A Multicenter Open-Label Treatment Protocol to Observe the Safety of Replagal® (Agalsidase Alfa) Enzyme Replacement Therapy in Canadian Patients With Fabry Disease
Phase: PHASE3
Conditions: Fabry Disease
Sponsor: Shire

Treatment Protocol:  HGT-REP-081
Study Title:
A Multicenter Open-label Treatment Protocol to Observe the Safety 
of Replagal(agalsidase alfa) Enzyme Replacement Therapy in 
Canadian Patients with Fabry Disease
Study Number:
HGT-REP-081
Study Phase:
Phase 3/4
Product Name:
Replagal (agalsidase alfa)
Indication:
Fabry disease
Investigators:
Multicenter
Sponsor:
Shire Human Genetic Therapies, Inc. (Shire)
Sponsor 
Contact:
300 Shire Way
Lexington, MA 02421, USA
Medical 
Monitor:
, MD, MPH
Date
Original Protocol:
30 September 2010
Amendment 1:
23 November 2010
Amendment 2:
06 December 2010
Amendment 3:
15 September 2011
Amendment 4:
28 March 2013
Amendment 5:
27 March 2015
Confidentiality Statement
This document is the proprietary and confidential property of Shire.
PPD
PPD

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SYNOPSIS
Sponsor:
Shire Human Genetic Therapies, Inc. (Shire)
Name of Finished Product:  Replagal
Name of Active Ingredient:  agalsidase alfa 
Study Title:
A Multicenter Open-label Treatment Protocol to Observe the Safety of Replagal
(agalsidase alfa) Enzyme Replacement Therapy in Canadian Patients with Fabry Disease
Study Number:  HGT-REP-081
Study Phase:  Phase 3/4
Objective(s):  
The objective of this study is to observe the safety of Replagal in Canadian patients with 
Fabry disease.
Study Design: 
A minimum of 60 patients and up to 200 patients are expected to participate in this 
treatment protocol. Two cohorts are included in this protocol:  Cohort 1 provides Replagal 
treatment on an every-other-week (EOW) regimen, and Cohort 2 is only for patients who 
participated in REP001a and provides Replagal treatment on a weekly regimen. Patients 
may begin to enroll in the treatment protocol as soon as the eligibility criteria are fulfilled 
and informed consent forms are signed.
All eligible patients may receive Replagal produced by the bioreactor process (Replagal 
AF) on this treatment plan until Replagal AF is commercially available for the patient, the 
patient’s participation is discontinued, or the study is discontinued, whichever comes first. 
Safety data will be collected throughout the treatment protocol.
Population:
The study population consists of Canadian patients with Fabry disease.
Test Product, Dose, and Mode of Administration:
For Cohort 1:  Replagal, at a dose of 0.2 mg/kg body weight, administered as an 
intravenous (IV) infusion over 40 minutes, EOW
For Cohort 2:  Replagal, at a dose of 0.2 mg/kg body weight, administered as an IV 
infusion over 40 minutes, weekly
Duration of Treatment:
Dosing will continue until Replagal AF is commercially available to the patient, the 
patient’s participation is discontinued, or the study is discontinued, whichever comes first.

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Efficacy Assessments:
Not applicable
Safety Assessments: 
Safety endpoints, including adverse events (AEs), vital signs, blood tests, and antibodies 
to agalsidase alfa, will be assessed throughout this study.
Statistical Methods:
No formal statistical tests will be conducted. Tabular summaries of patient baseline 
demographic and clinical characteristics, patient disposition, medical history, physical 
examination, vital signs, AEs, blood tests, anti-agalsidase alfa antibody, and infusion 
information will be produced for the safety population. The safety population includes all 
patients who receive at least 1 full or partial infusion of Replagal.
Adverse event tabular summaries will be based on all treatment-emergent AEs recorded; 
AEs will be coded using the Medical Dictionary for Regulatory Activities coding 
dictionary.
Date of Amendment 5 Approval:  27 March 2015

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TABLE OF CONTENTS
SYNOPSIS.................................................................................................................................2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS............................................7
1
INTRODUCTION .............................................................................................................9
1.1
Overview of Fabry Disease......................................................................................9
1.2
Nonclinical Studies................................................................................................10
1.3
Previous Human Experience..................................................................................10
1.4
Current Therapies...................................................................................................11
1.4.1
Replagal (agalsidase alfa)............................................................................11
1.4.2
Differences between Replagal and Fabrazyme Enzyme Replacement 
Therapies......................................................................................................12
1.4.3
Summary of Known and Potential Risks and Benefits to Human Subjects 12
1.5
Rationale ................................................................................................................12
2
OBJECTIVE ....................................................................................................................13
3
OVERALL DESIGN AND PLAN..................................................................................14
4
POPULATION SELECTION..........................................................................................15
5
STUDY TREATMENT(S)..............................................................................................17
5.1
Description of Treatment(s)...................................................................................17
5.2
Treatment Administration......................................................................................17
5.3
Selection and Timing of Dose for Each Patient.....................................................17
5.4
Method of Assigning Patients to Cohorts..............................................................18
5.5
Blinding..................................................................................................................18
5.6
Packaging and Labeling.........................................................................................18
5.7
Storage ...................................................................................................................18
5.8
Investigational Product Accountability and Destruction .......................................18
6
TREATMENT PROTOCOL PROCEDURES ................................................................19
6.1
Eligibility Criteria..................................................................................................19
6.2
Disease and Treatment History..............................................................................19
6.3
Demographics ........................................................................................................19
6.4
Medical History .....................................................................................................19
6.5
Physical Examination.............................................................................................20
6.6
Vital Signs..............................................................................................................20
6.7
Blood Tests ............................................................................................................20
6.8
Antibody Assessments...........................................................................................21
6.9
Replagal Administration........................................................................................21
6.10
Adverse Events Assessments.................................................................................21
6.10.1
Definitions of Adverse Events and Serious Adverse Events.......................21

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6.10.1.1
Adverse Event....................................................................................21
6.10.1.2
Infusion-related Reactions .................................................................22
6.10.1.3
Serious Adverse Event.......................................................................22
6.10.2
Classification of Adverse Events and Serious Adverse Events...................23
6.10.2.1
Clarification between Serious and Severe .........................................23
6.10.3
Relatedness of Adverse Events and Serious Adverse Events......................23
6.10.4
Procedures for Recording and Reporting Adverse Events ..........................24
6.10.4.1
Adverse Event Monitoring and Period of Observation......................24
6.10.4.2
Reporting Serious Adverse Events ....................................................24
6.11
Management of Infusion-related Adverse Events..................................................25
6.12
Pregnancy...............................................................................................................25
6.13
Removal of Patients from the Study......................................................................25
6.14
Institutional Review Board/Ethics Committee/Research Ethics Board.................26
6.15
Ethical Conduct of the Study.................................................................................27
6.16
Patient Information and Informed Consent............................................................27
6.17
Patient Confidentiality...........................................................................................28
6.18
Case Report Form Completion ..............................................................................28
6.19
Monitoring .............................................................................................................28
6.20
Regulatory Administration.....................................................................................28
6.21
Premature Closure of the Treatment Protocol .......................................................28
6.21.1
Treatment Protocol Termination..................................................................28
6.21.2
Site Termination ..........................................................................................29
6.22
Record Retention ...................................................................................................29
6.23
Publication and Disclosure Policy .........................................................................29
7
STATISTICAL METHODS............................................................................................30
7.1
Demographic and Clinical Characteristics.............................................................30
7.2
Patient Disposition.................................................................................................30
7.3
Treatment Exposure...............................................................................................30
7.4
Anti-agalsidase Alfa Antibodies............................................................................30
7.5
Adverse Events and Other Safety Assessments.....................................................30
7.6
Interim Analysis.....................................................................................................31
8
LIST OF REFERENCES.................................................................................................32

