Clinical trial NCT00230607
Conditions: Fabry Disease Alpha Galactosidase A Deficiency
Keywords: alpha Galactosidase A aGAL r-haGAL Fabry GL3 Fabrazyme Lysosomal Storage Disorder Enzyme Replacement Therapy (ERT)
Sponsor: Genzyme, a Sanofi Company
Start date: 2006-05-28; Completion date: 2024-02-09
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study was planned for up to 2 years (24 months). Planned full participation for both mother and infant was 24 months, planned full participation of mother and development of infant was 24 months, while planned full participation of mother and no infant participation was 6 months.

Detailed description:

Arms: arm 1: Mothers with Fabry disease who received commercially available Fabrazyme intravenous infusion as part of the standard of care while lactating/pregnant and their infants who were breastfed while the mothers were receiving Fabrazyme were enrolled in this study.
Interventions: intervention 1: agalsidase beta
Intervention descriptions: intervention 1: Pharmaceutical form: powder for reconstitution Route of administration: intravenous

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002579 VERSION N°14.0 (04-FEB-2016) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL NO. 08 
COMPOUND: Fabrazyme®/agalsidase beta/GZ419828 
A Multicenter, Multinational Study of the Effects of Fabrazyme® (agalsidase beta) 
Treatment on Lactation and Infants 
STUDY NUMBER: AGAL02603/MSC12868 
VERSION DATE / STATUS: 23-Mar-2018 / Approved 
Protocol Amendment 08 
Version number: 1 (electronic 1.0) 
Date : 23-Mar-2018 
Amended Clinical Trial Protocol 07  
Version number: 1 (electronic 1.0) 
Date : 10-Apr-2017 
Protocol Amendment 07 
Version number: 1 (electronic 1.0) 
Date : 10-Apr-2017 
Protocol Amendment 06 
Version number: 1 (electronic 1.0) 
Date : 23-Apr-2010 
Protocol Amendment 05 
Version number: 1 (electronic 1.0) 
Date : 05-Dec-2008 
Protocol Amendment 04 
Version number: 1 (electronic 1.0) 
Date : 16-Oct-2007 
Protocol Amendment 03 
Version number: 1 (electronic 1.0) 
Date : 07-Apr-2005 
Protocol Amendment 02  
Version number: 1 (electronic 1.0) 
Date : 31-Jan-2005 
Protocol Amendment 01 
Version number: 1 (electronic 1.0) 
Date : 29-Jul-2004 
Clinical Trial Protocol 
Version number: 1 (electronic 1.0) 
Date : 22-Aug-2003 
EudraCT  
2006-001910-33 
IND Number(s) 
7616 
Version Number: 
1 
WHO universal trial number 
not applicable 
Date: 
23-Mar-2018
Total number of pages: 
51 
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NCT00230607


Amended Clinical Trial Protocol No. 08  
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Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 2 
NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
  
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
SPONSOR 
  
Company: 
Address: 
 
 
 
 
Sanofi aventis recherche & développement  
1 avenue Pierre Brossolette, 91380  
Chilly-Mazarin  
FRANCE 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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Amended Clinical Trial Protocol No. 08  
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1 
SYNOPSIS 
NAME OF COMPANY 
Sanofi Genzyme 
500 Kendall Street 
Cambridge, MA 02142 
NAME OF FINISHED PRODUCT 
FabrazymeP 
NAME OF ACTIVE 
INGREDIENT 
agalsidase beta 
SUMMARY TABLE Referring 
to Part……… of the Dossier: 
Volume: Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
TITLE: 
A Multicenter, Multinational Study of the Effects of Fabrazyme® (agalsidase beta) Treatment on Lactation and Infants 
PROTOCOL NO.:  AGAL02603 / MSC12868 
INVESTIGATOR/STUDY CENTERS: 
Investigators at approximately 10 multinational study centers will participate. 
OBJECTIVES: 
TThe objectives of this study are: 
1. To determine whether αGAL (alpha-galactosidase A) activity is present in the breast milk of mothers with Fabry 
disease who are being treated with Fabrazyme during lactation. 
2. To measure breast milk production and composition (volume, protein and fat content) in women with Fabry disease 
who receive Fabrazyme during lactation. 
3. To determine whether Fabrazyme affects the growth, development, and immunologic response of infants born to 
mothers with Fabry disease who receive Fabrazyme during lactation. 
METHODOLOGY: 
This is a multicenter, multinational study of the potential effects of Fabrazyme on lactation and on the growth, development, and 
immunologic response of infants born to mothers with Fabry disease who are treated with Fabrazyme during lactation.  
Pregnant women who received Fabrazyme at any point during their pregnancy can be enrolled in the study. If woman is not 
receiving treatment with Fabrazyme at the Baseline visit, mother should start treatment with Fabrazyme between the delivery 
and Month 1 visit. 
Mother:  Breast milk will be collected at Months 1, 3, and 6 immediately prior to Fabrazyme infusion, just after the end of the 
infusion, and 2 hours after the end of the infusion.  Breast milk samples will be analyzed for volume, presence of αGAL 
activity, total fat content, and total protein concentration.  Blood samples from the mother will be drawn for pharmacokinetic 
(PK) analysis prior to each breast milk collection.  Lactation status, adverse events (AEs), and concomitant medications will be 
collected at every visit.  If infant genotyping is performed on the umbilical blood cord sample at Baseline visit, a buccal cell 
sample will be obtained from the mother to rule out contamination of the cord blood sample with maternal DNA 
(deoxyribonucleic acid) (maternal cell contamination (MCC) analysis).  The following data items will be collected through the 
Registry: medical history (including Fabrazyme status during pregnancy), pregnancy outcome, serum immunoglobulin G (IgG) 
antibodies, and genotyping. 
Infant:  If the parent(s)/legal guardian(s) consents to infant participation, the infant’s growth and development will be 
assessed at Months 1, 2, 3, and 6, then at 6-month intervals through Month 24.  The infant may also be tested for the 
formation or continued presence of IgG (immunoglobulin G) and IgM (immunoglobulin M) antibodies to recombinant human 
α galactosidase A (r-hαGAL) at Baseline, Months 2, 6, and 12 and for genotype at Baseline. 
NUMBER OF SUBJECTS: 
Mothers:  Approximately 10 mothers and up to 10 infants will be enrolled in this study. 
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Amended Clinical Trial Protocol No. 08  
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NAME OF COMPANY 
Sanofi Genzyme 
500 Kendall Street 
Cambridge, MA 02142 
NAME OF FINISHED PRODUCT 
FabrazymeP 
NAME OF ACTIVE 
INGREDIENT 
agalsidase beta 
SUMMARY TABLE Referring 
to Part……… of the Dossier: 
Volume: Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
DIAGNOSIS/INCLUSION-EXCLUSION CRITERIA: 
Inclusion Criteria - Mothers must meet the following criteria to be enrolled in this study: 
I 01. 
provide signed written informed consent to participate in this study, 
I 02. 
be enrolled in the Fabry Registry and receiving Fabrazyme while lactating, 
I 03. 
agree to adhere to the Fabry Registry recommended schedule of assessments for medical history, pregnancy 
outcome, genotyping, and antibody testing, and 
I 04. 
agree to adhere to the schedule of evaluations for this study.  
Inclusion Criteria - Infants must meet the following criteria to be enrolled in this study: 
I 05. 
have the signed written informed consent of the parent(s)/legal guardian(s) to participate in this study, 
I 06. 
be born to a mother who is receiving Fabrazyme during lactation, 
I 07. 
be receiving breast milk from the mother, and 
I 08. 
have the agreement of the parent(s)/legal guardian(s) to adhere to the schedule of evaluations for this study. 
Exclusion Criteria 
The mother and infant will be excluded from this study if the mother has received an investigational drug within 30 days prior 
to study enrollment. 
DOSE/ROUTE/REGIMEN: 
Mothers receive Fabrazyme treatment (commercially available) at their prescribed dose and regimen as determined by their 
treating physician.  
REFERENCE TREATMENT:  No reference treatment will be used in this study. 
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NAME OF COMPANY 
Sanofi Genzyme 
500 Kendall Street 
Cambridge, MA 02142 
NAME OF FINISHED PRODUCT 
FabrazymeP 
NAME OF ACTIVE 
INGREDIENT 
agalsidase beta 
SUMMARY TABLE Referring 
to Part……… of the Dossier: 
Volume: Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
CRITERIA FOR EVALUATION: 
TMother 
• 
TEfficacy:  Efficacy will not be measured in this study. 
• 
TPharmacokinetics:  Blood and breast milk samples will be taken from the mother at Months 1, 3, and 6 for measurement of 
αGAL concentrations (if mother is lactating at the time of the evaluation and is receiving Fabrazyme therapy).  Blood 
samples will be collected Uprior to each breast milk collectionU     as follows:  sample 1: immediately prior to Fabrazyme 
infusion and prior to breast milk collection; sample 2: just prior to the end of Fabrazyme infusion and prior to breast milk 
collection; and sample 3:  2 hours after Fabrazyme infusion and prior to breast milk collection.  Breast milk samples will be 
collected Uafter each plasma collectionU     for PK testing as follows:  sample 1:  immediately prior to Fabrazyme infusion and 
after plasma collection; sample 2:  immediately after Fabrazyme infusion and after plasma collection; and sample 3:  2 
hours after Fabrazyme infusion and after plasma collection.  The volume of breast milk expressed from each timepoint 
(immediately prior to infusion, from infusion start until end of infusion, and from end of infusion until 2 hours post-infusion) 
will be recorded and summarized. 
• 
TBreast Milk:  Samples of expressed breast milk will be collected by pump at Months 1, 3, and 6 (if mother is   lactating at 
the time of the evaluation and continues to receive Fabrazyme therapy) for PK assessment as above. 
TAdditionally, the 
volume, fat content, and protein content of breast milk samples will be determined. 
• Safety:  The IgG antibody titers and incidence of adverse events (AEs) occurring in mothers enrolled in this study will be 
summarized. T 
Infant 
• Efficacy:  Efficacy will not be measured in this study. 
• Immunoglobulins:  At birth, a sample of umbilical cord blood will be collected to determine the infant’s Baseline anti- r-
hαGAL IgM and IgG titers.  Testing for presence of IgG and IgM antibodies will also occur at Month 2, 6, and 12. 
• Development:  The infant’s growth and development will be monitored from birth to Month 24 through physical exams and 
the Denver II Developmental Screening Test. 
• Safety:  The incidence of adverse events occurring in infants enrolled in this study will be summarized. 
Genotype testing: will be conducted for all participating infants on umbilical cord blood to determine diagnosis of Fabry 
disease. In cases when umbilical blood cord sample is not collected at the Baseline visit, genotyping of the infant enrolled for 
full participation could be performed on the additional blood sample collected at visit month 12. If genotyping of the infant is 
performed as a part of standard care prior to visit month 12, this result will be recorded by Investigator in the CRF (Case 
Report Form). 
 
