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 III/IV
Product Name:
Replagal (agalsidase alfa)
Indication:
Fabry Disease
Investigators:
Multicenter
Sponsor:
Shire Human Genetic Therapies, Inc. (Shire HGT)
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
Confidentiality Statement
This document is the proprietary and confidential property of Shire Human Genetic 
Therapies, Inc.
PPD
PPD

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SYNOPSIS
Sponsor:
Shire Human Genetic Therapies, Inc.
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 III/IV
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 180 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 is signed.
All eligible patients may receive Replagal produced by the bioreactor process (AF 
Replagal) on this treatment plan until AF Replagal 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, every other week (EOW)
For Cohort 2: Replagal, at a dose of 0.2 mg/kg body weight, administered as an 
intravenous (IV) infusion over 40 minutes, weekly
Duration of Treatment:
Dosing will continue until AF Replagal is commercially available to the patient, the 
patient’s participation is discontinued, or the study is discontinued, whichever comes first.
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.

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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, adverse events, 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 one full or partial infusion of Replagal.
Adverse event tabular summaries will be based on all treatment-emergent adverse events 
recorded; AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary.
Date of Amendment 4 Approval:  28 March 2013

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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...........................................................................................20
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...................22
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 /Independent 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
LIST OF IN-TEXT TABLES
Table 6-1
Adverse Event Severity..............................................................................23
Table 6-2
Adverse Event Relatedness ........................................................................23

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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
Idiosyncratic Infusion Related Reactions in Patients with Fabry 
Disease Treated with Replagal...................................................................35
Appendix 4
Investigator’s Signature..............................................................................36
Appendix 5
Justification for Amendment 4 and Summary of Changes.........................37

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Term
Definition
AE
adverse event
AF Replagal
Replagal manufactured using the animal-component-free, bioreactor 
process (agalAF1)
CFDI
Canadian Fabry Disease Initiative
cGMP
current Good Manufacturing Practice
CRF/eCRF
case report form/electronic case report form
CRO
contract research organization
ECG
electrocardiogram
ELISA
enzyme-linked immunosorbent assay
EOW
every other week
ERT
enzyme replacement therapy
EU
European Union
Gb3
globotriaosylceramide
GCP
good clinical practice
GLA
α-galactosidase A
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRAE
infusion-related adverse event
IRB
institutional review board
IV
intravenous
LA
left atrium
LBBB
left branch bundle block
MedDRA
Medical Dictionary for Regulatory Activities
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
PLAX
parasternal long axis view
RB Replagal
roller bottle Replagal
REB
research ethics board
SAE
serious adverse event
Shire HGT
Shire Human Genetic Therapies
sNDS
Supplemental New Drug Submission
SOC
system organ class
TEAE
treatment-emergent adverse event
TIAs
transient ischemic attacks
UK
United Kingdom
USA
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 gene (GLA), 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 α-galactosidase A have a classic phenotype with rapidly progressing 
renal, cardiac, and cerebrovascular events whereas patients with reduced α-galactosidase A 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:  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 -galactosidase A 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 which must be confirmed by genotyping.  

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Prior to the advent of enzyme replacement therapy (ERT) in 2001, Fabry disease was an 
under-diagnosed 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 125I-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 kidney and heart.  Single and 
multiple-dose pharmacodynamic studies in knockout mice have demonstrated a significant 
reduction in Gb3 in the liver, heart, and kidney. 
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, United Kingdom, 
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 IV 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 United States; and
HGT-REP-082, a comparability study between Replagal produced from agalsidase alfa 
manufactured by 2 different processes in Canada.
There are 2 additional studies currently ongoing:  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).
Over 1000 patients have been treated worldwide with Replagal (agalsidase alfa).  In total, 
233 adults and 37 children received Replagal in Shire HGT-sponsored studies.  Long-term safety 
experience for patients up to 7.5 years 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 IB.
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 HGT) and agalsidase beta, (Fabrazyme; Genzyme).  Both 
are indicated for long-term treatment in patients with a confirmed diagnosis of Fabry disease 
(α-agalactosidase A deficiency).  Currently, only agalsidase beta is approved for use within the 
United Stated (US).  Replagal is currently approved in more than 45 countries worldwide.  
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, 

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with concomitant improvements in renal and cardiac function, metabolism, neuropathic pain, and 
quality of life.
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 (RB) process and eliminating animal-sourced raw materials.  There are no changes 
to the Replagal drug product formulation, manufacturing site, manufacturing process, and 
container closure.  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.
AF Replagal is currently approved and commercialized in more than 40 countries including all 
EU member states, Australia, Croatia, Israel, Switzerland, Mexico, Argentina, and Paraguay.  
Safety data is available from approximately 2,800 patients worldwide who are currently 
receiving commercially available AF Replagal.  No new safety concerns have been identified.