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LIST OF IN-TEXT TABLES
Table 6-1
Adverse Event Severity..............................................................................23
Table 6-2
Adverse Event Relatedness ........................................................................23
LIST OF APPENDICES
Appendix 1
Schedule of Events for Cohort 1 (EOW Replagal Dosing Regimen) ........33
Appendix 2
Schedule of Events for Cohort 2 (Weekly Replagal Dosing Regimen 
for Patients Who Participated in REP001a) ...............................................34
Appendix 3
Investigator’s Signature..............................................................................35
Appendix 4
Justification for Amendment 5 and Summary of Changes.........................36

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Term
Definition
2D
2-dimensional
AE
adverse event
CFDI
Canadian Fabry Disease Initiative
cGMP
current Good Manufacturing Practice
CRF/eCRF
case report form/electronic case report form
CRO
contract research organization
EC
Ethics Committee
ECG
electrocardiogram
EOS
end of study
EOW
every other week
ERT
enzyme replacement therapy
Gb3
globotriaosylceramide
GCP
good clinical practice
GFR
glomerular filtration rate
GLA
α-galactosidase A
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IRAE
infusion-related adverse event
IRB
Institutional Review Board
IV
intravenous
LA
left atrium
LBBB
left branch bundle block
LV
left ventricular
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDS
New Drug Submission
pHEK
primary human embryonic kidney

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Term
Definition
PK
pharmacokinetic
PT
preferred term
REB
Research Ethics Board
Replagal AF
Replagal manufactured using the animal component-free, bioreactor process (agalAF1)
Replagal
Replagal roller bottle
SAE
serious adverse event
Shire
Shire Human Genetic Therapies, Inc.
sNDS
Supplemental New Drug Submission
SOC
system organ class
TIA
transient ischemic attack
UK
United Kingdom
US/USA
United States/United States of America

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1
INTRODUCTION
1.1
Overview of Fabry Disease 
Fabry disease is a rare, progressive, debilitating, glycosphingolipid storage disorder. It is caused 
by deficient activity of the lysosomal enzyme α-galactosidase A, which results from a mutation 
in the α-galactosidase A (GLA) gene, located on chromosome Xq22.1. -galactosidase A 
cleaves galactose in the alfa-anomeric configuration from glycosphingolipids, in particular 
globotriaosylceramide (Gb3).1 Mutations in the GLA gene lead to decreased or complete absence 
of enzyme activity that, in turn, result in accumulation of varying amounts of Gb3 in cells in 
vascular beds, cardiomyocytes, and various other cells, tissues, and organs throughout the body. 
The clinical manifestations of Fabry disease typically include angiokeratomas, acroparesthesias, 
anhydrosis, anhedonia, chronic renal insufficiency leading to renal failure, hypertrophic 
cardiomyopathy with arrhythmias and infarction, and microvascular cerebral events including 
transient ischemic attacks (TIAs), stroke, and dolychoectasia.2 In general, patients with complete 
absence of GLA have a classic phenotype with rapidly progressing renal, cardiac, and 
cerebrovascular events whereas patients with reduced GLA have an attenuated clinical 
phenotype.3
Clinical onset of Fabry disease typically occurs during childhood or adolescence with recurrent 
episodes of severe neuropathic pain in the extremities, characteristic cutaneous lesions known as 
angiokeratomas, and a distinctive but asymptomatic corneal dystrophy termed cornea verticillata. 
Vital organs, especially the heart, kidneys, and brain, are progressively affected with increasing 
age.4
In contrast to classical X-linked disorders, females may also be affected, presumably from biased 
X-linked inactivation and lack of cross-cellular correction of lyonized cells by normal cells. 
Females may inherit an X-linked Fabry mutation from either parent and are not asymptomatic 
carriers. Females account for twice the number of male patients. Clinically, manifestations in 
females range from mild to severe phenotypes.5, 6 The onset of symptoms and age of diagnosis in 
females occur approximately 10 years later than in males.7
Before the availability of dialysis or renal transplantation, renal complications accounted for the 
mortality of male Fabry patients during the fourth or fifth decade of life.8 Median age of death in 
males is 50 to 55 years of age. Death in female patients with Fabry disease is, on average, a 
decade or more later than in males and occurs primarily as a result of cardiac or cerebrovascular 
complications.9, 10
Data on the true global incidence of Fabry disease are scarce, and estimates vary among 
1:117,000, ~1:50,000, and ~1:4,600 live births. Estimates suggest that the ratio of patients with 
the later-onset disease:  Classic phenotypes are 7:1.11, 12
The diagnosis of Fabry disease may be made in males based on low levels of plasma or 
leukocyte GLA activity or by the presence of a gene mutation. In females, a presumptive 
diagnosis of Fabry disease may be based on the presence of characteristic clinical findings that 
must be confirmed by genotyping. 

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Prior to the advent of enzyme replacement therapy (ERT) in 2001, Fabry disease was an 
underdiagnosed condition that was primarily recognized in males with symptoms of the classical 
disease severity. Women were rarely diagnosed.12-14
1.2
Nonclinical Studies
The nonclinical studies have demonstrated that agalsidase alfa is well tolerated in acute 
toxicology studies in mice and rats and in multiple dosing studies in rats, rabbits, and monkeys. 
Toxicology studies have included a single-dose intravenous (IV) toxicology study in rats testing 
doses up to 10.0 mg/kg (a dose that is 50-fold greater than the standard human dose of 0.2 mg/kg 
every other week (EOW) and 25-fold greater than the maximum human dose of 0.4 mg/kg once 
weekly tested in clinical studies [TKT027]). Chronic toxicology studies have included 13-week 
and a 26-week repeated IV dose studies in rats and a 13-week repeated IV dose study in 
cynomolgus monkeys where doses up to 1 mg/kg/week were tested, which was 10-fold greater 
than the standard human dose and 2.5-fold greater than the maximum tested human dose. None 
of these tests showed evidence of significant toxicity associated with agalsidase alfa. In addition, 
an in vitro tumorigenicity study in cultured primary human embryonic kidney (pHEK) cells was 
performed, and this study demonstrated that agalsidase alfa did not alter the in vitro 
tumorigenicity or growth rates of normal pHEK cells (data on file). 
Reproductive studies in male and female rats and female rabbits revealed no untoward effects on 
male or female reproductive function, histopathology of reproductive organs, or embryo-fetal 
development. The pharmacokinetic (PK) properties and biodistribution of agalsidase alfa in 
mice, rats, rabbits, and monkeys have been well characterized. Following a single IV 
administration, serum levels of agalsidase alfa followed a biphasic distribution in several animal 
species including rats and monkeys. The elimination half-lives were less than 2 hours in all 
species, and serum levels returned to predose values 24 hours after administration. Both the 
maximum serum concentration immediately after dosing and the area under the concentration 
time curve were approximately proportional to the administered dose in rats and monkeys. There 
were only minor effects on PK parameters following multiple dosing in rats and monkeys.
Biodistribution studies in rats using iodine-125-labeled agalsidase alfa have demonstrated that 
significant amounts of agalsidase alfa can be found in key organs pathologically affected in 
Fabry disease after IV administration, in particular the kidneys and heart. Single- and 
multiple-dose pharmacodynamic studies in knockout mice have demonstrated a significant 
reduction in Gb3 in the liver, heart, and kidneys. 
Further details on the nonclinical studies are provided in the Investigator’s Brochure (IB).
1.3
Previous Human Experience
Clinical studies of agalsidase alfa have been conducted in the United States (US), United 
Kingdom (UK), Canada, Australia, Europe, Brazil, and Japan. 

