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 
 
 
Date 
Original Protocol: 
30 September 2010 
Amendment 1: 
23 November 2010 
Amendment 2: 
06 December 2010 
Amendment 3: 
15 September 2011 
 
 
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 3 Approval:  15 September 2011 

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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..............................................................17 
5.5 
Blinding..................................................................................................................17 
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 ..........................23 
6.10.4.1 
Adverse Event Monitoring and Period of Observation......................23 
6.10.4.2 
Reporting Serious Adverse Events ....................................................24 
6.11 
Pregnancy...............................................................................................................25 
6.12 
Removal of Patients from the Study......................................................................25 
6.13 
Institutional Review Board /Independent Ethics Committee /Research Ethics 
Board (REB) ..........................................................................................................26 
6.14 
Ethical Conduct of the Study.................................................................................26 
6.15 
Patient Information and Informed Consent............................................................26 
6.16 
Patient Confidentiality ...........................................................................................27 
6.17 
Case Report Form Completion ..............................................................................28 
6.18 
Monitoring .............................................................................................................28 
6.19 
Regulatory Administration.....................................................................................28 
6.20 
Premature Closure of the Treatment Protocol .......................................................28 
6.20.1 
Treatment Protocol Termination..................................................................28 
6.20.2 
Site Termination...........................................................................................28 
6.21 
Record Retention ...................................................................................................29 
6.22 
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 
8 
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 3 and Summary of Changes................37 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
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 
IRB 
institutional review board 
IV 
intravenous 
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 
PK 
pharmacokinetic 
PLAX 
parasternal long axis view 
RB Replagal 
roller bottle Replagal 
REB 
research ethics board 

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SAE 
serious adverse event 
Shire HGT 
Shire Human Genetic Therapies 
sNDS 
Supplemental New Drug Submission 
SOC 
system organ class 
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.  α-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 α-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 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 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 primary human embryonic kidney (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 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. 
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 
US.  Replagal is currently approved in more than 40 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. 
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. 
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 (RB Replagal) are quickly dwindling in 
Canada, and this protocol provides a mechanism to maintain uninterrupted supply of Replagal to 
Canadian patients. 
AF Replagal is currently approved and commercialized in more than 30 countries including all 
EU member states, Australia, Croatia, Israel, Switzerland, Mexico, Argentina, and Paraguay.  
Safety data is available from approximately 1600 patients worldwide who are 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 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 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 Canadian Fabry Disease Initiative [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 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: 
• LV wall thickness>12 mm 
• LVH by electrocardiogram (ECG); Estes ECG score must be >5 
• 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 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, LBBB, 
ventricular or atrial tachyarrhythmias, sinus bradycardia (in the absence of drugs with 
negative chronotropic activity) 
• Delayed posterolateral left ventricular wall late enhancement on 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.  
e. Chronic, intractable neuropathic pain, refractory to analgesics and standard pain 
management for at least 6 months.  
 

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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 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 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 an infusion-related AE must receive 
their infusions at the clinical site until they have had 2 successive infusions without an 
infusion-related adverse event.  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 Procedure Manual provided 
separately from this protocol that outlines all operating procedures to be followed for this 
treatment protocol including drug transport, 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 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 minutes weekly (±2 days). 
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. 

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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, satellite sites, 
or patient residences 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 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). 
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  
• Weight (within 1 month prior to the first IV 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. 
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.   
These samples will be screened using an enzyme-linked immunosorbent assay (ELISA).   

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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. 
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 electronic case report form 
(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. 
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. 

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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 
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). 

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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. 
 
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. 

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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 
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.  
PPD
PPD
PPD
PPD
PPD
PPD

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If an SAE is assessed as severe and unexpected, or life-threatening, contact: 
 MD 
 
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 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. 
6.12 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: 
• 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. 
PPD
PPD
PPD
PPD
PPD
PPD

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• 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. 
6.13 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 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. 
6.14 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, 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. 
6.15 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.   

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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. 
Where applicable, signed assent(s) to participate in the treatment protocol will be obtained. 
6.16 Patient Confidentiality 
Patient names will not be supplied to the sponsor.  Only the patient number and patient initials 
will be recorded in the CRF/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 contract research organization 
(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. 