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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 180 patients are expected to participate in this protocol.  
Two cohorts are included in this protocol, Cohort 1 is for patients from 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 signed.  
All patients may continue to receive Replagal on this treatment plan until AF Replagal is 
commercially available for the patient, 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 enzyme replacement therapy for 
Fabry disease by meeting any of the following criteria:
a.
Age-adjusted glomerular filtration rate (GFR) <80 ml/min or a decline in GFR of >10% 
which 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/1.73m2 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 (LVH) by electrocardiogram (ECG); Estes ECG score 
must be >5
•
Left ventricular mass index (LVMI) by 2D echocardiogram 20% above normal for 
age
•
Diastolic filling abnormalities by 2D echocardiogram or by 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 three 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 (PLAX) >33mm; in four 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 left ventricular wall late enhancement on magnetic resonance 
imaging (MRI) 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
•
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. 

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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:
4.
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 HGT 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 must receive their infusions at the clinical site or 
qualified treatment center until they have had 2 successive infusions without severe or serious 
infusion-related adverse events (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 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 visits, the dose should be updated if the weight 
change is ± 5% from the initial weight or from the previous biannual 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 to 8°C (36 to 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 twice 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:
o
Head, neck, and thyroid
o
Eyes, ears, nose, and throat
o
Chest and lungs
o
Heart
o
Lymph nodes
o
Abdomen
o
Anorectal
o
Genitourinary
o
Skin
o
Musculoskeletal
o
Endocrine
o
Neurological

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o
Other
6.5
Physical Examination
Complete physical examinations will occur prior to the first dose of Replagal administration and 
during the biannual safety visits.  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 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 safety visits for the following assessments:  creatinine, glucose, urea, 
potassium, sodium, chloride, bicarbonate and fasting lipids profile.
6.8
Antibody Assessments
Blood samples will be collected for determination of anti-agalsidase alfa antibodies within 
6 months prior to the patient receiving the first dose of Replagal and at the biannual safety visits.
Blood samples collected for anti-agalsidase antibody determination will be evaluated at Shire 
HGT.  

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Anti-agalsidase alfa serum samples will be analyzed following a tiered approach. First, all 
samples will be screened using Enzyme-Linked Immunosorbent Assays (ELISAs) for the 
presence of anti-agalsidase alfa IgG, IgA, IgM and IgE isotype antibodies. If a sample meets the 
IgG, IgA, IgM, or IgE positive cut point criteria, the appropriate ELISA will be used to confirm 
the presence of antibodies and to determine titer. Samples that are confirmed positive for the 
presence of anti-agalsidase alfa IgG, IgA, IgM, or IgE antibodies will be further evaluated for the 
presence of neutralizing antibodies (NAb) using an enzyme inhibition assay.
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 
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 by abnormal clinical laboratory values.

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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 which 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 Appendix 3.
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 may 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 
(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 

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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 (see 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 (AEs) 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 HGT 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 HGT 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 HGT Medical Monitor by telephone; this is in addition to completing and 
PPD
PPD
PPD
PPD
PPD
PPD

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transmitting the SAE form as stated above.  The following provides contact information for the 
Shire HGT Medical Monitor. 
If an SAE is assessed as severe and unexpected, or life-threatening, contact:
, MD MPH
Shire Human Genetic Therapies, Inc.
300 Shire Way, Lexington, MA 02421, USA
Telephone:  
 Fax:  
 (USA)
Mobile:  
The Investigator must promptly report all required information to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC)/Research Ethics Boards (REB).  It is the 
responsibility of the Sponsor to ensure that each Investigator receives a copy of any CIOMS 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/IEC/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.  IRAEs 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 which, in the judgment of the Investigator, 
the Sponsor, or the Shire HGT 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 which, in 
the judgment of the Investigator, the Sponsor, or the Shire HGT 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 which 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, s/he develops an intercurrent illness that, in any way, justifies his 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 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 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 /Independent Ethics Committee /Research Ethics 
Board
Before initiation of the treatment protocol, the Investigator must provide the Sponsor with a copy 
of the written IRB/IEC/REB approval of the protocol and the informed consent form.  This 
approval must refer to the informed consent form 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/IEC/REB at least once per year.  The IRB/IEC/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/IEC/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/IEC/REB, including a list of all reports and 
documents submitted.  Adverse events which are reported to Health Canada or other regulatory 
agencies must be submitted promptly to the IRB/IEC/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 CFR 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 informed consent form 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 informed consent form 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 informed consent form 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 informed consent form 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/IEC/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 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 which 
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 HGT and the 
Investigators.  

