Conditions: Fabry Disease
Keywords: Lysosomal storage disease migalastat AT1001 Galafold
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 22
Healthy volunteers: no

Brief summary:
This was an open-label study to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of migalastat treatment in pediatric participants 12 to \<18 years of age with Fabry disease and amenable gene encoding α-galactosidase A (GLA) variants.

Detailed description:
This was a Phase 3b, 2-stage, open-label, uncontrolled, multicenter study to evaluate the safety, PK, PD, and efficacy of migalastat treatment in pediatric participants 12 to \<18 years of age and weighing ≥ 45 kilograms (99 pounds) with Fabry disease and amenable GLA variants. Participants must have been naïve to enzyme replacement therapy (ERT) or have stopped ERT at least 14 days at the time of screening.

Stage 1 was a treatment period of approximately 1 month (4 weeks); Stage 2 was a treatment period of 11 months and a 30-day (untreated) safety follow-up period. There was no break in treatment between Stages 1 and 2. Prior to Stage 1, there was a screening period lasting at least 14 days and up to 30 days (or more, if GLA genotyping was required). Stages 1 and 2 together consisted of a 12-month treatment period, and a 30-day safety follow-up period, for a total of approximately 13 months. Upon study completion, participants had the option to enroll in a long-term extension study conducted under a separate protocol (NCT04049760).

Participants were randomly assigned 1:1:1 to 1 of 3 PK sampling groups using interactive response technology (IRT). Four blood samples for the determination of migalastat concentrations in plasma were collected during Stage 1 study drug administration, and 1 PK (trough) sample was collected at Month 6 and again at Month 12.

Arms:
arm 1: One migalastat 123 milligrams (mg) capsule equivalent to 150 mg migalastat hydrochloride (HCl) (herein referred to as "migalastat") was administered every other day for 12 months.

Interventions: intervention 1: Migalastat HCl 150 mg
Intervention descriptions: intervention 1: migalastat HCl 150 mg capsule

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
AN OPEN-LABEL STUDY OF THE SAFETY, 
PHARMACOKINETICS, PHARMACODYNAMICS, AND 
EFFICACY OF 12-MONTH TREATMENT WITH 
MIGALASTAT IN PEDIATRIC SUBJECTS (AGED 12 TO 
< 18 YEARS) WITH FABRY DISEASE AND AMENABLE 
GLA VARIANTS 
Protocol Number: AT1001-020 
Version 5: Amendment 4 
Protocol Date: 13 June 2019 
Original Protocol: 20 February 2018 
Amendment 1 Protocol: 10 September 2018 
Amendment 2 Protocol: 31 October 2018 
Amendment 3 Protocol: 22 April 2019 (UK-specific) 
EudraCT No.: 2017-000146-21 
US IND Number: 068456 
Compound: Migalastat 
Sponsor 
Amicus Therapeutics UK Limited 
One Globeside,  
Fieldhouse Lane, Marlow  
Buckinghamshire SL7 1HZ 
United Kingdom 
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 of Amicus Therapeutics without the prior written consent of the company, 
except to the extent required under applicable laws or regulations.


Table 1: 
Serious Adverse Event Reporting and Medical Monitor Contact Information 
Role 
Name/Address 
Contact Information 
Safety Physician 
(Questions Regarding 
SAE Reporting) 
Amicus Therapeutics, Inc. 
1 Cedar Brook Drive 
Cranbury, NJ 08512 
USA 
Tel: +1 609-366-1164 
Email: 
SAE Reporting 
Primary method: 
Safety FAX number: 
+1 866-422-1278
If the primary method fails, please 
use: 
Safety Email address: 
safetyreporting@amicusrx.com 
Contract Medical Monitor 
Syneos Health  
3201 Beechleaf Court, Suite 600 
Raleigh, NC 27604 
USA 
Tel: +1 919-745-2723 
Email: 
Sponsor Medical Monitor 
Amicus Therapeutics, Inc. 
1 Cedar Brook Drive 
Cranbury, NJ 08512 
USA  
Tel: +1 609-662-2033 
Email: 
Abbreviation: SAE = serious adverse event 
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Amicus
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Amicus
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Amicus Therapeutics 
Protocol AT 1001-020 
Amendment4 
1. 
DECLARATIONS OF SPONSOR AND INVESTIGATOR 
1.1. 
Declaration of Sponsor 
This clinical study protocol is subject to critical review and has been approved by the sponsor, 
Amicus Therapeutics. 
The information it contains is consistent with the following: 
• 
the current benefit-risk evaluation of migalastat 
• 
the moral, ethical, and scientific principles governing clinical research, as set out in 
the current version of the Declaration of Helsinki, the principles of Good Clinical 
Practice (GCP) described in the United States (US) Code of Federal Regulations 
(CFR) Title 21 Parts 50, 54, 56, and 312, and in the International Conference on 
Harmonisation (ICH) GCP E6 guidelines 
Sponsor 
The investigator will be supplied with details of any significant or new findings related to 
treatment with migalastat. 
 
Date: /3:JIJN ;l{}/r 
Signature: -- -----------------
 
Amicus Therapeutics 
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 current 
version of the Declaration of Helsinki and the principles of Good Clinical Practice described in 
the United States CFR Title 21 Parts 50, 54, 56, and 312, and in the ICH GCP E6 guidelines. I 
will also work in accordance with applicable local requirements. 
Investigator 
Date: 
13 June 2019 
Confidential 
Signature: --------------------
Printed Name: 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Amicus Therapeutics (Amicus) 
Name of Investigational Product: 
Migalastat hydrochloride (HCl) 
Name of Active Ingredient: 
Migalastat 
Title of Study: 
An Open-label Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of 12-Month 
Treatment with Migalastat in Pediatric Subjects (aged 12 to < 18 years) with Fabry Disease and 
Amenable GLA Variants 
Study Centers: Global, multicenter 
Protocol Number: AT1001-020 
Studied Period: 
Estimated date first subject enrolled: Third quarter 2018 
Estimated date last subject completed: First quarter 2021 
Phase of Development: 
Phase 3b 
Objectives: 
Stage 1 
Primary Objectives 
• 
to characterize the PK of migalastat in adolescents with Fabry disease and to validate 
extrapolation of migalastat plasma exposure in adults to adolescents weighing ≥ 45 kg for 
the 150 mg migalastat capsule administered every other day (QOD) 
• 
to evaluate the safety of migalastat treatment in pediatric subjects diagnosed with Fabry 
disease and who have variants in the gene encoding α-galactosidase A (α-Gal A) (GLA) 
amenable to treatment with migalastat 
Secondary Objectives 
Not applicable 
Stage 2 
Primary Objective 
• 
to evaluate the safety of migalastat treatment in pediatric subjects diagnosed with Fabry 
disease and who have GLA variants amenable to treatment with migalastat 
Secondary Objectives 
• 
to characterize the pharmacodynamics (PD) of migalastat in pediatric subjects diagnosed 
with Fabry disease and who have GLA variants amenable to treatment with migalastat 
• 
to evaluate the efficacy of migalastat in pediatric subjects diagnosed with Fabry disease 
and who have GLA variants amenable to treatment with migalastat 
• 
to evaluate the relationship between exposure to migalastat and response 
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Methodology: 
This is a Phase 3b, 2-stage, open-label, uncontrolled, multicenter study to evaluate the safety, 
pharmacokinetics, pharmacodynamics, and efficacy of migalastat treatment in pediatric subjects 12 to 
< 18 years of age and weighing ≥ 45 kg (99 pounds) with Fabry disease and with amenable GLA 
variants. Subjects must be either naïve to enzyme replacement therapy (ERT) or have stopped ERT at 
least 14 days at the time of screening. 
The study will consist of 2 stages. Stage 1 will be a treatment period of approximately 1 month 
(4 weeks); Stage 2 will be a treatment period of 11 months and a 30-day (untreated) safety follow-up 
period. There will be no break in treatment between Stages 1 and 2. Prior to Stage 1, there will be a 
screening period lasting at least 14 days and up to 30 days (or more, if GLA genotyping is required). 
Stage 1 and 2 together will consist of a 12-month treatment period, and a 30-day safety follow-up 
period, for a total of approximately 14 months. Subjects may have the option to enroll in a long-term 
extension study conducted under a separate protocol. 
Number of Subjects (planned): 
Approximately 20 subjects are planned globally for enrollment in this study. An attempt will be made 
to enroll subjects of each sex. At least 7 to 10 of these subjects will be aged 12 to < 16 years for a 
subgroup analysis to be conducted at the end of Stage 1. 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria: 
Subjects must meet all of the following criteria to be considered for enrollment in the study: 
1. have a parent or legally-authorized representative who is willing and able to provide written 
informed consent and authorization for use and disclosure of personal health information or 
research-related health information, and subject provides assent, if applicable  
2. male or female, diagnosed with Fabry disease aged between 12 and < 18 years at baseline, and 
who might benefit from specific treatment for their condition, in the opinion of the investigator 
3. confirmed amenable GLA variant determined using the migalastat amenability assay 
Note: For subjects without a known amenable GLA variant, GLA genotyping must be 
performed prior to Visit 2. 
Note: For subjects with a GLA variant that has not yet been tested in the Migalastat 
Amenability Assay, amenability testing must be completed before Visit 2. 
4. weight of ≥ 45 kg (99 pounds) at screening 
5. treatment-naïve or discontinued ERT treatment at least 14 days prior to screening  
6. have at least one complication (ie, historical or current laboratory abnormality and/or 
sign/symptom) of Fabry disease, for example: 
a. corneal whorls 
b. neuropathic pain and/or acroparesthesia and/or acute crises persisting or recurring at least 
twice over the previous 3 months or longer, or; requiring management with analgesia 
c. Fabry disease-related gastrointestinal signs and symptoms (eg, diarrhea, abdominal pain) 
persisting or recurring at least twice over the previous 3 months or longer 
d. hypohidrosis (present for at least 3 months) 
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e. left ventricular mass index (LVMi) above the normal range for age and sex 
f. rhythm and/or conduction disturbances, for example:  
− 
episode of tachycardia or bradycardia,  
− 
arrhythmia, or; 
− 
abnormal PR, QRS, or QT interval 
g. reduced estimated glomerular filtration rate (eGFR) (using the Schwartz formula) for age 
and sex, or hyperfiltration (> 135 ml/min/1.73 m2) 
h. proteinuria or albuminuria in spot urine (early morning preferable) or as determined by the 
investigator (based on local laboratory results documented in the patient’s medical record) 
i. 
plasma globotriaosylsphingosine (lyso-Gb3) levels above normal (based on local 
laboratory results documented in the patient’s medical record) 
j. 
hearing impairment and/or tinnitus 
7. able to swallow capsules 
8. if of reproductive potential, agree to use medically accepted methods of contraception 
throughout the duration of the study and for up to 30 days after last dose of study medication 
Exclusion Criteria: 
Subjects who meet any of the following criteria will be excluded from participating in the study: 
1. moderate or severe renal impairment (eGFR < 60 mL/min/1.73 m2 at screening) 
2. advanced kidney disease requiring dialysis or kidney transplantation 
3. history of allergy or sensitivity to migalastat (including excipients) or other iminosugars 
(eg, miglustat, miglitol) 
4. subject has received any gene therapy at any time or anticipates starting gene therapy during 
the study period 
5. requires treatment with Glyset® (miglitol) or Zavesca® (miglustat), within 6 months before 
screening or throughout the study 
6. requires treatment with Replagal® (agalsidase alfa) or Fabrazyme® (agalsidase beta) within 
14 days before screening or throughout the study 
7. received any investigational/experimental drug, biologic or device within 30 days before 
screening 
8. any intercurrent illness or condition at screening or baseline 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 
9. is pregnant or breast-feeding, or is planning to become pregnant during the study period  
10. in the opinion of the investigator, the subject and/or parent or legally-authorized representative 
is unlikely or unable to comply with the study requirements 
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Investigational Product, Dosage and Mode of Administration: 
Migalastat will be supplied as capsules. Migalastat capsules contain 123 mg migalastat free base, 
which is equivalent to 150 mg migalastat HCl. 
Administration 
One migalastat 150 mg capsule will be administered with water every other day for 12 months. 
Subjects should take study drug at the same time of day during the every other day dosing schedule. 
Subjects will be instructed not to eat for at least 2 hours before and for 2 hours after administration of 
study drug. Water can be consumed during this period. 
During Stage 2, if a subject’s weight decreases to below 43 kg an unscheduled visit will be arranged 
2 to 4 weeks later in order to monitor the subject’s weight. If the subject’s weight remains below 43 kg 
at the follow-up visit, additional blood samples will be drawn for PK and PD (plasma lyso-Gb3) 
assessments. Based on the PK results and other parameters, at the discretion of the investigator and the 
Amicus medical monitor, the subject may remain on study drug with additional monthly follow-up 
visits until his/her weight returns to at least 43 kg. 
Duration of Treatment: 
There will be 2 stages of treatment administration totaling approximately 12 months. 
Reference Therapy, Dosage and Mode of Administration: 
There is no reference therapy for this study. 
Criteria for Evaluation: 
Safety 
Safety assessments include monitoring of adverse events (AEs), clinical laboratory tests, vital signs, 
physical examinations, body weight and height, 12-lead electrocardiograms (ECGs), echocardiograms, 
Tanner staging of sexual development, and use of concomitant medications. 
Safety endpoints are as follows: 
• 
incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), 
and AEs leading to discontinuation of study drug 
• 
changes in clinical laboratory test results from baseline over time 
• 
changes in vital signs from baseline over time 
• 
changes in physical examination findings from baseline over time 
• 
change in body weight and height from baseline over time 
• 
changes in ECG results from baseline over time 
• 
changes in echocardiogram parameters from baseline to Month 12/early termination (ET) 
• 
change in Tanner stage from baseline to Month 12/ET 
• 
use of concomitant medications 
Stage 1 Pharmacokinetic Assessments 
The schedule for sparse PK sampling is presented in the table below. All samples must be collected 
within a 24-hour period following the same dose of migalastat, between Day 15 and Day 30 following 
initiation of migalastat treatment. 
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PK Sampling 
Groupa 
Time Post-dose 
Sample 1 
Sample 2 
Sample 3 
Sample 4 
1 
1h to 1h 15min 
1h 30min to 2h 
5h to 5h 30min 
6h 30min to 7h 
2 
1h to 1h 15min 
2h 45min to  
3h 15min 
5h 15min to  
5h 45min 
10h 45min to  
11h 15min 
3 
3h 15min to  
3h 45min 
3h 45minb to  
4h 15min 
8h 15min to  
8h 45min 
8h 45minb to  
9h 15min 
Abbreviations: h = hour(s); min = minutes; PK = pharmacokinetic 
Note: The timing of PK samples was determined using optimal sampling theory using PopED and 
mrgsolve software packages in R using a D-optimality algorithm. 
a Subjects will be randomly assigned 1:1:1 to 1 of 3 PK sampling groups. In one 24-hour period 
between Day 15 and Day 30 following initiation of study drug administration, each subject will have 
4 PK samples collected at the times specified in the table above (relative to the last dose of study 
drug) according to their randomized PK sampling group assignment. 
b Sample should NOT be taken at the same time as the previous sample. Samples should be taken 
approximately 15 minutes apart at a minimum. 
In the event that follow-up PK assessments are required, at each follow-up visit additional sparse PK 
samples will be drawn at 4 time intervals according to the sampling group to which the subject was 
initially assigned. 
Stage 2 Pharmacokinetic Assessments 
Single blood samples for analysis of plasma migalastat concentration will be collected at the Month 6 
and Month 12/ET study visits, at the same time that samples are collected for clinical laboratory tests, 
ie, trough sample taken prior to migalastat administration. 
Pharmacokinetic endpoints are as follows: 
• 
population PK model that describes the relationship between weight and age and 
migalastat pharmacokinetics in pediatric subjects (with primary PK parameter outputs 
listed in the following text) 
• 
PK parameters based on simulated plasma-concentration data for migalastat after 
multiple-dose administration at steady-state concentration 
− 
Cmax: maximum observed plasma concentration 
− 
Cmin: minimum observed plasma concentration 
− 
tmax: time to reach Cmax 
− 
AUC0-τ: area under the plasma concentration-time curve from time 0 over the dosing 
interval (ie, 48 hours) 
− 
t½: terminal elimination half-life 
− 
CLss/F: apparent oral clearance at steady-state concentration 
− Vss/F: apparent oral volume of distribution at steady-state concentration 
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Pharmacodynamic Assessments  
The pharmacodynamic biomarker to be evaluated in this study is lyso-Gb3 levels in plasma. Blood 
samples will also be collected for exploratory biomarkers.  
The pharmacodynamic endpoint is change in plasma levels of lyso-Gb3 from baseline to Months 3, 6, 
and 12/ET. 
Efficacy Assessments 
Efficacy assessments include eGFR, urine protein and albumin levels, LVMi and other cardiac 
parameters using echocardiograms, and subject questionnaires (electronic diary [e-diary] for 
gastrointestinal signs and symptoms and pain [Short Fabry Disease Patient-Reported 
Outcome – Gastrointestinal Signs and Symptoms (FABPRO-GI and Pain Questionnaire for Clinical 
Trials (24-hour version)], Patient Global Impression of Change [PGI-C], Fabry-Specific Pediatric 
Health and Pain Questionnaire [FPHPQ], and Pediatric Quality of Life Inventory™ [PedsQL™]).  
Efficacy endpoints are as follows: 
• 
change in eGFR from baseline to Months 1, 3, 6, and 12/ET  
• 
change in urine protein and albumin levels from baseline to Months 3, 6, and 12/ET  
• 
change in LVMi and other echocardiogram parameters from baseline to Month 12/ET  
• 
change in gastrointestinal signs and symptoms and pain from baseline to Month 12/ET, as 
measured by e-diary responses (FABPRO-GI and Pain Questionnaire for Clinical Trials 
[24-hour version]) 
• 
mean PGI-C values at Months 3, 6, and 12/ET  
• 
change in FPHPQ scores from baseline to Month 12/ET  
• 
change in PedsQL scores from baseline to Month 12/ET 
Statistical Methods: 
The safety population will include all subjects who receive at least 1 dose of study drug. All safety and 
pharmacodynamic analyses will be performed using the safety population. 
The Stage 1PK population will include all subjects who have a complete set of sparse PK samples from 
the single day of collection at steady-state during Days 15 to 30 of Stage 1. There will be 2 interim PK 
analyses. One will be performed using the entire Stage 1 PK population of adolescents aged 12 to 
< 18 years. A second interim analysis will include a subpopulation of at least 7 to 10 subjects age 12 to 
less than 16 years.  
The final PK population will include all subjects with at least one quantifiable concentration and a 
known weight and eGFR. All final PK analyses will be performed using the final PK population. 
The intent-to-treat population will include all enrolled subjects. All efficacy analyses will be performed 
using intent-to-treat population. 
Data will be summarized using descriptive statistics. Continuous variables will be summarized by 
number of subjects, mean, standard deviation, median, minimum, and maximum values. Discrete 
variables will be summarized by counts and percentages. In general, data will be summarized by sex 
and combined across all subjects.  
For the population PK analysis, predicted median (2.5th and 97.5th percentile) concentration-time data 
based on a previously established population PK model will be visually compared with observed 
concentration-time data for all subjects and for the subgroup aged 12 to < 16 years at the end of 
Stage 1. 
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Sample Size: 
A sample size of at least 7 to 10 subjects per age/weight group is required for statistical comparison 
with adult exposure based on 2 methods described by Wang, Jadhav et al. 2012. 
First, assuming the final plasma clearance estimates and inter-individual variability of 28.5% 
(Migalastat Abbreviated Report of the Simulations of Migalastat in Pediatric Patients with Fabry 
Disease, 16 October 2016), 7 subjects is adequate to achieve at least 80% power for a study design 
with rich PK sampling intended for non-compartmental analysis.  
Second, according to the sample size calculation for a study with sparse/rich PK sampling intended for 
population PK analysis, (𝑒𝑒−𝑡𝑡(0.975,𝑑𝑑𝑑𝑑)×𝑆𝑆𝑆𝑆𝐿𝐿𝐿𝐿𝐿𝐿, 𝑒𝑒𝑡𝑡(0.975,𝑑𝑑𝑑𝑑)×𝑆𝑆𝑆𝑆𝐿𝐿𝐿𝐿𝐿𝐿) should be within the pre-defined 
criteria of (0.6, 1.4), where SELCL is the standard error for log-transformed pediatric clearance that 
relates to weight, and t (0.975, df) is the 97.5% upper quantile values from t distribution corresponding 
to the sample size. Mathematically, SELCL was approximately equal to the relative standard error of 
untransformed clearance, 0.16. Therefore, a sample size of approximately 10 subjects is adequate to 
achieve the pre-defined boundary of (0.6, 1.4). 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
DECLARATIONS OF SPONSOR AND INVESTIGATOR .......................................3 
1.1. 
Declaration of Sponsor .................................................................................................3 
1.2. 
Declaration of Investigator ...........................................................................................3 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............11 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................16 
5. 
INTRODUCTION AND STUDY RATIONALE ......................................................18 
5.1. 
Fabry Disease ..............................................................................................................18 
5.2. 
Migalastat ...................................................................................................................19 
5.3. 
Summary of Nonclinical and Clinical Safety Data .....................................................19 
5.3.1. 
Nonclinical Data .........................................................................................................19 
5.3.2. 
Clinical Data ...............................................................................................................20 
5.3.2.1. 
Pharmacology .............................................................................................................20 
5.3.2.2. 
Safety ..........................................................................................................................21 
5.3.2.3. 
Pharmacokinetics ........................................................................................................21 
5.4. 
Study Rationale ...........................................................................................................22 
5.5. 
Dose Selection ............................................................................................................23 
5.6. 
Justification for Proposed Dose and Regimen in Pediatric Subjects with 
Fabry Disease ..............................................................................................................23 
6. 
OBJECTIVES AND PURPOSE .................................................................................25 
6.1. 
Primary Objectives .....................................................................................................25 
6.2. 
Secondary Objectives .................................................................................................25 
7. 
INVESTIGATIONAL PLAN .....................................................................................26 
7.1. 
Study Design ...............................................................................................................26 
7.2. 
Details of Study Treatment .........................................................................................27 
7.2.1. 
Administration of Study Treatment ............................................................................27 
7.2.2. 
Study Drug Interruptions ............................................................................................28 
7.2.3. 
Treatment Compliance ................................................................................................28 
7.3. 
Concomitant Medications ...........................................................................................28 
7.4. 
Prohibited Medications ...............................................................................................28 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................29 
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8.1. 
Number of Subjects ....................................................................................................29 
8.2. 
Eligibility Criteria .......................................................................................................29 
8.2.1. 
Inclusion Criteria ........................................................................................................29 
8.2.2. 
Exclusion Criteria .......................................................................................................30 
8.3. 
Withdrawal Criteria ....................................................................................................31 
8.4. 
Replacement of Subjects .............................................................................................32 
8.5. 
Subjects of Childbearing Potential .............................................................................32 
9. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................34 
9.1. 
Description of Study Visits .........................................................................................38 
9.1.1. 
Screening Period .........................................................................................................38 
9.1.2. 
Baseline Visit ..............................................................................................................39 
9.1.3. 
Treatment Period Visits/Telephone Contacts .............................................................39 
9.1.4. 
Unscheduled Visits .....................................................................................................39 
9.1.5. 
Early Termination Visit ..............................................................................................39 
9.1.6. 
30-day Safety Follow-up Visit ....................................................................................39 
9.2. 
Description of Study Assessments ..............................................................................40 
9.2.1. 
Screening Assessments ...............................................................................................40 
9.2.2. 
Safety Assessments .....................................................................................................40 
9.2.2.1. 
Adverse Events and/or Serious Adverse Events .........................................................40 
9.2.2.2. 
Clinical Laboratory Tests ...........................................................................................40 
9.2.2.3. 
Vital Signs ..................................................................................................................41 
9.2.2.4. 
Physical Examination .................................................................................................42 
9.2.2.5. 
Body Weight and Height ............................................................................................42 
9.2.2.6. 
Electrocardiograms .....................................................................................................42 
9.2.2.7. 
Echocardiogram ..........................................................................................................42 
9.2.2.8. 
Tanner Staging ............................................................................................................42 
9.2.2.9. 
Concomitant Medications and Procedures .................................................................42 
9.2.3. 
Pharmacokinetic Assessments ....................................................................................43 
9.2.4. 
Pharmacodynamic Assessments .................................................................................43 
9.2.5. 
Efficacy Assessments .................................................................................................43 
9.2.5.1. 
Estimated Glomerular Filtration Rate .........................................................................43 
9.2.5.2. 
Urine Protein and Albumin Levels .............................................................................44 
9.2.5.3. 
Echocardiogram ..........................................................................................................44 
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9.2.5.4. 
Subject Questionnaires ...............................................................................................44 
10. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..................................46 
10.1. 
Definitions ..................................................................................................................46 
10.1.1. 
Adverse Event .............................................................................................................46 
10.1.2. 
Serious Adverse Event ................................................................................................47 
10.2. 
Relationship to Study Drug ........................................................................................48 
10.3. 
Severity Assessment ...................................................................................................49 
10.4. 
Reporting Events ........................................................................................................49 
10.4.1. 
Reporting Adverse Events ..........................................................................................49 
10.4.2. 
Reporting Serious Adverse Events .............................................................................49 
10.4.3. 
Additional Reporting Requirements for Suspected Unexpected Serious 
Adverse Reaction ........................................................................................................50 
10.5. 
Other Reporting Situations .........................................................................................51 
10.5.1. 
Pregnancy ...................................................................................................................51 
10.5.2. 
Medication Errors, Including Overdose and Under Dose ..........................................51 
10.5.3. 
Reporting of Possible Study Drug Product Quality Defects ......................................51 
11. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .............................52 
11.1. 
Endpoints ....................................................................................................................52 
11.1.1. 
Safety Endpoints .........................................................................................................52 
11.1.2. 
Pharmacokinetic Endpoints ........................................................................................52 
11.1.3. 
Pharmacodynamic Endpoints .....................................................................................53 
11.1.4. 
Efficacy Endpoints ......................................................................................................53 
11.2. 
Sample Size Considerations .......................................................................................53 
11.3. 
Data Analysis Considerations .....................................................................................53 
11.3.1. 
Analysis Populations ..................................................................................................53 
11.3.2. 
Statistical Methods ......................................................................................................54 
11.3.2.1. 
Interim Analysis ..........................................................................................................54 
11.3.2.2. 
Safety Analyses ..........................................................................................................54 
11.3.2.3. 
Pharmacokinetic Analyses ..........................................................................................54 
11.3.2.4. 
Pharmacodynamic Analyses .......................................................................................55 
11.3.2.5. 
Efficacy Analyses .......................................................................................................56 
11.3.2.6. 
Other Summaries ........................................................................................................56 
12. 
STUDY TREATMENTS ............................................................................................57 
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12.1. 
Description of Study Drug ..........................................................................................57 
12.2. 
Packaging and Labeling ..............................................................................................57 
12.3. 
Study Drug Accountability .........................................................................................57 
12.4. 
Handling, Storage, Return, and Disposal of Study Drugs ..........................................58 
13. 
STUDY MANAGEMENT .........................................................................................59 
13.1. 
Documentation of Protocol-required Information and Study Findings ......................59 
13.2. 
Data Management .......................................................................................................59 
13.3. 
Study Monitoring, Source Data Verification, and Onsite Audits ...............................59 
13.4. 
Records Retention .......................................................................................................60 
13.5. 
Use of Study Findings ................................................................................................61 
13.6. 
Study Close-out ..........................................................................................................61 
14. 
STUDY CONDUCT CONSIDERATIONS ...............................................................62 
14.1. 
Posting of Information on Publicly Available Clinical Trial Registers ......................62 
14.2. 
Ethical and Legal Aspects ..........................................................................................62 
14.2.1. 
Informed Consent/Assent Information .......................................................................62 
14.2.2. 
Ongoing Information for Independent Ethics Committee/Institutional 
Review Board .............................................................................................................63 
14.2.3. 
Compliance with Good Clinical Practice ...................................................................63 
14.2.3.1. 
Quality Control ...........................................................................................................63 
14.2.3.2. 
Quality Assurance .......................................................................................................64 
14.2.4. 
Confidentiality ............................................................................................................64 
14.3. 
Clinical Study Protocols and Amendments ................................................................64 
14.4. 
Delegation of Investigator Duties ...............................................................................65 
14.5. 
Liability and Insurance ...............................................................................................65 
14.6. 
Financial Disclosure ...................................................................................................65 
15. 
REFERENCES ...........................................................................................................66 
16. 
APPENDICES ............................................................................................................68 
APPENDIX A. TANNER STAGING ........................................................................................68 
 