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NAME OF COMPANY 
Sanofi Genzyme 
500 Kendall Street 
Cambridge, MA 02142 
NAME OF FINISHED PRODUCT 
FabrazymeP 
NAME OF ACTIVE 
INGREDIENT 
agalsidase beta 
SUMMARY TABLE Referring 
to Part……… of the Dossier: 
Volume: Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
STATISTICAL AND ANALYTICAL PLANS:  
Statistical Methods: 
Data collected in this study will be analyzed using descriptive statistics and reported using summary tables, graphs, 
figures, and/or patient data listings. No hypothesis testing will be performed.  Details of the statistical analysis will be specified in
the Statistical Analysis Plan. 
 
Study Variables 
Mother:  The following study variables from the mothers will be summarized: 
• 
Plasma αGAL activity 
• 
Milk αGAL to plasma αGAL ratio; 
• 
The levels of αGAL activity, volume, total fat and protein content in breast milk samples; 
• 
Lactation status; 
• 
Frequency of AEs, coded using the Medical Dictionary for Regulatory Activities (MedDRA); 
• 
Concomitant medications received. 
Each lactating woman will serve as her own control, with pre-infusion and post-infusion breast milk samples. The following data 
will be collected through the Registry and summarized: 
• 
Medical history (including Fabrazyme status during pregnancy); 
• 
Genotyping; 
• 
Pregnancy outcomes; 
• 
IgG antibody. 
Infant: The following study variables from the infants will be summarized: 
• 
Medical history; 
• 
Physical exam; 
• 
Gender; 
• 
Apgar scores at 1 minute and 5 minutes after birth; 
• 
Denver II Developmental Screening Test; 
• 
IgM antibody titer to r-hαGAL; 
• 
IgG antibody titer to r-hαGAL; 
• 
Genotype; 
• 
Frequency of AEs, coded using MedDRA; 
• 
Concomitant medications received. 
Sample Size: No formal statistical sample size calculations were performed for this study.  The sample size of approximately 10
mothers and up to 10 infants is based upon 1) the availability of mothers to study lactation in this rare disease and 2) the 
availability of infants whose parents or legal guardians consent to their participation in this study. 
Interim Analysis: After 5 mothers have contributed breast milk samples to this study, an interim analysis of αGAL activity in the
breast milk will be performed.  
 
In addition, status of this study will be summarized annually as part of the Fabry Registry Program Annual Report. 
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2 
TABLE OF CONTENTS 
1 
SYNOPSIS.......................................................................................................................................3 
2 
TABLE OF CONTENTS ..................................................................................................................7 
2.1 
LIST OF TABLES...........................................................................................................................11 
3 
LIST OF ABBREVIATIONS ..........................................................................................................12 
4 
INTRODUCTION AND RATIONALE.............................................................................................13 
4.1 
SUMMARY OF BENEFITS ............................................................................................................13 
4.2 
SUMMARY OF RISKS...................................................................................................................13 
5 
STUDY OBJECTIVES ...................................................................................................................15 
6 
INVESTIGATIONAL PLAN ...........................................................................................................16 
6.1 
STUDY DESIGN ............................................................................................................................16 
6.2 
STUDY RATIONALE......................................................................................................................16 
6.2.1 
Dosing Regimen.............................................................................................................................17 
6.2.2 
Study Duration ...............................................................................................................................17 
6.2.3 
Study Population............................................................................................................................17 
7 
PATIENT POPULATION AND SELECTION.................................................................................18 
7.1 
INCLUSION CRITERIA..................................................................................................................18 
7.2 
EXCLUSION CRITERIA ................................................................................................................18 
7.3 
WITHDRAWAL CRITERIA.............................................................................................................18 
7.3.1 
Patient Withdrawal .........................................................................................................................18 
7.3.2 
Study or Site Termination ..............................................................................................................19 
8 
STUDY TREATMENTS .................................................................................................................20 
8.1 
TREATMENTS ADMINISTERED ..................................................................................................20 
8.2 
INVESTIGATIONAL PRODUCT....................................................................................................20 
8.2.1 
Investigational Product Description and Preparation.....................................................................20 
8.2.2 
Packaging and Labeling.................................................................................................................20 
8.2.3 
Drug Storage..................................................................................................................................21 
8.2.4 
Study Drug Accountability..............................................................................................................21 
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8.3 
PATIENT NUMBERING.................................................................................................................21 
8.4 
PACKAGING AND LABELING ......................................................................................................21 
8.5 
PRIOR AND CONCOMITANT MEDICATIONS .............................................................................21 
8.6 
BLINDING AND RANDOMIZATION ..............................................................................................21 
9 
EFFICACY, PHARMACOKINETICS, AND SAFETY VARIABLES..............................................22 
9.1 
MEASUREMENTS ASSESSED AND STUDY FLOWCHART ......................................................22 
9.1.1 
Tests and Procedures for Mother Full Participation and Infant Full Participation..........................27 
9.1.1.1 
Baseline (Full/Full Participation) ....................................................................................................27 
9.1.1.2 
Month One (Full/Full Participation) ................................................................................................27 
9.1.1.3 
Month Two (Full/Full Participation) ................................................................................................28 
9.1.1.4 
Month Three (Full/Full Participation)..............................................................................................29 
9.1.1.5 
Month Six (Full/Full Participation) ..................................................................................................29 
9.1.1.6 
Month Twelve (Full/Full Participation)............................................................................................30 
9.1.1.7 
Month Eighteen (Full/Full Participation).........................................................................................31 
9.1.1.8 
Month Twenty-four/End of Study (Full/Full Participation) ..............................................................31 
9.1.2 
Tests and Procedures for Mother Full Participation and Infant Development ...............................32 
9.1.2.1 
Baseline (Full/Development Participation).....................................................................................32 
9.1.2.2 
Month One (Full/Development Participation).................................................................................32 
9.1.2.3 
Month Two (Full/Development Participation).................................................................................33 
9.1.2.4 
Month Three (Full/Development Participation) ..............................................................................33 
9.1.2.5 
Month Six (Full/Development Participation)...................................................................................34 
9.1.2.6 
Month Twelve (Full/Development Participation) ............................................................................35 
9.1.2.7 
Month Eighteen (Full/Development Participation) .........................................................................35 
9.1.2.8 
Month Twenty-four/End of Study (Full/Development Participation)...............................................36 
9.1.3 
Tests and Procedures for Mother (Full Participation) Infant (No Participation) .............................36 
9.1.3.1 
Baseline (Full/No Participation)......................................................................................................36 
9.1.3.2 
Month One (Full/No Participation)..................................................................................................36 
9.1.3.3 
Month Three (Full/No Participation)...............................................................................................37 
9.1.3.4 
Month Six/End of Study (Full/No Participation)..............................................................................37 
9.2 
EFFICACY ASSESSMENTS .........................................................................................................38 
9.3 
PHARMACOKINETIC ASSESSMENTS........................................................................................38 
9.4 
SAFETY ASSESSMENTS AND OTHER MEASUREMENTS .......................................................39 
9.4.1 
Adverse Events..............................................................................................................................39 
9.4.2 
Serious Adverse Events.................................................................................................................40 
9.4.3 
Adverse Event and Serious Adverse Event Reporting ..................................................................41 
9.4.4 
Clinical Laboratory Tests ...............................................................................................................41 
9.4.5 
Concomitant Medications...............................................................................................................41 
9.4.6 
Status of Lactation/Receiving Breast Milk .....................................................................................41 
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9.4.7 
Breast Milk Samples ......................................................................................................................42 
9.4.8 
Physical Examination.....................................................................................................................42 
9.4.9 
Developmental Assessment ..........................................................................................................42 
9.4.10 
Genotype Testing...........................................................................................................................42 
9.4.11 
Immunogenicity Testing .................................................................................................................43 
9.4.12 
Safety Follow-Up............................................................................................................................43 
10 
DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT......................................44 
10.1 
RECORDING OF DATA ................................................................................................................44 
10.2 
DATA QUALITY ASSURANCE......................................................................................................44 
10.3 
DATA MANAGEMENT...................................................................................................................44 
11 
STATISTICAL METHODS AND PLANNED ANALYSES.............................................................45 
11.1 
GENERAL CONSIDERATIONS ....................................................................................................45 
11.2 
DETERMINATION OF SAMPLE SIZE...........................................................................................45 
11.3 
ANALYSIS POPULATIONS...........................................................................................................45 
11.4 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS...........................................................45 
11.5 
PATIENT ACCOUNTABILITY........................................................................................................45 
11.6 
STUDY TREATMENT USAGE AND COMPLIANCE.....................................................................46 
11.7 
EFFICACY ANALYSIS...................................................................................................................46 
11.8 
SAFETY ANALYSIS.......................................................................................................................46 
11.9 
INTERIM ANALYSIS......................................................................................................................47 
11.10 
PHARMACOKINETICS ANALYSIS...............................................................................................47 
12 
SPECIAL REQUIREMENTS AND PROCEDURES ......................................................................48 
12.1 
INSTITUTIONAL AND ETHICAL REVIEW....................................................................................48 
12.2 
CHANGES TO THE CONDUCT OF THE STUDY OR PROTOCOL.............................................48 
12.3 
INVESTIGATOR'S RESPONSIBILITIES .......................................................................................48 
12.3.1 
Patient Informed Consent ..............................................................................................................48 
12.3.2 
Case Report Forms........................................................................................................................49 
12.3.3 
Record Retention ...........................................................................................................................49 
12.3.4 
Monitoring ......................................................................................................................................49 
12.3.5 
Materials Control............................................................................................................................50 
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12.3.6 
Disclosure of Data..........................................................................................................................50 
12.3.7 
Clinical Study Report......................................................................................................................50 
13 
REFERENCES...............................................................................................................................51 
 
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2.1 
LIST OF TABLES 
Table 1 - Schedule of Study Evaluations - Mother (Full Participation) and Infant (Full Participation) ..........23 
Table 2 - Schedule of Study Evaluations - Mother (Full Participation) and Infant (Development 
Participation)..................................................................................................................................................25 
Table 3 - Schedule of Study Evaluations - Mother (Full Participation) Infant (No Participation)...................26 
 