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In addition, a decision on the part of Shire HGT 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 
onsite 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 HGT, 
provided Shire HGT a copy of the draft document intended for publication, and obtained Shire 
HGT’s written consent for such publication.  All information obtained during the conduct of this 
study will be regarded as confidential.  Shire HGT 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 one 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 TEAEs recorded; AEs will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary.
AEs will be summarized by system organ class (SOC) and preferred term.  The total number of 
AEs by SOC and preferred term, 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 
preferred term.  AEs by SOC and preferred term 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 preferred term 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 
preferred term; 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 preferred term.  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 preferred term.  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(2):319-35.
2. Schiffmann R, Ries M. Fabry's disease--an important risk factor for stroke. Lancet 
2005;366(9499):1754-6.
3. Ries M, Kim HJ, Zalewski CK, et al. Neuropathic and cerebrovascular correlates of hearing 
loss in Fabry disease. Brain 2007;130(Pt 1):143-50.
4. Ries M, Gupta S, Moore DF, et al. Pediatric Fabry disease. Pediatrics 2005;115(3):e344-55.
5. 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(11):767-72.
6. 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(2):184-92.
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. J Med Genet 
2006;43(4):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. J Med Genet 2001;38(11):750-60.
9. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease:  clinical manifestations and 
impact of disease in a cohort of 60 obligate carrier females. J Med Genet 2001;38(11):769-75.
10. 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(5):261-8.
11. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders.
JAMA 1999;281(3):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(1):31-40.
13. Cho ME, Kopp JB. Fabry disease in the era of enzyme replacement therapy: a renal 
perspective. Pediatr Nephrol 2004;19(6):583-93.
14. Wilcox W, Oliveira J, Hopkin R, et al. Fabry Registry. Females with Fabry disease 
frequently have major organ involvement:  lessons from the Fabry Registry. Mol Genet Metab 
2008;93(2):112-28.

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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 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
Heightf and Weight 
Xe
X
Vital Signsc
X
X
Blood Testsd
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 visits are intended to coincide with visits in the Canadian Fabry Disease Initiative (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 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
Include blood pressure, pulse, respiratory rate, and temperature.  Vitals signs are taken immediately 
before and immediately after every infusion (10 minutes).
d
Includes creatinine, glucose, urea, potassium, sodium, chloride, bicarbonate and fasting lipids profile.
e
Subject weight should be obtained within 1 month prior to the first infusion
f
Height measured at baseline for all patients, and for patients <18 years at baseline height will also be 
measured at biannual safety visits until they are ≥18 years of age.

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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 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
Heightf and Weight 
Xe
X
Vital Signsc
X
X
Blood Testsd
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 visits are intended to coincide with visits in the Canadian Fabry Disease Initiative (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 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
Include blood pressure, pulse, respiratory rate, and temperature.  Vitals signs are taken immediately 
before and immediately after every infusion (10 minutes).
d
Includes creatinine, glucose, urea, potassium, sodium, chloride, bicarbonate and fasting lipids profile.
e
Subject weight should be obtained within 1 month prior to the first infusion.
f
Height measured at baseline for all patients, and for patients <18 years at baseline height will also be 
measured at biannual safety visits until they are ≥18 years of age.

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Appendix 3
Idiosyncratic Infusion Related Reactions in Patients with Fabry 
Disease Treated with Replagal
A total of 13.7% of patients treated with Replagal have experienced idiosyncratic 
infusion-related reactions.  The percentage of patients affected was significantly lower in females 
than males.  These effects have decreased with time, with the majority of them being reported 
within the first 6 months of treatment.  Symptoms have included predominantly rigors, headache, 
nausea, pyrexia, flushing, and fatigue, with patients commonly experiencing pain/discomfort 
including exacerbated neuropathic pain, vomiting, and chest or throat tightness.  Other 
infusion-related symptoms may include dizziness and hyperhidrosis.  All symptoms resolved 
with appropriate intervention, such as, stopping the infusion then restarting or medical therapy 
with antihistamines and/or corticosteroids.  Serious infusion reactions have been reported 
uncommonly; symptoms reported include pyrexia, rigors, tachycardia, urticaria, 
nausea/vomiting, angioneurotic oedema with throat tightness, stridor, and swollen tongue.