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LIST OF TABLES 
Table 1: 
Serious Adverse Event Reporting and Medical Monitor Contact Information ............2 
Table 2: 
Single Dose Plasma Pharmacokinetic Summary ........................................................22 
Table 3: 
Schedule of Assessments ............................................................................................35 
Table 4: 
Sparse Pharmacokinetic Sampling .............................................................................38 
Table 5: 
Total Blood Volume to be Collected (as Scheduled) per Subject ..............................38 
Table 6: 
Clinical Laboratory Parameters ..................................................................................40 
Table 7: 
Investigational Product (Capsule) ...............................................................................57 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................26 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Term 
Definition 
α-Gal A 
α-galactosidase A 
AE 
adverse event 
AT1001 
migalastat  
AUC 
area under the plasma concentration-time curve 
AUC0-τ 
area under the plasma concentration-time curve over the dosing interval 
(ie, 48 hours) 
AUC0-∞ 
area under the plasma concentration-time curve from time 0 extrapolated to infinity 
CFR 
Code of Federal Regulations 
CL/F 
plasma clearance 
Cmax 
maximum observed plasma concentration 
Cmin 
minimum observed plasma concentration 
CRO 
contract research organization 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
e-diary 
electronic diary 
eGFR 
estimated glomerular filtration rate 
ERT 
enzyme replacement therapy 
ET 
early termination 
EU 
European Union 
FABPRO-GI 
Fabry Disease Patient-Reported Outcome – Gastrointestinal Signs and Symptoms 
FPHPQ 
Fabry-Specific Pediatric Health and Pain Questionnaire 
GCP 
Good Clinical Practice 
GL-3 
globotriaosylceramide 
GLA 
gene encoding α-galactosidase A 
HCl 
hydrochloride 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
lyso-Gb3 
globotriaosylsphingosine 
LVMi 
left ventricular mass index 
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Term 
Definition 
PedsQL™ 
Pediatric Quality of Life Inventory™ 
PGI-C 
Patient Global Impression of Change 
PK 
pharmacokinetic 
QOD 
quaque altera die (once every other day) 
SAE 
serious adverse event 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach the maximum observed plasma concentration 
WBC 
white blood cell 
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5. 
INTRODUCTION AND STUDY RATIONALE 
5.1. 
Fabry Disease 
Fabry disease is a rare, progressive and devastating X-linked lysosomal storage disorder 
affecting males and females, with an estimated prevalence of 1:117,000 up to 
1:40,000 (Desnick and Schindler 2001; Germain 2010; Meikle, Hopwood et al. 1999; Eurordis 
2005). Newborn screening studies have identified a higher incidence of variants in GLA, the gene 
encoding the lysosomal enzyme, α-galactosidase A (α-Gal A) (Spada, Pagliardini et al. 2006; 
Mechtler, Stary et al. 2012), although the impact of these findings on disease prevalence has not 
been established. Disease-causing variants in the GLA gene result in a deficiency of α-Gal A, 
which is required for glycosphingolipid metabolism (Brady, Gal et al. 1967). Beginning early in 
life, the reduction in α-Gal A activity results in an accumulation of glycosphingolipids, including 
globotriaosylceramide (GL-3) and plasma globotriaosylsphingosine (lyso-Gb3), and leads to the 
symptoms and life-limiting sequelae of Fabry disease, which include pain, gastrointestinal 
symptoms, renal failure, cardiomyopathy, cerebrovascular events, and early mortality 
(Germain 2010). Early initiation of therapy and lifelong treatment may provide an opportunity to 
slow disease progression and prolong life expectancy. 
Fabry disease encompasses a spectrum of disease severity and age of onset, although it has 
traditionally been divided into 2 main phenotypes, “classic” and “late-onset” (Desnick, Ioannou 
et al. 2001; Filoni, Caciotti et al. 2010; Topaloglu, Ashley et al. 1999; Shabbeer, Yasuda et al. 
2002; Shabbeer, Yasuda et al. 2006; Ishii, Chang et al. 2007). The classic phenotype has been 
ascribed primarily to males with undetectable to low α-Gal A activity and is associated with 
earlier onset of renal, cardiac, and/or cerebrovascular manifestations. The late-onset phenotype 
has been ascribed primarily to males and females with higher residual α-Gal A activity and is 
associated with later onset of disease. Heterozygous female carriers typically express the 
late-onset phenotype, but may also display the classic phenotype depending on the pattern of 
X-chromosome inactivation. 
More than 1000 Fabry disease-causing GLA variants have been identified (data on file). 
Approximately 67% are missense variants, resulting in single amino acid substitutions in the 
α-Gal A enzyme (Germain 2010; Gal, Schäfer et al. 2006). Missense GLA variants often result in 
the production of abnormally folded and unstable forms of α-Gal A (Fan, Ishii et al. 1999; Ishii, 
Chang et al. 2007) and the majority are associated with the classic phenotype (Filoni, Caciotti 
et al. 2010; Topaloglu, Ashley et al. 1999; Shabbeer, Yasuda et al. 2002; Shabbeer, Yasuda et al. 
2006; Ishii, Chang et al. 2007). Normal cellular quality control mechanisms in the endoplasmic 
reticulum block the transit of these abnormal proteins to lysosomes and target them for 
premature degradation and elimination. Many missense mutant forms are targets for migalastat, 
an α-Gal A-specific pharmacological chaperone (Yam, Zuber et al. 2005; Yam, Bosshard et al. 
2006; Benjamin, Flanagan et al. 2009).  
Note: In the Migalastat Clinical Development Program, all subjects were previously, 
and continue to be, required to have a GLA variant that is amenable to migalastat 
treatment. Historically in Amicus Therapeutics (Amicus) documents, these variants 
were referred to as “mutations”. Mutation will be referred to as “variant” in all new or 
revised Amicus-sponsored protocols, consistent with the guidelines of the American 
Medical College of Genetics and Genomics. 
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5.2. 
Migalastat 
Migalastat (also known as AT1001), a low molecular weight iminosugar, is an analogue of the 
terminal galactose of GL-3/lyso-Gb3. Nonclinical in vitro and in vivo pharmacologic studies 
have demonstrated that migalastat acts as a pharmacological chaperone, selectively and 
reversibly binding with high affinity to the active site of wild-type α-Gal A and specific mutant 
forms of α-Gal A (Ishii, Chang et al. 2007), the genotypes of which are referred to as amenable 
variants. Migalastat is a precision medicine targeted specifically to patients with Fabry disease 
who express specific mutant variants of the GLA gene that can be functionally restored by 
migalastat. Migalastat binding stabilizes these mutant forms of α-Gal A in the endoplasmic 
reticulum, facilitating their proper trafficking to lysosomes where dissociation of migalastat 
allows the now active α-Gal A to reduce the level of GL-3 and other substrates (Yam, Zuber 
et al. 2005; Yam, Bosshard et al. 2006; Benjamin, Flanagan et al. 2009).  
The Migalastat Amenability Assay, which is compliant with Good Laboratory Practices and has 
been clinically validated, was developed to identify patients with variants amenable to treatment 
with migalastat. Amenable variants are those that translate to mutant forms of the enzyme and 
that show a relative increase in enzyme activity that is ≥ 1.20-fold above the baseline value and 
an absolute increase of ≥ 3.0% of wild-type at a threshold of 10 μM migalastat in the Migalastat 
Amenability Assay (Benjamin, Della Valle et al. 2017). Approximately 35% to 50% of patients 
with Fabry disease are currently estimated to have amenable variants, the majority of which are 
associated with the classic phenotype of the disease (Benjamin, Flanagan et al. 2009; Filoni, 
Caciotti et al. 2010; Germain, Shabbeer et al. 2002; Shabbeer, Yasuda et al. 2006). 
5.3. 
Summary of Nonclinical and Clinical Safety Data  
5.3.1. 
Nonclinical Data  
Available results from single-dose and repeat-dose nonclinical studies with migalastat having a 
wide margin of safety (ie, with doses that were ≥ 25-fold higher than those used in clinical 
studies) suggest no specific hazard regarding chronic toxicity to humans, based on values for 
area under the plasma concentration-time curve (AUC), with the exception of possible transient, 
fully reversible male infertility. In addition, a 39-week toxicity study in juvenile monkeys did not 
demonstrate a concern for toxicity, suggesting that migalastat does not induce adverse effects in 
the developing organ systems evaluated in that study. 
In nonclinical studies using hR301Q α-Gal A Tg/knockout mice, a 30-mg/kg dose of migalastat 
was found to be optimal (AUC, 18400 ng•hr/mL; Study RR1001-08); at this dose, significant 
increases in α-Gal A activity and GL-3 substrate reduction were demonstrated across all tissues. 
At higher doses, no further improvements were observed.  
Nonclinical studies also demonstrated that greater GL-3 reductions were observed with a 
regimen less frequent than daily administration, including every-other-day administration. 
In regard to safety, the pivotal chronic dosing studies utilized rats and monkeys of approximately 
6 weeks and 21 to 27 months of age, respectively, at the initiation of dosing. Developmentally, 
this corresponds to a human of approximately 12 years of age with respect to the rat, and less 
than 12 years of age with respect to the monkey (Beck 2006). 
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The main finding identified with migalastat in nonclinical studies was reversible infertility in 
male rats. Full fertility returned to the previously migalastat-treated animals after a 4 week 
washout period, a period of less than a full spermatogenic cycle (> 2 months). No effects on 
sperm count, morphology, or motility were detected to account for the reduction in male fertility. 
These observations with migalastat, and the published information on other iminosugars 
including miglustat, strongly suggest that the infertility is due to effects on sperm maturation or 
function (Zavesca Prescribing Information 2017). Numerous studies indicate that these effects 
are related to sexual maturation processes that only occur after puberty, and not an adverse effect 
on testicular spermatogenesis. There is no indication of adverse effects on the germinal 
epithelium or testicular spermatogenesis that would be of particular concern for the proposed 
pediatric use of migalastat. There were also no effects on sperm motility, count or morphology in 
rats, and no changes in organ weights or pathology in the testes or accessory sex organs reported 
in rats, mice or monkeys. In addition, there were also no observations suggesting that the 
reproductive effects may be mediated by endocrine disruption which also would be of 
importance in developing animals and relevant for the proposed use in young people. Based on 
these findings, the fertility effects are not considered to pose any increased risk to pediatric 
patients compared to adults. In addition, a 39-week toxicity study in juvenile monkeys did not 
demonstrate adverse effects in the developing organ systems evaluated in that study. 
5.3.2. 
Clinical Data 
Clinical data for migalastat are available for healthy adults, and adolescents (16 to < 18 years of 
age) and adult patients with Fabry disease. 
5.3.2.1. 
Pharmacology 
In adult subjects with Fabry disease and amenable variants, the dose and regimen of migalastat 
were selected to obtain the optimal balance between migalastat concentration and its subsequent 
clearance, in order to maximize in situ α-Gal A activity and GL-3 substrate reduction. Dose 
selection was based on findings from nonclinical and clinical studies. Exposure observed 
following a single oral dose of migalastat hydrochloride (HCl) 150 mg in humans (AUC, 
13521 ng•hr/mL) was similar to that observed after a 30-mg/kg dose in mice (see Section 5.3.1).  
In a Phase 1 repeat-dose study in healthy subjects, greater increases in wild-type α-Gal A activity 
levels were observed in white blood cells (WBCs) after oral administration of migalastat HCl 
150 mg twice daily (BID) for 7 days as compared to that seen after 50 mg BID. In five Phase 2 
studies, ranges of regimens and doses were explored in 27 subjects (18 males and 9 females): 
BID (25, 100, 250 mg), once daily (50 mg), every other day (50, 150, 250 mg), and 3 days 
on/4 days off (250, 500 mg). In these studies, migalastat HCl 150 mg every other day (QOD) 
resulted in the best balance of substrate (ie, urine GL-3) reduction and safety in subjects with 
amenable variants compared with other doses and regimens. Treatment with 150 mg QOD also 
resulted in decreases in kidney interstitial capillary GL-3 levels and was associated with 
long-term stability of renal function. In Study FAB-CL-205, when subjects were switched from 
150 mg QOD to higher, less frequent doses (250/500 mg 3 days on/4 days off), no further 
increases in WBC α-Gal A activity or reductions in urine GL-3 levels were observed. 
Additionally, a higher incidence of treatment-related adverse events (AEs) was observed at the 
250- and 500-mg dose levels. On the basis of these collective data, 150 mg every other day was 
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selected as the dose and regimen for Phase 3 studies of migalastat in adults (ie, ≥ 16 years of 
age).  
Migalastat is to be taken 2 hours before and 2 hours after a meal based on 2 food-effect studies 
(Study FAB-CL-103 and AT1001-016), which demonstrated that food reduces the bioavailability 
of migalastat as assessed using area under the plasma concentration-time curve from 
time 0 extrapolated to infinity (AUC0-∞), maximum observed plasma concentration (Cmax), and 
time to reach maximum observed plasma concentration (tmax) (Johnson, Mudd et al. 2015). 
Details of these studies are provided in the Investigator’s Brochure. 
5.3.2.2. 
Safety 
Migalastat has a favorable safety profile in adults based on results from a comprehensive 
development program. A total of 386 adult and adolescent (≥ 16 years of age) subjects have been 
exposed to migalastat in Phase 1, Phase 2, and Phase 3 clinical studies conducted globally. The 
extent of exposure to migalastat among subjects with Fabry disease in Phase 2 and Phase 3 
studies is approximately 595.2 patient-years, with the longest subject exposure being 11.2 years 
as of 17 March 2017. 
No treatment-related deaths have been reported in clinical studies, and most serious adverse 
events (SAEs) were not considered treatment-related. In Phase 1 studies, the most frequently 
reported adverse event (AE) was headache. In completed Phase 2 studies in subjects with Fabry 
disease (Study FAB-CL-201 through Study FAB-CL-204), the most frequently reported AEs 
were headache, arthralgia, diarrhea, and nausea. In completed Phase 3 studies in subjects with 
Fabry disease (Study AT1001-011, Study AT1001-012, and Study AT1001-041), the most 
frequently reported AEs were diarrhea, headache, arthralgia, pain in extremity, nausea, fatigue, 
nasopharyngitis, dizziness, and influenza, though the order by frequency was not necessarily the 
same in all 3 studies. 
5.3.2.3. 
Pharmacokinetics 
Pharmacokinetic parameters for migalastat from single-dose studies are summarized in Table 2. 
Migalastat had a moderate rate of absorption reaching Cmax in approximately 3 hours (tmax) after 
oral administration over the dose range of 25 to 2000 mg. Mean Cmax and AUC0–∞ values 
increased in a dose-proportional manner following oral doses from 75 to 1250 mg migalastat. 
The mean elimination half-lives (t½) ranged from 3.0 to 4.8 hours. 
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Table 2: 
Single Dose Plasma Pharmacokinetic Summary 
Dose Group 
(mg) 
N 
Cmax  
(ng/mL)a 
tmax  
(hours)b 
AUC0–∞ 
(ng•h/mL)a 
t½  
(hours)a 
CL/F  
(L/h)a 
25 
6 
211 (70) 
3.0 (2-4) 
1178 (353) 
3.0 (0.48) 
19.0 (6.5) 
75 
6 
693 (113) 
3.0 (1.5-5) 
4677 (429) 
4.0 (0.67) 
13.0 (1.1) 
150 
51 
1700 (464) 
3.0 (1-6) 
10,654 (2612) 
3.8 (0.39) 
NR 
225 
6 
2200 (921) 
3.0 (2-4) 
12,462 (5521) 
4.6 (0.71) 
18.6 (12.1) 
500 
6 
5330 (2009) 
3.0 (1.5-5) 
29,045 (12,586) 
4.3 (0.28) 
15.8 (5.4) 
675 
6 
6645 (1527) 
2.5 (2-4) 
36,419 (8228) 
4.2 (0.30) 
15.8 (3.6) 
1250 
58 
13,374 (3959) 
3.0 (2-4) 
75,522 (20,146) 
4.0 (0.45) 
13.9 (4.4) 
2000 
6 
17,752 (5370) 
2.5 (2.5-3.5) 
75,855 (17,765) 
4.8 (0.52) 
22.9 (6.8) 
Abbreviations: AUC0–∞ = area under the plasma concentration-time curve from time 0 extrapolated to infinity; 
CL/F = plasma clearance; Cmax = maximum observed plasma concentration; NR = not reported; t½ = elimination 
half-life; tmax = time to reach the maximum observed plasma concentration 
a Arithmetic mean (standard deviation) 
b Median (range)  
Source: Johnson, Mudd et al. 2013 
5.4. 
Study Rationale 
This is a Phase 3b, 2 stage, open-label, uncontrolled, multicenter study to evaluate the safety, 
pharmacokinetics, pharmacodynamics, and efficacy of migalastat treatment in pediatric subjects 
12 to < 18 years of age with Fabry disease and amenable GLA variants. The youngest pediatric 
subjects included in previous studies with migalastat were 16 years of age. 
Early signs and symptoms of Fabry disease tend to manifest during childhood and adolescent 
years (ie, < 18 years), particularly in males with the classic phenotype, and are followed later in 
life by the development of overt kidney, cardiovascular, and central nervous system 
complications. In the 2 largest disease registries, the Fabry Outcome Survey and the Fabry 
Registry (Ramaswami, Whybra et al. 2006; Hopkin, Bissler et al. 2008), the median age of 
symptom onset is reported to be approximately 6 years in boys and 8 to 9 years in girls. 
Diagnosis is often delayed due to the different manifestations of the disease, its relative rarity, 
and the lack of clinical awareness of the condition, making the median age of diagnosis 
approximately 9 years in boys and 9 to 13 years in girls. 
Data from these Fabry disease registries indicate that the most common symptom among 
pediatric subjects was neuropathic pain (eg, episodic pain crises, chronic pain, and 
acroparesthesia), which was reported more frequently by boys than by girls (58.8% versus 
40.5%), and with an earlier age of onset (7 vs 9 years). The gastrointestinal tract was the second 
most commonly involved organ system with 18% of children experiencing signs and symptoms 
(eg, abdominal pain and diarrhea); the median age at onset of symptoms was 5 years in boys and 
9.5 years in girls. The next most common sign was skin findings such as angiokeratomas. As 
with neuropathic pain, these symptoms and signs were more prevalent in boys than girls and 
occurred at an earlier age of onset. 
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Renal involvement appears less commonly in the younger population; however, a limited 
number of older adolescents have been reported to have impaired glomerular filtration rate 
(GFR), proteinuria, and hyperfiltration, along with cardiac abnormalities, pain, and 
gastrointestinal symptoms.  
Considering the young age of symptom onset, diagnosis, and the progressive nature of Fabry 
disease, early intervention and treatment for pediatric patients could be important in slowing the 
progression of this disease (Hopkin, Jefferies et al. 2016). 
5.5. 
Dose Selection 
The dose regimen of migalastat HCl proposed for evaluation in pediatric subjects aged 12 to 
< 18 years with Fabry disease is the same as the adult dose and is supported by simulation results 
from a population pharmacokinetic (PK) model derived using data from adults, based on body 
weight (Migalastat Abbreviated Report of the Simulations of Migalastat in Pediatric Patients 
with Fabry Disease, 20 October 2016). The proposed dose is 150 mg every other day for subjects 
aged 12 to < 18 years and weighing ≥ 45 kg (99 pounds). 
5.6. 
Justification for Proposed Dose and Regimen in Pediatric Subjects 
with Fabry Disease 
Migalastat has not been studied in pediatric subjects under 16 years of age. Although adolescent 
subjects with Fabry disease 16 to < 18 years of age were included in Phase 3 studies, the number 
of adolescent subjects included in those studies was limited. Therefore, simulations have been 
performed (100 subjects per age group) to select doses that match exposure in pediatric patients 
to exposure observed in adults receiving migalastat HCl 150 mg QOD. Area under the plasma 
concentration-time curve over the dosing interval (AUC0-τ) at steady-state concentration was 
selected as the target parameter for dose selection in pediatric subjects because existing safety 
and tolerability data in adults suggest that increased risk is not expected with increases in Cmax 
and that changes in minimum observed plasma concentration (Cmin) are not likely to affect 
efficacy given there is likely an indirect relationship between plasma concentrations and 
efficacy. The aim is to achieve AUC values in pediatric subjects that are similar to those in adults 
with Fabry disease and with normal renal function who were receiving migalastat HCl 150 mg 
every other day.  
The largest biological factor affecting migalastat plasma clearance (CL/F) is renal function. 
While many adult patients with Fabry disease have reduced renal function (15% and 42% of 
subjects in Study AT1001-011 with moderate or mild renal impairment, respectively, based on 
estimated glomerular filtration rate [eGFR]), pediatric patients with Fabry disease have relatively 
high values for eGFR (mean, 147 mL/min/1.73 m2) (Hopkin, Bissler et al. 2008).  
Body weight also explains variability in the pharmacokinetics of migalastat in individuals 
< 70 kg, with effects on CL/F, volume of distribution in the central compartment (V2/F), volume 
of distribution in the peripheral compartment (V3/F), and distribution clearance (Q/F). These 
effects were incorporated into the dose rationale simulations for pediatric subjects by using the 
range of weights from the Centers for Disease Control and Prevention weight chart (data on file).  
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Lastly, there is a very small change in CL/F (15%) and V2/F (31%) in the presence of Fabry 
disease. This effect was accounted for in the simulations, even though these differences result in 
exposures that are similar to those reported for healthy subjects. 
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6. 
OBJECTIVES AND PURPOSE 
6.1. 
Primary Objectives 
The primary objectives of this study are as follows:  
Stage 1 
• to characterize the PK of migalastat in adolescents with Fabry disease, and to validate 
extrapolation of migalastat plasma exposure in adults to adolescents weighing ≥ 45 kg 
for the 150 mg migalastat capsule administered QOD 
• to evaluate the safety of migalastat treatment in pediatric subjects diagnosed with 
Fabry disease and who have GLA variants amenable to treatment with migalastat 
Stage 2 
• to evaluate the safety of migalastat treatment in pediatric subjects diagnosed with 
Fabry disease and who have GLA variants amenable to treatment with migalastat 
6.2. 
Secondary Objectives 
The secondary objectives of this study are as follows: 
Stage 1 
Not applicable 
Stage 2 
• to characterize the pharmacodynamics of migalastat in pediatric subjects diagnosed 
with Fabry disease and who have GLA variants amenable to treatment with migalastat 
• to evaluate the efficacy of migalastat in pediatric subjects diagnosed with Fabry 
disease and who have GLA variants amenable to treatment with migalastat 
• to evaluate the relationship between exposure to migalastat and response 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Study Design  
This is a Phase 3b, 2-stage, open-label, uncontrolled, multicenter study to evaluate the safety, 
pharmacokinetics, pharmacodynamics, and efficacy of migalastat treatment in pediatric subjects 
12 to < 18 years of age and weighing ≥ 45 kg (99 pounds) with Fabry disease and with amenable 
GLA variants. Subjects must be either naïve to enzyme replacement therapy (ERT) or have 
stopped ERT at least 14 days at the time of screening. 
The study will consist of 2 stages. Stage 1 will be a treatment period of approximately 1 month 
(4 weeks); Stage 2 will be a treatment period of 11 months and a 30-day (untreated) safety 
follow-up period. There will be no break in treatment between Stages 1 and 2. Prior to Stage 1, 
there will be a screening period lasting at least 14 days and up to 30 days (or more, if GLA 
genotyping is required). Stage 1 and 2 together will consist of a 12-month treatment period, and a 
30-day safety follow-up period, for a total of approximately 14 months. Subjects may have the 
option to enroll in a long-term extension study conducted under a separate protocol. 
At screening, all subjects first must have a blood test to confirm their GLA variant prior to 
completing any additional screening assessments. Subjects with a documented variant (ie, those 
who have a full genotype report) that is known to be amenable to migalastat may continue to be 
screened according to the procedures outlined for Visit 1. 
For subjects without a known GLA variant, screening will resume after receipt of the variant 
result, if amenability is confirmed. For subjects with a GLA variant that has not yet been tested in 
the Migalastat Amenability Assay, amenability testing also will be performed. If variants are 
determined to be amenable according to the Migalastat Amenability Assay, screening procedures 
will resume at that time. If the variant is non-amenable, the subject will be considered a screen 
failure. (Note: the Migalastat Amenability Assay may take up to 8 weeks.)  
The study design is displayed in Figure 1. 
Figure 1: 
Study Design 
 