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6.17 Case Report Form Completion 
Case Report Forms (paper or electronic) 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. 
6.18 Monitoring 
Monitoring procedures that comply with current GCP guidelines will be followed.  Review of 
the CRF's 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.  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 design and regulatory requirements by frequent site visits and communications (letter, 
telephone, and facsimile). 
6.19 Regulatory Administration 
Appropriate regulatory documentation will be collected as mandated by Health Canada. 
6.20 Premature Closure of the Treatment Protocol 
6.20.1 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.   
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. 
6.20.2 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. 
 

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6.21 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. 
6.22 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, 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.  
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 adverse events 
recorded; AEs will be coded using the 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 serious adverse events 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. 

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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) 
Treatment Period 
Evaluation 
Within 6 
Months 
Prior to 
First Dose 
Dosing Every 
Other Week 
(±5 days) 
Biannual Visits 
to Sitea 
End of Study 
(30 days after 
last dose) 
Informed Consent 
X 
 
 
 
Treatment Protocol Entry Criteria 
X 
 
 
 
Medical History 
X 
 
 
 
Demographics 
X 
 
 
 
Disease and Treatment History 
X 
 
 
 
Physical Examinationb 
X 
 
X 
 
Height 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. 
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 
 

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Appendix 2 Schedule of Events for Cohort 2 (Weekly Replagal Dosing Regimen for 
Patients who Participated in REP001a) 
Treatment Period 
Evaluation 
Within 6 
Months 
Prior to 
First Dose 
Dosing Every 
Week (±2 days) 
Biannual Visits 
to Sitea 
End of Study 
(30 days after 
last dose) 
Informed Consent 
X 
 
 
 
Treatment Protocol Entry Criteria 
X 
 
 
 
Medical History 
X 
 
 
 
Demographics 
X 
 
 
 
Disease and Treatment History 
X 
 
 
 
Physical Examinationb 
X 
 
X 
 
Height 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. 
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. 
 

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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 3 and Summary of Changes 
The protocol was amended to update the inclusion criteria to match the current CFDI inclusion 
criteria.  The protocol was updated to provide a weekly Replagal treatment regimen for patients 
who participated in REP001a, these patients are being enrolled into Cohort 2.  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. 
Cover page: 
Administrative updates were made to the cover page, including updating the Shire HGT contact 
information and medical monitor. 
Other sections affected by this change:  None 
Section 1.4: Current Therapies 
Text was updated to include an additional ongoing study, which began after HGT-REP-081 was 
initiated. 
Now reads: 
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-0REP-082, a 
comparability study between Replagal produced from agalsidase alfa manufactured by the 
2 different processes in Canada.   
Section 3:  Overall Study Design and Plan 
The maximum number of patients was increased.  Text now reads: 
A minimum of 60 patients and up to 150 180 patients are expected to participate in this protocol.  
Patients may begin to enroll in the treatment protocol as soon as the eligibility criteria are 
fulfilled and informed consent is signed.  
Additionally a second cohort of patients from the REP001a study was added.  The following text 
was added: 
Two cohorts are included in this protocol, Cohort 1 is for patients from the 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. 

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Other sections affected by this change:   
• Protocol Synopsis 
• Section 5.1: Description of Treatment 
• Section 5.3:  Selection and Timing of Dose for Each Patient 
• Section 5.4: Methods of Assigning Patients into Treatment Groups Cohorts 
• Section 6: Treatment Protocol Procedures 
• Section 6.9: Replagal Administration 
• Section 7: Statistical Methods 
• Appendix 2: Schedule of Events for Cohort 2 (Weekly Replagal Dosing Regimen for Patients 
who Participated in REP001a) 
 