 
 
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3 
LIST OF ABBREVIATIONS 
 
AE: 
adverse event 
AUC: 
area under the concentration-time curve 
CHO: 
Chinese Hamster Ovary 
Cmax: 
maximum concentration 
CRF: 
case report form 
DNA: 
deoxyribonucleic acid 
GCP: 
Good Clinical Practice 
GL-3: 
globotriasylceramide 
HEENT: 
head, ears, eyes, nose, and throat 
IAR: 
infusion-associated reactions 
ICH: 
International Conference on Harmonization 
IEC: 
independent ethics committee 
IgG: 
Immunoglobulin G 
IgM: 
Immunoglobulin M 
IRB: 
institutional review board 
MCC: 
Maternal Cell Contamination 
MedDRA: 
Medical Dictionary for Regulatory Activities 
PK: 
pharmacokinetics 
q2w: 
every two weeks 
r-hαGAL: 
recombinant human alpha galactosidase A 
SAE: 
serious adverse event 
SOM: 
Study Operations Manual 
SOP: 
Standard Operating Procedure 
US: 
United States 
αGAL: 
alpha-galactosidase A 
 
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4 
INTRODUCTION AND RATIONALE 
α-Galactosidase A (αGAL) is a lysosomal hydrolase enzyme responsible for the metabolism of 
globotriaosylceramide (GL-3), the enzyme’s major glycosphingolipid substrate. In Fabry disease, 
an inherited deficiency of αGAL leads to widespread deposition of GL-3, and to a lesser extent 
other α-galactoside-containing glycolipids, in the heart(1), kidney(2), liver(3), skin(4), and 
intestines.(5) 
The major clinical signs and symptoms of Fabry disease include skin lesions, benign corneal and 
lenticular opacities, excruciating acral pain, paresthesias, autonomic dysfunction, cardiac disease, 
and renal failure.(6)  Progressive glycolipid deposition in the microvasculature lead to failure of 
target organs resulting in death in the third to fifth decades of life prior to the advent of kidney 
dialysis and renal transplantation.  Because the X-chromosome carries the αGAL gene, most 
affected patients are hemizygous males, although some heterozygous females can also be affected 
due to lyonization (random inactivation of 1 X-chromosome).(7) 
Fabrazyme® has been approved in more than 40 countries, including the European Union, 
Australia, Canada, Japan, and the United States (US).  Genzyme has manufactured a recombinant 
form of human α-galactosidase A (r-hαGAL; agalsidase beta) to provide replacement enzyme to 
patients with Fabry disease. 
More detailed information regarding the preclinical and clinical safety, including a complete 
listing of adverse events (AEs) and serious adverse events (SAEs), as well as efficacy of 
Fabrazyme is provided in the Investigator Brochure and/or product labeling. 
4.1 
SUMMARY OF BENEFITS 
Immediate benefits for infants enrolled in the study include the possible early diagnosis of Fabry 
disease, awareness of which can lead to early treatment of the disease.  Information collected 
regarding the potential effects of Fabrazyme on growth and development of infants and lactation 
of mothers is expected to be useful in planning the use of Fabrazyme therapy for female patients 
of child-bearing potential. 
4.2 
SUMMARY OF RISKS 
The r-hαGAL enzyme (Fabrazyme) is a highly purified form of human αGAL, made by 
recombinant DNA technology.  It is well known that immune response may occur following 
treatment with exogenous human proteins.  In the setting of an endogenous enzyme deficiency, 
infusion of an exogenous recombinant enzyme to patients’ naïve to the normal enzyme is 
expected to cause antibody response to the enzyme.  Of the 177 patients evaluated in 7 clinical 
studies in which a Fabrazyme dose of 1 mg/kg every two weeks (q2w) was used for the duration 
of the study, the majority developed IgG (immunoglobulin G) antibodies to Fabrazyme: 84% of 
163 males and 43% of 14 females seroconverted. Seroconversion occurred in a mean (SD) time of 
194.5 (130.24) days for the 6 females compared to 76.2 (71.16) days for the 124 males.  Of the 
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143 seropositive patients, the majority (a combined total of 66%) exhibit either consistently low 
titers or declining titers over time.  Continued safe treatment with Fabrazyme has not been 
precluded by IgG antibody development.  Across the 7 pooled clinical studies of Fabry patients 
treated with Fabrazyme 1 mg/kg q2w, the most common drug-related AEs were infusion 
associated reactions (IARs, defined as drug- related events occurring on the day of the infusion).  
The most common IARs included chills, pyrexia, nausea, feeling cold, headache, vomiting, 
paraesthesia, blood pressure increased, flushing, feeling hot, chest discomfort, pruritus, body 
temperature increased, urticaria, fatigue and somnolence.  Most IARs were mild to moderate in 
intensity and non-serious. 
There is no adequate safety data for the use of Fabrazyme in pregnant or lactating women or the 
possible effects on their infants.  It is not known if Fabrazyme passes through the placenta to the 
embryo or if it is excreted in breast milk.  Maternal IgG antibodies may be passively transferred 
transplacentally or via breast milk to the fetus/infant.  Whether maternal administration of 
Fabrazyme can lead to an IgG and/or IgM (immunoglobulin M) antibody response to Fabrazyme 
by the fetus/infant is not known. 
Some study specific procedures may cause increased risk to the mother or infant, eg, risks 
associated with phlebotomy include fainting, hematoma, excessive bleeding, or infection. 
 