-30 to -14 Days 
1 Month (4 weeks) 
       
 
11 Months  
 
 
 
 
30 Days 
    
 
Screening:              Stage 1: Safety/PK   Stage 2: Safety/PD/Efficacy            Follow-up: Safety 
  Genotyping 
 
A Data Monitoring Committee (DMC) will operate according to a charter that includes 
operational and logistical procedures for the DMC. The DMC will monitor and evaluate all 
available safety data from this study by reviewing summaries of safety data on a regular basis, 
evaluating risk/benefit where possible, identifying any clinically relevant trends through the 
study, and assessing whether it is safe for the subject and/or study to continue.  
Safety assessments include monitoring of AEs, clinical laboratory tests, vital signs, physical 
examinations, body weight and height, 12-lead electrocardiograms (ECGs), echocardiograms, 
Tanner staging of sexual development, and use of concomitant medications. Sparse blood 
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samples for determination of plasma migalastat concentrations and PK analysis will be collected. 
The pharmacodynamic biomarker to be evaluated in this study is lyso-Gb3 levels in plasma. 
Blood samples will also be collected for exploratory biomarkers. Efficacy assessments include 
eGFR, urine protein and albumin levels, left ventricular mass index (LVMi) using 
echocardiograms, and subject questionnaires (electronic diary [e-diary] for gastrointestinal signs 
and symptoms and pain [Short Fabry Disease Patient-Reported Outcome – Gastrointestinal Signs 
and Symptoms {FABPRO-GI and Pain Questionnaire for Clinical Trials (24-hour version)}], 
Patient Global Impression of Change [PGI-C], Fabry-Specific Pediatric Health and Pain 
Questionnaire [FPHPQ], and Pediatric Quality of Life Inventory™ [PedsQL™]). 
7.2. 
Details of Study Treatment 
Migalastat will be supplied as capsules that are generally referred to as “migalastat”; the term 
“migalastat HCl” refers to the salt form and is used only when referring to a specific dosage of 
migalastat for administration.  
Migalastat capsules contain 123 mg migalastat free base, which is equivalent to 150 mg 
migalastat HCl.  
7.2.1. 
Administration of Study Treatment 
One migalastat 150 mg capsule will be administered with water every other day continuously for 
12 months during Stages 1 and 2 of the study. Subjects should take study drug at the same time 
of day during the every other day dosing schedule. Subjects are to record the date and time of 
each migalastat administration in the Dosing Diary provided in the dosing wallet containing their 
study drug. 
Study drug should not be taken on 2 consecutive days. If a dose is missed entirely for the day, 
the subject should take the missed dose of study drug only if it is within 12 hours of the time the 
dose normally is taken. If more than 12 hours have passed, the subject should resume taking 
study drug at the next planned dosing day and time according to the every-other-day dosing 
schedule.  
Subjects will be instructed not to eat for at least 2 hours before and for 2 hours after 
administration of study drug. Water can be consumed during this period.  
Pharmacokinetic simulations suggest that if a subject’s weight decreases to 43 kg, their exposure 
following a 150 mg QOD dose is not substantially higher than exposure in subjects weighing 
≥ 45 kg. Therefore, in the event of weight loss down to 43 kg during Stage 2, subjects may 
continue on study drug with close monitoring. During Stage 2, if a subject’s weight decreases to 
below 43 kg, an unscheduled visit will be arranged 2 to 4 weeks later in order to monitor the 
subject’s weight. If the subject’s weight remains below 43 kg at the follow-up visit, additional 
blood samples will be drawn for PK and PD (plasma lyso-Gb3) assessments. Follow-up PK 
assessments will be drawn at 4 time intervals according to the sampling group the subject was 
initially assigned to. Based on the PK results and other parameters, at the discretion of the 
investigator and the Amicus medical monitor, the subject may remain on study drug with 
additional monthly follow-up visits until his/her weight returns to at least 43 kg. 
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7.2.2. 
Study Drug Interruptions 
The investigator may choose to interrupt administration of study drug in case of an AE 
(eg, abnormal result of an assessment or laboratory test) or for administrative reasons.  
Any interruption in dosing must be documented in the subject’s electronic case report forms 
(eCRFs) and source medical record. The Medical Monitor/Clinical Project Manager should be 
informed as soon as possible after the decision is made to interrupt study drug for a subject. 
7.2.3. 
Treatment Compliance 
Treatment compliance will be assessed at each clinic visit through subject interview, and by 
comparing the amount of study drug that should have been taken since the last study visit with 
the amount of study drug returned. If a subject is not compliant with study drug administration, 
the investigator (in consultation with the Medical Monitor) will consider whether the 
noncompliance should warrant withdrawal of the subject from the study. 
7.3. 
Concomitant Medications 
Concomitant medications, including vaccinations, taken within 1 month before screening or at 
any time throughout the study must be recorded in the eCRFs, along with the reason for use, 
dates of administration, dosage, frequency, and route of administration.  
7.4. 
Prohibited Medications  
Use of the following medications or treatments during this study is prohibited and will result in 
withdrawal from the study: 
• investigational/experimental therapy  
• ERT (eg, Replagal® [agalsidase alfa], Fabrazyme® [agalsidase beta]) 
• Glyset® [miglitol]  
• Zavesca® [miglustat] 
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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Number of Subjects 
Approximately 20 subjects are planned globally for enrollment in this study. An attempt will be 
made to enroll subjects of each sex. At least 7 to 10 of these subjects will be aged 12 to 
< 16 years for a subgroup analysis to be conducted at the end of Stage 1.  
8.2. 
Eligibility Criteria 
Adherence to the eligibility criteria for participation in this study is essential to ensure scientific 
integrity, regulatory acceptability, and subject safety. Waivers of inclusion/exclusion criteria will 
not be granted. 
8.2.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be considered for enrollment in the study: 
1. have a parent or legally-authorized representative who is willing and able to provide 
written informed consent and authorization for use and disclosure of personal health 
information or research-related health information, and subject provides assent, if 
applicable provides written informed consent  
2. male or female, diagnosed with Fabry disease aged between 12 and < 18 years at 
baseline, and who might benefit from specific treatment for their condition, in the opinion 
of the investigator 
3. confirmed, amenable GLA variant determined using the migalastat amenability assay 
Note: For subjects without a known amenable GLA variant, GLA genotyping must be 
performed prior to Visit 2. 
Note: For subjects with a GLA variant that has not yet been tested in the Migalastat 
Amenability Assay, amenability testing must be completed before Visit 2. 
4. weight of ≥ 45 kg (99 pounds) at screening 
5. treatment-naïve or discontinued ERT treatment at least 14 days prior to screening  
6. have at least one complication (ie, historical or current laboratory abnormality and/or 
sign/symptom) of Fabry disease, for example:  
a. corneal whorls 
b. neuropathic pain and/or acroparesthesia and/or acute crises persisting or recurring at 
least twice over the previous 3 months or longer, or; requiring management with 
analgesia  
c. Fabry disease-related gastrointestinal signs and symptoms (eg, diarrhea, abdominal 
pain) persisting or recurring at least twice over the previous 3 months or longer 
d. hypohidrosis (present for at least 3 months) 
e. LVMi above the normal range for age and sex 
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f. rhythm and/or conduction disturbances, for example:  
− episode of tachycardia or bradycardia,  
− arrhythmia, or; 
− abnormal PR, QRS, or QT interval 
g. reduced eGFR (using the Schwartz formula) for age and sex, or hyperfiltration 
(> 135 ml/min/1.73 m2) 
h. proteinuria or albuminuria in spot urine (early morning preferable) or as determined 
by the investigator (based on local laboratory results documented in the patient’s 
medical record) 
i. plasma lyso-Gb3 levels above normal (based on local laboratory results documented 
in the patient’s medical record) 
j. hearing impairment and/or tinnitus 
7. able to swallow capsules  
8. if of reproductive potential, agree to use medically accepted methods of contraception 
throughout the duration of the study and for up to 30 days after last dose of study 
medication 
8.2.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participating in the study: 
1. moderate or severe renal impairment (eGFR < 60 ml/min/1.73 m2 at screening) 
2. advanced kidney disease requiring dialysis or kidney transplantation 
3. history of allergy or sensitivity to migalastat (including excipients) or other iminosugars 
(eg, miglustat, miglitol) 
4. subject has received any gene therapy at any time or anticipates starting gene therapy 
during the study period 
5. requires treatment with Glyset (miglitol) or Zavesca (miglustat) within 6 months before 
screening or throughout the study 
6. requires treatment with Replagal (agalsidase alfa) or Fabrazyme (agalsidase beta) within 
14 days before screening or throughout the study 
7. received any investigational/experimental drug, biologic or device within 30 days before 
screening 
8. any intercurrent illness or condition at screening or baseline 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 
9. is pregnant or breast-feeding, or is planning to become pregnant during the study period  
10. in the opinion of the investigator, the subject and/or parent or legally-authorized 
representative is unlikely or unable to comply with the study requirements 
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Note: “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. 
8.3. 
Withdrawal Criteria 
Subjects may discontinue study drug, withdraw from the study, or be withdrawn from the study 
for any reason including, but not limited to, the following reasons:  
• at their own request or at the request of their parent 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 AE as determined by the investigator, subject, and/or 
parent or legally-authorized representative 
• inability to tolerate or comply with PK blood sampling procedures 
• failure of the subject to comply with the study visit schedule 
• persistent noncompliance, at the discretion of the investigator 
• pregnancy 
• inability to contact subject (ie, subject is lost to follow-up) 
• sponsor request 
The reason for and date of discontinuation or withdrawal must be recorded in the eCRF and in 
source documents. All subjects who discontinue study treatment will be encouraged to complete 
an early termination (ET) visit and follow-up safety assessments. 
The investigator must make every effort to contact subjects who are lost to follow-up to schedule 
end-of-study assessments. Attempts to contact subjects who are lost to follow-up (eg, times and 
dates of attempted telephone contact, documentation of a registered letter) must be recorded in 
the subject’s source document.  
If a subject wishes to discontinue treatment, the investigator must determine the extent that a 
subject may be willing to continue participation in the study, as follows: 
• the parent or legally-authorized representative and/or subject wants to discontinue 
study drug, but agrees to the follow-up procedures  
• the parent or legally-authorized representative and/or subject wants to discontinue 
study drug and all follow-up procedures  
• the parent or legally-authorized representative and/or subject wants to revoke 
consent/assent to collect and use further data  
Note: In the United States, the authorization to use and disclose data for research can 
only be revoked in writing by the subject, or parent or legally-authorized 
representative of minor subjects. 
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8.4. 
Replacement of Subjects  
Subjects who withdraw from the study may be replaced. Replacement of a subject may only 
occur after consultation with and written approval of the Amicus Medical Monitor. 
8.5. 
Subjects of Childbearing Potential 
Female subjects of reproductive potential, and all male subjects must use a medically accepted 
contraceptive regimen during their participation in the study and for 30 days after the last dose of 
migalastat. A medically acceptable birth control method is defined as one which results in a low 
failure rate (ie, < 1% per year) when used consistently and correctly. 
A female subject is considered of reproductive potential if she has functional ovaries, ducts, and 
uterus with no impairment that would cause sterility. This includes females with oligomenorrhea 
(even severe), and females who have just begun to menstruate. 
A female is considered of non-reproductive potential if she is at least 26 weeks status-post 
documented surgical sterilization (includes hysterectomy, bilateral oophorectomy, bilateral tubal 
ligation, or salpingectomy). 
The allowed methods of contraception described in the following text are only effective when 
used consistently, correctly, and, if applicable, in accordance with the product label. The 
investigator is responsible for ensuring subjects understand how to properly use these methods of 
contraception. 
Medically acceptable methods of contraception for female subjects enrolled in the study include 
the following: 
• total abstinence, which refers to refraining from penile-vaginal intercourse, when this 
is the female’s preferred and usual lifestyle 
• hormonal contraception (ie, combination oral contraceptive pills, implant, injection, 
ring, or patch) for at least 12 weeks before screening 
• intrauterine device that meets the < 1% failure per year rate, as stated in the product 
label, for at least 12 weeks before screening 
• double-barrier method, defined as condom and occlusive cap (eg, diaphragm or 
cervical/vault caps) used in combination with spermicide (eg, foam, gel, film, cream, 
suppository) 
− Note: the double-barrier method does not satisfy the requirements for an effective 
method of birth control in all countries and may not be utilized as a contraceptive 
method by subjects participating at sites in those countries. 
Medically acceptable methods of contraception for male subjects enrolled in the study include 
the following: 
• total abstinence, which refers to refraining from penile-vaginal intercourse, when this 
is the male’s preferred and usual lifestyle 
• surgical sterilization (eg, vasectomy with documentation of azoospermia) prior to the 
subject’s entry into the study 
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Note: For this definition, “documented” refers to the outcome of the investigator’s or 
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 
• double-barrier method, defined as condom and occlusive cap (eg, diaphragm or 
cervical/vault caps) used in combination with spermicide (eg, foam, gel, film, cream, 
suppository) 
− Note: the double-barrier method does not satisfy the requirements for an effective 
method of birth control in all countries and may not be utilized as a contraceptive 
method by subjects participating at sites in those countries. 
Any pregnancy (in a female subject or the female partner of a male subject) occurring during the 
study must be reported as described in Section 10.5.1. 
In the event of pregnancy in a female subject, migalastat must be discontinued immediately upon 
becoming aware of the pregnancy. Female subjects or a female partner of a male subject who 
becomes pregnant during the study must be monitored by the investigator until the outcome of 
the pregnancy is known. Both the detection and the outcome of the pregnancy must be reported 
to the sponsor. 
Periodic abstinence (eg, calendar, ovulation, symptom-thermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.  
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9. 
STUDY ASSESSMENTS AND PROCEDURES  
The schedule of study assessments and procedures is presented in Table 3. The schedule for 
sparse PK sampling (all samples must be collected within a 24-hour period following the same 
dose of migalastat between Day 15 and Day 30 following initiation of migalastat treatment) is 
presented in Table 4; additional PK sampling time points are included in Table 3. Total blood 
volume to be drawn per subject is presented in Table 5. 
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 assessments that occur during the study, where applicable and to the extent possible, should 
be completed during the designated visit, preferably in the order specified below. Once 
established, every effort should be made to maintain the order of procedures at each study visit 
throughout the study.  
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Table 3: 
Schedule of Assessments 
 
Screeninga 
Treatment Period 
Treatment 
Period 
Stage 1 
Stage 2 
 
 
Assessments 
Day  
-30 to -14 
Baselineb 
Day 1 
Day 
15-30 
Month 
1 
Month 
2  
(TC) 
Month 
3 
Month 
4  
(TC) 
Month 
5  
(TC) 
Month 
6 
Month 
7  
(TC) 
Month 
8  
(TC) 
Month 
9 
Month 
10 
(TC) 
Month 
11 
(TC) 
Month 
12/ET 
30-Day 
Safetyc 
Window (days) 
— 
— 
 
±3 
±3 
±3 
±3 
±3 
±6 
±6 
±6 
±6 
±6 
±6 
±6 
+6 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Informed 
consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confirmatory GLA 
Genotyping 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
amenable GLA 
variant 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing diary 
 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
 
FABPRO-GI and 
Pain Questionnaire 
 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
 
FPHPQ 
questionnaire 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
PedsQL 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
PGI-C 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
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Table 3: 
Schedule of Assessments (Continued) 
 
Screeninga 
Treatment Period 
Treatment 
Period 
Stage 1 
Stage 2 
 
 
Assessments 
Day  
-30 to -14 
Baselineb 
Day 1 
Day 
15-30 
Month 
1 
Month 
2  
(TC) 
Month 
3 
Month 
4  
(TC) 
Month 
5  
(TC) 
Month 
6 
Month 
7  
(TC) 
Month 
8  
(TC) 
Month 
9 
Month 
10 
(TC) 
Month 
11 
(TC) 
Month 
12/ET 
30-Day 
Safetyc 
Window (days) 
— 
— 
 
±3 
±3 
±3 
±3 
±3 
±6 
±6 
±6 
±6 
±6 
±6 
±6 
+6 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Complete physical 
examination 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
Brief physical 
examination 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (BP, HR, 
RR, Temp) 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Body weight 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Height 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Tanner Staging 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
12-Lead ECG 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Chemistry (including 
eGFR using 
Schwartz formula) 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
Hematology 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Plasma lyso-Gb3 and 
analogs 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
Exploratory PD 
biomarkers 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
PK blood samples  
 
 
Xd 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
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Table 3: 
Schedule of Assessments (Continued) 
 
Screeninga 
Treatment Period 
Treatment 
Period 
Stage 1 
Stage 2 
 
 
Assessments 
Day  
-30 to -14 
Baselineb 
Day 1 
Day 
15-30 
Month 
1 
Month 
2  
(TC) 
Month 
3 
Month 
4  
(TC) 
Month 
5  
(TC) 
Month 
6 
Month 
7  
(TC) 
Month 
8  
(TC) 
Month 
9 
Month 
10 
(TC) 
Month 
11 
(TC) 
Month 
12/ET 
30-Day 
Safetyc 
Window (days) 
— 
— 
 
±3 
±3 
±3 
±3 
±3 
±6 
±6 
±6 
±6 
±6 
±6 
±6 
+6 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Urinalysis (urine 
protein and albumin or 
microalbumin levels) 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
 
