vital signs assessments for subjects with potentially clinically significant vital signs 
any time during the study will be provided.  
18.4. LABORATORY EVALUATIONS 
Results of continuous variables from the Q2 Solutions Clinical Lab (QLAB) will be summarized in the reporting for 
Hematology, Serum Chemistry, Urinalysis (excluding the 24-hour urine), and 24-hour Urine Collection (excluding 
24-hour urine protein). Similar to 24-hour urine protein, any other 24-hour parameters including 24-hour urine
albumin and creatinine with a collection duration not equal to 24 hours will be adjusted to 24-hour. A list of
laboratory parameters to be included in the outputs can be found below in Tables 3, 4, and 5. The lab results will be
converted to SI units prior to any analysis and all presentations will be based on SI units.
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 
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Blood urea nitrogen (BUN) 
Phosphorous 
Calcium, total 
Potassium 
Carbon dioxide, total (bicarbonate) 
Protein, total 
Chloride 
Sodium 
Alanine aminotransferase (ALT) 
Creatinine, serum 
Creatine phosphokinase 
Low density lipoprotein (LDL) cholesterol 
Uric acid 
High density lipoprotein (HDL) cholesterol 
Cystatin C 
triglycerides 
Table 4 Hematology Parameters 
Platelet count 
Automated WBC Differential: 
RBC count 
Neutrophils 
WBC count (absolute) 
Lymphocytes 
Hematocrit 
Monocytes 
Hemoglobin 
Eosinophils 
Basophils 
Table 5 Urinalysis Parameters 
Color 
Ketones 
Appearance 
Blood 
Specific gravity 
WBC 
pH 
Nitrite 
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Protein 
Bilirubin 
Glucose 
Microscopy of sediment 
For parameters not having Baseline assessments, the data of last visit is imported from the previous study AT1001-
012 and will serve as the baseline for this study.  
Quantitative laboratory measurements reported as “< X”, e.g. below the lower limit of quantification (BLQ), or 
“> X”, e.g. above the upper limit of quantification (ULQ), will be converted to X for the purpose of quantitative 
summaries, but will be presented as recorded, e.g. as “< X” or “> X” in the listings. 
Listings presenting lab results in each subcategory (e.g. Hematology, Serum Chemistry, Urinalysis, 24-hour Urine, 
Serum Pregnancy, and Urine Pregnancy) will be provided.  
A listing of subjects with at least one assessment falling outside of the normal range will also be provided and 
clinical significance will be included in this listing.  
A listing including all historical laboratory data will be provided. 
18.4.1. 
LABORATORY REFERENCE RANGES AND CLINICAL SIGNIFICANCE 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in SI units and 
categorized as: 
•
Low: Below the lower limit of the laboratory reference range.
•
Normal: Within the laboratory reference range (upper and lower limit included).
•
High: Above the upper limit of the laboratory reference range.
For reference range with a single boundary, there will be only two of the three categories presented for the 
parameter (either Low/Normal, or Normal/High), e.g. Magnesium concentration is deemed High if result > 1.25 
mmol/L, and Normal if at or below 1.25 mmol/L.  
For categorical results in Urinalysis, they will be categorized into two categories, i.e. Normal/Abnormal if the result 
is different from that of the normal reference value. Shifts from baseline to any post-baseline visit summary tables 
based on the Low/Normal/High categories (and the variants) described above will be provided.  
In addition to the high and low quantitative laboratory assignments, any result deemed clinically significant by the 
PI will be captured in the eCRF, and will be presented in the summary tables.  
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18.5. 12 LEAD ECG (ECG) EVALUATIONS 
Results from the central ECG (Electrocardiogram) Reading Centre will be included in the reporting of this study. 
The following ECG parameters will be reported in summary tables using descriptive statistics for this study: 
•
PR Interval (msec)
•
QRS Interval (msec)
•
QT Interval (msec)
•
QTcF Interval (msec)
•
HR (bpm)
•
RR (msec)
All findings, including clinically significant findings, will be captured by the eCRF for the overall ECG evaluation, 
and categorized into Normal; Abnormal, NCS; and Abnormal, CS. 