  
A small number of patients have experienced anaphylactoid reactions some of which were 
considered life-threatening.  Signs or symptoms of possible anaphylactoid reactions have included 
events of localized angioedema, generalized urticaria, bronchospasm, and hypotension.  The risks 
and benefits of re-administering Fabrazyme following a severe hypersensitivity or anaphylactoid 
reaction should be carefully considered. 
A complete overview of the safety profile of Fabrazyme can be found in the Investigator’s 
Brochure and/or product labeling. 
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5 
STUDY OBJECTIVES 
The objectives of this study are: 
1. To determine whether αGAL activity is present in the breast milk of mothers with Fabry 
disease who are being treated with Fabrazyme during lactation. 
2. To measure breast milk production and composition (volume, protein and fat content) in 
women with Fabry disease who receive Fabrazyme during lactation. 
3. To determine whether Fabrazyme affects the growth, development, and immunologic 
response of infants born to mothers with Fabry disease who receive Fabrazyme during 
lactation. 
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6 
INVESTIGATIONAL PLAN 
6.1 
STUDY DESIGN 
This is a phase 4, multicenter, multinational study of the effects of Fabrazyme on lactation and on 
the growth, development, and immunologic response of infants born to mothers with Fabry 
disease who are treated with Fabrazyme during lactation.  There are 3 participation scenarios: 
mother/infant full participation, mother full participation/infant development only, and mother full 
participation/infant no participation (see Section 9.1). 
Whether or not the mother continues to lactate will be assessed at each visit.  Breast milk will be 
collected at Months 1, 3, and 6 immediately prior to Fabrazyme infusion, just after the end of the 
infusion, and 2 hours after the end of the infusion.  Breast milk samples will be analyzed for 
volume, presence of αGAL activity, total fat content, and total protein concentration. Blood 
samples from the mother will be drawn for pharmacokinetic (PK) analysis prior to each breast 
milk collection.  If infant genotyping is performed on the umbilical blood cord sample collected at 
Baseline visit, a buccal cell sample will be obtained from the mother to rule out contamination of 
the cord blood sample with maternal DNA. 
If the parent(s)/legal guardian(s) consent to infant participation, the infant’s growth and 
development will be assessed.  The infant may also be tested for the formation or continued 
presence of serum IgG and IgM antibodies to r-hαGAL and for genotype. 
For the purposes of this study, the mother and the infant will each be considered a study patient. 
The mother must be enrolled in the Fabry Registry and will be followed using the Fabry Registry 
assessment schedule and CRFs as well as this study’s CRF.  During this study, infants will be 
evaluated, ie, the infant may be tested for IgG and IgM antibodies to r-hαGAL at birth and 
Months 2, 6, and 12 and will be tested developmentally at each visit for 24 months, or until the 
parent(s)/legal guardian(s) withdraws consent and discontinues the infant’s study participation, 
the infant is discontinued from the study by the Investigator (see Section 7.3.1), or the study is 
terminated (see Section 7.3.2). 
If the mother is no longer lactating, the mother will discontinue this study but continue to be 
followed in the Fabry Registry.  The infant will be followed for development only for the 
remainder of this 24 month study. 
6.2 
STUDY RATIONALE 
It is anticipated that with Fabrazyme becoming widely available, more women of childbearing age 
with Fabry disease will receive Fabrazyme.  It is not known whether Fabrazyme is excreted in 
human milk and there is limited data involving infants of mothers receiving Fabrazyme during 
lactation.  This study is being conducted 1) to determine whether αGAL is present in the breast 
milk of mothers with Fabry disease who receive Fabrazyme during lactation; 2) to measure breast 
milk production and composition (volume and protein and fat content) in women with Fabry 
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disease who receive Fabrazyme during lactation; and 3) to determine whether Fabrazyme affects 
the growth, development, and immunologic response of infants born to these mothers.  Antibody 
formation to r-hαGAL in infants will be monitored postpartum for up to 1 year (Month 12).  
Blood samples for maternal PK analysis will be drawn to assess the clearance of αGAL post-
partum and during the lactating period for up to Month 6.  Data on concomitant medications and 
AEs for both mothers and infants will also be collected at each visit and coded using Medical 
Dictionary for Regulatory Activities (MedDRA). 
6.2.1 Dosing Regimen 
Mothers who are receiving Fabrazyme during lactation will continue to receive Fabrazyme 
treatment (commercially available) during study participation at their prescribed dosage regimen 
as determined by their treating physician.  Each Fabrazyme infusion will be prepared in the 
standard approved manner (refer to appropriate country labeling information). 
6.2.2 Study Duration 
This study will last for up to 2 years (24 months). 
If the mother is no longer lactating or the mother is no longer receiving Fabrazyme treatment, the 
mother will discontinue this study but continue to be followed in the Fabry Registry.  The infant 
will be followed, for development only, for the remainder of this 24 month study. 
6.2.3 Study Population 
Females treated with Fabrazyme while lactating and their infants will be eligible for enrollment 
into this study. Pregnant women who received Fabrazyme at any point during their pregnancy can 
be enrolled in the study. If woman is not receiving treatment with Fabrazyme at the Baseline visit, 
mother should start treatment with Fabrazyme between the delivery and Month 1 visit.  Females 
being treated with Fabrazyme infusion during lactation will have to provide signed written 
informed consent for themselves and for their infant to participate as study patients prior to any 
protocol-related procedures being performed. 
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7 
PATIENT POPULATION AND SELECTION 
Approximately 10 females and up to 10 of their infants (who must be receiving breast milk while 
the mother is receiving Fabrazyme therapy) will be enrolled in this study, at approximately 10 
study centers.  Mothers will receive Fabrazyme treatment as part of the standard of care of Fabry 
disease and will be followed through the Fabry Registry. 
7.1 
INCLUSION CRITERIA 
Mothers must meet the following criteria to be enrolled in this study: 
1. provide signed written informed consent to participate in this study, 
2. be enrolled in the Fabry Registry* and receiving Fabrazyme while lactating, 
3. agree to adhere to the Fabry Registry recommended schedule of assessments for medical 
history, pregnancy outcome, genotyping, and antibody testing, and 
4. agree to adhere to the schedule of evaluations (Table 1, Table 2, or Table 3) for this study. 
*The Fabry Registry is a global, observational, and voluntary program for patients with Fabry 
disease, intended to explore and define the natural course and clinical characteristics of the 
disease as well as to track and characterize response to treatments. 
Infants must meet the following criteria to be enrolled in this study: 
1. have the signed written informed consent of the parent(s)/legal guardian(s) to participate in 
this study, 
2. be born to a mother who is receiving Fabrazyme during lactation, 
3. be receiving breast milk from the mother, and 
4. have the agreement of the parent(s)/legal guardian(s) to adhere to the schedule of 
evaluations (Table 1 or Table 2) for this study. 
7.2 
EXCLUSION CRITERIA 
The mother and infant will be excluded from this study if the mother has received an 
investigational drug within 30 days prior to study enrollment. 
7.3 
WITHDRAWAL CRITERIA 
7.3.1 Patient Withdrawal 
The mother (or the legal guardian acting on behalf of the infant and/or the mother) is free to 
withdraw consent and discontinue her participation as well as the infant’s participation in the 
study at any time, without prejudice to further treatment.  The mother and infant’s participation in 
the study may be discontinued at any time at the discretion of the Investigator.  The following 
may be justifiable reasons for the Investigator to remove a patient from the study: 
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Mother: 
• The mother is uncooperative/noncompliant and will not adhere to study responsibilities, 
including failure to appear at scheduled study visits, or failure to undergo study 
assessments, and/or failure to comply with the Registry schedule of assessments. 
• The mother was erroneously included in the study. 
• The mother experiences an intolerable AE. 
• The mother stops lactating. 
• The study is terminated by the Sponsor.  
Infant: 
• The mother and/or infant was erroneously included in the study. 
• The infant experiences an intolerable AE. 
• The study is terminated by the Sponsor. 
If the mother and/or the infant discontinues participation in the study, or their participation is 
discontinued by the Investigator, the mother and/or infant’s legal guardian should be contacted by 
the Study Investigator in order to obtain information about the reason(s) for discontinuation and 
collection of any potential AEs.  Whenever possible the patient should return to the study site for 
the final clinical assessments as specified in Section 9.1.1.8, Section 9.1.2.8, or Section 9.1.3.4, as 
appropriate.  The Study Investigator will describe the reason for discontinuation on the 
appropriate CRF. 
7.3.2 Study or Site Termination 
If the Sponsor, Study Investigator, Medical Monitor, or regulatory authorities discover conditions 
during the study that indicate that the study or study site should be terminated, this action may be 
taken after appropriate consultation between the Sponsor, Study Investigator, and Medical 
Monitor.  Conditions that may warrant termination of the study or study site include, but are not 
limited to: 
• The discovery of an unexpected, serious, or unacceptable risk to patients enrolled in the 
study; 
• The decision on the part of the Sponsor to suspend or discontinue the study; 
• Failure of the Study Investigator to comply with pertinent regulatory authority regulations; 
• Submission of knowingly false information from the research facility to the Sponsor, 
Clinical Monitor, or regulatory authorities; or 
• Insufficient adherence to protocol requirements. 
Study termination and follow-up will be performed in compliance with the conditions set forth in 
applicable local regulations and Sponsor Standard Operating Procedures (SOPs). 
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8 
STUDY TREATMENTS 
8.1 
TREATMENTS ADMINISTERED 
Mothers will receive Fabrazyme treatment (commercially available) at their currently prescribed 
dosage regimen as determined by their treating physician.  The Fabrazyme infusions will be 
prepared in the standard approved manner (refer to appropriate country labeling information). 
8.2 
INVESTIGATIONAL PRODUCT 
8.2.1 Investigational Product Description and Preparation 
Description: 
recombinant human α-galactosidase A (r-hαGAL; Fabrazyme) is produced 
by mammalian cell culture technology using a Chinese Hamster Ovary 
(CHO) cell line. 
Chemical Name: 
recombinant human α-galactosidase A (r-hαGAL)  
CAS Registry Number: 104138-64-9 
USAN (WHO/INN): agalsidase beta 
Chemical Structure: r-hαGAL is comprised of two subunits of 398 amino acids (approximately 
51 kD), each of which contains three N-linked glycosylation sites. α-
galactosidase A catalyzes the hydrolysis of GL-3 and other α-galactyl-
terminated neutral glycosphingolipids, such as galabiosylceramide and 
blood group B substances to ceramide dihexoside and galactose. 
Molecular Weight: 
r-hαGAL is a homodimeric glycoprotein with a molecular weight of 
approximately 100 kD. 
Commercial Fabrazyme is supplied as a sterile, nonpyrogenic, white to off-white, lyophilized 
cake or powder for reconstitution with Sterile Water for Injection, USP.  Each 35 mg vial contains 
37 mg of agalsidase beta, as well as 222 mg mannitol, 20.4 mg sodium phosphate monobasic 
monohydrate, and 59.2 mg sodium phosphate dibasic heptahydrate.  Following reconstitution as 
directed, 35 mg of agalsidase beta (7 mL) may be extracted from each 35 mg vial.  Each 5 mg vial 
contains 5.5 mg of agalsidase beta, as well as 33.0 mg mannitol, 3.0 mg sodium phosphate 
monobasic monohydrate, and 8.8 mg sodium phosphate dibasic heptahydrate.  Following 
reconstitution as directed, 5 mg of agalsidase beta (1 mL) may be extracted from each 5 mg vial. 
8.2.2 Packaging and Labeling 
Commercially supplied Fabrazyme is to be used. 
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8.2.3 Drug Storage 
All drug supplies must be kept in a secure place with restricted access and stored at 2° to 8°C. 
8.2.4 Study Drug Accountability 
Not applicable. 
8.3 
PATIENT NUMBERING 
After the mother has signed written informed consent for her and her infant to participate, the 
infant will be assigned a unique 5-digit identification number, which will consist of a 3 digit 
assigned site number and 2 digit sequential patient number, beginning with 01.  The mother’s 
patient identification number will be the number assigned to her through the Fabry Registry. 
8.4 
PACKAGING AND LABELING 
Refer to appropriate country labeling information for packaging and labeling information for 
Fabrazyme. 
8.5 
PRIOR AND CONCOMITANT MEDICATIONS 
All medications taken by the mother and all medications taken by the infant from the time the 
Informed Consent Form is signed until the end of study participation will be recorded on the 
Concomitant Medication CRF. 
8.6 
BLINDING AND RANDOMIZATION 
Not applicable for this open-label study. 
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9 
EFFICACY, PHARMACOKINETICS, AND SAFETY VARIABLES 
Efficacy will not be measured in this study. 
The effects of Fabrazyme treatment on lactation and infants will be monitored continuously 
throughout study participation and will be assessed in terms of incidence of AEs, concomitant 
medication, immunogenicity testing, vital signs, and physical examination results including the 
infant’s growth and development.  Pharmacokinetics testing will be conducted on the mother’s 
plasma and breast milk. 
Refer to Table 1, Table 2, or Table 3 for the schedules of assessments (mother/infant full 
participation, mother full participation/infant development only, and mother full 
participation/infant no participation, respectively). 
9.1 
MEASUREMENTS ASSESSED AND STUDY FLOWCHART 
After obtaining signed, written informed consent, the study will be conducted as outlined in the 
following sections.  Table 1 summarizes the schedules of study evaluations at each study visit for 
mothers and infants enrolled for full participation (eg, full/full participation through Month 24).  If 
the mother is enrolled for full participation but the infant is enrolled only for developmental 
assessments (eg, full/development) (see Table 2), the mother and infant schedules are the same as 
full/full participation, except the infant blood samples are omitted.  If only the mother is 
participating in the study (eg, full/no) (see Table 3), her assessment schedule is the same as full 
participation except study participation is stopped and considered complete at Month 6.  Refer to 
the Study Operations Manual (SOM) for guidelines regarding test assessments and procedures for 
handling/shipment of all laboratory samples. 
The timing of study procedures will be based on calendar weeks starting with Baseline; defined 
for the mother as during the month prior to delivery and at birth for the infant.  Thus Month 1 is 1 
month postpartum.  The study procedures and assessments are scheduled so that the maximum 
time the mother and the infant may participate in the study is approximately 24 months. 
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Table 1 - Schedule of Study Evaluations - Mother (Full Participation) and Infant (Full Participation) 
Months Postpartumb 
Evaluations 
Baselinea 
1 
2 
3 
6 
12 
18 
24/End of Study 
Mother 
 
 
 
 
 
 
 
 
Written Informed Consent 
X 
 
 
 
 
 
 
 
Confirm Registry Enrollment 
X 
 
 
 
 
 
 
 
Blood Samples for PK Testing 
 
Xc 
 
Xc 
Xc 
 
 
 
Breast Milk Samples for PK, αGAL activity, 
volume, and protein and fat contentd 
 
Xe 
 
Xe 
Xe 
 
 
 
Lactation Status 
Xf 
X 
X 
X 
X 
X 
X 
X 
Buccal Cell Sample 
Xh, j 
 
 
 
 
 
 
 
Concomitant Medications Review 
Continuous Monitoring 
Adverse Events Assessment 
Continuous Monitoring 
Infant 
 
 
 
 
 
 
 
 
Written Informed Consent 
(provided by parent[s]/legal guardian[s]) 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Physical Examination 
Xg 
X 
X 
X 
X 
X 
X 
X 
Denver II Developmental Screening Test 
 
X 
X 
X 
X 
X 
X 
X 
Record Receiving Breast Milk Status 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Samples for Antibodies to r-hαGAL 
Xh 
 