Urine pregnancy test 
or date of LMP (as 
applicable)e 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Echocardiogram 
(LVMi and 
additional 
parameters) 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Study treatment 
supply/ 
Resupply/Return 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Abbreviations: BP = blood pressure; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; ET = early termination; FABPRO-GI = Fabry 
Disease Patient-Reported Outcome-Gastrointestinal; FPHPQ = Fabry-Specific Pediatric Health and Pain Questionnaire; GLA = gene encoding α-galactosidase A; 
HR = heart rate; LMP = last menstrual period; LVMi = left ventricular mass index; lyso-Gb3 = globotriaosylsphingosine; PD = pharmacodynamic; 
PedsQL = Pediatric Quality of Life Inventory; PGI-C = Patient Global Impression of Change; PK = pharmacokinetic; RR = respiration rate; TC = telephone call; 
Temp = body temperature  
a For subjects without a documented GLA variant, screening procedures will be suspended until such time that a confirmed, amenable variant is determined. 
b All baseline assessments must be completed BEFORE the first dose of migalastat is administered. 
c Only for subjects who do not enroll in a long-term extension study 
d Blood samples for plasma migalastat concentrations will be taken during one 24-hour period between Day 15 and 30 following initiation of study drug 
administration. 
e Female subjects only 
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Table 4: 
Sparse Pharmacokinetic Sampling 
PK Sampling 
Groupa 
Time Post-dose 
Sample 1 
Sample 2 
Sample 3 
Sample 4 
1 
1h to 1h 15min 
1h 30min to 2h 
5h to 5h 30min 
6h 30min to 7h 
2 
1h to 1h 15min 
2h 45min to  
3h 15min 
5h 15min to  
5h 45min 
10h 45min to  
11h 15min 
3 
3h 15min to  
3h 45min 
3h 45minb to  
4h 15min 
8h 15min to  
8h 45min 
8h 45minb to  
9h 15min 
Abbreviations: h = hour(s); min = minutes; PK = pharmacokinetic 
Note: The timing of PK samples was determined using optimal sampling theory using PopED and mrgsolve 
software packages in R using a D-optimality algorithm. 
a Subjects will be randomly assigned 1:1:1 to 1 of 3 PK sampling groups. In one 24-hour period between Day 15 
and Day 30 following initiation of study drug administration, each subject will have 4 PK samples collected at the 
times specified in the table above (relative to the last dose of study drug) according to their randomized PK 
sampling group assignment. 
b Sample should NOT be taken at the same time as the previous sample. Samples should be taken approximately 
15 minutes apart at a minimum. 
Table 5: 
Total Blood Volume to be Collected (as Scheduled) per Subject 
 
Blood Volume per Test (mL) 
Assessments 
Screening 
Baseline 
Day 15 
to 30 
Month 
1 
Month 
3 
Month 
6 
Month 
12/ET 
Total 
GLA Genotyping 
4 
 
 
 
 
 
 
4 
Chemistry 
4 
4 
 
 
4 
4 
4 
20 
Hematology 
 
2 
 
 
 
2 
2 
6 
Plasma lyso-Gb3 
 
2 
 
 
2 
2 
2 
8 
PK blood sample  
 
 
1 × 4a 
 
 
1 
1 
6 
PD blood sample 
 
2 
 
 
 
2 
2 
6 
Total: 
50 mL 
Abbreviations: ET = early termination; GLA = gene encoding α-galactosidase A; 
lyso-Gb3 = globotriaosylsphingosine; PD = pharmacodynamic; PK = pharmacokinetic 
Note: Total collection volume does not take into account additional blood samples drawn during potential follow-up 
visits. 
a Four serial samples (Table 4) will be collected. 
9.1. 
Description of Study Visits 
9.1.1. 
Screening Period 
With the exception of determination of amenable GLA variant status for subjects whose GLA 
variant status is unknown at screening, screening assessments must be performed within 14 to 
30 days before Day 1. At least 14 days must be allowed between screening and baseline in order 
to allow time for return of screening assessment results.  
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Subjects for whom GLA genotyping must be performed may require additional time for 
screening (see Section 7.1). Genotyping must be completed prior to any other screening 
procedures. Screening for subjects without a known variant will resume following receipt of the 
genotyping result and confirmation of amenability. 
9.1.2. 
Baseline Visit 
Baseline assessments will be performed pre-dose on Day 1, which should be scheduled as soon 
as possible after a subject is determined to be eligible for participation in the study.  
All inclusion/exclusion criteria must be reviewed and verified at this visit to ensure that there 
have been no changes to a subject’s health that would affect that subject’s eligibility to 
participate in the study. If a subject is not well at the time the Baseline Visit is scheduled, the 
Baseline Visit should be postponed. 
9.1.3. 
Treatment Period Visits/Telephone Contacts 
Periodic visits are scheduled between Days 15 and Day 30 and at Month 1 (end of Stage 1), and 
at Months 3, 6, 9, and 12 (Stage 2). Telephone contacts are scheduled for interim months, 
Months 2, 4, 5, 7, 8, 10, and 11 (Stage 2). A month will be defined as 30 days. 
Telephone contacts will include questions regarding any AEs or pregnancies (ie, including delay 
in menstrual period for female subjects with regular menses) that may have occurred and any 
changes in concomitant medications. 
Visits during which sparse PK samples will be collected may be conducted at the subject’s 
residence by a visiting nurse. 
9.1.4. 
Unscheduled Visits 
Unscheduled visits for medical reasons such as evaluation of AEs and/or repeat laboratory tests 
can be performed at any time at the investigator’s discretion. The date and reason for the visit, in 
addition to all information collected during the visit, should be captured in source documents and 
on the appropriate eCRFs. 
Follow-up visits triggered by subjects’ weight monitoring also are considered unscheduled visits 
for data management purposes.  
9.1.5. 
Early Termination Visit 
Subjects who are withdrawn from the study should complete Month 12/ET procedures as soon as 
possible. If early termination coincides with a scheduled visit (ie, Visit 4, 6, or 10), all 
procedures outlined for the ET visit should be performed. 
9.1.6. 
30-day Safety Follow-up Visit 
All subjects who do not enroll in a long-term extension study, including subjects who 
discontinue study drug or withdraw from the study, should complete a 30-day safety follow-up 
visit, to be scheduled at least 30 days after the last dose of study drug.  
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9.2. 
Description of Study Assessments 
All assessments will be conducted according to the schedule presented in Table 3. Assessments 
may be repeated if requested by the Medical Monitor.  
9.2.1. 
Screening Assessments 
Informed consent/assent will be obtained before any study-specific procedures are performed. 
Screening assessments will include review of inclusion and exclusion criteria, collection of 
demography information (date of birth, sex, and race; ethnicity in the US only), collection of 
medical history (including menarcheal status), review of prior/current medications, confirmatory 
GLA genotyping, confirmation of documented amenable GLA variant, a complete physical 
examination, vital signs, body weight, a 12-lead ECG, chemistry (including calculation of 
eGFR), measurement of plasma lyso-Gb3 levels, urinalysis, urine pregnancy test (if applicable), 
and echocardiogram. 
For subjects whose GLA variant amenability status in regard to migalastat treatment is not known 
at screening, the migalastat amenability assay must be performed and results must be received 
before other screening procedures are performed. If a subject’s GLA variant is amenable to 
treatment with migalastat, the 30-day screening period will begin when the first of the remaining 
screening procedures is performed. If a subject’s GLA variant is not amenable to treatment with 
migalastat, that subject will be considered a screen failure.  
9.2.2. 
Safety Assessments 
9.2.2.1. 
Adverse Events and/or Serious Adverse Events 
Throughout the study, subjects will be given an opportunity to report AEs. The definitions, 
reporting, and monitoring of AEs and SAEs are described in Section 10. 
9.2.2.2. 
Clinical Laboratory Tests 
9.2.2.2.1. Safety Laboratory Tests 
Samples for chemistry, hematology, and urinalysis are outlined in Table 6. Laboratory samples 
collected on a dose administration day will be collected predose.  
Table 6: 
Clinical Laboratory Parameters 
Chemistry 
Hematology 
Urinalysis 
ALT 
Platelet count 
Color 
Alkaline phosphatase 
RBC count 
Appearance 
AST 
WBC count (absolute) 
Specific gravity 
Albumin 
Hematocrit 
pH 
Bilirubin, total 
Hemoglobin 
Protein 
BUN 
Automated WBC differential 
Albumin or microalbumin 
Calcium, total 
Neutrophils 
Glucose 
Carbon dioxide, total (bicarbonate) 
Lymphocytes 
Ketones 
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Table 6: 
Clinical Laboratory Parameters (Continued) 
Chemistry 
Hematology 
Urinalysis 
Chloride 
Monocytes 
Blood  
CPK 
Eosinophils 
WBCs 
Creatinine, serum 
Basophils 
Nitrite  
GGT 
 