In addition to the change from baseline descriptive statistics summary, the number and percentage of subjects will 
be presented in a table for the overall ECG evaluation of clinical significance at any time of the study including  
unscheduled visits. A shift table by visits will also be constructed for change from baseline to post-baseline visits 
with regards to the three categories of the overall ECG evaluation. 
A listing presenting all available ECG assessments will be provided. In addition, a listing of subjects with at least 
one clinically significant finding will be provided. 
18.6. ECHOCARDIOGRAPHY (ECHO) 
ECHO parameters are categorized into Normal, Mildly Abnormal, Moderately Abnormal, Severely Abnormal (or 
Low, Normal, High) by gender (or age) based on the criteria below for safety purpose, and a table presenting counts 
and percentages of each category by parameter and visit will be provided. A table presenting Severely Abnormal 
incidence at any visits through the study including unscheduled visits will be included. 
ECHO Parameters 
Criteria for Female 
Criteria for Male 
Abnormality Category 
Left Ventricular Posterior Wall 
Thickness Diastole (cm) 
(LVPWTD) 
0.6 - 0.9 
0.6 - 1.0 
Normal 
1.0 - 1.2 
1.1 - 1.3 
Mildly Abnormal 
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ECHO Parameters 
Criteria for Female 
Criteria for Male 
Abnormality Category 
1.3 - 1.5 
1.4 - 1.6 
Moderately Abnormal 
>= 1.6 
>= 1.7 
Severely Abnormal 
Intraventricular Septum Thickness 
Diastolic (cm) (IVSTD) 
0.6 - 0.9 
0.6 - 1.0 
Normal 
1.0 - 1.2 
1.1 - 1.3 
Mildly Abnormal 
1.3 - 1.5 
1.4 - 1.6 
Moderately Abnormal 
>= 1.6 
>= 1.7 
Severely Abnormal 
Left Ventricular Ejection Fraction 
(%) (LVEF) 
>= 55 
Same as female 
Normal 
45 - 54 
Same as female 
Mildly Abnormal 
30 - 44 
Same as female 
Moderately Abnormal 
< 30 
Same as female 
Severely Abnormal 
Fractional Shortening (%) (FS) 
27 - 45 
25 - 43 
Normal 
22 - 26 
20 - 24 
Mildly Abnormal 
17 - 21 
15 - 19 
Moderately Abnormal 
<= 16 
<= 14 
Severely Abnormal 
Left Ventricular Mass (g) (LVM) 
67 - 162 
88 - 224 
Normal 
163 - 186 
225 - 258 
Mildly Abnormal 
187 - 210 
259 - 292 
Moderately Abnormal 
>= 211 
>= 293 
Severely Abnormal 
Left Ventricular Mass Index 
(g/m2) (LVMi) 
43 - 95 
49 - 115 
Normal 
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ECHO Parameters 
Criteria for Female 
Criteria for Male 
Abnormality Category 
96 - 108 
116 - 131 
Mildly Abnormal 
109 - 121 
132 - 148 
Moderately Abnormal 
>= 122 
>= 149 
Severely Abnormal 
Peak Mitral Inflow Velocity E 
(cm/s) (EPOINT) 
For age < 50 
Same as female 
< 58 
Same as female 
Low 
58 - 86 
Same as female 
Normal 
> 86
Same as female 
High 
For age >= 50 
Same as female 
< 48 
Same as female 
Low 
48 - 76 
Same as female 
Normal 
> 76
Same as female 
High 
Peak Mitral Inflow Velocity A 
(cm/s) (APOINT) 
For age < 50 
Same as female 
< 30 
Same as female 
Low 
30 - 50 
Same as female 
Normal 
> 50
Same as female 
High 
For age >= 50 
Same as female 
< 45 
Same as female 
Low 
45 - 73 
Same as female 
Normal 
> 73
Same as female 
High 
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ECHO Parameters 
Criteria for Female 
Criteria for Male 
Abnormality Category 
Mitral Valve E/A Ratio 
(EARATIO) 
For age < 50 
Same as female 
< 1.3 
Same as female 
Low 
1.3 - 2.5 
Same as female 
Normal 
> 2.5
Same as female 
High 
For age >= 50 
Same as female 
< 0.8 
Same as female 
Low 
0.8 - 1.4 
Same as female 
Normal 
> 1.4
Same as female 
High 
Left Ventricular Internal 
Dimension at End Diastole (cm) 
(LVIDd) 
3.5 - 5.3 
4.2 - 5.9 
Normal 
5.4 - 5.7 
6.0 - 6.3 
Mildly Abnormal 
5.8 - 6.1 
6.4 - 6.8 
Moderately Abnormal 
>= 6.2 
>= 6.9 
Severely Abnormal 
Left Ventricular Internal 
Dimension at End Systole (cm) 
(LVIDs) 
2.49 - 3.15 
2.87 - 3.61 
Normal 
Midwall Fractional Shortening 
(%) (MWFS) 
15 - 23 
14 - 22 
Normal 
13 - 14 
12 - 13 
Mildly Abnormal 
11 - 12 
11 
Moderately Abnormal 
<= 10 
<= 10 
Severely Abnormal 
Systolic and diastolic function grading with respect to the abnormality categories are available in the data and will 
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Author: 
Version 
Number: 
Final v1.0 
Version Date: 
21AUG2019 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
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Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
be presented in the same table as parameters listed above. 