X 
 
X 
X i 
 
 
Blood sample for Genotyping 
Xh,i 
 
 
 
 
 
 
 
Concomitant Medications Review 
Continuous Monitoring 
Adverse Events Assessment 
Continuous Monitoring 
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Months Postpartumb 
Evaluations 
Baselinea 
1 
2 
3 
6 
12 
18 
24/End of Study 
a Baseline is defined as within 1 month prior to delivery (mother) and at birth (infant). 
b All visits will be within ±7 days of the scheduled visit. 
c Blood samples will be collected prior to each breast milk collection as follows: sample 1:  immediately prior to Fabrazyme infusion and prior to breast milk collection; sample 2: just prior to the 
end of Fabrazyme infusion and prior to breast milk collection; and sample 3:  2 hours after Fabrazyme infusion and prior to breast milk collection. 
d The mother must be lactating and receiving Fabrazyme therapy during the evaluation period. 
e Breast milk samples will be collected after each plasma collection for PK testing as follows:  sample 1: immediately prior to Fabrazyme infusion and after plasma collection; sample 2: 
immediately after Fabrazyme infusion and after plasma collection; and sample 3:  2 hours after Fabrazyme infusion and after plasma collection. 
f At baseline, record plans for breast milk feeding. 
g Includes Apgar score assessed at 1 minute and 5 minutes after birth. 
h Blood samples for Baseline IgG and IgM antibodies to r-hαGAL and genotyping of the infant will be obtained from umbilical cord immediately after birth.  A buccal cell sample will be obtained 
(by buccal swab) from the mother to rule out contamination of the cord blood sample with maternal DNA (maternal cell contamination analysis). 
i 
In cases when umbilical blood cord sample is not collected at the Baseline visit, genotyping of the infant could be performed on the additional blood sample collected at visit month 12. 
j 
At birth, in case when umbilical cord blood sample was collected. 
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Table 2 - Schedule of Study Evaluations - Mother (Full Participation) and Infant (Development Participation) 
Months Postpartumb 
Evaluations 
Baselinea  
1 
2 
3 
6 
12 
18 
24/End of Study 
Mother 
 
 
 
 
 
 
 
 
Written Informed Consent 
X 
 
 
 
 
 
 
 
Confirm Registry Enrollment 
X 
 
 
 
 
 
 
 
Blood Samples for PK Testing 
 
Xc 
 
Xc 
Xc 
 
 
 
Breast Milk Samples for PK, αGAL activity, 
volume, and protein and fat contentd 
 
Xe 
 
Xe 
Xe 
 
 
 
Lactation Status 
Xf 
X 
X 
X 
X 
X 
X 
X 
Buccal Cell Sample 
Xh, i 
 
 
 
 
 
 
 
Concomitant Medications Review 
Continuous Monitoring 
Adverse Events Assessment 
Continuous Monitoring 
Infant 
 
 
 
 
 
 
 
 
Written Informed Consent 
(provided by parent[s]/legal guardian[s]) 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Physical Examination 
Xg 
X 
X 
X 
X 
X 
X 
X 
Denver II Developmental Screening Test 
 
X 
X 
X 
X 
X 
X 
X 
Record Receiving Breast Milk Status 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample for Genotyping 
Xh 
 
 
 
 
 
 
 
Concomitant Medications Review 
Continuous Monitoring 
Adverse Events Assessment 
Continuous Monitoring 
a Baseline is defined as within 1 month prior to delivery (mother) and at birth (infant). 
b All visits will be within ±7 days of the scheduled visit. 
c Blood samples will be collected prior to each breast milk collection as follows: sample 1:  immediately prior to Fabrazyme infusion and prior to breast milk collection; sample 2: just prior to the 
end of Fabrazyme infusion and prior to breast milk collection; and sample 3:  2 hours after Fabrazyme infusion and prior to breast milk collection. 
d The mother must be lactating and receiving Fabrazyme therapy during the evaluation period. 
e Breast milk samples will be collected after each plasma collection for PK testing as follows:  sample 1: immediately prior to Fabrazyme infusion and after plasma collection; sample 2: 
immediately after Fabrazyme infusion and after plasma collection; and sample 3:  2 hours after Fabrazyme infusion and after plasma collection. 
f At baseline, record plans for breast milk feeding. 
g Includes Apgar score assessed at 1 minute and 5 minutes after birth. 
h Blood sample for genotyping of the infant will be obtained from umbilical cord blood immediately after birth. A buccal cell sample will be obtained (by buccal swab) from the mother to rule out 
contamination of the cord blood sample with maternal DNA (maternal cell contamination analysis). 
i 
At birth, in case when umbilical cord blood sample was collected. 
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Table 3 - Schedule of Study Evaluations - Mother (Full Participation) Infant (No Participation) 
                                                            Months Postpartumb 
Evaluations 
Baselinea 
1 
   3 
                6/ End of Study 
 
 
 
Mother 
 
 
 
 
 
 
 
 
Written Informed Consent 
X 
 
 
 
 
 
 
 
Confirm Registry Enrollment 
X 
 
 
 
 
 
 
 
Blood Samples for PK Testing 
 
Xc 
 
Xc 
Xc 
 
 
 
Breast Milk Samples for PK, αGAL activity, 
volume, and protein and fat contentd 
 
Xe 
 
Xe 
Xe 
 
 
 
Lactation Status 
X 
X 
 
X 
X 
 
 
 