Bilirubin 
Glucose 
 
Microscopy of sediment 
Lactate dehydrogenase  
 
 
Magnesium 
 
 
Phosphorous 
 
 
Potassium 
 
 
Protein, total 
 
 
Sodium 
 
 
Uric acid 
 
 
Abbreviations: ALT = alanine transaminase; AST = aspartate transaminase; BUN = blood urea nitrogen; 
CPK = creatine phosphokinase; GGT = gamma-glutamyltransferase; RBC = red blood cell; WBC = white blood cell 
Safety laboratory tests will be performed at a central laboratory. Instructions for the collection, 
processing, and shipment of clinical laboratory samples will be provided in the Laboratory 
Manual.  
The investigator or a designee will review laboratory results and assess any out-of-range 
laboratory results as “not clinically significant” or “clinically significant.” Any results that are 
considered clinically significant may 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 levels or until an etiology is determined. The investigator or a designee 
will sign and date all laboratory reports.  
Clinically significant laboratory abnormalities must be captured as AEs or SAEs, as appropriate. 
9.2.2.2.2. Other Laboratory Tests  
GLA genotyping will be performed at screening for all subjects. 
Urine pregnancy tests will be performed for all female subjects of childbearing potential (as 
defined in Section 8.5); date of last menstrual period, as applicable, will be recorded during 
telephone contacts.  
Any subject who has a positive urine pregnancy test result should have a serum pregnancy test 
performed as soon as possible for confirmation. Any subject who becomes pregnant must 
discontinue study drug. Procedures for pregnancy reporting are described in Section 10.5.1.  
9.2.2.3. 
Vital Signs 
Vital signs include blood pressure (systolic and diastolic), respiration rate, heart rate, and body 
temperature. Measurements are to be taken with the subject in a sitting or supine position after 
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having rested for 5 minutes, and the same position should be used at all visits. Blood pressure 
should be obtained using the same arm for all measurements.  
9.2.2.4. 
Physical Examination 
Complete physical examinations will include assessment of head/eyes/ears/nose/throat, skin, 
thyroid, neurological system, lungs, cardiovascular system, abdomen (liver and spleen), lymph 
nodes, and extremities. Brief physical examinations will include assessment of the skin, lungs, 
cardiovascular system, abdomen (liver and spleen), and any other systems, as clinically 
indicated. 
9.2.2.5. 
Body Weight and Height 
Body weight (kg) must be measured with the subject’s shoes and clothes (except underwear) 
removed and will be rounded to the nearest whole number. The same scale should be used for 
individual subjects throughout the study and scales should be calibrated periodically throughout 
the study to ensure accuracy of measurement. 
Height (cm) must be measured with the subject’s shoes removed. 
9.2.2.6. 
Electrocardiograms 
A standard 12-lead ECG will be performed.  
Subjects will rest for approximately 5 minutes before the ECG recording begins and will be in 
the supine position throughout the ECG evaluation. Electrocardiograms will be read centrally. 
Clinically significant findings not present before the start of treatment, which meet the definition 
of an AE, must be recorded in the eCRF. 
9.2.2.7. 
Echocardiogram 
Echocardiogram parameters considered for safety include LVMi, ejection fraction, fractional 
shortening, left ventricular internal diameter end diastole and end systole, midwall fractional 
shortening, and wall thickness.  
Echocardiograms will be read centrally. 
9.2.2.8. 
Tanner Staging 
Tanner Staging will be performed for all subjects.  
Because reversible infertility was noted in nonclinical studies with male rats, Tanner Staging will 
be used to assess sexual development, ie, breast development (B1 to B5) and pubic hair 
development (Ph-1 to Ph-5) in females and pubic hair and genital development (G-1 to G-5) in 
males (see Appendix A).  
9.2.2.9. 
Concomitant Medications and Procedures 
Subjects will be asked to report any new or changes in previously reported prescription and 
non-prescription medications, including dosage, frequency, and administration dates. 
Information will be entered in the eCRF and source records. Information regarding any 
procedures performed since the last visit will also be collected. 
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9.2.3. 
Pharmacokinetic Assessments 
The timing of PK samples was determined using optimal sampling theory using PopED and 
mrgsolve software packages in R using a D-optimality algorithm. The exact times for dosing and 
sample collection will be recorded. Migalastat concentrations in plasma will be determined using 
a validated LCMS assay and will be used for pharmacokinetic analyses. 
Stage 1  
Subjects will be randomly assigned 1:1:1 to 1 of 3 PK sampling groups using interactive 
response technology (IRT). Four blood samples for determination of migalastat concentrations in 
plasma will be collected in one 24-hour period between Day 15 and Day 30 following initiation 
of study drug administration. If they are to be done at the site, the PK collection visit should be 
scheduled on a migalastat administration day and subjects are to be instructed to bring their study 
drug with them. Blood sampling for PK is relative to migalastat administration and collection 
times must be recorded on the appropriate eCRF page. Each subject will have 4 PK samples 
collected at the times specified in Table 4 according to their randomized PK sampling group 
assignment. 
Alternately, PK blood collections may be done by a home healthcare professional. In either case, 
the collections must follow migalastat administration at the times specified in Table 4 and the 
time of migalastat administration prior to the collections and the times of each collection must 
be recorded. 
Stage 2 
In addition, blood samples for analysis of plasma migalastat concentration will be collected at 
the Month 6 and Month 12/ET study visits, at the same time that samples are collected for 
clinical laboratory tests. 
In the event that follow-up PK assessments are required, at each follow-up visit additional sparse 
PK samples will be drawn at the 4 time intervals according to the sampling group to which the 
subject was initially assigned. 
Details regarding processing, storage, and shipping procedures will be provided in the 
Laboratory Manual. The actual date and time of the last dose before sampling and each blood 
sample collection will be recorded.  
9.2.4. 
Pharmacodynamic Assessments 
Blood samples will be collected for measurement of lyso-Gb3 levels in plasma. In addition, to get 
a better understanding of early PD biomarkers for Fabry disease, blood will be collected for 
exploratory cardiac biomarkers such as high sensitivity tropin and NT-proBRN. Plasma levels of 
lyso-Gb3 will be measured using a validated LCMS assay. 
9.2.5. 
Efficacy Assessments 
9.2.5.1. 
Estimated Glomerular Filtration Rate 
Estimated GFR will be calculated using the Schwartz formula according to the standards of the 
central laboratory. 
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9.2.5.2. 
Urine Protein and Albumin Levels 
Protein and albumin (or microalbumin) levels in urine (as part of urinalysis) will be measured. 
9.2.5.3. 
Echocardiogram 
The key echocardiogram parameter considered for efficacy is LVMi. In addition, ejection 
fraction, fractional shortening, left ventricular internal diameter end diastole and end systole, 
midwall fractional shortening, and wall thickness will be assessed. 
Echocardiograms will be read centrally.  
9.2.5.4. 
Subject Questionnaires 
All Questionnaires will be provided in a separate Patient Outcomes Manual. 
9.2.5.4.1. Electronic Diary 
Subjects will be asked to complete daily diary entries at approximately the same time of day 
(preferably in the evening before bed time) beginning on Day 1 and for the duration of the study. 
Diary entries will include completion of the FABPRO-GI and Pain Questionnaire for Clinical 
Trials (24-hour version).  
The FABPRO-GI and Pain Questionnaire for Clinical Trials (24-hour version) consists of 
4 questions regarding gastrointestinal signs and symptoms and 2 questions regarding pain 
relative to the past 24 hours. Subjects will record the frequency and consistency of stools using 
the Bristol Stool Scale, a pictorial chart and descriptive text for 7 types of stool, ranging from 
Type 1 (separate hard lumps, like nuts – hard to pass) through Type 7 (watery, no solid 
pieces – entirely liquid). Subjects will also rate the severity of their worst occurrence of diarrhea, 
constipation, tummy pain, and overall pain from 0 (none) to 10 (worst possible); for tummy pain, 
subjects will indicate the location of any tummy pain using a diagram. 
9.2.5.4.2. Patient Global Impression of Change  
The PGI-C consists of 4 questions regarding diarrhea, abdominal pain, overall pain, and daily 
living to be answered using a 7-point scale. Subjects will complete the questions by themselves 
without assistance from their parents or legal guardians.  
9.2.5.4.3. Fabry-Specific Pediatric Health and Pain Questionnaire 
The FPHPQ includes questions about Fabry disease-specific symptoms (eg, sweating, pain, 
dizziness and tiredness, heat and cold intolerance, swollen eyelids, gastrointestinal symptoms, 
feeling thirsty, difficulty hearing, ringing or buzzing noise in the ears, and ability and enjoyment 
to participate in sports). The frequency of these symptoms will be rated using a 5-point Likert 
scale (always, often, sometimes, seldom, never). Pain intensity is measured on a 10-point scale, 
numeric responses are given for onset of pain and school days missed, and yes/no questions are 
posed about difficulty hearing and other problems not specifically mentioned. There are 
2 age-specific self-report versions for children 8 to 12 years and 13 to 18 years, respectively. 
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9.2.5.4.4. Pediatric Quality of Life Inventory  
The PedsQL™ is a modular approach to measuring health-related quality of life in healthy 
children and adolescents and those with acute and chronic health conditions. It consists of 
23 items and includes questions about physical functioning, emotional functioning, social 
functioning, and school functioning relative to the prior 7 days, using a 5-point scale. Both 
parents or legally-authorized representatives and subjects complete the appropriate version of the 
PedsQL independently of one another. Parents or legally-authorized representatives and subjects 
may self-administer the questions after introductory instructions are given by study site 
personnel. 
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10. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Investigators and study site personnel are responsible for detecting, documenting, and reporting 
AEs and SAEs. For each subject, reporting of AEs and SAEs begins after written informed 
consent is provided.  
10.1. 
Definitions 
10.1.1. 
Adverse Event 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
Therefore, AEs include the following: 
• the onset of new signs, symptoms, conditions, and illnesses 
• exacerbation of pre-existing conditions or illnesses 
• abnormal laboratory findings deemed clinically significant by the investigator 
• physical examination changes deemed clinically significant by the investigator 
• abnormal medical evaluation findings (eg, ECG) that are not documented at screening 
and/or, in the investigator’s opinion, represent a clinically significant change in the 
subject’s health during study participation 
Note: Screening medical evaluation findings (eg, ECG) that were not previously 
provided as medical history and can be determined as starting before screening, are 
not considered AEs and will be recorded as medical history. 
Adverse events will be recorded in the eCRF and subject’s source record beginning from the 
time written consent (assent) is provided through the follow-up visit (at least 30 days after the 
last dose of study drug). 
A single diagnosis should be entered when known. If a clear diagnosis cannot be determined at 
the time of eCRF completion and the subject’s source record entry, each sign and symptom must 
be recorded individually, until a final diagnosis is established. Conditions, signs, symptoms, etc 
that are present in the subjects’ medical history at screening should only be reported as AEs if 
they worsen (ie, increase in severity) since screening. 
Adverse events that begin after the first dose of study drug will be considered 
treatment-emergent adverse events (TEAEs).  
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10.1.2. 
Serious Adverse Event 
An SAE is any AE occurring at any dose that results in any of the following outcomes:  
• death 
• a life-threatening event 
− This includes any AE that in the view of either the investigator or sponsor places 
the subject at immediate risk of death. It does not include an AE that, had it 
occurred in a more serious form, might have caused death. 
• requires inpatient hospitalization or prolongs existing hospitalization 
− Hospitalization signifies the subject has been admitted, regardless of duration, for 
observation and/or treatment that would not have been appropriate in a 
physician’s office or outpatient setting. 
− Hospitalizations for elective or pre-planned treatment of a pre-existing condition 
do not have to be reported as SAEs if the following criteria are met: 
− the condition is documented in the subject’s medical history and has not 
worsened since the informed consent form was first signed; and 
− the condition and planned procedure are documented in the subject’s source 
records at screening. 
− Emergency room/department or outpatient treatments that do not result in 
admission do not have to be reported as an SAE, unless another SAE criterion is 
met. Events assessed and treated in these circumstances should be captured as 
AEs in the eCRF and documented in the subject’s source records. 
− Hospitalizations solely based on subject logistics (eg, subject is admitted due to 
limited hospital accessibility for what would otherwise be an out-subject 
procedure) do not have to be reported as SAEs provided that the hospitalizations 
are clearly defined as such in the subject’s source record. 
• persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• congenital anomaly/birth defect 
An important medical event that does not result in one of the above serious outcomes may be 
considered an SAE when, based upon appropriate medical judgment, it may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the listed serious 
outcomes. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias, or convulsions that do not result 
in inpatient hospitalization, or development of drug dependency or drug abuse. 
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If the following 4 elements are known, the event must be reported as described in Section 10.4.2: 
• identifiable subject 
• event term 
• study drug 
• identifiable reporter 
Additionally, the investigator’s assessment of an event’s relationship to study drug 
(see Section 10.2) is essential for the sponsor to appropriately process the report and must be 
included. 
Subjects and parents or legally-authorized representatives must be informed and understand that 
they should report events meeting the definition for SAE to study site personnel as soon as 
possible (and not wait until their next study visit). 
If a non-serious event becomes serious, the change in status must be appropriately entered in the 
eCRF and the subject’s source record, and reported to the sponsor as described in Section 10.4.2. 
If the investigator becomes aware of an SAE that occurs more than 30 days after the last dose of 
study drug, and considers the event possibly, probably, or definitely related to study drug, the 
investigator should contact the Medical Monitor (see Table 1)/Clinical Operations Lead to 
determine how the SAE should be documented and reported.  
10.2. 
Relationship to Study Drug 
The investigator or a medically qualified sub-investigator will review each event and assess its 
relationship to study drug based on available information and according to the following 
guidelines: 
• Definite: a reaction that follows a distinct temporal relationship from administration of 
study drug; that follows a known reaction to the agent or chemical group of the study 
drug; and that cannot be explained by the subject’s clinical state or other factors 
• Probable: a reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the suspected study 
drug; and that could not be reasonably explained by the known characteristics of the 
subject’s clinical state 
• Possible: a reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the suspected study 
drug; but that could readily have been produced by a number of other factors 
• Unlikely: a reaction that does not follow a reasonable temporal sequence from 
administration of study drug; however, causality from the study drug cannot be ruled out 
• Unrelated: a reaction for which sufficient data exist to indicate that the etiology is 
unrelated to study drug 
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For the purpose of expedited SAE regulatory reporting obligations (ie, to regulatory authorities 
and Institutional Review Boards [IRBs]/Independent Ethics Committees [IECs]), events assessed 
by the investigator as definitely, probably, or possibly related to study drug will be considered 
“related” to study drug (ie, associated with the use of study drug). Events assessed as unlikely or 
unrelated will be considered “not related” to study drug (ie, not associated with the use of study 
drug). 
10.3. 
Severity Assessment 
The investigator or a qualified sub-investigator will review each event and use the following 
definitions for rating intensity: 
• Mild: awareness of sign, symptom or event, but the AE is easily tolerated and does not 
interfere with daily activity 
• Moderate: discomfort enough to cause interference with usual activity and may warrant 
intervention, but the subject is still able to function 
• Severe: incapacitating with inability to do usual activities or significantly affects clinical 
status, and requires medical intervention 
It is important to distinguish the difference between events that meet the definition of serious and 
events that are deemed as severe in intensity. Adverse events assessed as severe in intensity are 
not SAEs unless at least 1 of the definitions in Section 10.1.2 is met. Adverse events of any 
intensity must be reported as SAEs if at least 1 definition in Section 10.1.2 is met.  
10.4. 
Reporting Events 
10.4.1. 
Reporting Adverse Events 
Information regarding AEs is to be obtained by questioning or examining the subject and/or 
parents or legally-authorized representatives. 
As noted in Section 10.1.1, AEs will be recorded in the eCRF and subject source record 
beginning from the time written consent (assent) is provided through the follow-up visit (at least 
30 days after the last dose of study drug). Required information will be detailed in the eCRF 
Completion Guidelines.  
10.4.2. 
Reporting Serious Adverse Events 
Serious adverse events must be documented and reported to the sponsor immediately, but no 
later than within 24 hours of any knowledge by study site personnel of events. Serious adverse 
event reports must be faxed to the designated safety fax number (Table 1) to ensure appropriate 
dissemination and processing of the information. An alternate email address is provided as a 
backup, if the fax transmission is unsuccessful.  
Serious adverse event forms, which will be provided by the sponsor, should be as complete as 
possible, with all information known at the time included. All relevant supporting documentation 
(eg, admission and progress notes, results of diagnostic evaluations/procedures/examinations, 
etc) available at the time of reporting, should be included in the fax (or email, if necessary) along 
with the SAE report form. All supporting documents must be thoroughly reviewed and 
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de-identified in accordance with local data privacy regulations prior to sending to the sponsor. 
The subject’s study number must be included on each page included in the faxed report or in the 
subject line of the email. Reporting timelines (as described above) must not be delayed while 
obtaining or preparing supporting information.  
If more than 1 SAE is identified in 1 subject simultaneously, separate SAE reports should be 
generated for each event. 
Information not available at the time of the initial report (eg, event end date and outcome, 
supporting documents (eg, discharge summary, etc) must be reported to the sponsor within 
24 hours of any knowledge/receipt by study site personnel of the information. Information 
must be faxed (or emailed, if necessary) to the designated safety fax number (or email address) 
(Table 1) to ensure appropriate dissemination and processing. All supporting documents must be 
thoroughly reviewed and de-identified in accordance with local data privacy regulations prior to 
sending to the sponsor. The subject’s study number must be included on each page included in 
the fax or in the subject line of the email. 
Medical history, concomitant medication, and AE information obtained through SAE reporting 
must also be consistently recorded in the eCRF. 
10.4.3. 
Additional Reporting Requirements for Suspected Unexpected Serious Adverse 
Reaction  
The sponsor is responsible for processing suspected unexpected serious adverse reactions 
(SUSARs). SUSARs are also referred to as alert reports, expedited safety reports, and 
investigational new drug application (IND) safety reports. 
A SUSAR is defined as any SAE that is determined to be associated with the use of study drug 
and is unexpected (not currently listed in the safety reference information or is not listed at the 
specificity or severity that been observed). The sponsor will notify all investigators currently 
conducting migalastat clinical studies of all SUSARs in accordance with applicable regulations. 
SUSARs will be reported to the relevant regulatory authorities and IRBs/IECs according to the 
rules in effect in each country where study sites are located:  
• If the SUSAR is fatal or life-threatening, regulatory authorities and ethics committees 
will be notified within 7 calendar days after the sponsor learns of the event.  
• If the SUSAR is not fatal or life-threatening, regulatory authorities and ethics 
committees will be notified within 15 calendar days after the sponsor learns of the 
event. 
These notifications will need to be filed in each site’s Study File Notebook and submitted to each 
site’s IRB/IEC in accordance with policy. 
Safety updates will be provided periodically to the regulatory authorities and IRBs/IECs 
responsible for the study according to the rules in effect in each country where study sites are 
located. These updates will include information on SUSARs and other relevant safety findings. 
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10.5. 
Other Reporting Situations 
10.5.1. 
Pregnancy 
Pregnancy information for female subjects and female partners of male subjects participating in 
the study is collected by the sponsor. Pregnancy, in and of itself, is not regarded as an AE (unless 
there is a suspicion that study drug may have interfered with the effectiveness of a contraceptive 
medication).  
If a female subject becomes pregnant during the course of the study, or if the female partner of a 
male subject becomes pregnant during the subject’s participation in the study, the sponsor must 
be informed within 5 working days of any knowledge of the pregnancy by study site personnel. 
If an SAE occurs in conjunction with the pregnancy, the SAE must be reported as described in 
Section 10.4.2. The sponsor will provide pregnancy report forms (initial and follow-up) and 
instructions to study site personnel regarding collection of pregnancy and outcome information 
(subject to receipt of data privacy release approvals where required under local privacy laws). 
Pregnancy report forms must be faxed (or emailed, if necessary) to the designated safety fax 
number (or email) (Table 1) to ensure appropriate dissemination and processing of the 
information.  
10.5.2. 
Medication Errors, Including Overdose and Under Dose 
Medication error refers to any unintended error in the dispensing or administration of a study 
drug.  
If a subject experiences an overdose (defined as ≥ 20% higher than the assigned dose of study 
drug for that period in the protocol) or an under dose (defined as ≥ 20% lower than the assigned 
dose of study drug for that period in the protocol) during the course of the study (whether 
symptomatic or not), the Amicus’ medical monitor must be notified within 5 working days of the 
investigator or study staff first becoming aware of the overdose.  
Medication errors, including overdose and under dose, should be captured in subjects’ source 
records and recorded in the eCRFs. Any AE or SAE that occurs as a result of a medication error 
should be reported according to AE/SAE reporting requirements (see Section 10.4). 
10.5.3. 
Reporting of Possible Study Drug Product Quality Defects 
Any defect or possible defect associated with study drug must be reported to the sponsor 
(clinicalcomplaints@amicusrx.com) within 1 working day of any study site personnel knowledge 
of the possible defect. The study drug and packaging components in question, if available, 
must be segregated and stored in a secure area at the site under the specified storage conditions 
(see Section 12.4) until it is determined whether or not the study drug and/or 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 in Section 10.4.2. The SAE report must include the 
possible study drug defect complaint. 
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11. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
Details of the data handling rules and statistical calculations will be provided in the statistical 
analysis plan.  
11.1. 
Endpoints 
11.1.1. 
Safety Endpoints 
Safety endpoints are as follows: 
• incidence of TEAEs, SAEs, and AEs leading to discontinuation of study drug  
• changes in clinical laboratory test results from baseline over time 
• changes in vital signs from baseline over time 
• changes in physical examination findings from baseline over time 
• change in body weight and height from baseline over time  
• changes in ECG results from baseline over time 
• changes in echocardiogram parameters from baseline to Month 12/ET 
• change in Tanner stage from baseline to Month 12/ET 
• use of concomitant medications 
11.1.2. 
Pharmacokinetic Endpoints 
Pharmacokinetic endpoints are as follows: 
• population PK model that describes the relationship between weight and age and 
migalastat pharmacokinetics in pediatric subjects (with primary PK parameter outputs 
listed in the following text)  
• PK parameters based on simulated plasma-concentration data for migalastat after 
multiple-dose administration at steady-state concentration 
− Cmax: maximum observed plasma concentration 
− Cmin: minimum observed plasma concentration 
− tmax: time to reach Cmax 
− AUC0-τ: area under the plasma concentration-time curve from time 0 over the 
dosing interval (ie, 48 hours) 
− t½: terminal elimination half-life 
− CLss/F: apparent oral clearance at steady-state concentration 
− Vss/F: apparent oral volume of distribution at steady-state concentration 
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11.1.3. 
Pharmacodynamic Endpoints 
The pharmacodynamic endpoint is the change in plasma levels of lyso-Gb3 from baseline to 
Months 3, 6, and 12/ET. 
11.1.4. 
Efficacy Endpoints 
Efficacy endpoints are as follows: 
• change in eGFR from baseline to Months 3, 6, and 12/ET 
• change in urine protein and albumin levels from baseline to Months 3, 6, and 12/ET  
• change in LVMi and other echocardiogram parameters from baseline to Month 12/ET  
• change in gastrointestinal signs and symptoms and pain from baseline to 
Month 12/ET, as measured by e-diary responses (FABPRO-GI and Pain 
Questionnaire for Clinical Trials [24-hour version]) 
• mean PGI-C values at Months 3, 6, and 12/ET 
• change in FPHPQ scores from baseline to Month 12/ET  
• change in PedsQL scores from baseline to Month 12/ET 
11.2. 
Sample Size Considerations 
A sample size of at least 7 to 10 subjects per age/weight group is required for statistical 
comparison with adult exposure based on 2 methods described by Wang, Jadhav et al. 2012.  
First, assuming the final CL/F estimates and inter-individual variability of 28.5% (Migalastat 
Abbreviated Report of the Simulations of Migalastat in Pediatric Patients with Fabry Disease, 
16 October 2016), 7 subjects is adequate to achieve at least 80% power for a study design with 
rich PK sampling intended for non-compartmental analysis.  
Second, according to the sample size calculation for a study with sparse/rich PK sampling 
intended for population PK analysis, (𝑒𝑒−𝑡𝑡(0.975,𝑑𝑑𝑑𝑑)×𝑆𝑆𝑆𝑆𝐿𝐿𝐿𝐿𝐿𝐿, 𝑒𝑒𝑡𝑡(0.975,𝑑𝑑𝑑𝑑)×𝑆𝑆𝑆𝑆𝐿𝐿𝐿𝐿𝐿𝐿) should be within the 
pre-defined criteria of (0.6, 1.4), where SELCL is the standard error for log-transformed pediatric 
clearance that relates to weight, and t (0.975, df) is the 97.5% upper quantile values from 
t distribution corresponding to the sample size. Mathematically, SELCL was approximately equal 
to the relative standard error of untransformed clearance, 0.16. Therefore, a sample size of 
approximately 10 subjects is adequate to achieve the pre-defined boundary of (0.6, 1.4).  
11.3. 
Data Analysis Considerations 
11.3.1. 
Analysis Populations 
The safety population will include all subjects who receive at least 1 dose or partial dose of study 
drug. All safety and pharmacodynamic analyses will be performed using the safety population. 
The Stage 1 PK population will include all subjects who have a complete set of sparse PK 
samples from the single day of collection at steady-state between Day 15 and Day 30 of Stage 1.  
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The final PK population will include all subjects with at least one quantifiable concentration and 
a known weight and eGFR. All final PK analyses will be performed using the final PK 
population.  
The intent-to-treat population will include all enrolled subjects. All efficacy analyses will be 
performed using intent-to-treat population. 
11.3.2. 
Statistical Methods 
Data will be summarized using descriptive statistics. Continuous variables will be summarized 
by number of subjects, mean, standard deviation, median, minimum, and maximum values. 
Discrete variables will be summarized by counts and percentages.  
In general, data will be summarized by sex and combined across all subjects.  
A month will be defined as 30 days. 
No missing data imputation method is planned to handle missing data. Data will be summarized 
as observed. All data will be listed. 
11.3.2.1. Interim Analysis 
The interim PK endpoint is a graphical presentation of plasma-concentration time data (observed 
versus predicted).  
Interim analysis of the plasma concentration-time data collected during Stage 1 will be 
conducted when these results are available. There will be 2 interim PK analyses. One analysis 
will be performed using the entire Stage 1 PK population of adolescents aged 12 to < 18 years. A 
second analysis will include a subpopulation of at least 7 to 10 subjects age 12 to < 16 years.  
11.3.2.2. Safety Analyses 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and summarized by system organ class and preferred term. Summaries will be provided for 
TEAEs, TEAEs by severity, and TEAEs by relationship to study drug as well as deaths, SAEs, 
and TEAEs leading to discontinuation of study treatment. Listings will also be provided for 
SAEs and TEAEs leading to discontinuation of study treatment. 
Actual values and changes from baseline for clinical laboratory test results, vital signs, body 
weight and height, ECG parameters, echocardiogram parameters (other than LVMi) and Tanner 
stages will be summarized using descriptive statistics. Shift tables will also be provided for 
clinical laboratory tests and ECG results. Physical examination findings will be summarized by 
body system.  
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary and will be summarized by Anatomical-Therapeutic-Chemical classification.  
11.3.2.3. Pharmacokinetic Analyses 
For the population PK analysis, predicted median (2.5th and 97.5th percentile) concentration-time 
data based on a previously established population PK model will be visually compared with 
observed concentration-time data for all patients and for the subgroup aged 12 to < 16 years at 
the end of Stage 1.  
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The PK analyses for the current study will be performed according to the following steps: 
• Step 1: After combining previous concentration-time data from adults with pediatric 
data from the current study, the population PK model established previously 
(Migalastat Amended Population Pharmacokinetic Analysis of Migalastat, 
Amendment 02; Migalastat Abbreviated Report of the Simulations of Migalastat in 
Pediatric Patients with Fabry Disease, 20 October 2016) will be updated. Most 
importantly, the allometric scaling functions for CL/F and volume parameters 
(ie, V2/F, V3/F) will be re-evaluated and corrected, if necessary. Other covariates that 
are predictive of drug disposition (eg, age, weight, body surface area) may be 
evaluated.  
• Step 2: Using the updated population PK model, clinical trial simulations will be 
conducted assuming administration of migalastat to steady-state concentration for 
each pediatric subject and for adults (with equivalent renal function) receiving 
migalastat HCl 150 mg every other day. The simulations will use population PK 
parameter uncertainty from a nonparametric bootstrap, inter-individual variability, 
and residual variability. At least 1000 clinical trials will be simulated assuming at 
least 24 subjects per age group.  
• Step 3: Pharmacokinetic endpoints (ie, Cmax, Cmin, and AUC0-τ) for migalastat will be 
calculated from simulated concentration-time data in pediatric groups and in adults. 
The AUC0-τ and Cmax in 12 to < 18 year olds will be compared to the values in adults 
with equivalent renal function using an analysis of variance (ANOVA). The 
90% confidence intervals (CIs) for the ratio of the geometric least squares means of 
Cmax and AUC0-τ will be constructed for comparison of the pediatric group with adult 
group. These 90% CIs will be obtained by exponentiation of the 90% CIs for the 
difference between the least squares means based on an ln-transformed scale. 
• Step 4: Exposures in the pediatric group and adults will be considered equivalent 
when 90% CIs of the ratio of the geometric least squares means of AUC0-τ are within 
the range of 0.8 to 1.25 (ie, 80% to 125%). Intervals obtained from Step 3 will be 
evaluated according to these a priori criteria. The ratios and CIs will also be 
determined for Cmax. 
• Step 5: If the bioequivalence criteria cannot be met in Step 4 using the dosing 
regimen listed in Section 7.2.1, adjusted dosing regimens will be proposed to achieve 
bioequivalence considering dose proportionality, if necessary, and used for future 
pediatric clinical trial simulations. 
• Step 6: The proposed dose for pediatric subjects (12 to < 18 years and 12 to 
< 16 years) will then be considered the dosage regimen producing an AUC0-τ meeting 
the 80% to 125% rule and a Cmax that either meets this rule or, if not possible, is as 
close as possible balancing the available dosage strengths with safety. 
11.3.2.4. Pharmacodynamic Analyses 
Actual values and changes from baseline in plasma lyso-Gb3 levels will be summarized using 
descriptive statistics. 
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Pharmacodynamic endpoints (ie, changes from baseline in plasma lyso-Gb3 at 3, 6, and 
12 months) and simulated PK exposures (ie, AUC0-τ and Cmax) will be plotted and graphically 
examined for potential exposure-response relationships.  
11.3.2.5. Efficacy Analyses 
Actual values and changes from baseline (as applicable) in eGFR, urine levels of protein and 
albumin, LVMi, e-diary responses, FPHPQ scores, and PedsQL scores, and actual values for 
PGI-C responses will be summarized using descriptive statistics.  
Efficacy endpoints (ie, changes from baseline in eGFR, urine levels of protein and albumin, 
LVMi, e-diary responses, FPHPQ scores, and PedsQL scores and actual values for PGI-C 
responses) and simulated PK exposures (ie, AUC0-τ and Cmax) will be plotted and graphically 
examined for potential exposure-response relationships. If data permit, mathematical modeling 
approach will be used; if conducted, this analysis will be reported separately. 
11.3.2.6. Other Summaries 
A summary of subject disposition will include number of subjects enrolled, number of subjects 
in each analysis population, number of subjects who completed the study, and number of 
subjects who did not complete the study by reason for discontinuation. 
Demographics and baseline characteristics will be summarized using descriptive statistics. 
Baseline characteristics will include height, body weight, body mass index, number of years 
since diagnosis of Fabry disease, previous use of ERT, and previous and current use of 
angiotensin-converting enzyme inhibitors, renin inhibitors, and angiotensin receptor blockers. 
Protocol deviations will be listed. 
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12. 
STUDY TREATMENTS 
12.1. 
Description of Study Drug 
Migalastat (also known as AT1001) is an iminosugar that functions as a selective and reversible 
pharmacological chaperone of agalsidase beta. Migalastat will be supplied as a gelatin capsule 
(Table 7). Migalastat capsules must be swallowed whole and must not be cut, crushed, or 
chewed. 
Table 7: 
Investigational Product (Capsule) 
 