Section 4: Population Selection 
Inclusion criteria were updated to reflect the current CFDI inclusion criteria and include patients 
from study REP001a.  Also an additional inclusion criterion was added specifying that patients 
could not participate in any other clinical trials excepts for the CFDI. 
Formerly read: 
Each patient must meet the following criteria to receive treatment: 
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 having one of the following: 
a. Age-adjusted 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.  
b. Evidence of cardiac involvement related to Fabry disease including cardiac hypertrophy, 
valvular disease, or conduction system abnormalities.  
c. Stroke or TIA prior to the age of 65 (documented by a neurologist) or unexplained 
progressive white matter changes consistent with microvascular changes on magnetic 
resonance imaging.  
d. Chronic, intractable diarrhea and/or abdominal pain/cramps, refractory to standard 
management for at least 1 year.  
e. Chronic, intractable neuropathic pain, refractory to analgesics and standard pain 
management for at least 1 year. 
 
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. 
 

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Now reads: 
Each patient in Cohort 1 must meet the following criteria to receive treatment: 
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 having one of the following: 
a. Age-adjusted 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: 
• LV wall thickness>12 mm 
• LVH by ECG; Estes ECG score must be >5 
• 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 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, 
LBBB, ventricular or atrial tachyarrhythmias, sinus bradycardia (in the absence 
of drugs with negative chronotropic activity) 
• Delayed posterolateral left ventricular wall late enhancement on 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.  
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. 

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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. 
 
Other sections affected by this change:  none 
Section 5.8:  Investigational Product Accountability and Destruction 
Clarification about the procedure for returning unused drug was provided. 
Formerly read: 
All used, partially used, and unopened study drug vials must either be returned to the Sponsor or 
destroyed according to Sponsor requirements. 
Now reads: 
All used, partially used, and unopened study drug vials must be returned to the Sponsor 
designated pharmacy. 
Other sections affected by this change:  none 
Section 6: Treatment Protocol Procedures 
Incorrect website was removed from the protocol. 
Now reads: 
Patients enrolled in this study must be treated in accordance with current Canadian guidelines for 
the treatment of Fabry disease.  These guidelines are provided at the following web site:  
www/cihr irsc.gc.ca/e/39587.html. 
Other sections affected by this change: none 
Section 6.5: Physical Examination 
The window around the weight collection time point was extended up to 1 month prior to 
treatment. 
Now reads: 
• Weight (within 1 week of 1 month prior to the first IV Replagal infusion) 
 

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Other sections affected by this change:  Schedule of Events 
Section 6.7: Blood Tests 
Redundancy was removed from blood tests. 
Now reads: 
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:  serum electrolytes, creatinine, 
glucose, urea, potassium, sodium, chloride, bicarbonate and fasting lipids profile. 
Other sections affected by this change:  Schedule of Events 
Section 6.8: Antibody Assessments 
Clarity was added to antibody assessment text: 
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. 
Other sections affected by this change:  None 
Section 6.9: Replagal Administration 
Clarity was added about home infusions. 
Now reads: 
Replagal administration will occur as described in Section 5.2; home infusions may occur at the 
discretion of the investigator. 
Section 6.10: Adverse Events Assessment 
Adverse event text was replaced with current Shire template adverse event language and updated 
medical monitor information. The numbering of subsections after Section 6.10 has changed. 
Formerly read: 
6.10 
Adverse Events Assessments 
6.10.1 Definitions 
6.10.1.1 
Adverse Event Definition 
An adverse event (AE) is any noxious, pathologic, or unintended change in anatomical, 
physiologic, or metabolic function as indicated by physical signs, symptoms, and/or laboratory 