Concomitant Medications Review 
Continuous Monitoring 
Adverse Events Assessment 
Continuous Monitoring 
a Baseline is defined as within 1 month prior to delivery (mother) and at birth (infant). 
b All visits will be within ±7 days of the scheduled visit. 
c Blood samples will be collected prior to each breast milk collection as follows: sample 1:  immediately prior to Fabrazyme infusion and prior to breast milk collection; sample 2: just prior to the 
end of Fabrazyme infusion and prior to breast milk collection; and sample 3:  2 hours after Fabrazyme infusion and prior to breast milk collection. 
d The mother must be lactating and receiving Fabrazyme therapy during the evaluation period. 
e Breast milk samples will be collected after each plasma collection for PK testing as follows:  sample 1: immediately prior to Fabrazyme infusion and after plasma collection; sample 2: 
immediately after Fabrazyme infusion and after plasma collection; and sample 3:  2 hours after Fabrazyme infusion and after plasma collection.. 
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9.1.1 Tests and Procedures for Mother Full Participation and Infant Full Participation 
9.1.1.1 Baseline (Full/Full Participation) 
The following assessments will be completed at Baseline: Mother (within 1 month prior to the 
infant’s birth): 
• Provide signed, written informed consent (Note: mothers must also be enrolled in the 
Fabry Registry with a signed written informed consent maintained within the Registry.) 
• Record plans for feeding the infant breast milk. 
• Collect buccal cell sample by buccal swab for MCC analysis at birth if umbilical cord 
blood sample was collected for genotyping of the infant. 
• Record AEs on the study CRF, from the time of signing the study informed consent. 
• Record concomitant medications on the study CRF, from the time of signing informed 
consent. 
Infant (at birth): 
• Parent(s)/legal guardian(s) provide signed written informed consent for the infant. (May be 
collected/provided prior to birth.) 
• Record the Apgar score at 1 minute and 5 minutes after birth. 
• Collect umbilical cord blood sample for IgG and IgM antibodies to r-hαGAL and for 
genotyping. 
• Record the medical history and conduct a physical examination. 
• Record status of receiving breast milk. 
• Record AEs, from birth. 
• Record concomitant medications, from the time the informed consent is signed/or from 
birth. 
9.1.1.2 Month One (Full/Full Participation) 
The following assessments will be completed at Month 1 (1 month ±7 days postpartum):  
Mother: 
• Collect blood samples for PK testing prior to each breast milk collection as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and prior to breast milk collection; 
- 
sample 2: just prior to the end of Fabrazyme infusion and prior to breast milk 
collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and prior to breast milk collection. 
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• Collect breast milk samples for presence of αGAL as well as measurement of volume and 
fat and protein levels after each plasma collection for PK testing as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and after plasma collection; 
sample 2: immediately after Fabrazyme infusion and after plasma collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and after plasma collection. 
• Record lactation status. 
• Record AEs. 
• Record concomitant medications.  
Infant: 
• Conduct a physical examination. 
• Administer the Denver II Developmental Screening Test. 
• Record status of receiving breast milk. 
• Record AEs. 
• Record concomitant medications. 
9.1.1.3 Month Two (Full/Full Participation) 
The following assessments will be completed at Month 2 (2 months ±7 days postpartum):  
Mother: 
• Record lactation status. 
• Record AEs. 
• Record concomitant medications.  
Infant: 
• Conduct a physical examination. 
• Administer the Denver II Developmental Screening Test. 
• Collect a blood sample for IgG and IgM antibodies to r-hαGAL.  
• Record status of receiving breast milk. 
• Record AEs. 
• Record concomitant medications. 
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9.1.1.4 Month Three (Full/Full Participation) 
The following assessments will be completed at Month 3 (3 months ±7 days postpartum):  
Mother: 
• Collect blood samples for PK testing prior to each breast milk collection as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and prior to breast milk collection; 
- 
sample 2: just prior to the end of Fabrazyme infusion and prior to breast milk 
collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and prior to breast milk collection. 
• Collect breast milk samples for presence of αGAL as well as measurement of volume and 
fat and protein levels after each plasma collection for PK testing as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and after plasma collection; 
- 
sample 2: immediately after Fabrazyme infusion and after plasma collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and after plasma collection. 
• Record lactation status. 
• Record AEs. 
• Record concomitant medications.  
Infant: 
• Conduct a physical examination. 
• Administer the Denver II Developmental Screening Test. 
• Record status of receiving breast milk. 
• Record AEs. 
• Record concomitant medications. 
9.1.1.5 Month Six (Full/Full Participation) 
The following assessments will be completed at Month 6 (6 months ±7 days postpartum):  
Mother: 
• Collect blood samples for PK testing prior to each breast milk collection as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and prior to breast milk collection; 
- 
sample 2: just prior to the end of Fabrazyme infusion and prior to breast milk 
collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and prior to breast milk collection. 
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• Collect breast milk samples for presence of αGAL as well as measurement of volume and 
fat and protein levels after each plasma collection for PK testing as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and after plasma collection; 
- 
sample 2: immediately after Fabrazyme infusion and after plasma collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and after plasma collection. 
• Record lactation status 
• Record AEs. 
• Record concomitant medications.  
Infant: 
• Conduct a physical examination. 
• Administer the Denver II Developmental Screening Test. 
• Collect a blood sample for IgG and IgM antibodies to r-hαGAL. 
• Record status of receiving breast milk. 
• Record AEs. 
• Record concomitant medications. 
9.1.1.6 Month Twelve (Full/Full Participation) 
The following assessments will be completed at Month 12 (12 months ±7 days postpartum):  
Mother: 
• Record lactation status. 
• Record AEs. 
• Record concomitant medications.  
Infant: 
• Conduct a physical examination. 
• Administer the Denver II Developmental Screening Test. 
• Record status of receiving breast milk. 
• Collect a blood sample for IgG and IgM antibodies to r-hαGAL. 
• Collect a blood sample for genotyping (only if umbilical blood cord sample was not 
collected at the Baseline visit and infant genotyping  was not performed as a part of 
standard care prior to visit month 12). 
• Record AEs. 
• Record concomitant medications. 
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9.1.1.7 Month Eighteen (Full/Full Participation) 
The following assessments will be completed at Month 18 (18 months ±7 days postpartum):  
Mother: 
• Record lactation status. 
• Record AEs. 
• Record concomitant medications.  
Infant: 
• Conduct a physical examination. 
• Administer the Denver II Developmental Screening Test. 
• Record status of receiving breast milk. 
• Record AEs. 
• Record concomitant medications. 
9.1.1.8 Month Twenty-four/End of Study (Full/Full Participation) 
The following assessments will be completed at Month 24 (24 months ±7 days postpartum) or at 
early withdrawal: 
Mother: 
• Record lactation status. 
• Record AEs. 
• Record concomitant medications.  
Infant: 
• Conduct a physical examination. 
• Administer the Denver II Developmental Screening Test. 
• Record status of receiving breast milk. 
• Record AEs. 
• Record concomitant medications. 
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9.1.2 Tests and Procedures for Mother Full Participation and Infant Development 
9.1.2.1 Baseline (Full/Development Participation) 
The following assessments will be completed at Baseline:  
Mother (within 1 month prior to the infant’s birth): 
• Provide signed, written informed consent (Note: mothers must also be enrolled in the 
Fabry Registry with a signed written informed consent maintained within the Registry.) 
• Record plans for feeding the infant breast milk. 
• Collect buccal cell sample by buccal swab for MCC analysis at birth if umbilical cord 
blood sample was collected for genotyping of the infant. 
• Record AEs on the study CRF, from the time of signing the study informed consent. 
• Record concomitant medications on the study CRF, from the time of signing informed 
consent. 
Infant (at birth): 
• Parent(s)/legal guardian(s) provide signed written informed consent for the infant. 
• Record the Apgar score at 1 minute and 5 minutes after birth. 
• Collect umbilical cord blood sample for genotyping. 
• Record the medical history and conduct a physical examination. 
• Record status of receiving breast milk. 
• Record AEs. 
• Record concomitant medications. 
9.1.2.2 Month One (Full/Development Participation) 
The following assessments will be completed at Month 1 (1 month ±7 days postpartum):  
Mother: 
• Collect blood samples for PK testing prior to each breast milk collection as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and prior to breast milk collection; 
- 
sample 2: just prior to the end of Fabrazyme infusion and prior to breast milk 
collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and prior to breast milk collection. 
• Collect breast milk samples for presence of αGAL as well as measurement of volume and 
fat and protein levels after each plasma collection for PK testing as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and after plasma collection; 
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sample 2: immediately after Fabrazyme infusion and after plasma collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and after plasma collection. 
• Record lactation status. 
• Record AEs. 
• Record concomitant medications.  
Infant: 
• Conduct a physical examination. 
• Administer the Denver II Developmental Screening Test. 
• Record status of receiving breast milk. 
• Record AEs. 
• Record concomitant medications. 
9.1.2.3 Month Two (Full/Development Participation) 
The following assessments will be completed at Month 2 (2 months ±7 days postpartum):  
Mother: 
• Record lactation status. 
• Record AEs. 
• Record concomitant medications.  
Infant: 
• Conduct a physical examination. 
• Administer the Denver II Developmental Screening Test. 
• Record status of receiving breast milk. 
• Record AEs. 
• Record concomitant medications. 
9.1.2.4 Month Three (Full/Development Participation) 
The following assessments will be completed at Month 3 (3 months ±7 days postpartum): 
Mother: 
• Collect blood samples for PK testing prior to each breast milk collection as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and prior to breast milk collection; 
- 
sample 2: just prior to the end of Fabrazyme infusion and prior to breast milk 
collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and prior to breast milk collection. 
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• Collect breast milk samples for presence of αGAL as well as measurement of volume and 
fat and protein levels after each plasma collection for PK testing as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and after plasma collection; 
- 
sample 2: immediately after Fabrazyme infusion and after plasma collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and after plasma collection. 
• Record lactation status. 
• Record AEs. 
• Record concomitant medications.  
Infant: 
• Conduct a physical examination. 
• Administer the Denver II Developmental Screening Test. 
• Record status of receiving breast milk. 
• Record AEs. 
• Record concomitant medications. 
9.1.2.5 Month Six (Full/Development Participation) 
The following assessments will be completed at Month 6 (6 months ±7 days postpartum):  
Mother: 
• Collect blood samples for PK testing prior to each breast milk collection as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and prior to breast milk collection; 
- 
sample 2: just prior to the end of Fabrazyme infusion and prior to breast milk 
collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and prior to breast milk collection. 
• Collect breast milk samples for presence of αGAL as well as measurement of volume and 
fat and protein levels after each plasma collection for PK testing as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and after plasma collection; 
- 
sample 2: immediately after Fabrazyme infusion and after plasma collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and after plasma collection. 
• Record lactation status. 
• Record AEs. 
• Record concomitant medications.  
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Infant: 
• Conduct a physical examination. 
• Administer the Denver II Developmental Screening Test. 
• Record status of receiving breast milk. 
• Record AEs. 
• Record concomitant medications. 
9.1.2.6 Month Twelve (Full/Development Participation) 
The following assessments will be completed at Month 12 (12 months ±7 days postpartum):  
Mother: 
• Record lactation status. 
• Record AEs. 
• Record concomitant medications.  
Infant: 
• Conduct a physical examination. 
• Administer the Denver II Developmental Screening Test. 
• Record status of receiving breast milk. 
• Record AEs. 
• Record concomitant medications. 
9.1.2.7 Month Eighteen (Full/Development Participation) 
The following assessments will be completed at Month 18 (18 months ±7 days postpartum):  
Mother: 
• Record lactation status. 
• Record AEs. 
• Record concomitant medications.  
Infant: 
• Conduct a physical examination. 
• Administer the Denver II Developmental Screening Test. 
• Record status of receiving breast milk. 
• Record AEs. 
• Record concomitant medications. 
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9.1.2.8 Month Twenty-four/End of Study (Full/Development Participation) 
The following assessments will be completed at Month 24 (24 months ±7 days postpartum) or at 
early withdrawal:  
Mother: 
• Record lactation status. 
• Record AEs. 
• Record concomitant medications.  
Infant: 
• Conduct a physical examination. 
• Administer the Denver II Developmental Screening Test. 
• Record status of receiving breast milk. 
• Record AEs. 
• Record concomitant medications. 
9.1.3 Tests and Procedures for Mother (Full Participation) Infant (No Participation) 
9.1.3.1 Baseline (Full/No Participation) 
The following assessments will be completed at Baseline:  
Mother (within 1 month prior to the infant’s birth): 
• Provide signed, written informed consent (Note: mothers must also be enrolled in the 
Fabry Registry with a signed written informed consent maintained within the Registry.) 
• Record plans for feeding the infant breast milk. 
• Record AEs on the study CRF, from the time of signing the study informed consent. 
• Record concomitant medications on the study CRF, from the time of signing informed 
consent. 
9.1.3.2 Month One (Full/No Participation) 
The following assessments will be completed at Month 1 (1 month ±7 days postpartum): 
• Collect blood samples for PK testing prior to each breast milk collection as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and prior to breast milk collection; 
- 
sample 2: just prior to the end of Fabrazyme infusion and prior to breast milk 
collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and prior to breast milk collection. 
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• Collect breast milk samples for presence of αGAL as well as measurement of volume and 
fat and protein levels after each plasma collection for PK testing as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and after plasma collection; 
- 
sample 2: immediately after Fabrazyme infusion and after plasma collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and after plasma collection. 
• Record lactation status. 
• Record AEs. 
• Record concomitant medications. 
9.1.3.3 Month Three (Full/No Participation) 
The following assessments will be completed at Month 3 (3 months ±7 days postpartum): 
• Collect blood samples for PK testing prior to each breast milk collection as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and prior to breast milk collection; 
- 
sample 2: just prior to the end of Fabrazyme infusion and prior to breast milk 
collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and prior to breast milk collection. 
• Collect breast milk samples for presence of αGAL as well as measurement of volume and 
fat and protein levels after each plasma collection for PK testing as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and after plasma collection; 
- 
sample 2: immediately after Fabrazyme infusion and after plasma collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and after plasma collection. 
• Record lactation status. 
• Record AEs. 
• Record concomitant medications. 
9.1.3.4 Month Six/End of Study (Full/No Participation) 
The following assessments will be completed at Month 6 (6 months ±7 days postpartum) or at 
early withdrawal: 
• Collect blood samples for PK testing prior to each breast milk collection as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and prior to breast milk collection; 
- 
sample 2: just prior to the end of Fabrazyme infusion and prior to breast milk 
collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and prior to breast milk collection. 
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• Collect breast milk samples for presence of αGAL as well as measurement of volume and 
fat and protein levels after each plasma collection for PK testing as follows: 
- 
sample 1: immediately prior to Fabrazyme infusion and after plasma collection; 
- 
sample 2: immediately after Fabrazyme infusion and after plasma collection; and 
- 
sample 3: 2 hours after Fabrazyme infusion and after plasma collection. 
• Record lactation status. 
• Record AEs. 
• Record concomitant medications. 
9.2 
EFFICACY ASSESSMENTS 
Not Applicable. 
9.3 
PHARMACOKINETIC ASSESSMENTS 
Pharmacokinetic Sampling 
Blood and breast milk samples will be taken from the mother for measurement of αGAL 
concentrations. Sample collection, processing, and shipping instructions are provided in the SOM. 
Blood samples will be taken from the mother at Months 1, 3, and 6 for PK testing (if mother is 
lactating at the time of the evaluation and is receiving Fabrazyme therapy).  Blood samples will be 
collected prior to each breast milk collection as follows: sample 1: immediately prior to 
Fabrazyme infusion and prior to breast milk collection; sample 2: just prior to the end of 
Fabrazyme infusion and prior to breast milk collection; and sample 3: 2 hours after Fabrazyme 
infusion and prior to breast milk collection. 
Bioanalytical Method. 
 