Investigational Product 
Product Name 
Migalastat 
Dosage Form 
Capsule 
Unit Dose 
123 mg (equivalent to 150 mg migalastat HCl) 
Excipients 
Pregelatinized starch, magnesium stearate 
Route of Administration 
Oral 
Physical Description 
White opaque/blue opaque, hard gelatin capsules (size “2”), 
printed with an identifying code "SGXXX" or “A1001” and 
supplied in blister packs 
Manufacturer 
Almac Pharma Services Limited 
Seagoe Industrial Estate 
Portadown 
Craigavon 
County Armagh 
BT63 5UA United Kingdom 
Abbreviation: HCl = hydrochloride 
12.2. 
Packaging and Labeling 
Migalastat HCl 150-mg oral capsules will be supplied by the sponsor as hard gelatin capsules in 
blister packs. 
Each container will be labeled in conformance with regulatory requirements and where 
applicable, local laws. All labels will be printed with the following information at a minimum: 
study identifier, identity of drug and dosage, sponsor name and contact details (and/or details of 
a local designee contact), dosing instructions, storage information, and other applicable local law 
statements.  
12.3. 
Study Drug Accountability 
In accordance with local regulatory requirements, the investigator or designee 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 the sponsor 
(or designee). Product accountability records must be maintained throughout the study. 
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The study monitor will periodically check the supplies of study drugs held at the site to verify 
accountability of all study drugs used and to verify that the drug accountability logs are 
completed and maintained in the investigator study file. When instructed by the study monitor, 
the investigator will return all original containers of study drugs, whether empty, or containing 
used or unused study drugs to the sponsor or designee for destruction. Sites may not destroy 
study drugs on site unless the sponsor has provided prior written approval. 
12.4. 
Handling, Storage, Return, and Disposal of Study Drugs 
Sites will be instructed to store migalastat capsules at room temperature (15°C to 25°C/59°F to 
77°F) with excursions permitted to 30°C/86°F in a secure area with temperature monitoring, free 
from environmental extremes, and with restricted access.  
The study drug is to be stored only at the site listed on the United States Food and Drug 
Administration (FDA) Form 1572. Study drug is to be dispensed only to subjects from/for whom 
written informed consent/assent has been obtained, have met all entry criteria, and are assigned 
subject numbers. 
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13. 
STUDY MANAGEMENT 
13.1. 
Documentation of Protocol-required Information and Study 
Findings 
For this study, eCRFs with remote electronic data capture (EDC) provided through a qualified 
third party vendor will be used. The data will be entered on the eCRFs in a timely manner on an 
ongoing basis as defined in the Data Management Plan. The investigator, or designated 
representative, should complete the eCRF pages as soon as possible after information is 
collected, preferably on the same day that the subject is seen for an examination, treatment, or 
any other study procedure. Any outstanding entries must be completed immediately after the 
final examination. All data must be documented separately in source records. An explanation 
should be given for all missing data. 
Details of eCRF completion and correction will be explained to the investigator. The investigator 
is responsible for ensuring that data are properly recorded on each subject’s eCRFs and related 
documents. If the investigator authorizes other persons to make entries onto the eCRFs, the 
names, positions, signatures, and initials of these persons must be documented in writing and 
supplied to the sponsor.  
The completed eCRFs must be reviewed and electronically signed by the investigator who 
signed the study protocol signature page to ensure that the observations and findings are recorded 
on the eCRFs correctly and completely 
13.2. 
Data Management 
Only data specified in the protocol will be collected as part of this study. All eCRF data will be 
entered into the EDC system and managed by a contract research organization (CRO). 
Additional protocol-specified data, such as laboratory and ECG data, may be collected through 
third party vendors and integrated with eCRF data by the CRO to create complete datasets for 
analysis. All protocol-specified data will be transmitted electronically to the sponsor (or the 
CRO). 
Management of clinical data will be performed in accordance with applicable standards and data 
cleaning procedures as defined in the Data Management Plan to ensure the integrity of the data 
(eg, determining errors and inconsistencies in the data, and ensuring data are corrected by study 
site personnel or designees).  
After database lock, each site will receive an electronic copy containing all of their site-specific 
eCRF data as entered into the EDC system for the study, including full discrepancy and audit 
history. Additionally, an electronic copy of all data from the study collected at that study center 
will be retained by the sponsor or designee for storage. 
13.3. 
Study Monitoring, Source Data Verification, and Onsite Audits 
Monitoring and auditing procedures developed or endorsed by the sponsor will be followed, in 
compliance with Good Clinical Practice (GCP). Direct access to the onsite study documentation 
and source documents must be ensured by the investigator. 
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Monitoring will be performed by personal visits from a sponsor representative (ie, study 
monitor) who will check the eCRFs for completeness and clarity, and crosscheck them with 
source documents (see essential documents, Section 13.4). In addition to the monitoring visits, 
frequent communications (eg, letter, e-mail, telephone, and fax) by the study monitor will ensure 
that the study is conducted according to the protocol design and regulatory requirements. 
Domestic and foreign regulatory authorities, the IRB/IEC, and/or an auditor authorized by the 
sponsor may request access to all source documents, eCRFs, and other study-related 
documentations for onsite audit or inspection. Direct access to these documents must be 
guaranteed by the investigator, who must provide support at all times for these activities. 
Medical records and other study documents may be copied during audit or inspection provided 
that subject names, family member names, telephone numbers, and addresses are obliterated on 
the copies to ensure confidentiality. 
The investigator should contact the sponsor immediately if contacted by a regulatory authority 
regarding an inspection or audit. 
13.4. 
Records Retention 
The investigator must obtain approval in writing from the sponsor before destruction of any 
records. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an International Conference on Harmonisation (ICH) region and until 
there are no pending or contemplated marketing applications in an ICH region, or at least 2 years 
have elapsed since the formal discontinuation of clinical development of migalastat. However, 
because of international regulatory requirements or country-specific requirements, the sponsor 
may request retention for a longer period. 
Prior to any decision regarding the disposal or destruction of study documents, the investigator 
should contact the sponsor. The sponsor may request that the site take alternative actions other 
than disposal or destruction of study documents. 
Essential documents include the following: 
• signed informed consent/assent documents for all subjects 
• subject identification code list, screening log (if applicable), and enrollment log 
Note: European Union (EU) legislation requires this list to be maintained for a 
minimum of 15 years. 
• composition of the IEC/IRB and record of all communications between the 
investigator and IEC/IRB as well as between the investigator and sponsor or CRO 
• list of sub-investigators and other appropriately qualified persons to whom the 
investigator has delegated significant study-related duties, together with their roles in 
the study and their signatures 
• copies of eCRFs and documentation of corrections for all subjects 
• investigational product accountability records 
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• record of any body fluids or tissue samples retained 
• all other source documents (eg, subject medical records, hospital records, laboratory 
records, etc) 
• all other documents as listed in Section 8 of the ICH GCP E6 guidelines (ie, Essential 
Documents for the Conduct of a Clinical Trial) 
Normally, these records will be held in the investigator’s archives. If investigators are unable to 
meet this obligation, they must ask the sponsor for permission to make alternative arrangements. 
Details of these arrangements must be documented in writing. 
13.5. 
Use of Study Findings 
All information concerning migalastat as well as any matter concerning the operation of the 
sponsor, such as clinical indications for migalastat, its formula, methods of manufacture, and 
other scientific data relating to it, that has been provided by the sponsor and are unpublished, are 
confidential and must remain the sole property of 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. 
Amicus 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. 
Regulatory 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 study results. 
As required by local regulation or by the IEC/IRB, a summary of the study will be submitted by 
the sponsor to the regulatory authorities and by the investigator to the IEC/IRB. 
13.6. 
Study Close-out  
The end of study is defined as date of database lock. 
The study must be closed at each site on completion. Study close-out will be performed by the 
study monitor upon closure of the study. 
Completion or premature termination of the study will be reported by the sponsor to regulatory 
authorities and by the sponsor or by the investigator to the IEC/IRB as required by local 
regulation or by the IEC/IRB. 
Furthermore, the sponsor or the investigator has the right to close any study site at any time. The 
reason(s) for closure will be documented in writing. As much as possible, premature closure 
would occur after mutual consultation. 
Study materials must be returned, disposed of, or retained as directed by the sponsor 
(Section 12.4). 
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14. 
STUDY CONDUCT CONSIDERATIONS 
This global study will include both IND (US) and non-IND (foreign) sites. All investigators will 
be required to certify their compliance with both ICH E6 GCP and their respective country’s 
applicable laws and regulations. Both IND and non-IND sites will be operating under a single 
protocol (ie, there will not be a separate protocol for non-IND sites). The sponsor will ensure that 
the conduct, monitoring, auditing, recording, analysis, and reporting of clinical trial results are in 
accordance with ICH GCP, providing assurance that the data and reported results are credible 
and accurate and that the rights, safety, and well-being of trial subjects are protected. 
14.1. 
Posting of Information on Publicly Available Clinical Trial Registers 
The sponsor will be responsible for registering this study in a public registry that meets the 
requirements specified by the International Council of Medical Journal Editors, such as 
www.clinicaltrials.gov. 
14.2. 
Ethical and Legal Aspects 
14.2.1. 
Informed Consent/Assent Information 
Signed written informed consent/assent is to be obtained for each subject prior to any 
study-related assessments being performed. If the subject is under the legal age of consent, the 
consent form must be signed by the subject’s parent or legally-authorized representative in 
accordance with the relevant country and local regulatory requirements. The document must be 
in a language understandable to the subject and/or the subject’s parent or legally-authorized 
representative and must specify who informed the subject and/or the subject’s parent or legally 
authorized representative. Where required by local law, the person who informs the subject must 
be a physician. 
The subject and/or subject’s parent or legally-authorized representative must be given the 
opportunity to read the informed consent/assent document and have all their questions and 
concerns addressed before giving consent/assent in writing. If the subject and/or subject’s parent 
or legally-authorized representative is unable to read, oral presentation and explanation of the 
written informed consent/assent form and information to be supplied to the subject must take 
place in the presence of an impartial witness. Consent/assent must be confirmed at the time it is 
orally provided and by the personally dated signature of the subject and parent or 
legally-authorized representative by a local legally recognized alternative (eg, thumbprint or 
mark). Details about why oral presentation was used, how the information was presented, and 
how the subject provided consent must be described in the medical records. 
The subject’s consent/assent must be confirmed at the time of consent/assent by the personally 
dated signature (or thumbprint or mark) of the subject and parent or subject’s legally-authorized 
representative and by the personally dated signature of the person conducting the informed 
consent discussions. A copy of the signed informed consent/assent form will be given to the 
subject and the original will be retained by the site. An entry must be made in the subject’s dated 
source documents to confirm that informed consent/assent was obtained prior to any 
study-related procedures and that the subject received a copy of the signed informed 
consent/assent. 
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The witness and the person conducting the informed consent/assent discussions must also sign 
and personally date the consent/assent document. Until a signed written consent/assent has been 
obtained, the investigator will not perform any measures specifically required for this study. 
The investigator must inform the subject’s primary physician about the subject’s participation in 
the study if the subject has a primary physician and if the subject agrees to the primary physician 
being informed. 
14.2.2. 
Ongoing Information for Independent Ethics Committee/Institutional Review 
Board  
The information listed below must be submitted to IECs/IRBs according to timelines specified 
by individual IEC/IRB documented submission policies and procedures, or by local law. 
Submissions may be made by the sponsor (or designee) or by the investigator. The parties 
responsible for submissions will be identified and documented prior to shipment of study drugs. 
• AE information 
• expedited safety reports 
• periodic reports on the progress of the study 
• revised informed consent forms 
• amendments to the protocol 
• updated Investigator’s Brochure 
14.2.3. 
Compliance with Good Clinical Practice 
This study is to be conducted according to globally accepted standards of GCP (as defined in the 
ICH GCP E6 guidelines), in agreement with the current version of Declaration of Helsinki, and 
in keeping with local regulations. 
14.2.3.1. Quality Control  
In accordance with applicable regulations, GCP, and sponsor procedures, the sponsor or its 
designee will contact the site prior to the start of the study to review with the study site personnel 
the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and the 
sponsor’s or its designee’s requirements. When reviewing data collection procedures, the 
discussion will include identification, agreement, and documentation of data items that will be 
recorded in the eCRF and requirements for source documentation. 
The sponsor or its designee will monitor the study to ensure the following: 
• data are authentic, accurate, and complete 
• safety and rights of subjects are being protected 
• 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. 
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14.2.3.2. Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
authorities 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 medical 
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 during the regulatory audit or inspection. 
14.2.4. 
Confidentiality 
Subject names (and the names of family members, telephone numbers, and addresses) will not be 
supplied to the sponsor. A unique subject number will be recorded in the eCRF, and if the 
subject name appears on any other document (eg, laboratory report), it must be obliterated on the 
copy of the document to be supplied to the sponsor. Study findings stored on a computer will be 
stored in accordance with local data protection laws (eg, EU Directive 95/46/EC, EU Directive 
94/45/EC, and the General Data Protection Regulation (GDPR) (EU) 2016/679]). The subject 
and the subject’s parent or legally-authorized representative will be informed that representatives 
of the sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws. 
The investigator will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 
14.3. 
Clinical Study Protocols and Amendments 
Any non-administrative changes to the protocol, initiated either by the sponsor or by the 
investigator, will require a formal amendment procedure. Approval of all amendments must be 
obtained from the sponsor, relevant IEC/IRB, and regulatory authorities (in accordance with 
local requirements) prior to implementation. Changes to the administrative aspects of the study 
will not require formal protocol amendments or IEC/IRB approval, but can be treated as 
administrative amendments. However, the IEC/IRB should be kept informed of such changes. 
Changes in study staffing or contact information are examples of administrative changes not 
requiring formal protocol amendments. 
Protocol deviations to eligibility criteria, addition or deletion of tests, dosing, duration of 
treatment, and/or any other aspect of the study design that may significantly impact subject 
safety or scientific integrity, are not permitted under GCP or by the sponsor, unless necessary to 
eliminate an immediate hazard to the subject(s). 
Where the sponsor and/or investigator must take urgent safety measures to protect the subjects 
from an immediate hazard, a protocol deviation may be allowed prior to obtaining approval from 
the relevant IEC/IRB (and/or regulatory authorities) according to the US Code of Federal 
Regulations (CFR) Title 21 Part 312.30(b)(2). In such cases, the sponsor and the IEC/IRB must 
be notified within 1 business day. 
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The sponsor and the relevant IEC/IRB, where required by local law, must be informed of all 
protocol deviations and violations and the investigators will document such protocol deviations 
and violations in subject source documents and eCRFs. 
14.4. 
Delegation of Investigator Duties 
The investigator must ensure that all persons assisting with this study are adequately qualified 
and informed about their study-related duties and functions, the protocol and any amendments to 
the protocol, and the study treatment. 
Investigators must maintain a list of sub-investigators and other appropriately qualified persons 
to whom they delegate significant study-related duties. 
Should the investigator delegate the supervision of the administration of the study drugs to a 
designated person, the designee should have the appropriate medical qualifications to effectively 
conduct or supervise any potential resuscitation procedures. 
14.5. 
Liability and Insurance 
Liability and insurance provisions for this study are given in separate agreements. 
14.6. 
Financial Disclosure 
Before the start of the study, the investigator will disclose to the sponsor any proprietary or 
financial interests he or she might hold in the investigational products, migalastat, or Amicus as 
required by CFR Title 21 Part 54 and outlined in the financial disclosure form provided by the 
sponsor. The investigator agrees to update this information in case of significant changes during 
the study and within 1 year of its completion. The investigator also agrees that, where required 
by law or regulation, the sponsor may submit this financial information to domestic or foreign 
regulatory authorities in applications for marketing authorizations. 
Where required by regulation, the investigator or sponsor on behalf of the investigator, will also 
disclose these financial interests to the IRB/IEC and the investigator will disclose his/her 
financial interests to the subjects in the informed consent information. 
Where required by regulation, the sponsor or the investigator will also submit the financial 
arrangements for the study to the regulatory authorities or to the IRB/IEC. 
Financial disclosures will also be provided by each sub-investigator to whom the investigator 
delegates significant study-related responsibilities. 
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15. 
REFERENCES 
Beck, M. J. (2006). Ch 8 Nonclinical Juvenile Toxicity Testing. In Hood, RD, ed. 
Developmental and reproductive toxicology. Taylor&Francis: 263-327. 
Benjamin ER, Flanagan JJ, Schilling A, Chang HH, Agarwal L, Katz E et al. (2009). The 
pharmacological chaperone 1-deoxygalactonojirimycin increases α-galactosidase A levels in 
Fabry patient cell lines. Journal of Inherited Metabolic Disease. 32:424-440. 
Benjamin, ER, Della Valle MC, Wu X, Katz E, Pruthi F, Bond S, et al. (2017). The validation of 
pharmacogenetics for the identification of Fabry patients to be treated with migalastat. Genetics 
in Medicine. 19(4):430-438. 
Brady RO, Gal AE, Bradley RM, Martensson E, Warshaw AL, Laster L. (1967). Enzymatic 
defect in Fabry's disease: ceramidetrihexosidase deficiency. New England Journal of Medicine. 
276:1163-1167. 
Desnick RJ, Ioannou YA, Eng CM. (2001). α-Galactosidase A deficiency: Fabry disease. In 
Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited 
Disease. New York: McGraw-Hill. 
Desnick RJ, Schindler D. (2001). α-N-Aceytylgalactosaminidase Deficiency: Schindler Disease, 
McGraw-Hill. Accessed May 9, 2006. www.ommbid.com. 
Eurordis. (2005). ECRD Report 2005. In European Conference on Rare Diseases. Luxemborg: 
Eurordis. 
Fan JQ, Ishii S, Asano N, Suzuki Y. (1999). Accelerated transport and maturation of lysosomal 
α-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nature Medicine. 5:112-115. 
Filoni C, Caciotti A, Carraresi L, Cavicchi C, Parini R, Antuzzi D et al. (2010). Functional 
studies of new GLA gene mutations leading to conformational Fabry disease. Biochimica et 
Biophysica Acta. 1802:247-252. 
Gal A, Schäfer E, Rohard I. (2006). The genetic basis of Fabry disease. In Mehta A, Beck M, 
Sunder-Plassmann G, eds. Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford 
PharmaGenesis. 
Germain DP. (2010). Fabry disease. Orphanet Journal of Rare Diseases. 5:30. 
Germain DP, Shabbeer J, Cotigny S, Desnick RJ. (2002). Fabry disease: twenty novel 
α-galactosidase A mutations and genotype-phenotype correlations in classical and variant 
phenotypes. Molecular Medicine. 8:306-312. 
Hopkin RJ, Bissler J, Banikazemi M, Clarke L, Eng CM, Germain DP, Lemay R, 
Tylki-Szymanska A, Wilcox WR. (2008). Characterization of Fabry Disease in 352 Pediatric 
Patients in the Fabry Registry. Pediatric Research. 64:550-555. 
Hopkin RJ, Jefferies JL, Laney DA, Lawson VH, Mauer M, Taylor MR, Wilcox WR, on behalf 
of the Fabry Pediatric Expert Panel. (2016). The management and treatment of children with 
Fabry disease: a United States-based perspective. Molecular Genetics and Metabolism. 
117:104-113. 
Amicus Therapeutics
Protocol AT1001-020 
Amendment 4
13 June 2019 
Confidential
Page 66 of 70


Ishii S, Chang HH, Kawasaki K, Yasuda K, Wu HL, Garman SC, Fan JQ. (2007). Mutant 
α-galactosidase A enzymes identified in Fabry disease patients with residual enzyme activity: 
biochemical characterization and restoration of normal intracellular processing by 
1-deoxygalactonojirimycin. Biochemical Journal. 406:285-295. 
Johnson RK, Mudd PN, Bragat A, Adera M, and Boudes P (2013). Pharmacokinetics and safety 
of migalastat HCl and effects on Agalsidase activity in healthy volunteers. Clinical 
Pharmacology in Drug Development 2(2):120-132. 
Johnson FK, Mudd PN Jr, Janmohamed SG. (2015). Relative bioavailability and the effect of 
meal type and timing on the pharmacokinetics of migalastat in healthy volunteers. Clinical 
Pharmacology in Drug Development. 4(3):193-202. 
Mechtler TP, Stary S, Metz TF, De Jesús VR, Greber-Platzer S, Pollak A et al. (2012). Neonatal 
screening for lysosomal storage disorders: feasibility and incidence from a nationwide study in 
Austria. The Lancet. 379:335-341. 
Meikle PJ, Hopwood JJ, Clague AE, Carey WF. (1999). Prevalence of lysosomal storage 
disorders. Journal of the American Medical Association. 281:249-254. 
Ramaswami U, Whybra C, Parini R, Pintos-Morell G, Mehta A, Sunder-Plassmann G, 
Widmer U, Beck M, on behalf of the FOS European Investigators. (2006). Clinical 
manifestations of Fabry disease in children: data from the Fabry Outcome Survey. 
Acta Pædiatrica. 95:86-92. 
Shabbeer J, Yasuda M, Benson SD, Desnick RJ. (2006). Fabry disease: identification of 50 novel 
α-galactosidase A mutations causing the classic phenotype and three-dimensional structural 
analysis of 29 missense mutations. Human Genomics. 2:297-309. 
Shabbeer J, Yasuda M, Luca E, Desnick RJ. (2002). Fabry disease: 45 novel mutations in the 
α-galactosidase A gene causing the classical phenotype. Molecular Genetics and Metabolism. 
76:23-30. 
Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H et al. (2006). High 
incidence of later-onset Fabry disease revealed by newborn screening. American Journal of 
Human Genetics. 79:31-40. 
Topaloglu AK, Ashley GA, Tong B, Shabbeer J, Astrin KH, Eng CM et al. (1999). Twenty novel 
mutations in the α-galactosidase A gene causing Fabry disease. Molecular Medicine. 5:806-811. 
Wang Y, Jadhav P, Lala M, Gobburu J. (2012). Clarification on precision criteria to derive 
sample size when designing pediatric pharmacokinetic studies. The Journal of Clinical 
Pharmacology. 52:1601-1606. 
Yam GH, Bosshard N, Zuber C, Steinmann B, Roth J. (2006). Pharmacological chaperone 
corrects lysosomal storage in Fabry disease caused by trafficking-incompetent variants. 
American Journal of Physiology - Cell Physiology. 290:C1076-1082. 
Yam GH, Zuber C, Roth J. (2005). A synthetic chaperone corrects the trafficking defect and 
disease phenotype in a protein misfolding disorder. FASEB Journal. 19:12-18. 
Zavesca Package Insert (2017). miglustat capsules, 100mg. South San Francisco, CA, Actelion 
Pharmaceuticals US Inc. 
Amicus Therapeutics
Protocol AT1001-020 
Amendment 4
13 June 2019 
Confidential
Page 67 of 70


16. 
APPENDICES 
APPENDIX A. TANNER STAGING 
Provided by Endotext 
Beccuti G and Ghizzoni L. Normal and Abnormal Puberty. In: De Groot LJ, Chrousos G, 
Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, 
New M, Purnell J, Rebar R, Singer F, Vinik A, editors. Endotext [Internet]. South Dartmouth 
(MA): MDText.com, Inc.; 2000-2015 Aug 8. PMID: 25905253 
Amicus Therapeutics
Protocol AT1001-020 
Amendment 4
13 June 2019 
Confidential
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SAP_001.pdf: 
 
This document is confidential. 
 
 
Statistical Analysis Plan 
 
Study Drug: 
Migalastat Hydrochloride 
 
Protocol Number: AT1001-020 
 
Study Title: 
An Open-label Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of 12-Month 
Treatment with Migalastat in Pediatric Subjects (aged 12 to <18 years) with Fabry Disease and Amenable 
GLA Variants 
 
 
Version: 1.0 
 
Date: 20Oct2020 
 
Based on: Protocol Amendment 4 (13Jun2019)  
 
 
Sponsor: 
Amicus Therapeutics, Inc. 
1 Cedar Brook Drive 
Cranbury, NJ 08512 
Phone: +1-609-662-2000 
 
 
  
 
 
 
Notice of Confidential and Proprietary Information: 
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 of 
Amicus Therapeutics without the prior written consent of the company, except to the extent required 
under applicable laws or regulations. 


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Revision History 
Version # 
Date (DDMmmYYYY) 
Document Owner 
Revision Summary 
1.0 
20Oct2020 
Final Version 
Amicus


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I confirm that I have reviewed this document and agree with the content. 
Approvals 
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Signature 
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Signature 
Date (DD-Mmm-YYYY) 
Amicus Therapeutics Approval 
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Signature 
Date (DD-Mmm-YYYY) 
Date: Nov 6  2020 09:41 EST
Date: Nov 10, 2020 10:58 EST
DocuSign Envelope ID: 53870636-EF08-4D75-B5E6-8220A695DE1A
ember 2020 | 16:11 GMT
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Table of Contents 
Revision History .......................................................................................................................... 2 
Approvals .................................................................................................................................. 3 
 
Glossary of Abbreviations ................................................................................................... 7 
 
Introduction ...................................................................................................................... 10 
 
Study Objectives and Endpoints ....................................................................................... 11 
 
Study Design .................................................................................................................... 13 
 
Analysis Population .......................................................................................................... 18 
 
General Aspects for Statistical Analysis ........................................................................... 19 


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Demographic, Other Baseline Characteristics and Medication ......................................... 23 
Efficacy ............................................................................................................................ 25 
Analysis of Pharmacokinetics ........................................................................................... 28 
Analysis of Pharmacodynamics ........................................................................................ 29 


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Safety ............................................................................................................................... 30 
 
Reference List .................................................................................................................. 33 
 
Interim Analyses ............................................................................................................... 34 
 
Changes from Analysis Planned in Protocol ..................................................................... 35 
 
Programming Considerations ........................................................................................... 36 
 
Quality Control ................................................................................................................. 41 
 


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Glossary of Abbreviations 
Abbreviation 
Description 
α-Gal A  
α-Galactosidase A 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AT1001 
Migalastat 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CDISC 
Clinical Data Interchange Standards Consortium 
cm 
Centimeters 
CRF 
Case Case Report Form 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
DOB 
Date of Birth 
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
eCRF 
Electronic Case Report Form 
e-diary 
Electronic Diary 
eGFR 
Estimated Glomerular Filtration Rate 
ERT 
Enzyme Replacement Therapy 
ET 
Early Termination 
FABPRO-GI 
Fabry Disease Patient-Reported Outcome – Gastrointestinal Signs and 
Symptoms 
FPHPQ 
Fabry-Specific Pediatric Health and Pain Questionnaire 
GI 
Gastrointestinal 
GLA 
Gene Encoding α-Galactosidase A 
h 
Hours 
HEENT 
Head, Eyes, Ears, Neck and Throat 
ICH 
International Conference on Harmonisation 
IRT 
Interactive Response Technology 
ITT 
Intent to Treat 
kg 
Kilograms 


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Abbreviation 
Description 
LCL 
Lower Confidence Limit 
LVMi 
Left Ventricular Mass Index 
lyso-Gb3 
Globotriaosylsphingosine 
m 
Meters 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
min 
Minutes 
PCS 
Potential Clinical Significance 
PedsQL™ 
Pediatric Quality of Life Inventory™ 
PGI-C 
Patient Global Impression of Change 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
PKAP 
PK Analysis Plan 
PR 
PR Interval 
PT 
Preferred Term 
QOD 
Every other day 
QRS 
QRS Complex 
QT 
QT Interval 
QTc 
Corrected QT Interval 
QTcB 
Corrected QT Interval with Bazett's Formula 
QTcF 
Corrected QT Interval with Fridericia's Formula 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SI 
Système International 
SYNH 
Syneos Health 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 


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Abbreviation 
Description 
TEAE 
Treatment-Emergent Adverse Event 
TLF 
Tables, Listings and Figures 
WHO-DD 
World Health Organization Drug Dictionary (WHO Drug Enhanced + Herbal B3 
March 2018 or latest available version) 
 


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Introduction 
This Statistical Analysis Plan (SAP) is created based on Protocol Number AT1001-020, Amendment 4, 
13Jun2019. The purpose of this SAP is to outline the planned analyses by Syneos Health (SYNH) to 
support the completion of the Clinical Study Report (CSR). This SAP describes in detail the statistical 
methodology and the statistical analyses to be conducted for the above mentioned protocol. The planned 
analyses identified in this SAP are following International Conference on Harmonisation (ICH) guidelines 
E9 (R1) Statistical Principles for Clinical Trials. They will be included in regulatory submissions and/or 
future manuscripts. 
 
Responsibilities 
SYNH will perform the statistical analyses and is responsible for the production and quality control of all 
tables, listings and figures (TLFs). Syneos Health will not be responsible for the pharmacokinetic (PK) 
analysis; it will be analyzed separately by another vendor and detailed in a PK Analysis Plan (PKAP). 
 
Timings of Analyses 
The primary analysis of safety and efficacy is planned after all subjects complete the final study visit or 
terminate early from the study. Unless otherwise specified, the analysis includes all data collected in the 
database through the time of the database lock. 


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Study Objectives and Endpoints 
 
Study Objectives 
 
Primary Objectives 
The primary objectives of Stage 1 are as follows: 
• 
to characterize the PK of migalastat in adolescents with Fabry disease and to validate 
extrapolation of migalastat plasma exposure in adults to adolescents weighing ≥ 45 kilograms 
(kg) for the 150 milligrams (mg) migalastat capsule administered every other day (QOD); 
• 
to evaluate the safety of migalastat treatment in pediatric subjects diagnosed with Fabry disease 
and who have variants in the gene encoding α-galactosidase A (α-Gal A) (GLA) amenable to 
treatment with migalastat. 
The primary objective of Stage 2 is as follows: 
• 
to evaluate the safety of migalastat treatment in pediatric subjects diagnosed with Fabry disease 
and who have GLA variants amenable to treatment with migalastat. 
 
Secondary Objective(s) 
The secondary objectives are as follows: 
Stage 1: 
• 
Not applicable. 
Stage 2: 
• 
to characterize the pharmacodynamics (PD) of migalastat in pediatric subjects diagnosed with 
Fabry disease and who have GLA variants amenable to treatment with migalastat; 
• 
to evaluate the efficacy of migalastat in pediatric subjects diagnosed with Fabry disease and who 
have GLA variants amenable to treatment with migalastat; 
• 
to evaluate the relationship between exposure to migalastat and response. 
 