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The clinical development program has included 3 placebo-controlled clinical studies of 6-month 
dosing duration in adults (TKT003, TKT005, TKT010) and open-label maintenance studies for 
patients continuing from these and other studies (TKT006, TKT007, TKT011, TKT013, and 
TKT015). 
Additionally, a study in female patients (TKT014), a study in dialysis and renal transplant 
patients (TKT019), and a single-center, open-label, compassionate use study (TKT012) have also 
been performed. Three completed studies have been conducted in children (TKT023, TKT029, 
and TKT5S001). An additional study (TKT028) was conducted in patients with left ventricular 
hypertrophy. Other completed studies include REP001a, a Phase 4 study of alternative dosing 
regimens for Replagal in Canadian patients with Fabry disease; HGT-REP-059, a treatment 
protocol to provide access to Replagal for patients with Fabry disease in the US; HGT-REP-082, 
a comparability study between Replagal produced from agalsidase alfa manufactured by 
2 different processes in Canada; HGT-REP-060, an open-label extension study for TKT028; and 
HGT-REP-084, a study of treatment-naïve children using Replagal manufactured using the 
bioreactor process (Replagal AF).
In total, 514 adults and 67 children have received Replagal in completed Shire-sponsored 
studies. Long-term safety experience demonstrates that Replagal therapy has been generally well 
tolerated in clinical studies, as well as in commercial and compassionate use.
Additional details of these clinical studies are available in the Investigator Brochure.
1.4
Current Therapies
The current approved treatment for Fabry disease is ERT. There are 2 products in this therapeutic 
class: agalsidase alfa (marketed under the trade name of Replagalin countries outside the 
United States, by Shire) and agalsidase beta (Fabrazyme; Genzyme). Both are indicated for 
long-term treatment in patients with a confirmed diagnosis of Fabry disease (GLA deficiency). 
Replagal is currently approved in 52 countries worldwide and has investigational status in 
Canada.
1.4.1
Replagal (agalsidase alfa)
Replagal is manufactured from agalsidase alfa using an aseptic filling process in a facility in 
compliance with current Good Manufacturing Practice (cGMP) regulations. Replagal is 
formulated as a sterile product suitable for parenteral administration. The formulation of 
Replagal includes sodium phosphate as a buffering agent, polysorbate 20 as a stabilizing agent, 
and sodium chloride as an isotonic agent.
Replagal is intended for use as ERT for patients with Fabry disease. It is anticipated that 
replacement of the deficient enzyme may contribute to correction of the enzymatic defect and 
allow for improved metabolism of the natural substrate for the enzyme. Over time, chronic 
replacement of the deficient enzyme could theoretically alter the natural history of Fabry disease, 
with concomitant improvements in renal and cardiac function, metabolism, neuropathic pain, and 
quality of life.

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1.4.2
Differences between Replagal and Fabrazyme Enzyme Replacement Therapies
Replagal is produced by a genetically engineered continuous human cell line. Fabrazyme is 
produced using a Chinese hamster ovary cell line. Other differences include post-translational 
modification of mannose residues such as glycosylation, sialylation, and phosphorylation, which 
can potentially influence the tissue uptake and the rate of development of antibodies to the 
exogenously administered enzymes. Formulation excipients may also contribute to differences in 
individual patient sensitivities to the treatments.
1.4.3
Summary of Known and Potential Risks and Benefits to Human Subjects
A summary of the risks and benefits for Replagal is provided in the IB.
1.5
Rationale
The original Replagal New Drug Submission (NDS) was approved in Canada in 2004, indicated 
for long-term treatment in patients with Fabry disease. In March 2009, Shire submitted a 
Supplemental New Drug Submission (sNDS) for Replagal bioreactor (agalAF1 or AF) drug 
substance process by implementing a bioreactor process in place of the previously employed 
roller bottle process and eliminating animal-sourced raw materials. There are no changes to the 
Replagal drug product formulation, manufacturing site, manufacturing process, and container 
closure. A supplemental NDS (SNDS) for the new manufacturing process was submitted to 
Health Canada in March 2009. Approval of the new manufacturing process was not granted. 
Supplies of the roller bottle Replagal (Replagal RB) are no longer manufactured, and this 
protocol provides a mechanism to maintain uninterrupted supply of Replagal (Replagal AF) to 
Canadian patients.
As of 01 March 2015, Replagal 1 mg/mL concentrate for solution for infusion has been approved 
in 52 countries. The approved dose for Replagal in these countries is 0.2 mg/kg EOW
administered by intravenous (IV) infusion over 40 minutes. As of 31 August 2014, the estimated 
cumulative worldwide patient exposure of Replagal RB and AF is 17,222 person-years 
treatment; the estimated cumulative worldwide patient exposure of Replagal AF is 11,626 
person-years. No new safety concerns have been identified upon the change in manufacturing 
process from Replagal RB to Replagal AF.

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2
OBJECTIVE
The objective of this protocol is to observe the safety of Replagal in Canadian patients with 
Fabry disease.

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3
OVERALL DESIGN AND PLAN
A minimum of 60 patients and up to 200 patients are expected to participate in this protocol. 
Two cohorts are included in this protocol: Cohort 1 is for patients who may also be enrolled in 
the Canadian Fabry Disease Initiative (CFDI) and provides Replagal treatment on an EOW 
regimen, and Cohort 2 is only for patients who participated in REP001a and provides Replagal 
treatment on a weekly regimen. Patients may begin to enroll in the treatment protocol as soon as 
the eligibility criteria are fulfilled and informed consent is obtained. 
All patients may continue to receive Replagal on this treatment plan until Replagal is 
commercially available for the patient or the patient’s participation or the study is discontinued, 
whichever comes first. Safety data will be collected throughout the treatment protocol.