 
 
Pharmacokinetic parameters 
The following pharmacokinetic parameters will be calculated, using noncompartmental methods from 
plasma αGAL concentrations and milk αGAL concentrations 
- 
maximum plasma concentration observed (CBmax
B) in plasma and milk 
- 
area under the plasma αGAL concentration versus time curve calculated using the 
trapezoidal method from 0 to 2 hours post end of infusion (AUCB0-2 plasma
B). 
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- 
The amount of αGAL in milk calculated as the product of αGAL activity times the 
milk volume 
- 
area under the milk αGAL concentration versus time curve calculated using the 
trapezoidal method from 0 to 2 hours post end of infusion (AUCB0-2 milk
B). 
- 
Lactation clearance determined in the 0-2 hours interval, according to the following equation : 
amount of αGAL excreted over the sampling period divided by the AUC during the 
sampling period 
The milk to plasma ratio for AUCB0-2 will also be computed. 
9.4 
SAFETY ASSESSMENTS AND OTHER MEASUREMENTS 
9.4.1 Adverse Events 
An AE is any undesirable physical, psychological, or behavioral effect experienced by a patient or 
subject during their participation in an investigational study whether or not product-related.  This 
includes any untoward signs or symptoms experienced by the mother and/or infant from the time 
of signing of the informed consent until completion of the study.  AEs may include, but are not 
limited to: 
• Subjective or objective symptoms spontaneously demonstrated by the infant and/or 
observed by the mother, guardian, investigator, or medical staff. 
• Laboratory abnormalities of clinical significance. 
Disease signs, symptoms, and/or laboratory abnormalities already existing prior to the use of the 
study medication are not considered AEs after treatment unless they reoccur after the patient has 
recovered from the pre-existing condition or they represent an exacerbation in intensity or 
frequency. 
All AEs ongoing at the time of withdrawal, study termination, or study completion require a 
follow up at approximately 28 days after discontinuation of study participation.  The Investigator 
will be asked to follow-up on all SAEs that were ongoing at the time of withdrawal, termination 
or completion until resolution, until both the sponsor and investigator agree follow-up is deemed 
no longer medically necessary or until the patient is lost to follow-up. 
If any new SAEs are identified during the course of this follow-up of ongoing SAEs, additional 
follow-up of these new SAEs may be performed.  The Investigator and sponsor will determine if 
the follow-up is clinically warranted and relevant to the evaluation of the safety of the trial 
treatment or until patient is lost to follow up.  The investigator must follow patients with AEs until 
their condition resolves or stabilizes. Certain conditions that are not expected to resolve, such as 
metastatic cancer, need not be followed indefinitely by the investigator. 
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9.4.2 Serious Adverse Events 
SAEs will be recorded from signed consent through the Month 24 visit (or through the Month 6 
visit if only the mother is participating in the study).  For patients who discontinue prematurely 
from the study, SAEs will be reported from signed consent through the last patient study visit.  A 
serious adverse event is defined as any AE that results in any of the following outcomes: 
• Death 
• Life-threatening experience 
• Required or prolonged inpatient hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect 
• Important medical events, based upon appropriate medical judgment, that may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent 1 of the 
outcomes listed above 
Life-threatening experience: any AE that places the patient, in the view of the reporter, at 
immediate risk of death from the AE as it occurred, ie, does not include an AE that had it occurred 
in a more severe form might have caused death. 
Persistent or significant disability/incapacity: the AE that resulted in a substantial disruption of a 
person’s ability to conduct normal life functions. 
Important medical events based upon appropriate medical judgment, that may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed above: an AE that may not result in death, be life-threatening, or require hospitalization may 
be considered an SAE when, based upon appropriate medical judgment, it may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed above. 
The Investigator will be asked to assess the severity of the adverse drug/biologic event using the 
following categories: Mild, Moderate, and Severe. This assessment is subjective and the 
Investigator should use medical judgment to compare the reported AE to similar types of events 
observed in clinical practice. Below are listed guidelines for severity assessment: 
Mild: Symptom(s) barely noticeable to the subject/patient or does not make the subject/patient 
uncomfortable.  The AE does not influence performance or functioning.  Prescription drugs are 
not ordinarily needed for relief of symptom(s). 
Moderate: Symptom(s) of a sufficient severity to make the subject/patient uncomfortable. 
Performance of daily activities is influenced. Treatment of symptom(s) may be needed. 
Severe: Symptom(s) of a sufficient severity to cause the subject/patient severe discomfort. 
Severity may cause cessation of treatment with the study drug.  Treatment for symptom(s) may be 
given. 
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9.4.3 Adverse Event and Serious Adverse Event Reporting 
All SAEs will be documented on the study CRF and reported within 24 hours of the Study 
Investigator's knowledge of the event, even if the experience does not appear to be related to 
Fabrazyme.  The following central global contact information should be used for reporting to the 
Sponsor’s Global Pharmacovigilance and Epidemiology (GPE): 
 
 
 
 
Fax: +33 1 60 49 70 70 
 
 
 
 
Email: CL-CPV-receipt@sanofi.com 
For all SAEs, a detailed written description that includes copies of relevant patient records, 
autopsy reports, and other documents will be sent to Sponsor’s Global Pharmacovigilance and 
Epidemiology (GPE) Department as directed above. 
During the course of the study, Sanofi Genzyme is responsible for reporting in an expedited 
manner all SAEs that are both unexpected and at least reasonably related to the study drug to the 
regulatory authorities, independent ethics committee (IECs)/institutional review boards (IRBs) as 
appropriate, and to the Investigators. Additionally, Sanofi Genzyme is responsible for expedited 
reporting of all SAEs that are expected and at least reasonably related to the study drug to the 
regulatory authorities, according to the local regulations. 
9.4.4 Clinical Laboratory Tests 
Not applicable. 
9.4.5 Concomitant Medications 
A concomitant medication is any medication, prescription or over the counter, taken by a patient 
during their participation in an investigational study.  All medications taken from the time of 
signing the Informed Consent through to study completion will be recorded on the CRF.  In 
addition, at every visit, the site personnel will record any medication used by the patient since a 
previous visit. 
Administration of concomitant medication(s) signals that an AE should be recorded. 
9.4.6 Status of Lactation/Receiving Breast Milk 
Whether or not the mother is lactating will be recorded at each visit on the mother’s CRF.  
If the infant is participating in this study, whether or not the infant is receiving breast milk will be 
recorded at each visit on the infant’s CRF. 
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9.4.7 Breast Milk Samples 
Breast milk samples of mothers receiving Fabrazyme will be tested for αGAL activity, volume, 
and fat and protein content. Since αGAL is a protein, it is a normal component of breast milk and 
it is possible that the women enrolled in the study naturally produce αGAL in the breast milk 
samples. The current assay cannot differentiate between endogenous αGAL and Fabrazyme. As 
breast milk samples are not available prior to the mother having started Fabrazyme therapy, breast 
milk samples will be tested just prior to the Fabrazyme infusion and at timed intervals as specified 
above (see Section 9.3) to see if there is an increase in the αGAL levels in breast milk. 
Each breast milk collection should first be measured for total volume. An aliquot of each breast 
milk sample collected at the site is to be set aside for testing and the remainder of the sample may 
be fed to the infant. Refer to the SOM for further details on breast milk sampling. 
9.4.8 Physical Examination 
Each infant physical examination will include the following physical observations: Length; 
Weight; Head Circumference; Vital Signs; General Appearance; Skin; Head, Ears, Eyes, Nose, 
and Throat (HEENT); Lymph Nodes; Heart; Lungs; Abdomen; Extremities/Joints; Neurological; 
Mental Status; and External Genitalia. 
If clinically significant worsening of the physical examination assessments compared to Baseline 
is noted, the change will be documented as an AE on the AE CRF and will be followed as an AE 
consistent with the procedures outlined in Section 9.4.1.  Clinical significance is defined as any 
variation in physical findings that has medical relevance resulting in an alteration in medical care. 
The infant's Apgar score will be determined at 1 minute and 5 minutes after birth. 
9.4.9 Developmental Assessment 
The Denver II Developmental Screening Test will be used as an evaluation tool for developmental 
abnormalities. The Denver II Developmental Screening Test is used to evaluate 4 developmental 
areas: personal-social, fine motor, language, and gross motor. Information regarding the Denver II 
Developmental Screening Test is provided in the SOM. If the assessment is abnormal, more in-
depth testing will be undertaken based on the local standards of care. 
9.4.10 Genotype Testing 
Genotype testing will be conducted for all participating infants on umbilical cord blood to 
determine diagnosis of Fabry disease. Buccal cells will be collected from the mother by buccal 
swab to rule out contamination of the cord blood sample with maternal DNA (MCC analysis). The 
basic premise of the MCC test is the comparison of highly polymorphic short tandem repeat loci 
between the maternal and fetal DNA samples following polymerase chain reaction.(8) 
In cases when umbilical blood cord sample is not collected at the Baseline visit, genotyping of the 
infant enrolled for full participation could be performed on the additional blood sample collected 
at visit month 12. If genotyping of the infant is performed as a part of standard care prior to visit 
month 12, this result will be recorded by Investigator in the CRF.  
Blood and buccal cell sample collection, processing, and shipping instructions are provided in the 
SOM. 
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9.4.11 Immunogenicity Testing 
Immunogenicity testing will be conducted in those infants with parent(s)/legal guardian(s) 
consent. Blood collection, processing, and shipping instructions for infant blood samples for 
antibodies (IgG and IgM) to r-hαGAL are provided in the SOM. 
9.4.12 Safety Follow-Up 
Study sites will attempt to reach all study participants by telephone approximately 28 days after 
the final study procedures are completed, to conduct concomitant medication and adverse 
experience/event assessment. 
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10 
DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT  
10.1 
RECORDING OF DATA 
All required data will be recorded in the CRF provided by Genzyme. All missing data will be 
explained.  If a space is blank because the item was not done, the item will be marked “ND.”  If 
the item is unknown, the item will be marked “UNK.”  If the item is not applicable to the 
individual case, the space will be marked “NA.” If the item is not available, it will be marked 
“NAV.”  All entries will be recorded in black ink.  Any erroneous entries made on the CRFs will 
be crossed out with a single line, initialed and dated, and the correct entry, if appropriate, will be 
recorded.  Errors may not be erased and whiteout may not be used. 
10.2 
DATA QUALITY ASSURANCE 
The CRFs will be reviewed by a clinical monitor from Genzyme or designee for completeness and 
accuracy. Source document verification will be performed. The data will also be reviewed 
internally by Genzyme data management or designee and if necessary, the investigational sites 
will be queried for corrections and/or clarifications. 
10.3 
DATA MANAGEMENT 
The format and content of the CRF will be approved by Genzyme or designee prior to the start of 
the trial. Genzyme or designee will be responsible for database creation and management of data 
from other sources (eg, non-safety specialty lab data). 
Prior to finalizing and locking the database, all decisions concerning the inclusion or exclusion of 
patient data for analysis will be determined by appropriate clinical and statistical personnel. Any 
exclusion will be documented. Protocol deviations will be tracked by Genzyme or its designee. 
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11 
STATISTICAL METHODS AND PLANNED ANALYSES 
11.1 
GENERAL CONSIDERATIONS 
Genzyme will be responsible for data entry and editing, reviewing all the information in the 
CRFs, statistical analysis, and generation of the clinical report. 
Clinical data will be double-entered and validated in an Oracle database using Clintrial 4.5.  
The Genzyme Biomedical Data and Informatics will perform the statistical analysis of the data 
derived from this study.  The analysis will be performed using the SAS® statistical software 
system. (9)(10) The status of this study will be summarized annually as part of the Fabry Registry 
Program Annual Report. 
Any missing or invalid data will not be replaced or imputed. 
Data collected in this study will be reported using summary tables, graphs, figures, and/or patient 
data listings. 
No hypothesis testing will be performed. 
11.2 
DETERMINATION OF SAMPLE SIZE 
No formal statistical sample size calculations were performed for this study. The sample size of 
approximately 10 mothers and up to 10 infants is based upon 1) the availability of mothers to 
study lactation in this rare disease and 2) the availability of infants whose parents or legal 
guardians consent to their participation in this study. 
11.3 
ANALYSIS POPULATIONS 
The patient populations will consist of all the mothers and all the infants who were enrolled in the 
study. 
11.4 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographic and Baseline characteristics data will be summarized for the mothers and for the 
infants. 
11.5 
PATIENT ACCOUNTABILITY 
Data from all patients who are enrolled in the study will be included in the summary of patient 
accountability.  The frequency and percentage of patients who are enrolled in the study, attended 
each visit, are discontinued from the study, and completed the study will be summarized for the 
mothers and for the infants. 
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11.6 
STUDY TREATMENT USAGE AND COMPLIANCE 
Not applicable. 
11.7 
EFFICACY ANALYSIS 
Not applicable. 
11.8 
SAFETY ANALYSIS 
The following study variables will be summarized as appropriate for the mothers: 
• Medical history (including Fabrazyme status during pregnancy) 
• Genotyping 
• Pregnancy outcome 
• IgG antibody status 
• Lactation status 
• Plasma and breast milk PK testing 
• The level of αGAL, volume, and fat and protein content in breast milk samples 
• Frequency of AEs 
• Frequency of concomitant medications 
The following study variables will be summarized as appropriate for the infants: 
• Medical history 
• Physical examination 
• Gender 
• Genotype 
• Apgar score at 1 minute and 5 minutes after birth 
• Denver II Developmental Screening Test 
• IgM antibodies to r-hαGAL – presence, time to development, level of titers present 
• IgG antibodies to r-hαGAL – presence, time to development, level of titers present 
• Frequency of AEs 
• Frequency of concomitant medications 
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11.9 
INTERIM ANALYSIS 
After 5 mothers have contributed breast milk samples to this study, an interim analysis of αGAL 
activity in the breast milk will be performed. 
 