Study Endpoints 
 
Efficacy Endpoints 
Efficacy endpoints are as follows: 
• 
change in estimated glomerular filtration rate (eGFR) from baseline to Months 3, 6, and 12/Early 
Termination (ET), and annualized rate of change from baseline 
• 
change in urine protein and albumin levels from baseline to Months 3, 6, and 12/ET 
• 
change in left ventricular mass index (LVMi) and other echocardiogram (ECHO) parameters from 
baseline to Month 12/ET 
• 
change in gastrointestinal signs and symptoms and pain from baseline to Month 12/ET, as 
measured by e-diary (electronic diary) responses (Short Fabry Disease Patient-Reported 
Outcome – Gastrointestinal Signs and Symptoms [FABPRO-GI] and Pain Questionnaire for 
Clinical trials [24-hour version]) 
• 
mean Patient Global Impression of Change (PGI-C) values at Months 3, 6 and 12/ET 


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• 
change in Fabry-Specific Pediatric Health and Pain Questionnaire (FPHPQ) scores from baseline 
to Month 12/ET 
• 
change in Pediatric Quality of Life Inventory™ (PedsQLTM) scores from baseline to Month 12/ET 
 
Pharmacodynamic Endpoints 
Pharmacodynamic endpoint is as follows: 
• 
change in plasma levels of lyso-Gb3 (Globotriaosylsphingosine) from baseline to Months 3, 6, and 
12/ET. 
 
Safety Endpoints 
Safety endpoints are as follows: 
• 
incidence of treatment-emergent adverse events (TEAEs), Serious Adverse Events (SAEs), and 
adverse events (AEs) leading to discontinuation of study drug 
• 
changes in clinical laboratory test results from baseline over time 
• 
changes in vital signs from baseline over time 
• 
changes in physical examination findings from baseline over time 
• 
changes in body weight and height from baseline over time 
• 
changes in 12-lead electrocardiogram (ECG) results from baseline over time 
• 
changes in ECHO parameters from baseline to Month 12/ET 
• 
change in Tanner stage from baseline to Month 12/ET 
• 
use of concomitant medications 


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Study Design 
 
Summary of Study Design 
This is a Phase 3b, 2-stage, open-label, uncontrolled, multicenter study to evaluate the safety, PK, PD, 
and efficacy of migalastat treatment in pediatric subjects 12 to < 18 years of age and weighing ≥ 45 kg 
(99 pounds) with Fabry disease and with amenable GLA variants. Subjects must be either naïve to 
enzyme replacement therapy (ERT) or have stopped ERT at least 14 days at the time of screening. 
 
The study will consist of 2 stages. Stage 1 will be a treatment period of approximately 1 month (4 weeks); 
Stage 2 will be a treatment period of 11 months and a 30-day (untreated) safety follow-up period. There 
will be no break in treatment between Stages 1 and 2. Prior to Stage 1, there will be a screening period 
lasting at least 14 days and up to 30 days (or more, if GLA genotyping is required). The study will consist 
of a screening period up to 30 days, a 12-month treatment period, and a 30-day safety follow-up period, 
for a total of approximately 14 months. 
 
Figure 1: Study Design 
 
-30 to -14 Days       1 Month (4 weeks)               11 Months 
 
 
       30 Days 
 
Screening:               Stage 1: Safety/PK 
 
 Stage 2: Safety/PD/Efficacy 
       Follow-up: Safety 
  Genotyping 
Safety assessments include monitoring AEs, clinical laboratory tests, vital signs, physical examinations, 
body weight and height, 12-lead ECGs, ECHOs, Tanner staging of sexual development, and use of 
concomitant medications. Sparse blood samples for determination of plasma migalastat concentrations 
and PK analysis will be collected. The PD biomarker to be evaluated in this study is lyso-Gb3 levels in 
plasma. Blood samples will also be collected for exploratory biomarkers. 
Efficacy assessments include eGFR, urine protein and albumin levels, ECHO parameters, and subject 
questionnaires (FABPRO-GI and Pain Questionnaire, PGI-C, FPHPQ, and PedsQLTM). The key ECHO 
parameter considered for efficacy is LVMi. In addition, ejection fraction, fractional shortening, left 
ventricular internal diameter end diastole and end systole, midwall fractional shortening, and wall 
thickness will be assessed. Echocardiograms will be read centrally. 
A Data Monitoring Committee (DMC) will operate according to a charter that includes operational and 
logistical procedures for the DMC. The DMC will monitor and evaluate all available safety data from this 
study by reviewing summaries of safety data on a regular basis, evaluating risk/benefit where possible, 
identifying any clinically relevant trends through the study, and assessing whether it is safe for the subject 
and/or study to continue. 
 
Subject Selection 
Inclusion and exclusion criteria for this study can be found in Section 8.2 of the study protocol. Waivers of 
inclusion/ exclusion criteria will not be granted. 
 
Determination of Sample Size 
A sample size of at least 7 to 10 subjects per age/weight group is required for statistical comparison with 
adult exposure based on 2 methods described by Wang et al. 2012. 


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First, assuming the final plasma clearance estimates and inter-individual variability of 28.5% (Migalastat 
Abbreviated Report of the Simulations of Migalastat in Pediatric Patients with Fabry Disease, 
16 October 2016), a sample size of 7 subjects is adequate to achieve at least 80% power for a study 
design with rich PK sampling intended for non-compartmental analysis. 
Second, according to the sample size calculation for a study with sparse/rich PK sampling intended for 
population PK analysis, (e^(-t(0.975,df)×〖SE〗_LCL ),e^(t(0.975,df)×〖SE〗_LCL )) [SE= Standard 
Error, LCL=Lower Confidence Interval] should be within the pre-defined criteria of (0.6, 1.4), where 
SE_LCL is the standard error for log-transformed pediatric clearance that relates to weight, and 
t (0.975, df) is the 97.5% upper quantile values from t distribution corresponding to the sample size. 
Mathematically, SE_LCL was approximately equal to the relative standard error of untransformed 
clearance, 0.16. Therefore, a sample size of approximately 10 subjects is adequate to achieve the 
pre-defined boundary of (0.6, 1.4). 
 
Randomization 
As all subjects receive migalastat in this study, no randomization to treatment will be performed. 
Randomization will be used for sparse PK sampling as described below. The timing of PK samples was 
determined using optimal sampling theory using PopED and mrgsolve software packages in R using a 
D-optimality algorithm.  
Subjects will be randomly assigned 1:1:1 to 1 of 3 PK sampling groups using interactive response 
technology (IRT). Four blood samples for determination of migalastat concentrations in plasma will be 
collected in one 24-hour period between Day 15 and Day 30 following initiation of study drug 
administration. Blood sampling for PK is relative to migalastat administration. Each subject will have 4 PK 
samples collected at the times specified in Table 2 according to their randomized PK sampling group 
assignment. 
Table 1. Sparse Pharmacokinetic Sampling  
PK Sampling 
Groupa 
Time Post-dose 
Sample 1 
Sample 2 
Sample 3 
Sample 4 
1 
1 hour (h) to 1h 15 
minutes (min) 
1h 30min to 2h 
5h to 5h 30min 
6h 30min to 7h 
2 
1h to 1h 15min 
2h 45min to 3h 
15min 
5h 15min to 5h 
45min 
10h 45min to 11h 
15min 
3 
3h 15min to 3h 45min 
3h 45minb to 4h 
15min 
8h 15min to 8h 
45min 
8h 45minb to 9h 
15min 
a Sample should NOT be taken at the same time as the previous sample. Samples should be taken 
approximately 15 minutes apart at a minimum. 
 
Administration of Study Medication 
One migalastat 150 mg capsule will be administered with water every other day continuously for 12 months 
during Stages 1 and 2 of the study. Subjects should take study drug at the same time of day during the 
every other day dosing schedule and not eat for at least 2 hours before and after administration. 
 
Study Procedures and Flowchart 
The below table details the schedule of assessments:


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Table 2. Schedule of Assessments 
 
Screeninga 
Treatment Period 
Treatment 
Period 
Stage 1 
Stage 2 
 
Assessments 
Day  
-30 to -14 
Baselineb 
Day 1 
Day 15-
30 
Month 1 Month 2  
(TC) 
Month 3 Month 4  
(TC) 
Month 5  
(TC) 
Month 6 Month 7  
(TC) 
Month 8  
(TC) 
Month 9 Month 10 
(TC) 
Month 11 
(TC) 
Month 
12/ET 
30-Day 
Safetye 
Window (days) 
— 
— 
 
±3 
±3 
±3 
±3 
±3 
±6 
±6 
±6 
±6 
±6 
±6 
±6 
+6 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confirmatory GLA 
Genotyping 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of amenable 
GLA variant 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing diary 
 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
 
FABPRO-GI and Pain 
Questionnaire 
 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
 
FPHPQ questionnaire 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
PedsQLTM 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
PGI-C 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Complete physical 
examination 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 


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Table 2. Schedule of Assessments (Continued) 
 
Screeninga 
Treatment Period 
Treatment 
Period 
Stage 1 
Stage 2 
 
Assessments 
Day  
-30 to -14 
Baselineb 
Day 1 
Day 15-
30 
Month 1 Month 2  
(TC) 
Month 3 Month 4  
(TC) 
Month 5  
(TC) 
Month 6 Month 7  
(TC) 
Month 8  
(TC) 
Month 9 Month 10 
(TC) 
Month 11 
(TC) 
Month 
12/ET 
30-Day 
Safetye 
Window (days) 
— 
— 
 
±3 
±3 
±3 
±3 
±3 
±6 
±6 
±6 
±6 
±6 
±6 
±6 
+6 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Brief physical examination 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (BP, HR, RR, 
Temp) 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Body weight 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Height 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Tanner Staging 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
12-Lead ECG 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Chemistry (including eGFR 
using Schwartz formula) 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
Hematology 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Plasma lyso-Gb3 and 
analogs 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
Exploratory PD biomarkers 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
PK blood samples  
 
 
Xc 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Urinalysis (urine protein and 
albumin or microalbumin 
levels) 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 


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Table 2. Schedule of Assessments (Continued) 
 
Screeninga 
Treatment Period 
Treatment 
Period 
Stage 1 
Stage 2 
 
Assessments 
Day  
-30 to -14 
Baselineb 
Day 1 
Day 15-
30 
Month 1 Month 2  
(TC) 
Month 3 Month 4  
(TC) 
Month 5  
(TC) 
Month 6 Month 7  
(TC) 
Month 8  
(TC) 
Month 9 Month 10 
(TC) 
Month 11 
(TC) 
Month 
12/ET 
30-Day 
Safetye 
Window (days) 
— 
— 
 
±3 
±3 
±3 
±3 
±3 
±6 
±6 
±6 
±6 
±6 
±6 
±6 
+6 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Urine pregnancy test or 
date of LMP (as applicable)d 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Echocardiogram (LVMi and 
additional parameters) 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Study treatment supply/ 
Resupply/Return 
 
Xb 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Abbreviations: BP = blood pressure;HR = heart rate; LMP = last menstrual period; RR = respiration rate; TC = telephone call; Temp = body temperature 
a For subjects without a documented GLA variant, screening procedures will be suspended until such time that a confirmed, amenable variant is determined. 
b All baseline assessments must be completed BEFORE the first dose of migalastat is administered. 
c Blood samples for plasma migalastat concentrations will be taken during one 24-hour period between Day 15 and 30 following initiation of study drug 
administration. 
d Female subjects only 
e Only for subjects who do not enroll in a long-term extension study 


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Analysis Population 
 
Safety Population 
The safety population will include all subjects who receive at least 1 dose or partial dose of study drug. All 
safety and PD analyses will be performed using the safety population. 
 
Intent-to-Treat Population 
The intent-to-treat (ITT) population will include all enrolled subjects. All efficacy analyses will be 
performed using the ITT population. 
 
Pharmacokinetic Population 
The Stage 1 PK population will include all subjects who have a complete set of sparse PK samples from 
the single day of collection at steady-state between Day 15 and Day 30 of Stage 1. 
The final PK population will include all subjects with at least one quantifiable concentration and a known 
weight and eGFR. All final PK analyses will be performed using the final PK population. 
The PK analysis will be included in a separate PKAP. 
 
Protocol Deviations 
Protocol deviations are defined as instances in which subjects or investigational site study personnel fail 
to adhere to the protocol requirements (eg, eligibility criteria, addition or deletion of tests, dosing, duration 
of treatment, and/or any other aspect of the study design). Deviations are collected on the electronic 
Case Report Forms (eCRF). 
A list of protocol and site deviations will be provided with the date the deviation occurs, the category 
(eg, inclusion/exclusion criteria, informed consent/subject privacy, and randomization), and the 
description of the deviation. 


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General Aspects for Statistical Analysis 
This section addresses the definitions, algorithms, imputations, and conventions that apply to the analysis 
and handling of the data. 
 
General Summary Table and Individual Subject Data Listing Considerations 
Summary tables and listings will have text (eg, headers or footers) providing explanatory notes that cover, 
as appropriate: date of data extraction, date of output generation, Statistical Analysis System (SAS®) 
program name, and any other output-specific details that require further elaboration. 
The descriptive summary statistics will be prepared for baseline, each visit, and change from baseline to 
each visit (if appropriate). 
Row entries in post text tables are made only if data exist for at least one subject (eg, a row with all 
zeroes will not appear). The only exception to this rule applies to tables that summarize the study 
termination status of subjects (eg, reasons for not completing the study). In this case, zeroes will appear 
for study termination reasons that no subject satisfied. The summary tables will clearly indicate the 
number of subjects to which the data apply and data that is unknown or not performed will be 
distinguished from missing data. All data collected will be reported in data listings. 
Missing dates will be imputed as described in Section 6.7. Missing AE intensity and relationship will be 
imputed as described in Section 6.7.2. No other missing data imputation will be performed. When imputed 
or derived data are included in the individual subject data listings, they will be flagged. 
 
General Post Text Summary Table and Individual Subject Data Listing Format 
Considerations 
The convention will be to number tables and listings using a decimal system to reflect main levels of 
unique tables and listings and sub-levels of replicate tables and listings. The first level number will be 
consistent with the corresponding CSR appendix in which the tables or listings will appear. Thus, all post 
text tables will have a main number level 14 and listings will have a main number level 16. 
Subject accounting and final disposition, analysis populations, protocol deviations and/or violations, 
demographics and baseline profile will appear as the second level number (Table 14.1 series). Efficacy 
tables will come next (Table 14.2 series). Safety tables will be at the end (Table 14.3 series). Similar 
conventions will be applied to the subject data listings and figures/graphs. 
For tables, the last line of the title will provide the analysis group being summarized (eg, Intent-to-treat 
Population). Whether in the title or body of a table or listing, units will always be specified for all 
appropriate data. Metric system units will be used (eg, degrees Celsius [°C] for temperature, kg for body 
weight, and centimeters [cm] for height). 
In general, the listings will be sorted and presented by investigational site and subject number. From left 
to right, the columns will include the subject number, visit number, visit name, visit date, treatment and 
days relative to first dose in the study. 
 
Data Management 
Datasets will be created according to Clinical Data Interchange Standards Consortium (CDISC) 
standards. The most current or latest version of the Study Data Tabulation Model (SDTM) datasets will be 
used. All statistical and data analyses, SDTMs and Analysis Data Model (ADaM) datasets will be created 


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using (SAS®) software version 9.4 or later. The data specifications and reviewer’s guide will also be 
created. 
 
Data Presentation Conventions 
 
Descriptive Statistics 
Data will be summarized with descriptive statistics and/or response frequencies. For numerical data, 
descriptive statistics will include number of subjects with non-missing data (n), mean, standard deviation 
(SD), median, minimum, and maximum. For categorical data, descriptive statistics will be categorized by 
frequency counts and proportions (or percentages) of the number of subjects used in the analysis. The 
counts for the categories of ‘Missing,’ ‘Unknown,’ or ‘Not applicable’ will be provided as appropriate, but 
the percentages will not be provided. 
 
Rounding 
In general, the minimum and maximum will be reported to the same number of decimal places as the 
data. The mean, median, and confidence intervals will be rounded to one more decimal place than the 
data. The SD will be rounded to two more decimal places than the data. Proportions will be reported as 
percentages rounded to one decimal place. 
Each subject’s age will be truncated to a whole number (rather than rounded). 
 
p-values 
Not applicable. 
 
Dictionaries 
The Medical Dictionary for Regulatory Activities (MedDRA, version 21.0 or later version) will be used to 
code AEs and medical history into system organ class (SOC) and preferred term (PT) within SOC. The 
enhanced version of the World Health Organization Drug Dictionary (WHO-DD, WHO Drug Enhanced + 
Herbal B3 March 2018, or latest available version) will be used to code all medications (prior and 
concomitant) to anatomical therapeutic chemical (ATC) class and preferred drug names. 
 
Baseline Definition 
For all safety data, the baseline value is defined as the last non-missing measurement obtained on or 
before the administration of the first dose of study drug. 
 
Derived and Transformed Data 
 
Calculations Using Dates 
6.6.1.1. 
Baseline Age 
Age for enrolled subjects will be calculated as the truncated difference (eg, fractional part ignored) 
between the date of the informed consent and the subject’s birth date (DOB) adjusted for years 
(ie, AGE = int[(Visit 1 – DOB) / 365.25]). 
6.6.1.2. 
Study Day 
There is no Day 0. Study Day 1 denotes the day of the first dose and is the reference start date for all 
safety analyses in this study. Study days (or visit days) are defined relative to Day 1 unless otherwise 
specified. Days prior to Day 1 are negative and days after Day 1 are positive. That is, 


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Relative Day = (Date of Assessment) – (Date of First Dose of Study Drug) + 1, if assessment is 
on or after the date of first dose of study drug; 
Relative Day = (Date of Assessment) – (Date of First Dose of Study Drug), if assessment is 
before the date of first dose of study drug. 
6.6.1.3. 
Other Calculations Using Dates 
Total duration of treatment will be calculated as the difference between the dates of last and first dose of 
study drug plus 1 day. 
All other calculations of duration for enrolled subjects (eg, time since the primary diagnosis or age of first 
diagnosis) will be performed relative to the first dose of study drug and will follow the algorithm: 
Duration = (Target Date – First Dose Date + 1). 
6.6.1.4. 
Change from Baseline 
The change from baseline will be calculated as the post-baseline visit value minus the baseline value (the 
value prior to or on the date of first administration of the study drug). 
6.6.1.5. 
Visit Windows 
There will be no derivation for visit windows in terms of summary assessments. Nominal visits will be 
used for by-visit tables. There is visit mapping rule only for monthly average scores of FABPRO-GI and 
Pain Questionnaire, see Section 8.3.1 for details. 
6.6.1.6. 
Multiple Assessments 
If multiple assessments including assessments at the unscheduled visit, are associated with a nominal 
visit post-baseline, the last assessment will be used. 
 
Handling of Missing Data 
 
Missing Start and Stop Dates for Adverse Events 
For AEs, partially missing start dates will be imputed for the purpose of determining treatment emergence 
only. 
Partially missing start dates will be imputed as follows: 
For a missing day, 
• 
If the month and year are equal to the month and year of the date of the first dose of study drug, 
then the date of the first dose of study drug will be used. 
• 
Otherwise, the first day of the month will be used. 
For a missing day and month, 
• 
If the year is equal to the year of the first dose of study drug, then the date of the first dose of 
study drug will be used. 
• 
Otherwise, the first day of the month and the first month of the year will be used. 
If the stop date is not missing and the imputed start date is after the stop date, then the stop date will be 
used. 


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If the start date is completely missing and the stop date is on or after the date of first dose of study drug, 
the AE will be considered a TEAE. 
If both the start date and stop date are missing, the AE will be considered a TEAE. 
Missing stop dates for adverse events will not be imputed. 
 
Missing Adverse Event Intensity and Relationship 
If an AE is missing the intensity or relationship to study drug, the AE will be classified under the maximum 
intensity (ie, severe) or the maximum relationship (ie, definite), respectively. 
 
Missing Start and Stop Dates for Prior and Concomitant Medications 
Partially missing medication start dates will be imputed in a similar manner as described in Section 6.7.1 
for imputing missing AE start dates. Missing stop dates for medications will not be imputed. If when using 
these rules, the imputed start date is after the stop date, then the start date will be left as missing and the 
medication will be considered a concomitant medication for the purpose of the analysis. 


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Demographic, Other Baseline Characteristics and Medication 
 
Subject Disposition and Withdrawals 
Frequency counts and percentages of all subjects who are enrolled but do not take study drug, and 
subjects who are enrolled and complete the study drug/study or discontinue study drug/study early will be 
presented. All subjects who discontinue from the study will be identified, and their reason for 
discontinuation in the study will be reported. The denominators for the percentage calculations will be the 
number of subjects in ITT population.  
The following frequencies (number and percentage) will be displayed: 
• 
Subjects in the ITT population 
• 
Subjects in the safety population 
• 
Subjects in the PK population 
• 
Subjects who completed the study 
• 
Subjects who discontinued early overall and by reason 
In addition, the number of screened subjects and screen failures will be provided. 
A listing of all study subjects, whether they discontinued the study or not, and the reasons for study 
discontinuations will be provided for the ITT population. 
 
Demographic and Other Baseline Characteristics 
Demographic and baseline data will be summarized by means of descriptive statistics: continuous 
variables as mean, SD, median, minimum, and maximum, and categorical variables as frequencies and 
percentages, based on the ITT population. Demographic data will include age (continuous and 
categorical), gender, race, ethnicity, reproductive potential, height, body weight, and body mass index 
(BMI). Baseline characteristics will include number of years since diagnosis of Fabry disease, previous 
use of ERT, and previous and current use of angiotensin-converting enzyme inhibitors, renin inhibitors, 
and angiotensin receptor blockers. The following calculations will be utilized: 
• 
Age = (informed consent date - date of birth + 1) / 365.25 and truncated to complete years 
• 
Weight (in kg) = weight (in pounds) *0.4536 
• 
Height (in cm) = height (in inches) * 2.54 
• 
BMI (kg/m2) = weight(kg)/[(height(cm)/100)2], where m = meters 
• 
Number of years since diagnosis of Fabry disease = (informed consent date - date of diagnosis of 
Fabry disease + 1) / 365.25 and rounded to 1 decimal; for any missing days or months, years will 
be used for the calculation: Number of years since diagnosis of Fabry disease = (year of informed 
consent date – year of date of diagnosis of Fabry disease; for missing years, number of years will 
be missing. 
• 
A month will be defined as 30 days. 
• 
ERT status is defined as ERT naïve and ERT experienced. 
All demographic and baseline characteristic data will also be listed, including the protocol version 
(captured in eCRF) under which the subject was screened and the date of informed consent. 


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Medical History 
A summary table of the number and percentage of subjects for medical history by SOC and PT will be 
produced for subjects in the safety population. Medical history will be sorted alphabetically by SOC and 
PT within the same SOC using the MedDRA coding dictionary, version 21.0 or later version. For the 
summary tables, a subject may appear more than once if he/she has more than one medical history 
coded under different SOC or PT categories. However, the subject will be counted only once in the 
overall category. A by-subject listing with coded SOC and PT along with verbatim Case Report Form 
(CRF) term will also be provided. 
 
Prior and Concomitant Medications 
Medications will be classified as prior (started prior to the first dose of study treatment) and concomitant 
(continued past or started on or after the first dose of study treatment). 
All prior and concomitant medications will be classified using the ATC classification coded terms and 
preferred drug names from the WHO-DD. 
Summaries of prior and concomitant medications will be presented separately in tabular form using the 
level 4 ATC term as an upper classification level and the preferred drug name as a lower classification 
level. All medications will be summarized and sorted alphabetically by level 4 ATC term and preferred 
drug name within a given level 4 ATC term. The summary will consist of the frequency and percentage of 
safety subjects who used the medication at least once.  
For each subject, the medication will be counted only once within a level 4 ATC term and only once under 
a given preferred drug name. A subject may appear more than once if he/she has more than one 
concomitant medication coded under different ATC terms or preferred drug names; however, the subject 
will be counted only once in the overall category. 
A by-subject listing with coded terms will also be provided along with calculated study days. 
Prior ERT will be summarized by preferred drug name for the safety population. 