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Appendix 5
Justification for Amendment 4 and Summary of Changes
The protocol was amended to provide clarifications about assessments in order to prevent 
protocol deviations.  Additionally administrative changes were made.
DETAILED SUMMARY OF CHANGES FOR THE AMENDMENT 
This is a section that has been updated to describe the changes from the previous protocol 
version.  Significant changes and additions to the protocol text are captured below.  Bold text 
indicates new text.  Strikethrough text indicates deleted text.
Changes to grammar, punctuation, and formatting are not included here.
Section 1.3:  Previous Clinical Experience
Section has been updated to reflect current clinical trial status.
Formerly read:
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 studies have been conducted in children, 2 completed (TKT023 and 
TKT5S001), and 1 ongoing, open label maintenance study (TKT029).  An additional study 
(TKT028) is ongoing in patients with left ventricular hypertrophy.
There are 4 additional studies currently ongoing:  Rep001a, a Phase IV 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 United 
States; HGT REP 060, an open label extension study for TKT028; and HGT REP 082, a 
comparability study between Replagal produced from agalsidase alfa manufactured by 
2 different processes in Canada.
Now reads:
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 IV 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 
United States; and HGT-REP-082, a comparability study between Replagal produced from 
agalsidase alfa manufactured by 2 different processes in Canada.
There are 2 additional studies currently ongoing:  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).

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Other sections affected by this change:  none
Section 1.4:  Current Therapies
Section has been updated to reflect current approval status.
Now reads:
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 HGT) and agalsidase beta, (Fabrazyme; Genzyme).  Both 
are indicated for long-term treatment in patients with a confirmed diagnosis of Fabry disease 
(α-agalactosidase A deficiency).  Currently, only agalsidase beta is approved for use within the 
US.  Replagal is currently approved in more than 40 45 countries worldwide.  
Other sections affected by this change:  none
Section 1.4.2: Differences between Replagal and Fabrazyme Enzyme Replacement 
Therapies
Text deleted as it is no longer relevant.
Deleted text:
The global shortage of agalsidase beta has caused a significant number of patients 
(approximately 700 patients globally including 500 patients in the European Union [EU] since 
July 2009 by Company estimates) who were previously treated with agalsidase beta to switch to 
treatment with agalsidase alfa.  It is realized that patients switching from one ERT to another 
may be under the risk of carry over effects such as emergence of adverse events observed on 
prior ERT or appearance of new clinical symptomology due to cross reacting antibodies.  Safety 
reporting has been closely monitored.  There have been no unexpected safety findings and the 
safety profile has remained consistent over 9 years of cumulative experience.
Other sections affected by this change:  none
Section 1.5: Rationale
Text updated to reflect current status of Replagal products.
Now reads:
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 (RB) process and eliminating animal-sourced raw materials.  There are no changes 
to the Replagal drug product formulation, manufacturing site, manufacturing process, and 
container closure.  Supplies of the roller bottle Replagal (RB Replagal RB) are quickly 

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dwindling in Canada no longer manufactured, and this protocol provides a mechanism to 
maintain uninterrupted supply of Replagal (Replagal AF) to Canadian patients.
AF Replagal is currently approved and commercialized in more than 30 40 countries including 
all EU member states, Australia, Croatia, Israel, Switzerland, Mexico, Argentina, and Paraguay.  
Safety data is available from approximately 1600 2,800 patients worldwide who are currently
receiving commercially available AF Replagal.  No new safety concerns have been identified.
Other sections affected by this change:  none
Section 5.1: Description of Treatment(s)
A 10-minute window was added to clarify the infusion times for Replagal.
Now reads:
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).
Other sections affected by this change:  Section 5.3
Section 5.3: Selection and Timing of Dose for Each Patient
Clarification about dose adjustment based on weight changes was added.
Now reads:
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 visits, the dose should be updated if the 
weight change is ± 5% from the initial weight or from the previous biannual visit, or at the 
discretion of the investigator.
Other sections affected by this change: none
Section 5.7: Storage
Clarification about home storage was provided.
Now reads:

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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 to 8°C (36 to 46°F).  A 
minute amount of fine particulate matter, causing the solution to appear slightly hazy, may be 
present during storage. 
Other sections affected by this change:  none
Section 5.8:  Investigational Product Accountability and Destruction 
Clarification that text applies to all investigational product was made. 
Now reads: 
The final disposition of all investigational product delivered to an Investigator 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). 
Other sections affected by this change:  none 
Section 6.5:  Physical Examination 
Clarifications about height and weight were added. 
Now reads: 
•
Height (measured at baseline for all patients, and for patients <18 years at baseline 
height will also be measured at biannual safety visits until they are ≥18 years of age.) 
•
Weight (within 1 month prior to the first IV Replagal infusion) 
Other Sections affected by this change:  Appendix 1, Appendix 2
Section 6.7: Vital Signs 
A window was added for to clarify the time for vital sign assessments. 
Now reads: 
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). 
Other sections affected by this change:  Appendix 1, Appendix 2
Section 6.8: Antibody Assessments 
Clarity was added to antibody assessment text. 
Formerly read: 