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4
POPULATION SELECTION
The population consists of Canadian patients with Fabry disease.
Each patient in Cohort 1 must meet the following criteria to receive treatment (inclusion criteria 
for Cohort 1 are consistent with the CFDI):
1. The patient has a documented diagnosis of Fabry disease.
2. The patient is sufficiently compliant with study activities to participate in this treatment plan, 
as judged by the investigator.
3. The patient must meet current Canadian guidelines for ERT for Fabry disease15 by meeting 
any of the following criteria:
a.
Age-adjusted glomerular filtration rate (GFR) <80 mL/min or a decline in GFR of >10% 
that is sustained for 3 months and for which other causes of declining renal function have 
been excluded by a nephrologist or any 2 of the following:
•
Isolated proteinuria ≥500 mg/day/1.73 m2 without other cause
•
Nephrogenic diabetes insipidus
•
Fanconi syndrome
•
Hypertension
b. Evidence of cardiac involvement related to Fabry disease including any 2 of the 
following:
•
Left ventricular (LV) wall thickness >12 mm
•
Left ventricular hypertrophy by electrocardiogram (ECG); Estes ECG score must be 
>5
•
Left ventricular mass index by 2-dimensional (2D) echocardiogram 20% above 
normal for age
•
Diastolic filling abnormalities by 2D echocardiogram or other accepted measures of 
diastolic filling. E/A ratio >2.0 and deceleration time <140 msec 
•
Increase of LV mass of at least 5 g/m2/year, with 3 measurements over a minimum of 
12 months
•
Increase of left atrium (LA) size on 2D echo at least 10% above normal for age. In 
parasternal long axis view >33 mm; in 4-chamber view >42 mm
•
Cardiac conduction and rhythm abnormalities:  AV block, short PR interval, left 
branch bundle block (LBBB), ventricular or atrial tachyarrhythmias, 
sinus bradycardia (in the absence of drugs with negative chronotropic activity)
•
Delayed posterolateral LV wall late enhancement on magnetic resonance imaging as 
evidence of advanced cardiac disease with fibrosis. 
c.
Evidence of neurological involvement related to Fabry disease, including 1 of the 
following:
•
Stroke or TIA prior to the age of 55 documented by a neurologist
•
Acute onset unilateral hearing loss

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•
Acute monocular visual loss without other cause
d. Chronic, intractable diarrhea and/or abdominal pain/cramps, refractory to standard 
management for at least 6 months 
e.
Chronic, intractable neuropathic pain, refractory to analgesics and standard pain 
management for at least 6 months 
Each patient in Cohort 2 must meet the following criteria to receive treatment:
1. Patient must have participated in REP001a.
Patients who meet any of the following criteria will be excluded from the study:
1. The patient has experienced an anaphylactic or anaphylactoid reaction or other 
infusion-related reaction which, in the opinion of the investigator, precludes further treatment 
with Replagal or may interfere with the interpretation of the study.
2. The patient is otherwise unsuitable for the study, in the opinion of the investigator.
3. The patient is enrolled in another clinical study, other than the CFDI.

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5
STUDY TREATMENT(S)
5.1
Description of Treatment(s)
Patients in Cohort 1 will receive Replagal at a dose of 0.2 mg/kg body weight administered as an 
IV infusion over 40 (10) minutes EOW (5 days). 
Patients in Cohort 2 will continue to receive Replagal at a dose of 0.2 mg/kg body weight 
administered as an IV infusion over 40 (10) minutes weekly (2 days).
Refer to the Infusion and Pharmacy Manuals for detailed instructions on special precautions and 
handling.
5.2
Treatment Administration
Replagal will be provided by Shire in vials as a concentrate for solution for infusion. 
Replagal infusions may occur at the clinical site, at home, or at a qualified satellite treatment 
center at the investigator’s discretion. Patients experiencing severe or serious adverse events 
(AEs) that are also infusion-related AEs (IRAEs) must receive their infusions at the clinical site 
or qualified treatment center until they have had 2 successive infusions without severe or serious 
IRAEs. Clinical judgment of the investigator for management of any other IRAEs occurring 
during home infusions will be used. Patients receiving Replagal as home therapy are required to 
return to the clinical site for biannual or annual safety visits as indicated in the schedule of events 
(Appendix 1 and Appendix 2).
The qualified, trained medical personnel will follow the Study Pharmacy and/or Infusion 
Manuals provided separately from this protocol that outlines all operating procedures to be 
followed for this treatment protocol, including drug receipt, reconstitution, and the required 
patient assessments before, during, and after infusion of study drug. Clinical evaluations will 
remain under the medical supervision of the investigator.
5.3
Selection and Timing of Dose for Each Patient
For patients in Cohort 1, Replagal will be administered at a dose of 0.2 mg/kg body weight as an 
IV infusion over 40 (10) minutes EOW (5 days).
For patients in Cohort 2, Replagal will be administered at a dose of 0.2 mg/kg body weight as an 
IV infusion over 40 (10) minutes weekly (2 days).
Based on the weights obtained at the biannual or annual visits, as applicable, the dose should be 
updated if the weight change is ±5% from the initial weight or from the previous visit or at the 
discretion of the investigator.

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5.4
Method of Assigning Patients to Cohorts
Only patients who have participated in REP001a will be enrolled into Cohort 2 to receive weekly 
dosing with Replagal. All other patients will be enrolled into Cohort 1 to receive EOW dosing 
with Replagal. 
5.5
Blinding
Not applicable.
5.6
Packaging and Labeling
Replagal is supplied as a sterile, clear, colorless concentrate for dilution for IV infusion. 
Replagal will be provided in single-use, 5 mL vials containing 3.5 mL of concentrate at a 
concentration of 1 mg/mL. 
Study drug labels will contain information necessary to meet the applicable regulatory 
requirements.
5.7
Storage
Replagal will be provided by the sponsor (or designee) to the clinical study sites, qualified 
satellite sites, or patient residences (or other approved location) in a temperature-controlled, 
monitored container. The vials should be stored in a refrigerator at 2-8°C (36-46°F). A minute 
amount of fine particulate matter, causing the solution to appear slightly hazy, may be present 
during storage.
5.8
Investigational Product Accountability and Destruction
The final disposition of all investigational product must be recorded on a patient-by-patient basis. 
The date and time of administration of the study drug will be documented on the appropriate case 
report form/electronic case report form (CRF/eCRF).
All used, partially used, and unopened study drug vials must be returned to the 
sponsor-designated pharmacy.