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Efficacy 
Observed values and changes from baseline for each efficacy endpoint in Section 3.2.1 will be 
summarized with descriptive statistics at each scheduled time point based on the ITT population. Mean 
plots including standard error bars at each visit for the numerical observed values and changes from 
baseline of the indicated laboratory assessments, ECHO results and subject questionnaires will be 
provided by sex (male, female), ERT status (ERT naïve, ERT experienced), and overall, if feasible. 
 
Laboratory Assessments 
Efficacy analyses will include summaries of observed and change from baseline values for the eGFR, 
urine protein and albumin for scheduled visits, indicated in Section 4.6. Scheduled visits will only be 
included for by-visit summary. 
Annualized rate of change from baseline of eGFR will be included in the summary table. Annualized rate 
of change from baseline of eGFR is defined as change from baseline to last visit divided by the duration 
from baseline to the last visit (Last assessment date – First dose date +1) and multiplied by 365.25. 
A by-subject listing will be presented for each laboratory test. 
 
Echocardiography  
A summary table of observed and change from baseline values in numerical echocardiography results will 
be provided at each scheduled visit. 
A by-subject listing will be presented for each ECHO parameter, including LVMi measurement, and other 
cardiac parameters, such as ejection fraction, fractional shortening, left ventricular internal diameter end 
diastole and end systole, midwall fractional shortening, and wall thickness. 
 
Subject Questionnaires 
 
Electronic Diary (FABPRO-GI and Pain Questionnaire for Clinical Trials [24-hour version]) 
Subjects are asked to complete daily diary entries at approximately the same time of day (preferably in 
the evening before bed time) beginning on Day 1 and for the duration of the study. Diary entries will 
include completion of the short FABPRO-GI and Pain Questionnaire. 
The FABPRO-GI and Pain Questionnaire for Clinical Trials (24-hour version) consists of 4 questions 
regarding gastrointestinal signs and symptoms and 2 questions regarding pain relative to the past 
24 hours. Subjects will record the frequency and consistency of stools using the Bristol Stool Scale, a 
pictorial chart and descriptive text for 7 types of stool, ranging from Type 1 (separate hard lumps, like 
nuts – hard to pass) through Type 7 (watery, no solid pieces – entirely liquid). Subjects will also rate the 
severity of their worst occurrence of diarrhea, constipation, tummy pain, and overall pain from 0 (none) to 
10 (worst possible); for tummy pain, subjects will indicate the location of any tummy pain using a diagram. 
Descriptive summary tables will be provided for observed monthly average scores of e-diary responses 
for FABPRO-GI and Pain Questionnaires for Clinical Trials (24-hour version) by subgroup, ie, sex (male, 
female), ERT status (ERT naïve, ERT experienced), and overall if feasible. 


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e-diary responses will include: 
1) Monthly average of worst tummy pain in past 24 hours score based on the tummy pain question 
in the FABPRO-GI and Pain Questionnaire for Clinical Trials (24-hour version) with its 0 to 
10 scale (0 = no pain, 10 = worst possible pain) 
2) Monthly average of overall pain in past 24 hours score in the (FABPRO-GI and Pain 
Questionnaire for Clinical Trials (24-hour version) with its 0 to 10 scale (0 = no pain, 10 = worst 
possible pain) 
3) Monthly average of daily ratings of severity will be assessed separately for each of the following 
items: diarrhea and constipation. 
Visit mapping: 
FABPRO-GI and Pain questionnaires are assessed daily. For each subject, there are scheduled visits at 
Month 1, 3, 6, 9 and 12/ET. The closest date to the date of the scheduled visits are mapped to the 
corresponding visits. If there are multiple dates at the same distance to the scheduled date, the later date 
will be assigned to the scheduled visit. 
Monthly averaged scores: 
The monthly average score is calculated as the sum of the total scores of each test from 30 day prior to 
the scheduled dates of Month 1, 3, 6, 9 and 12/ET divided by the number of days when actual 
assessments were done. If there are more than 6 days of missing assessments, then the total score for 
the monthly scheduled visit is set as missing, since less than 80% assessments are available. 
A by-subject listing of responses from FABPRO-GI and Pain Questionnaires for Clinical Trials (24-hour 
version) will be provided. 
 
Patient Global Impression of Change 
The PGI-C consists of 4 questions regarding diarrhea, abdominal (tummy) pain, overall pain, and daily 
living to be answered using a 7-point scale. Descriptive by visit summary tables at Month 3, 6 and 12/ET 
will be provided for observed PGI-C scores and average of overall Gastrointestinal (GI) symptoms scores. 
Categorical summary of improved and worsened status for each question at Month 3, 6 and 12/ET will 
also be summarized by visit and subgroup, ie, sex (male, female), ERT status (ERT naïve, ERT 
experienced), and overall if feasible. Improved status includes “Much better”, “Better” and “A little better”; 
Worsened status includes “A little worse”, “Worse” and “Much worse”; “The same” will be categorized 
separately. 
A by-subject listing of PGI-C Questionnaires will be provided. 
 
Fabry-Specific Pediatric Health and Pain Questionnaire 
The FPHPQ includes questions about Fabry disease-specific symptoms (eg, sweating, pain, dizziness 
and tiredness, heat and cold intolerance, swollen eyelids, gastrointestinal symptoms, feeling thirsty, 
difficulty hearing, ringing or buzzing noise in the ears, and ability and enjoyment to participate in sports). 
The frequency of these symptoms will be rated using a 5-point Likert scale (0=Never, 1=Seldom, 
2=Sometimes, 3=Often, 4=Always). Pain intensity is measured on an 11-point scale, numeric responses 
are given for onset of pain and school days missed, and yes/no questions are posed about difficulty 
hearing and other problems not specifically mentioned. There are 2 age-specific self-report versions for 
children 8 to 12 years and 13 to 18 years, respectively. 


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Descriptive summaries will be provided for the FPHPQ observed and change from baseline scores by 
visit and subgroup, ie, sex (male, female), ERT status (ERT naïve, ERT experienced), and overall if 
feasible. Unscheduled visits will not be included. 
A by-subject listing of FPHPQ scores will be provided. 
 
Pediatric Quality of Life Inventory 
The PedsQL™ is a modular approach to measuring health-related quality of life in healthy children and 
adolescents and those with acute and chronic health conditions. It consists of 23 items and includes 
questions about physical functioning (8 items), emotional functioning (5 items), social functioning 
(5 items), and school functioning (5 items) relative to the prior 7 days, using a 5-point scale (0=Never, 
1=Seldom, 2=Sometimes, 3=Often, 4=Always). Both parents or legally-authorized representatives and 
subjects complete the appropriate version of the PedsQLTM independently of one another. Parents or 
legally-authorized representatives and subjects may self-administer the questions after introductory 
instructions are given by study site personnel. 
PedsQLTM scoring procedure is as listed below: 
Step 1: Transform Score: 
Item scores are reversed and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 
4=0. 
Step 2: Calculate Scores: 
Score by Dimensions: 
If more than 50% of the items in the scale are missing, the scores should not be computed. 
Mean score = Sum of the items over the number of items answered. 
Psychosocial Health Summary Score = Sum of the items over the number of items answered in the 
Emotional, Social, and School Functioning Scales; 
Physical Health Summary Score = Physical Functioning Score; 
Total Score: Sum of all the items over the number of items answered on all the scales. 
Descriptive summary tables will be provided for the PedsQLTM observed and change from baseline of 
psychosocial, physical and total scores by visit and subgroup, ie, sex (male, female), ERT status (ERT 
naïve, ERT experienced), and overall if feasible. 
A by-subject listing of PedsQLTM scores for each single question as well as psychosocial, physical and 
total scores will be provided. 


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Analysis of Pharmacokinetics 
Analysis of PK will be described in a separate PKAP. 


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 Analysis of Pharmacodynamics 
 
Primary PD Endpoint and Analysis 
The PD endpoint is change in plasma levels of lyso-Gb3. Descriptive summaries will be provided for the 
change from baseline to Month 3, Month 6, and Month 12/ET by sex (male and female) , ERT status 
(ERT naïve, ERT experienced), and overall based on the safety population. 
A by-subject listing will also be provided. 
 
Other PD Analogs Analysis 
Other PD endpoints are change in plasma levels of lyso-Gb3 analogs. Descriptive summaries will be 
provided for the change from baseline to Month 3, Month 6, and Month 12/ET by sex (male and female), 
ERT status (ERT naïve, ERT experienced), and overall based on the safety population. 
A by-subject listing will also be provided. 


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 Safety 
The analysis population used for safety analyses will be the safety population. Safety will be assessed on 
the basis of extent of exposure, incidence of TEAEs, SAEs and AEs leading to discontinuation, clinical 
laboratory data, vital signs including body weight and height, ECHO, ECG parameters, physical 
examinations, and tanner stage. 
 
Extent of Exposure and Drug Compliance 
The duration of study drug exposure (in days) and the number of doses of study drug exposure will be 
summarized for the safety population. 
Average Dose Every Other Day is defined as: 
Average Dose Every Other Day = [Total dose received/ (Duration of exposure + 1)] * 2 
Drug Compliance is defined as: 
Drug Compliance (%) = Average Dose Every Other Day/Planned Dose Every Other Day (ie, 150 mg) 
Drug Compliance will be summarized using descriptive summaries. The number and percentage of 
subjects with Drug Compliance <80%, ≥80% will be summarized. 
A detailed listing of exposure to study drug and drug compliance will be presented. 
 
Adverse Events 
An overall summary of TEAEs, will be tabulated, including the number and percentage of subjects 
reporting: 
• 
TEAEs 
• 
Treatment-related TEAEs 
• 
SAEs 
• 
TEAEs leading to discontinuation of study drug 
• 
TEAEs leading to death 
The number of events and incidence rates will also be provided in the overall summary table. Incidence 
rate is calculated as: total events divided by the total patient years of exposure. Total patient years of 
exposure are the sum of the duration of exposure in years for all subjects. 
Further, the following TEAE summaries will be provided by sex and overall: 
• 
Any TEAEs by SOC and PT 
• 
Any TEAEs by PT 
• 
Treatment related TEAEs by SOC and PT 
• 
TEAEs by intensity, by SOC and PT 
• 
Serious TEAEs by SOC and PT 
• 
Any non-serious TEAE by PT 


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The number and percentage of subjects reporting TEAEs will be tabulated by SOC and PT. Subjects are 
counted only once within each SOC and PT. TEAEs will be presented alphabetically by SOC and PT. 
The number and percentage of subjects reporting TEAEs will also be tabulated by PT. Subjects are 
counted only once in each PT. TEAEs will be presented in the order of descending frequency in the 
overall group. 
The number and percentage of subjects reporting TEAEs will be tabulated by SOC, PT and maximum 
severity. If a subject has more than one event within a given SOC or PT at different severities, the 
maximum severity will be tabulated. For example, if a subject had two events with the same preferred 
term, but one was moderate and the other severe, the severe TEAE will be included in the tabulation. 
The number and percentage of subjects reporting treatment-related serious TEAEs will be tabulated by 
SOC and PT. Subjects are counted only once within each SOC and PT. Subject listings will also be 
provided for subjects with SAEs. 
 
Laboratory Evaluations 
Clinical laboratory test values (hematology, serum chemistry, and urinalysis) and changes from baseline 
will be summarized by each visit and subgroup, ie, sex (male, female), ERT status (ERT naïve, ERT 
experienced), and overall if feasible for the safety population. In addition, the following clinical summaries 
will be presented: 
• 
The frequencies and percentages of potential clinically significant (PCS) abnormalities at any 
time; 
• 
Tables displaying shifts from baseline to each assessment time-point in laboratory test values 
from normal to high or low using normal range including eGFR, urine protein, and albumin. 
Potential clinically significant abnormalities will be determined both by investigator assessment or 
derivation from lab alert ranges provided by Amicus. 
Clinically significant abnormal assessments for eGFR, urine protein and albumin will be summarized with 
frequency tables by sex (male, female), ERT status (ERT naïve, ERT experienced), and overall if 
feasible. Unscheduled visits will be included. Clinically significant abnormal values will be collected from 
investigator assessment on the CRF page. 
By-subject safety laboratory listings will be generated incorporating information and assessment results 
obtained from the designated laboratory which provided normal range and reported out of range flags. All 
laboratory results in Systѐme International (SI) units will be presented in data listings. Tests will be listed 
in alphabetical order within their respective panels (hematology, serum chemistry, and urinalysis). 
 
Vital Signs, Body Weight, and Height 
Vital signs (blood pressure, pulse rate, respiratory rate, and oral temperature), height, and weight will be 
assessed at the scheduled visits specified in Section 4.6. 
A summary table of observed and change from baseline values will be provided at each scheduled visit 
for the safety population, from baseline at Day 1-15, Month 1, Month 3, Month 6, Month 9 and 
Month 12/ET. Clinically significant abnormal results, in which unscheduled visits will be included, will be 
summarized with the frequency tables by sex (male, female), ERT status (ERT naïve, ERT experienced), 
and overall if feasible. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Amicus Therapeutics; Protocol No.: AT1001-020 
 
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A by-subject listing will be provided for each vital sign parameter. 
 
Echocardiography 
For categorical echocardiography results, an observed summary table will be provided by each parameter 
and visit in safety population. Scheduled visits will be included for by-visit summary tables. 
Clinically significant abnormal assessments for each parameter will be summarized with frequency tables 
by sex (male, female), ERT status (ERT naïve, ERT experienced), and overall if feasible. Unscheduled 
visits will be included. Clinically significant abnormal values will be collected from investigator assessment 
on the CRF page. 
 
ECG 
A summary table of observed and change from baseline values in ECG results will be provided at each 
scheduled visit for the safety population. A summary table displaying shifts from baseline to worst 
post-baseline interpretation assessment (including unscheduled assessments as applicable) will be 
provided by sex (male, female), ERT status (ERT naïve, ERT experienced), and overall if feasible. 
A by-subject listing will be provided, including each ECG parameter: heart rate (beats per minute [bpm]), 
RR interval [msec], PR interval [msec], QRS interval [msec], QT interval mean [msec], QTc (QTcF or 
QTcB) [msec] and interpretation. QTc = corrected QT interval, QTcF = corrected QT interval with 
Fridericia’s formula, and QTcB = corrected QT interval with Bazett’s formula. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Amicus Therapeutics; Protocol No.: AT1001-020 
 
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 Reference List 
Wang Y, Jadhav P, Lala M, Gobburu J. (2012). Clarification on precision criteria to derive sample size 
when designing pediatric pharmacokinetic studies. The Journal of Clinical Pharmacology. 52:1601-1606. 
Online source for PedsQLTM scoring: 
http://www.lsebn.nhs.uk/website/X13911/files/20%20scoring_PedsQL_v13[1].pdf 
 
Physical Examination 
Complete physical examination, including HEENT (Head, Eyes, Ears, Neck and Throat), Respiratory, 
Cardiovascular, Dermatological, Lymph Nodes, Gastrointestinal, Neurological, Thyroid, Musculoskeletal 
and other assessments, will be conducted at baseline and Month 3, 6, and 12/ET visits. A categorical 
summary table will be provided of the physical examination findings at each scheduled visit for the safety 
population by sex (male, female), ERT status (ERT naïve, ERT experienced), and overall if feasible. A 
by-subject listing will be presented for each body system. 
Brief physical examination will be summarized at Day 15-30, Month 1 and 9 visits. A by-subject listing will 
also be presented. 
 
Tanner Stage 
A summary table of assessment results in Tanner stage will include Baseline, Month 6 and12/ET visits for 
the safety population by sex (male, female), ERT status (ERT naïve, ERT experienced). A by-subject 
listing will be presented for each Tanner stage parameter, including pubic hair development, breast 
development, and genital development. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Amicus Therapeutics; Protocol No.: AT1001-020 
 
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 Interim Analyses 
An interim analysis was conducted on Stage 1 data for PK and safety assessments. The details are 
provided in a separate Interim SAP. 


Statistical Analysis Plan for Interventional Studies 
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 Changes from Analysis Planned in Protocol 
No changes are planned from the analyses described in the protocol, amendment 1 (10Sep2018), 
amendment 2 (31Oct2018), Protocol Amendment 3 (22Apr2019), and Protocol Amendment 4 
(13Jun2019). 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Amicus Therapeutics; Protocol No.: AT1001-020 
 
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 Programming Considerations 
All TLFs and statistical analyses will be generated using SAS® for Windows, Release 9.4 (SAS® Institute 
Inc., Cary, NC, USA). Computer-generated table, listing and figure output will adhere to the following 
specifications. 
 
General Considerations 
One SAS® program can create several outputs. 
Each output will be stored in a separate file. 
Output files will be delivered in Word format or portable document format (pdf). 
Numbering of TLFs will follow ICH E3 guidance  
 
Table, Listing, and Figure Format 
 
General 
• 
All TLFs will be produced in landscape format on A4/American letter size, unless otherwise 
specified. 
• All TLFs will be produced using the Courier New font, size 8. 
• The data displays for all TLFs will have a minimum 1-inch blank margin on all 4 sides. 
• Headers and footers for figures will be in Courier New font, size 8. 
• Legends will be used for all figures with more than 1 variable, group, or item displayed. 
• TLFs will be in black and white (no color), unless otherwise specified. 
• Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TLFs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used. 
• Only standard keyboard characters will be used in the TLFs. Special characters, such as 
non-printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (eg, μ). Certain subscripts and superscripts (eg, cm2, Cmax) will be employed 
on a case-by-case basis. 
• Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate. 
 
Headers 
• All output should have the following header at the top left of each page: 
Amicus Therapeutics 
Protocol: AT1001-020 
• All output should have the Data Cut-off Date at the top right of each page. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Amicus Therapeutics; Protocol No.: AT1001-020 
 
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• All output should have Page n of N at the top or bottom right corner of each page. TLFs are 
internally paginated in relation to the total length (ie, the page number should appear sequentially 
as page n of N, where N is the total number of pages in the table). 
• The date output was generated should appear along with the program name as a footer on each 
page. Each table should have the relevant listing number containing the raw data as a footer. 
 
Display Titles 
• Each TLF are identified by the designation and a numeral. (ie, Table 14.1.1). ICH E3 numbering 
convention will be followed. A decimal system (x.y and x.y.z) are used to identify TLFs with related 
contents. The title is centered. The analysis population is identified on the line immediately 
following the title. The title and table designation are single spaced. A solid line spanning the 
margins will separate the display titles from the 
•  Column headers. There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
(ITT population) 
 
Column Headers 
• Column headings are displayed immediately below the solid line described above in initial 
upper-case characters. 
• In the case of efficacy tables, the variable (or characteristic) column will be on the far left followed 
by the total column. 
• For numeric variables, include “unit” in column or row heading when appropriate. 
• Analysis population sizes will be presented for each column heading as (N=xx) (or in the row 
headings, if applicable). This is distinct from the ‘n’ used for the descriptive statistics representing 
the number of subjects in the analysis population. 
 
Body of the Data Display 
15.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
• Alphanumeric values are left-justified; 
• Whole numbers (eg, counts) are right-justified; and 
• Numbers containing fractional portions are decimal aligned. 
15.2.5.2. 
Table Conventions 
• The summary tables will clearly indicate the number of subjects to which the data apply and 
unknown or not performed are distinguished from missing data. 
• Units will be included where available 


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• If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category are presented in the table, even if n=0 in a given category that is between the 
minimum and maximum level for that parameter. For example, the frequency distribution for 
symptom severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be presented and so counts 
of 0 will be presented as 0 and not as 0 (0%). 
• If the categories are not ordered (eg, Medical History, Reasons for Discontinuation from the Study, 
etc.), then only those categories for which there is at least 1 subject represented in 1 or more 
groups are included. 
• An Unknown or Missing category are added to each parameter for which information is not 
available for 1 or more subjects. 
• Unless otherwise specified, the estimated mean and median for a set of values are printed out to 
1 more significant digit than the original values, and SD are printed out to 2 more significant digits 
than the original values. The minimum and maximum should report the same significant digits as 
the original values. For example, for systolic blood pressure: 
n 
  XX 
Mean 
XXX.X 
SD 
     X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
• P-values are output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal places. 
P-values less than 0.001 will be presented as <0.001. If a p-value is less than 0.0001, then present 
as <0.0001. If the p-value is returned as >0.999, then present as >0.999. 
• Percentage values are printed to one decimal place, in parentheses with no spaces, one space 
after the count (eg, 7 (12.8%), 13 (5.4%)). Unless otherwise noted, for all percentages, the number 
of subjects in the analysis population who have an observation will be the denominator. 
Percentages equating to 100% are presented as 100%, without decimal places. 
• Tabular display of data for medical history, prior/concomitant medications, and all tabular displays 
of adverse event data are presented by the body system, treatment class, or SOC, PT, assuming 
all terms are coded. If incidence for more than 1 term is identical, they should then be sorted 
alphabetically. Missing descriptive statistics or p-values which cannot be estimated are reported as 
“-”. 
• The percentage of subjects is normally calculated as a proportion of the number of subjects 
assessed for the analysis population presented. However, careful consideration is required in many 


Statistical Analysis Plan for Interventional Studies 
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instances due to the complicated nature of selecting the denominator, usually the appropriate 
number of subjects. Describe details of this in footnotes or programming notes. 
• For categorical summaries (number and percentage of subjects) where a subject can be included 
in more than one category, describe in a footnote or programming note if the subject are included 
in the summary statistics for all relevant categories or just 1 category and the criteria for selecting 
the criteria. 
• Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by “(cont)” at the top of each subsequent page. The 
overall summary statistics for the subheading should only be output on the first relevant page. 
15.2.5.3. 
Listing Conventions 
• Listings will include days relative to the initiation of treatment as applicable. 
• Listings will be sorted for presentation in order of subject number, visit/collection day, and 
visit/collection time. 
• Missing data are represented on subject listings as either a hyphen (“-”) with a corresponding 
footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = not applicable”, 
whichever is appropriate. 
• Dates are printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of dates 
are represented on subject listings as dashes (--JUL2000). Dates that are missing because they 
are not applicable for the subject are output as “N/A”, unless otherwise specified. 
• All observed time values are to be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(eg, 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
• Units will be included where available 
15.2.5.4. 
Figure Conventions 
• Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(eg, treatment mean change from Baseline) values will be displayed on the Y-axis. 
 
Footnotes 
• A solid line spanning the margins will separate the body of the data display from the footnotes. 
• All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display. 
• Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a 
reference footnote. Each new footnote should start on a new line, where possible. 
• Subject specific footnotes are avoided, where possible. 
• Footnotes will be used sparingly and add value to the table, figure, or data listing. If more than six 
lines of footnotes are planned, then a cover page may be used to display footnotes, and only those 
essential to comprehension of the data will be repeated on each page. 


Statistical Analysis Plan for Interventional Studies 
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• The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, date the program was run, and the listing source 
(ie, ‘Program: myprogram.sas, Listing source: 16.x.y.z’). 


Statistical Analysis Plan for Interventional Studies 
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 Quality Control 
SAS® programs are developed to produce output such as analysis data sets, summary tables, data 
listings, figures or statistical analyses. An overview of the development of programs is detailed in Syneos 
Health Standard Operating Procedure (SOP) Developing Statistical Programs (3907). 
Syneos Health SOPs Developing Statistical Programs (3907) and Quality Deliveries (SDTM, ADaM, TLF) 
(3908) describes the quality control procedures that are performed for all SAS® programs and output. 
Quality control is defined here as the operational techniques and activities undertaken to verify that the 
SAS® programs produce the output by checking for their logic, efficiency and commenting and by review 
of the produced output.