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changes occurring in any phase of a clinical study, and whether or not considered study 
drug related.  This includes an exacerbation of a pre existing condition.  Adverse events will be 
collected from informed consent until 30 days after the last dose of study drug and/or until the 
event has been resolved/stabilized or an outcome is reached, whichever comes first.  For patients 
who discontinue or are withdrawn, AEs will be followed up to 30 days after their last infusion of 
Replagal. 
Adverse events include: 
• Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
treatment plan 
• Intercurrent illnesses 
• Drug interactions 
• Abnormal laboratory values (this includes significant shifts 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 treatment protocol, the Investigator must record all AEs on the AE CRF/eCRF, 
regardless of the severity or relationship to study drug.  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, or 
abnormal electrocardiogram (ECG). 
In addition, AEs may also include unexpected laboratory values that become significantly 
out of range and determined to be clinically significant by the Investigator.   
In the event of an unexpected 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. 
6.10.1.2 
Infusion related Adverse Event Definition 
An infusion related adverse event will be defined as an adverse event 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.  Infusion related adverse events are to be managed as defined in Section 0. 
6.10.2 Performing Adverse Events Assessments 
Patients should be asked non leading questions, eg, “How do you feel?” and further questions 
should be posed if there is indication of an AE.  The questioning should be conducted with due 
regard for objectivity and, in particular, the questioner should gather information regarding AEs 
from questioning the patient, spontaneous reporting by the patient, laboratory reports, and any 
health care provider’s observations. 
The onset date, resolution date, treatment administered, and outcome of each AE must be 
recorded on the appropriate CRF.  In addition, the relationship of each AE to study drug must be 
recorded. 

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6.10.3 Timing of Adverse Event Assessments 
Adverse events will be assessed from the time the patient provides signed informed consent until 
30 days after the patient’s final infusion of Replagal on this treatment plan.  The final AE 
assessment may be performed at the clinical site or by telephone call. 
6.10.4 Relationship and Severity 
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 3.0 grading scale should be referenced when assessing the severity of an AE.  If an AE 
is not described in the NCI CTCAE v3.0, 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. 
Relationship to Product(s) 
Definition 
Not Related 
Unrelated to study drug. 
 
 
Possibly Related 
A clinical event/laboratory abnormality with a reasonable 
time sequence to administration of study drug, but which 
could also be explained by concurrent disease or other 
drugs/chemicals. 
 
 
Probably Related 
A clinical event/laboratory abnormality with a reasonable 
time sequence to administration of study drug, 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/laboratory 
abnormality must also have some biologic plausibility, at 
least on theoretical grounds. 
 
AE 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. 
 
6.10.5 Clarification Between Serious and Severe Adverse Events 
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 

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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. 
6.10.6 Protocol Deviations for Medical Emergency or Adverse Events 
During and following a patient’s participation in the treatment protocol, the Investigator should 
ensure that adequate medical care is provided to a patient for any AEs, including clinically 
significant laboratory test results.  The Investigator should inform the patient, the patient’s 
parent(s), or the patient’s legally authorized representative when medical care is needed for 
intercurrent illness(es) of which the Investigator becomes aware.  In an emergency situation, the 
Investigator should contact the Shire HGT Medical Monitor. 
Only when an emergency occurs that requires an immediate deviation from the protocol for the 
safety of a patient, will there be such a deviation, and this will be only for that patient.  The 
Investigator or other physician in attendance in such an emergency must contact the Shire HGT 
Medical Monitor as soon as possible.  The Investigator, along with the Shire HGT Medical 
Monitor, will make a decision as to whether or not the patient should continue in the treatment 
protocol.  The departure from the protocol and the grounds for it should be stated in the CRF. 
6.11 
Management of Infusion related Adverse Events 
If a patient has an infusion related adverse event during the infusion of study drug, the 
Investigator should decide, based on his or her clinical judgment, whether the infusion should be 
slowed, or temporarily or permanently discontinued.  Infusion related adverse events that occur 
post infusion should be assessed and treated in a similar manner.   
Patients experiencing a recurrent infusion related adverse event may be premedicated.  If 
infusions continue without incident, then tapering of medications can be considered.  
In case of severe infusion related adverse events, the Investigator should consult with the Shire 
HGT Medical Monitor prior to the patient’s next dose to determine the appropriate course of 
action for future infusions. 
6.12 
Serious Adverse Events 
6.12.1 Definition 
A serious adverse event (SAE) is defined by federal regulation as any AE occurring at any dose 
that results in any of the following outcomes:  death, life threatening AE, hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a 
congenital anomaly/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 subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic 