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6
TREATMENT PROTOCOL PROCEDURES
Complete schedules of events for Cohort 1 and Cohort 2 are provided in Appendix 1 and
Appendix 2. This protocol is intended to follow the same schedule and assessments as the CFDI 
protocol, and the safety visits in this protocol are intended to coincide with the biannual or 
annual visits recommended by the CFDI. 
Patients enrolled in this study must be treated in accordance with current Canadian guidelines for 
the treatment of Fabry disease. 
6.1
Eligibility Criteria
Eligibility criteria (provided in Section 4) will be reviewed, and patient eligibility will be 
determined prior to the patient receiving the first dose of Replagal.
6.2
Disease and Treatment History
Documentation of diagnosis with Fabry disease will be collected up to 6 months prior to the 
patient receiving the first dose of Replagal.
6.3
Demographics
Patient demographics, including patient sex, age, and race, will be collected. 
6.4
Medical History
A review of the patient’s medical history will occur up to 6 months prior to the patient receiving 
the first dose of Replagal. This review will include a review of body systems, documentation of 
current procedures, and documentation of current concomitant medication usage. In addition, the 
patient will be queried on the following:
•
Relevant intercurrent illness and chronic disease update
•
Medication use and dose (particularly those used to treat Fabry disease)
•
Site of prior ERT (ie, hospital, infusion center, doctor’s office, home, other)
•
Disease-specific review of symptoms, including:
-
Head, neck, and thyroid
-
Eyes, ears, nose, and throat
-
Chest and lungs
-
Heart
-
Lymph nodes
-
Abdomen
-
Anorectal
-
Genitourinary
-
Skin
-
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-
Endocrine
-
Neurological
-
Other
6.5
Physical Examination
Complete physical examinations will occur prior to the first dose of Replagal administration and 
during the biannual or annual safety visits, as applicable. The physical examinations will include 
assessments of:
•
Head, neck, and thyroid
•
Eyes, ears, nose, and throat
•
Chest and lungs
•
Heart
•
Lymph nodes
•
Abdomen
•
Anorectal
•
Genitourinary
•
Skin
•
Musculoskeletal
•
Endocrine
•
Neurological
•
Height (measured at baseline for all patients, and for patients <18 years at baseline, height 
will also be measured at biannual or annual safety visits until they are ≥18 years of age)
•
Weight (within 1 month prior to the first Replagal infusion)
•
Other
Clinically significant findings from the physical examinations are to be reported as AEs.
6.6
Vital Signs
Vital signs, including blood pressure, pulse, respiratory rate, and temperature, will be measured 
immediately prior to each infusion and immediately following each infusion (10 minutes).
6.7
Blood Tests
Blood will be collected within 6 months prior to the patient receiving the first dose of Replagal 
and at the biannual or annual safety visits for the following assessments:  creatinine, glucose, 
urea, potassium, sodium, chloride, bicarbonate, and fasting lipids profile.

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6.8
Antibody Assessments
Serum samples will be collected for evaluation of anti-agalsidase alfa antibodies within 6 months 
prior to the patient receiving the first dose of Replagal and at the biannual or annual safety visits, 
as applicable. Analysis of anti-agalsidase alfa antibodies will be performed using a validated 
electrochemiluminescent immunoassay following a tiered approach (screening, confirmatory, 
and titer). Samples that are confirmed positive for the presence of anti-agalsidase alfa antibodies 
will be further evaluated for the presence of neutralizing antibodies using an enzyme inhibition 
assay. Sample collection, processing, and shipping instructions will be detailed in the study 
laboratory manual. This manual is to be provided by the central laboratory.
6.9
Replagal Administration
Patients in Cohort 1 will receive Replagal IV infusions EOW until Replagal is commercially 
available to the patient or the patient’s participation or the study is discontinued. 
Patients in Cohort 2 will receive Replagal IV infusions weekly until Replagal is commercially 
available to the patient or the patient’s participation or the study is discontinued.
Replagal administration will occur as described in Section 5.2; home infusions may occur at the 
discretion of the investigator.
6.10
Adverse Events Assessments
6.10.1
Definitions of Adverse Events and Serious Adverse Events
6.10.1.1
Adverse Event
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered investigational product-related. This 
includes an exacerbation of a pre-existing condition. 
Adverse events include:
•
Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study
•
Intercurrent illnesses
•
Drug interactions
•
Events related to or possibly related to concomitant medications
•
Abnormal laboratory values (This includes significant shifts from baseline within the range 
of normal that the Investigator considers to be clinically important.)
•
Clinically significant abnormalities in physical examination, vital signs, and weight
Throughout the study, the investigator must record all AEs on the AE eCRF, regardless of the 
severity or relationship to investigational product. The investigator should treat patients with 

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AEs appropriately and observe them at suitable intervals until the events stabilize or resolve. 
Adverse events may be discovered through observation or examination of the patient, 
questioning of the patient, complaint by the patient, or abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become significantly out of range as 
determined by the investigator or in the opinion of the investigator. In the event of an 
out-of-range value, the laboratory test should be repeated until it returns to normal or can be 
explained and the patient’s safety is not at risk.
Additional illnesses present at the time when informed consent is obtained are regarded as 
concomitant illnesses and will be documented on the appropriate pages of the eCRF. Illnesses 
first occurring or detected during the study, and worsening of a concomitant illness during the 
study, are to be regarded as AEs and must be documented as such in the eCRF.
6.10.1.2
Infusion-related Reactions
An infusion-related reaction will be defined as an AE that 1) begins either during or within 
12 hours after the start of the infusion and 2) is judged as possibly or probably related to study 
drug. Adverse events that are considered infusion-related reactions will be noted as such in the 
appropriate field on the eCRF. Other AEs that occur prior to the infusion, along with AEs 
associated with protocol-defined testing and assessments (laboratory testing and physical 
examinations) that were performed prior to the infusion, will not be defined as infusion-related 
reactions. All AEs should be recorded, together with causality assessment. 
A list of the most common infusion-related reactions that have been reported in patients with 
Fabry disease during Replagal infusions is included in the current Replagal IB.
6.10.1.3
Serious Adverse Event
A serious AE (SAE) is any AE occurring at any dose that results in any of the following 
outcomes:
•
Death
•
Is life-threatening
•
Requires hospitalization
•
Requires prolongation of existing hospitalization
•
A persistent or significant disability or incapacity
•
A congenital anomaly or birth defect
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. A life-threatening AE is defined as an AE that placed the 
patient, in the view of the initial reporter, at immediate risk of death from the AE as it occurred 

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(ie, it does not include an AE that, had it occurred in a more severe form, might have caused 
death).
6.10.2
Classification of Adverse Events and Serious Adverse Events
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
grading scale should be referenced when assessing the severity of an AE. If an AE is not 
described in the NCI CTCAE, the severity should be recorded based on the scale below. The 
severity of all AEs/SAEs should be recorded on the appropriate CRF/eCRF page as Grade 1, 2, 
3, or 4 corresponding, respectively, to a severity of mild, moderate, severe, or life-threatening 
(Table 6-1).
Table 6-1
Adverse Event Severity
Severity
Definition
Grade 1 (Mild)
No limitation of usual activities.
Grade 2 (Moderate)
Some limitation of usual activities.
Grade 3 (Severe)
Inability to carry out usual activities.
Grade 4 (Life-threatening)
Immediate risk of death.
6.10.2.1
Clarification between Serious and Severe
The term severe is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as “serious,” which is based 
on the outcome or action criteria usually associated with events that pose a threat to life or 
functioning. Seriousness (not severity) and causality serve as a guide for defining regulatory 
reporting obligations.
6.10.3
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product is to be determined by the investigator 
based on the following definitions (Table 6-2).
Table 6-2
Adverse Event Relatedness
Relationship to Product(s)
Definition
Not Related
Unrelated to investigational product
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, but which could 
also be explained by concurrent disease or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, unlikely to be 
attributable to concurrent disease or other drugs and chemicals and 
which follows a clinically reasonable response on de-challenge. The 
association of the clinical event or laboratory abnormality must also 
have some biologic plausibility, at least on theoretical grounds.