ECHO comments and other information (parameters other than those listed above) will be presented in two other 
listings. 
18.7. OTHER SAFETY ASSESSMENTS 
Use of Medications will also be presented. Refer to Section 14 for how the Use of Medications will be presented. 
19.
DATA NOT SUMMARIZED OR PRESENTED
The other variables and/or domains not summarized or presented are: 
•
Comments
These domains and/or variables will not be summarized or presented, but will be available in the clinical study 
database, SDTM and/or ADaM datasets. 
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Author: 
Version 
Number: 
Final v1.0 
Version Date: 
21AUG2019 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary to IQVIA 
Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
DATES & TIMES 
Depending on data available, dates and times will take the ISO8601 form yyyy-mm-ddThh:mm:ss. 
SPELLING FORMAT 
English US. 
PRESENTATION OF TREATMENT GROUPS 
In this OLE study, there will be only one treatment administered, e.g. investigational product AT1001, therefore, all 
summary tables and figures will present the treatment group as “AT1001”. 
PRESENTATION OF VISITS 
For outputs of ITT population, visits will be represented as follows and in that order: 
Long Name (default) 
Baseline (V1) 
6 Months (V2) 
12 Months (V3) 
… 
End of Study 
Unscheduled visits will be in a form of “Unscheduled Visit x.y”, where x refers to the closest previous scheduled 
visit, and y is an increasing two-digit sequence number starting from 01 to 99 with a step of 1 chronologically.  
For subjects re-enrolled under addendum 1.1.2, the visits are planned with a 3-month interval, followed by follow-
up visits one month after. It can be presented as n Months (VxA) and n+1 Months FU A, where n refers to 3, 6, 9, 
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Author: 
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Number: 
Final v1.0 
Version Date: 
21AUG2019 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
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Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
…, e.g. 9 Months FU Addendum, and x refers to the chronological visit number. The baseline and end of study visit 
are presented as “Baseline (V1A)” and “End of Study (A)”, respectively. 
SCHEDULE OF PHARMACOKINETIC ASSESSMENTS FOR ADDENDUM SUBJECT 
QOD = every other day; Q3D = every third day; Q4D = every fourth day; Q5D = every fifth day; Q6D = every sixth 
day; Q7dD = every seventh day 
1.
Trough sample, to be collected just prior to the next scheduled migalastat administration
SCHEDULE OF BASELINE URINE COLLECTION FOR ADDENDUM SUBJECT 
1.
Total urine volumes will be collected on these days, if possible.
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Author: 
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Number: 
Final v1.0 
Version Date: 
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Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
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Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
TOTAL URINE VOLUME COLLECTION FOLLOWING DOSE REGIMEN CHANGES 
1.
Home healthcare provider will deliver collection bottles and/or pick up previous day’s urine collection.
2.
Four separate urine collections at time intervals shown
LISTINGS 
All data will be presented in listings if not otherwise specified. All listings will be ordered by the following (unless 
otherwise indicated in the template): 
•
Subject ID
•
Safety or efficacy parameters
•
Date (and time where applicable)
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