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bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Hospitalizations, which are the result of elective or previously scheduled surgery for preexisting 
conditions, which have not worsened after initiation of treatment, should not be classified as 
SAEs.  For example, an admission for a previously scheduled ventral hernia repair would not be 
classified as an SAE.  If however complications were to develop they would be evaluated to 
determine if serious criteria had been met. 
6.12.2 Reporting Serious Adverse Events 
Any SAE, regardless of relationship to study medication and which occurs in a patient after 
informed consent is obtained, should be recorded by the clinical site on a SAE form that is to be 
transmitted to the Shire HGT Medical Monitor and Shire’s Global Pharmacovigilance 
Department at the fax contact number provided below.  The SAE must be completely described 
on the patient’s CRF/eCRF, including the judgment of the Investigator as to the relationship of 
the SAE to the study drug.  The Investigator will promptly supply all information identified and 
requested by Shire HGT (and/or contract research organization [CRO]) regarding the SAE.  The 
Investigator must report the SAE to Shire Global Pharmacovigilance and to the Shire HGT 
Medical Monitor on a SAE form.   
This form must be completed and FAXED within 24 hours of the Investigator learning of the 
event to: 
Fax SAE Form to 
Shire Pharmacovigilance and Risk Management Department:   
International FAX:  
 (UK) OR United States FAX:  
And 
Telephone: 
or 
 
AND  
Shire HGT Medical Monitor:  FAX 
 (USA) 
 
Any follow up information must also be completed on a SAE form and faxed to the same 
numbers listed above. 
In the event of a severe, unexpected, fatal or life threatening and possibly or probably related 
SAE, the clinical site should complete the SAE form and transmit the SAE form to the Shire 
HGT Medical Monitor and to Shire’s Global Pharmacovigilance Department (as stated above) 
within 24 hours.  In addition, the clinical site must contact the Shire HGT Medical Monitor or 
the Shire Global Pharmacovigilance Department immediately by telephone or e mail.  The 
following provides contact information for the Shire Global Pharmacovigilance Department and 
the Shire HGT Medical Monitor. 
PPD
PPD
PPD
PPD
PPD
PPD

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If an SAE is assessed as severe or life threatening and possibly/probably related, 
contact by phone:  
 MD 
Shire Human Genetic Therapies, Inc. 
700 Main Street Cambridge, MA 02139, USA 
Telephone:  
 Fax:  
(USA) 
Mobile:  
  
AND 
Shire Global Pharmacovigilance 
Telephone: 
 or 
Fax:  
 
 
In the event that the Shire’s Global Pharmacovigilance Department and the Shire HGT Medical 
Monitor cannot be reached, a message and fax must be left at the emergency numbers listed 
above within 24 hours of the incident.  
The Investigator must promptly report in a timely manner to his/her IRB/IEC/REB, all SAEs and 
any unanticipated problems involving risk to human patients.  It is the responsibility of Shire 
HGT to ensure that each Investigator receives a copy of any CIOMS I/Med Watch report that has 
been submitted to the appropriate regulatory agency(ies) notifying them of a related 
SAE/SUSAR.  The Investigator or Shire HGT must ensure that the IRB/IEC/REB receives a 
copy of the report and that a copy is also filed within their study files.  In addition, Shire HGT 
will also notify the Investigators and IRBs/IECs/REBs of any deaths occurring during the 
treatment protocol. 
Now reads: 
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. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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• 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 electronic case report form 
(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. 
 
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. 

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• 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 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). 

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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. 
 
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: 

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Shire Pharmacovigilance and Risk Management Department: 
International FAX: 
 (UK) OR United States or Canada 
FAX:  
AND 
Shire HGT Medical Monitor: 
, MD 
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 
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. 
Other sections affected by this change:   
• Section 7.5: Adverse Events and Other Safety Assessments 
• Appendix 3 (newly added): Idiosyncratic Infusion Related Reactions in Patients with Fabry 
Disease Treated with Replagal 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Section 6.12:  Removal of Patients from the Study 
Reference to efficacy was removed, as this study only collects data related to safety. 
Now reads: 
At the time of discontinuation or withdrawal, patients will undergo all safety and efficacy 
evaluations required for the End of Study visit.  The Investigator will complete the appropriate 
CRF describing the reason for discontinuation.   
Other sections affected by this change:  None 
Appendix 5: Justification for Amendment 3 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.