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6.10.4
Procedures for Recording and Reporting Adverse Events
6.10.4.1
Adverse Event Monitoring and Period of Observation
Adverse events will be monitored continuously throughout the study.
For the purposes of this study, the period of observation extends from the time at which the 
patient, the patient’s parent(s), or the patient’s legally authorized representative gives informed 
consent until the patient’s final evaluation of the study. For safety purposes, the final evaluation 
will be defined as the follow-up evaluation performed approximately 30 days after the last dose 
for patients who complete the study.
If the investigator considers it necessary to report an AE in a study patient after the end of the 
safety observation period, he or she should contact the sponsor to determine how the AE should 
be documented and reported.
6.10.4.2
Reporting Serious Adverse Events
Any SAE, regardless of relationship to investigational product, which occurs in a patient after 
informed consent, should be recorded by the clinical site on an SAE form. The SAE must be 
completely described on the patient’s eCRF, including the judgment of the investigator as to the 
relationship of the SAE to the investigational product. The investigator will promptly supply all 
information identified and requested by the sponsor (or contract research organization [CRO]) 
regarding the SAE. 
The investigator must report the SAE to the Shire Pharmacovigilance and Risk Management 
Department AND to the Shire medical monitor on an SAE form. This form must be completed 
and FAXED or EMAILED within 24 hours of the investigator’s learning of the 
event to:
Shire Pharmacovigilance and Risk Management Department:
International FAX:  
(UK) OR United States and Canada
FAX:  
AND
Shire Medical Monitor:  
, MD, MPH
FAX:  
(USA)
Any follow-up information must also be completed on an SAE form and faxed or emailed to the 
same numbers listed above.
In the event of a severe and unexpected, fatal, or life-threatening SAE, the clinical site must 
contact the Shire medical monitor by telephone; this is in addition to completing and transmitting 
the SAE form as stated above. The following provides contact information for the Shire medical 
monitor. 
PPD
PPD
PPD
PPD
PPD
PPD

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If an SAE is assessed as severe and unexpected or life-threatening, contact:
, MD, MPH
Shire300 Shire Way, Lexington, MA 02421, USA
Telephone: 
Fax: 
 (USA)
Mobile:  
The investigator must promptly report all required information to the Institutional Review Board 
(IRB)/Ethics Committee (EC)/Research Ethics Boards (REB). It is the responsibility of the 
sponsor to ensure that each investigator receives a copy of any Council for International 
Organizations of Medical Sciences I/MedWatch report that has been submitted to the appropriate 
regulatory agencies notifying them of an unexpected related SAE. The investigator or sponsor 
must ensure that the IRB/EC/REB receives a copy of the report and that a copy is also filed 
within their study files.
6.11
Management of Infusion-related Adverse Events
If a patient has an IRAE during the infusion of study drug, the investigator or the home infusion 
nurse should decide, based on his or her clinical judgment, whether the infusion should be 
slowed or temporarily or permanently discontinued. Mild and transient effects may not require 
medical treatment or discontinuation of the infusion. Infusion-related AEs that occur 
post-infusion should be assessed and treated symptomatically as needed. If severe allergic or 
anaphylactic-type reactions occur, the administration of Replagal should be discontinued 
immediately and appropriate treatment initiated. The current medical standards for emergency 
treatment are to be observed.
Patients experiencing a recurrent IRAE may be premedicated. Pretreatment, generally with oral 
antihistamines and corticosteroids, from 1 to 3 hours prior to infusion has prevented subsequent 
reactions in those cases where symptomatic treatment was required. If infusions continue without 
incident, then tapering of medications can be considered.
6.12
Pregnancy
The sponsor must be notified in the event of a pregnancy occurring during the course of the 
study and through 30 days after the patient’s last dose of study drug. Pregnancy is not to be 
reported as an AE; the pregnancy form should be used to report the pregnancy. The pregnancy 
will be followed through delivery or final outcome.
6.13
Removal of Patients from the Study
Patients may withdraw from the treatment protocol at any time. The investigator or sponsor may
withdraw a patient from the treatment protocol for the following medical or administrative 
reasons:
PPD
PPD
PPD
PPD
PPD
PPD

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•
Adverse event:  If a patient experiences an AE that, in the judgment of the investigator, the 
sponsor, or the Shire medical monitor, presents an unacceptable consequence or risk to the 
patient, the patient will be withdrawn from the treatment protocol.
•
Adverse laboratory experience:  If a patient has an adverse laboratory experience that, in the 
judgment of the investigator, the sponsor, or the Shire medical monitor, presents an 
unacceptable consequence or risk to the patient, the patient will be withdrawn from the 
treatment protocol.
•
Comorbidity:  If a patient develops a comorbidity during the course of the treatment protocol 
that is not associated with the condition under study, and that requires treatment that is not 
consistent with protocol requirements, the patient will be withdrawn from the treatment 
protocol. A patient will be withdrawn from the treatment protocol if, in the judgment of the 
investigator, he or she develops an intercurrent illness that, in any way, justifies his or her 
withdrawal.
•
Refusal of treatment:  If for any reason the patient refuses treatment during the treatment 
protocol, the patient will be withdrawn from the treatment protocol, and the reason for refusal 
will be documented on the CRF. Reasonable efforts will be made to monitor the patient for 
AEs following such discontinuation. Such efforts will be documented in the CRF.
•
Withdrawal of informed consent:  A patient may withdraw his or her informed consent to 
participate in the treatment protocol at any time and for any reason.
•
Lack of efficacy:  The patient will be withdrawn from the treatment protocol if, in the 
opinion of the CFDI investigator, a lack of efficacy is observed. 
At the time of discontinuation or withdrawal, patients will undergo all safety evaluations 
required for the end-of-study (EOS) visit. The investigator will complete the appropriate eCRF 
describing the reason for discontinuation. 
In addition, patients who withdraw or are discontinued will have a follow-up assessment for 
safety at the clinical site 30 days after their last infusion of Replagal.
6.14
Institutional Review Board/Ethics Committee/Research Ethics Board
Before initiation of the treatment protocol, the investigator must provide the sponsor with a copy 
of the written IRB/EC/REB approval of the protocol and the ICF. This approval must refer to the 
ICF and to the study title, study number, and version and date of issue of treatment protocol, as 
given by the sponsor on the cover page of the protocol. Local IRBs may be given the option to 
delegate to the central IRB identified for the study.
Status reports must be submitted to the IRB/EC/REB at least once per year. The IRB/EC/REB 
must be notified of completion of the treatment protocol. Within 3 months of treatment protocol 
completion or termination, a final report must be provided to the IRB/EC/REB. A copy of these 
reports shall be sent to the site’s study monitor. The investigators must maintain an accurate and 
complete record of all submissions made to the IRB/EC/REB, including a list of all reports and 
documents submitted. Adverse events that are reported to Health Canada or other regulatory 
agencies must be submitted promptly to the IRB/EC/REB.