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Blood samples will be collected for determination of anti-agalsidase alfa antibodies within 
6 months prior to the patient receiving the first dose of Replagal and at the biannual safety visits.
Blood samples collected for anti-agalsidase antibody determination will be evaluated at Shire 
HGT.  
These samples will be screened using an enzyme linked immunosorbent assay (ELISA).  
Positive samples will be isotyped (IgG, IgA, IgM, or IgE).  In addition, positive samples will be 
tested for enzyme neutralizing activity using an in vitro assay.
Now reads:
Blood samples will be collected for determination of anti-agalsidase alfa antibodies within 
6 months prior to the patient receiving the first dose of Replagal and at the biannual safety visits.
Blood samples collected for anti-agalsidase antibody determination will be evaluated at Shire 
HGT.  
Anti-agalsidase alfa serum samples will be analyzed following a tiered approach. First, all 
samples will be screened using enzyme-linked immunosorbent assays (ELISAs) for the 
presence of anti-agalsidase alfa IgG, IgA, IgM and IgE isotype antibodies. If a sample 
meets the IgG, IgA, IgM, or IgE positive cut point criteria, the appropriate ELISA will be 
used to confirm the presence of antibodies and to determine titer. Samples that are 
confirmed positive for the presence of anti-agalsidase alfa IgG, IgA, IgM, or IgE antibodies 
will be further evaluated for the presence of neutralizing antibodies (NAb) using an enzyme 
inhibition assay.
Other sections affected by this change:  none
Section 6.10.4.2: Reporting Serious Adverse Events
The medical monitor contact information was updated.
Now reads:
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 HGT 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:

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Shire Pharmacovigilance and Risk Management Department:
International FAX: 
 (UK) OR United States and Canada
FAX: 
AND
Shire HGT 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 HGT 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 HGT Medical Monitor. 
If an SAE is assessed as severe and unexpected, or life-threatening, contact:
, MD MPH
Shire Human Genetic Therapies, Inc.
300 Shire Way, Lexington, MA 02421, USA
Telephone: 
 Fax: 
 (USA)
Mobile:  
Other sections affected by this change:  Cover page
Section 6.11 (New Section):  Management of Infusion-related Adverse Events
A new section was added to describe the management of patients with infusion-related adverse 
events.
Now reads:
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.   IRAEs 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.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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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.
Other sections affected by this change:  Section 5.2: Treatment Administration
Section 6.14:  Institutional Review Board/Independent Ethics Committee/Research Ethics 
Board
Clarification about the study monitor was added.
Now reads:
Status reports must be submitted to the IRB/IEC/REB at least once per year. The IRB/IEC/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/IEC/REB. A copy of these 
reports shall be sent to the site's study clinical monitor. The Investigators must maintain an 
accurate and complete record of all submissions made to the IRB/IEC/REB, including a list of all 
reports and documents submitted. Adverse events which are reported to Health Canada or other 
regulatory agencies must be submitted promptly to the IRB/IEC/REB.
Other sections affected by this change:  none
Section 6.15:  Ethical Conduct of the Study
Cross-reference to relevant 21 CFR parts was updated.
Now reads:
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 CFR 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.
Other sections affected by this change:  none
Section 6.19:  Monitoring
Deletion of redundant text.
Now reads:
The study will be monitored by the Sponsor or its designee. Monitoring will be performed by a 
representative of the Sponsor (Clinical Study Monitor), who will review the CRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 

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design and regulatory requirements by frequent site visits and communications (letter, telephone, 
and facsimile).
Other sections affected by this change:  none
Section 7: Statistical Methods
Clarification about data presentation was added.
Now reads: 
No formal statistical tests will be conducted.  Tabular summaries of patient baseline 
demographic and clinical characteristics, patient disposition, medical history, physical 
examination, vital signs, adverse events, anti-agalsidase alfa antibody, and infusion information 
will be produced for the safety population.  The safety population includes all patients who 
receive at least one 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.
Other sections affected by this change:  none
Section 7.6 (New Section):  Interim Analysis
A new section was added to describe the interim analyses, should they be deemed necessary.
Now reads:
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.
Other sections affected by this change:  none
Appendix 5: Justification for Amendment 4 and Summary of Changes
To conform to the Shire standards, the final appendix of the amendment, which includes the 
justification for the amendment and the summary of changes, has been updated to include 
information relevant to the most recent amendment.