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6.15
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigators abide by 
good clinical practice (GCP) as described in the 21 Code of Federal Regulations Parts 50, 54, 56, 
and 312 and the International Conference on Harmonisation (ICH) GCP Guidelines Compliance 
with these regulations and guidelines also constitutes compliance with the ethical principles 
described in the Declaration of Helsinki.
6.16
Patient Information and Informed Consent
Before enrolling in the treatment protocol, each patient, the patient’s parent(s), or the patient’s 
legally authorized representative(s) must consent to participate after the nature, scope, and 
possible consequences of the treatment protocol have been explained in a form understandable to 
him/her. An ICF that includes information about the treatment protocol will be prepared and 
given to the patient, the patient’s parent(s), or the patient’s legally authorized representative. This 
document will contain all Health Canada- and ICH-required elements. 
The ICF must be in a language understandable to the patient, the patient’s parent(s), or the 
patient’s legally authorized representative(s) and must specify who informed the patient, the 
patient’s parent(s), or the patient’s legally authorized representative(s).
After reading the informed consent document, the patient, the patient’s parent(s), or the patient’s 
legally authorized representative must give consent in writing. The patient’s consent must be 
confirmed at the time of consent by the personally dated signature of the patient, the patient’s 
parent(s), or the patient’s legally authorized representative and by the personally dated signature 
of the person conducting the informed consent discussions. 
If the patient, the patient’s parent(s), or the patient’s legally authorized representative is unable to 
read, oral presentation and explanation of the written ICF and information to be supplied to the 
patient must take place in the presence of an impartial witness. Consent must be confirmed at the 
time of consent orally and by the personally dated signature of the patient or by a local legally 
recognized alternative (eg, the patient’s thumbprint or mark) or by the personally dated signature 
of the patient’s parent(s) or the patient’s legally authorized representative. The witness and the 
person conducting the informed consent discussions must also sign and personally date the 
informed consent document. It should be recorded and dated in the source document that consent 
was given.
A copy of the signed and dated consent document(s) must be given to the patient, the patient’s 
parent(s), or the patient’s legally authorized representative. The original signed consent 
document will be retained by the investigator.
The investigator will not undertake any measures specifically required solely for the treatment 
protocol until valid consent has been obtained.
A model of the ICF to be used in this treatment protocol will be provided to the sites separately 
from this protocol.

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Where applicable, signed assent(s) to participate in the treatment protocol will be obtained.
6.17
Patient Confidentiality
Patient names will not be supplied to the sponsor. Only the patient number and patient initials 
will be recorded in the eCRF, and if the patient name appears on any other document, it must be 
obliterated before a copy of the document is supplied to the sponsor. Study findings stored on a 
computer will be stored in accordance with local data protection laws. The patients will be told 
that representatives of the sponsor, a designated CRO, the IRB/EC/REB, 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 patient 
identification list (patient numbers with the corresponding patient names) to enable records to be 
identified.
6.18
Case Report Form Completion
Case report forms are provided for each patient. All forms must be filled out by authorized study 
personnel. All corrections to the original CRF entry must indicate the reason for change. 
The investigator is required to sign the CRF after all data have been captured for each patient. If 
corrections are made after review and signature by the investigator, he or she must be made 
aware of the changes and his or her awareness must be documented by resigning the CRF.
6.19
Monitoring
Monitoring procedures that comply with current GCP guidelines will be followed. Review of the 
CRFs for completeness and clarity, cross-checking with source documents, and clarification of 
administrative matters will be performed.
The study will be monitored by the sponsor or its designee, who will review the CRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent site visits and communications (letter, telephone, 
and facsimile).
6.20
Regulatory Administration
Appropriate regulatory documentation will be collected as mandated by Health Canada.
6.21
Premature Closure of the Treatment Protocol
6.21.1
Treatment Protocol Termination
If the sponsor or an investigator discovers conditions arising during the treatment protocol that 
indicate that the clinical investigation should be halted due to an unacceptable patient risk, the 
treatment protocol may be terminated after appropriate consultation between Shire and the 
investigators. 

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In addition, a decision on the part of Shire to suspend or discontinue development of the test 
material may be made at any time.
6.21.2
Site Termination
A specific site may be terminated separate from the general treatment protocol for, but not 
limited to, the following conditions:
•
The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled at 
the site
•
Insufficient adherence by the investigator to protocol or regulatory requirements
6.22
Record Retention
Essential documents should be retained by the site for at least 2 years after the last approval of a 
marketing application and until there is no pending or contemplated marketing applications or at 
least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. The sponsor will notify the investigator if these documents must be 
retained for a longer period of time. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
Records will be maintained by the sponsor for a period of 25 years and will be accessible for on-
site inspection by Health Canada inspectors.
6.23
Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the sponsor and not 
previously published, are considered confidential and will remain the sole property of the 
sponsor. The investigator agrees to use this information only in accomplishing this study and will 
not use it for other purposes.
It is understood by the investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies. 
In order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the sponsor with complete test results and all data developed 
in the study in a timely manner.
The investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire, 
provided Shire a copy of the draft document intended for publication, and obtained Shire’s 
written consent for such publication. All information obtained during the conduct of this study 
will be regarded as confidential. Shire will use the information for registration purposes and for 
the general development of the drug.

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7
STATISTICAL METHODS
No formal statistical tests will be conducted. Tabular summaries of patient baseline demographic 
and clinical characteristics, patient disposition, medical history, physical examination, vital 
signs, AEs, anti-agalsidase alfa antibody, and infusion information will be produced for the 
safety population. The safety population includes all patients who receive at least 1 full or partial 
infusion of Replagal. Continuous data collected prior to receiving study drug and at subsequent 
visits will be summarized using descriptive statistics (n, mean, median, minimum, maximum, 
and standard deviation). Categorical data will be summarized as frequencies and percentages. All 
data summaries will be presented for each cohort and overall all as appropriate, unless otherwise 
indicated.
7.1
Demographic and Clinical Characteristics
Baseline demographics and other patient characteristics, including disease history, physical 
exam, vital signs, and medical history, will be presented by cohort. 
7.2
Patient Disposition
The disposition of all enrolled patients will be summarized with frequencies and percentages 
including patients who completed the study and patient who discontinued study treatment prior 
to the end of study visit. 
7.3
Treatment Exposure
Infusion information will be listed by patient and visit. The cumulative dose of study drug taken 
and the duration of study drug exposure will be summarized descriptively by cohort.
7.4
Anti-agalsidase Alfa Antibodies
Antibody data will be listed by patient and visit. The status of antibodies and neutralizing 
antibody will be summarized descriptively by cohort.
7.5
Adverse Events and Other Safety Assessments
Adverse event tabular summaries will be based on all treatment-emergent AEs recorded; AEs 
will be coded using the Medical Dictionary for Regulatory Activities coding dictionary.
Adverse events will be summarized by system organ class (SOC) and preferred term (PT). The 
total number of AEs by SOC and PT, as well as the number and proportion of patients 
experiencing an AE, will be tabulated by cohort; a patient will be counted only once within each 
SOC and PT. Adverse events by SOC and PT will be tabulated by cohort and severity. In the 
case of multiple occurrences of the same AEs (at the preferred term level) in an individual
patient, the AE that is classified as the most severe (ie, maximum severity) will be identified for 
the analysis by severity. In addition, AEs by SOC and PT will be tabulated by cohort and 
relationship to study drug by reporting the episode with the closest relationship to study drug.

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The number and percentage of patients reporting SAEs will be presented by cohort, SOC, and 
PT; in addition, an SAE listing will be presented.
The number and percentage of patients reporting an infusion-related reaction will be presented 
by cohort, SOC, and PT. An infusion-related reaction is defined as an AE that:  (1) begins either 
during or within 12 hours after the start of the infusion and (2) is judged by the investigator to be 
possibly or probably related to study drug.
The number and proportion of patients experiencing an AE(s) that led to permanent 
discontinuation will be summarized by cohort, SOC, and PT. Furthermore, a listing of all 
patients who permanently discontinued due to an AE(s) will be provided.
Furthermore, safety will be evaluated by assessing vital signs and blood tests. Data for vital signs 
and blood tests will be listed for each patient and abnormal values will be flagged. Shift tables 
from baseline to last visit may be presented for vital signs, and a summary table may be 
presented for blood tests.
7.6
Interim Analysis
One or more interim analyses may be performed for purposes of data submissions to regulatory 
authorities. If the analysis is deemed to be necessary, then a prospective statistical analysis plan
will be developed prior to the analysis. The plan will included, at a minimum: (1) rationale to 
perform the interim analysis; (2) endpoints to be analyzed; and (3) the distribution list for the 
interim analysis results. The trial will not stop due to the results from the interim analysis. In 
addition, as this is a single-arm study, no multiplicity adjustment will be made due to the interim 
analysis.

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8
LIST OF REFERENCES 
1. Garman SC, Garboczi DN. The molecular defect leading to Fabry disease: structure of 
human alpha-galactosidase. J Mol Biol 2004;337:319-35.
2. Schiffmann R, Ries M. Fabry's disease--an important risk factor for stroke. Lancet 
2005;366:1754-6.
3. Ries M, Kim HJ, Zalewski CK, et al. Neuropathic and cerebrovascular correlates of hearing 
loss in Fabry disease. Brain 2007;130:143-50.
4. Ries M, Gupta S, Moore DF, et al. Pediatric Fabry disease. Pediatrics 2005;115:e344-55.
5. Eng CM, Fletcher J, Wilcox WR, et al. Fabry disease: baseline medical characteristics of a 
cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis 2007;30:184-92.
6. Ries M, Ramaswami U, Parini R, et al. The early clinical phenotype of Fabry disease: a study 
on 35 European children and adolescents. Eur J Pediatr 2003;162:767-72.
7. Deegan PB, Baehner AF, Barba Romero MA, Hughes DA, Kampmann C, Beck M. Natural 
history of Fabry disease in females in the Fabry Outcome Survey. Journal of medical 
genetics 2006;43:347-52.
8. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations 
and impact of disease in a cohort of 98 hemizygous males. Journal of medical genetics 
2001;38:750-60.
9. Gupta S, Ries M, Kotsopoulos S, Schiffmann R. The relationship of vascular glycolipid 
storage to clinical manifestations of Fabry disease: a cross-sectional study of a large cohort of 
clinically affected heterozygous women. Medicine (Baltimore) 2005;84:261-8.
10. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations 
and impact of disease in a cohort of 60 obligate carrier females. Journal of medical genetics 
2001;38:769-75.
11. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA : The Journal of the American Medical Association 1999;281:249-54.
12. Spada M, Pagliardini S, Yasuda M, et al. High incidence of later-onset Fabry disease 
revealed by newborn screening. Am J Hum Genet 2006;79:31-40.
13. Cho ME, Kopp JB. Fabry disease in the era of enzyme replacement therapy: a renal 
perspective. Pediatric nephrology 2004;19:583-93.
14. Wilcox WR, Banikazemi M, Guffon N, et al. Long-term safety and efficacy of enzyme 
replacement therapy for Fabry disease. Am J Hum Genet 2004;75:65-74.
15. Canadian Fabry Disease Guidelines 2012. (Accessed March 10, 2015, at 
http://www.garrod.ca/?page_id=472.)

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Appendix 1
Schedule of Events for Cohort 1 (EOW Replagal Dosing Regimen)
Evaluation
Within 6 
Months 
Prior to 
First Dose
Treatment Period
End of Study
(30 Days 
after Last 
Dose)
Dosing Every 
Other Week 
(5 days)
Biannual/Annual 
Visits to Sitea
Informed Consent
X
Treatment Protocol Entry Criteria
X
Medical History
X
Demographics
X
Disease and Treatment History
X
Physical Examinationb
X
X
Heightc and Weight 
Xd
X
Vital Signse
X
X
Blood Testsf
X
X
Serum Anti-agalsidase alfa 
Antibody
X
X
Drug Administration
X
X
AE Assessment
X
X
X
Abbreviations:  AE=adverse event; CFDI=Canadian Fabry Disease Initiative; EOW=every other week
a
Biannual or annual visits, as applicable, are intended to coincide with visits in the CFDI protocol. 
Procedures and study assessments during these visits will be performed at the clinical site. For patients 
receiving home infusions, the infusions given at the biannual or annual visits may be administered at the 
clinical site.
b
Physical examination includes assessments of head, neck, and thyroid; eyes, ears, nose, and throat; 
chest and lungs; heart; lymph nodes; abdomen; anorectal; genitourinary; skin; musculoskeletal; 
endocrine; neurological; and other.
c
Height is measured at baseline for all patients and for patients <18 years at baseline, height will also be 
measured at biannual or annual safety visits until they are ≥18 years of age.
d
Subject weight should be obtained within 1 month prior to the first infusion.
e
Include blood pressure, pulse, respiratory rate, and temperature. Vital signs are taken immediately 
before and immediately after every infusion (10 minutes).
f
Includes creatinine, glucose, urea, potassium, sodium, chloride, bicarbonate, and fasting lipids profile.

Replagal(agalsidase alfa)
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Appendix 2
Schedule of Events for Cohort 2 (Weekly Replagal Dosing Regimen for 
Patients Who Participated in REP001a)
Evaluation
Within 6 
Months 
Prior to 
First Dose
Treatment Period
End of Study
(30 Days 
after Last 
Dose)
Dosing Every 
Week (2 days)
Biannual/Annual 
Visits to Sitea
Informed Consent
X
Treatment Protocol Entry Criteria
X
Medical History
X
Demographics
X
Disease and Treatment History
X
Physical Examinationb
X
X
Heightc and Weight 
Xd
X
Vital Signse
X
X
Blood Testsf
X
X
Serum Anti-agalsidase alfa 
Antibody
X
X
Drug Administration
X
X
AE Assessment
X
X
X
Abbreviations:  AE=adverse event; CFDI=Canadian Fabry Disease Initiative
a
Biannual or annual visits, as applicable, are intended to coincide with visits in the CFDI protocol. 
Procedures and study assessments during these visits will be performed at the clinical site. For patients 
receiving home infusions, the infusions given at the biannual or annual visits may be administered at the 
clinical site.
b
Physical examination includes assessments of head, neck, and thyroid; eyes, ears, nose, and throat; 
chest and lungs; heart; lymph nodes; abdomen; anorectal; genitourinary; skin; musculoskeletal; 
endocrine; neurological; and other.
c
Height is measured at baseline for all patients and for patients <18 years at baseline, height will also be 
measured at biannual or annual safety visits until they are ≥18 years of age.
d
Subject weight should be obtained within 1 month prior to the first infusion.
e
Include blood pressure, pulse, respiratory rate, and temperature. Vital signs are taken immediately 
before and immediately after every infusion (10 minutes).
f
Includes creatinine, glucose, urea, potassium, sodium, chloride, bicarbonate, and fasting lipids profile.