 
In addition, the status of this study will be summarized annually as part of the Fabry Registry 
Program Annual Report and the Fabrazyme Post-Marketing Commitment Annual Report. 
11.10 PHARMACOKINETICS ANALYSIS 
Because of the limited sampling schedule, the only PK parameters that will be reported are 
maximum concentration (Cmax) and area under the plasma αGAL concentration-time curve (AUC) 
from 0 to 2 hours post end of infusion (AUC0-2). A more complete PK profile is not being done 
because it is not the objective of the study to characterize the pharmacokinetics of αGAL in 
lactating mothers. 
Lactation clearance will be determined using the same calculations used to assess renal clearance. 
Breast milk will be collected at Baseline (sample 1) to empty each breast of milk, at end of 
infusion (sample 2), and 2 hours post-dose (sample 3).  The amount of αGAL will be calculated as 
the product of αGAL activity times the milk volume.  AUC from Baseline to 2 hours after the end 
of infusion will be calculated using a linear trapezoid.  Lactation clearance will be estimated as 
the amount of αGAL excreted over the sampling period divided by the AUC during the sampling 
period.  The milk to plasma ratio calculated as the AUCmilk to AUCplasma from time 0 (sample 2) to 
2 hours after the end of infusion (sample 3) will also be computed. 
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12 
SPECIAL REQUIREMENTS AND PROCEDURES  
This protocol was designed and will be conducted, recorded, and reported in compliance with the 
principles of Good Clinical Practice (GCP).  These requirements are stated in “Guidance for Good 
Clinical Practice,” International Conference on Harmonization (ICH) of Technical Requirements 
for Registration of Pharmaceuticals for Human Use and national regulations. 
12.1 
INSTITUTIONAL AND ETHICAL REVIEW 
This protocol and patient informed consent form must be reviewed and approved by an IRB or 
IEC complying with the national regulations and the guidelines of the ICH before enrollment of 
patients. A copy of the letter or certificate of approval from the IRB or IEC and the approved 
consent form must be received by Genzyme prior to initiation of the study. 
12.2 
CHANGES TO THE CONDUCT OF THE STUDY OR PROTOCOL 
No change in the study procedures, except to eliminate an immediate hazard, shall be effected 
without the mutual agreement of the Investigator and Genzyme. All changes must be documented 
by signed protocol amendments. If changes to the design of the study are made, the amendment 
must be submitted to and approved by the IRB, IEC, or any other appropriate regulatory authority, 
signed by the Investigator, and returned to Genzyme. 
12.3 
INVESTIGATOR'S RESPONSIBILITIES 
12.3.1 Patient Informed Consent 
Before a patient’s participation in the clinical trial, study informed consent forms for mother and 
parents/legal guardian, where required by law separate genetic informed consent forms for mother 
and parents/legal guardian will be signed and personally dated by the patient or by the patient’s 
legally acceptable representative, and by the person who conducted the informed consent 
discussion.  A copy of each signed and dated written informed consent form will be provided to 
the patient. 
The informed consent form and where required by law the separate genetic informed consent  
form used by the investigator for obtaining the patient's informed consent must be reviewed and 
approved by the sponsor before submission to the appropriate ethics committee (IRB/IEC) for 
approval/favorable opinion.  Upon approval by the IRB or IEC, the Investigator must furnish the 
Sponsor with: (1) a photocopy of the approved informed consent and (2) a copy of the letter 
stating formal approval has been granted by the institution, prior to initiation of the study. 
Signed, written informed consent from the infant’s parent(s) or legal guardian(s) is required prior 
to enrollment in the study. It is the responsibility of the Investigator to obtain such consent. 
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12.3.2 Case Report Forms 
CRFs will be filled out legibly and completely (black ballpoint pen). Refer to Section 10.1 for 
further guidance on completion of CRFs. 
The original CRFs will be provided to Genzyme. A copy of the CRFs will be maintained in the 
Investigator's file. Designated site personnel must complete CRFs in a timely manner. 
Illegible or incomplete entries will be returned and queried to the Investigator for clarification. 
Patient records in connection with the study, including patient charts, laboratory data, etc. will be 
made available to Genzyme for review. 
12.3.3 Record Retention 
The investigator must maintain confidentiality of all study documentation and take measures to 
prevent accidental or premature destruction of these documents. 
The investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements will be taken into account in the event that a longer 
period is required. 
The investigator must notify the sponsor before destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the investigator shall inform the sponsor and the relevant records shall be transferred to a mutually 
agreed upon designee. 
12.3.4 Monitoring 
A representative of Genzyme will visit the Investigator periodically for the purpose of monitoring 
the progress of this study in accordance with national regulations and ICH-GCP guidelines. It is 
the responsibility of the Investigator to be present or available for consultation during such 
scheduled monitoring visits. During these routine visits, all data pertaining to a patient's 
participation in this clinical investigation must be made available to the monitor. 
Genzyme personnel or their designee may perform an audit at any time during or after completion 
of the clinical study. All study-related documentation must be made available to the designated 
auditor. 
In addition, a representative of a regulatory agency may choose to inspect a study center at any 
time prior to, during, or after completion of the clinical study. A Genzyme representative will be 
available to assist in the preparation for such an inspection. All pertinent study data should be 
made available to the regulatory authority for verification, audit, or inspection purposes. 
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12.3.5 Materials Control 
There will be no clinical trial supplies provided for this study. 
For specific information concerning warnings, precautions, and contraindications, the Investigator 
is asked to refer to the appropriate section of the Investigator Brochure and/or product labeling. 
Because of the possibility of AEs, a fully equipped emergency cart, or equivalent supplies and 
equipment, and personnel competent in recognizing and treating adverse reactions of all types 
should be immediately available. 
12.3.6 Disclosure of Data 
All information obtained during the conduct of this study will be regarded as confidential and 
written permission from Genzyme is required prior to disclosing any information relative to this 
study. Manuscripts prepared for publication will be in accordance with the policy previously 
presented by Genzyme to the Investigator. Submission to the Sponsor for review and comment 
prior to submission to the publisher will be required.  This requirement should not be construed as 
a means of restricting publication, but is intended solely to assure concurrence regarding data, 
evaluations, and conclusions and to provide an opportunity to share with the Investigator any new 
and/or unpublished information of which he/she may be unaware. 
12.3.7 Clinical Study Report 
If deemed appropriate by the Sponsor, an Investigator may be designated to sign the completed 
clinical study report at the end of this study. 
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13 
REFERENCES 
1. Ferrans VJ, Hibbs RG, Burda CD. The heart in Fabry's disease. A histochemical and electron 
microscopic study. Am J Cardiol. 1969 Jul;24(1):95-110. 
2. Gubler MC, Lenoir G, Grunfield JP, Ulmann A, Droz D, Habib R. Early renal changes in 
hemizygous and heterozygous patients with Fabry's disease. Kidney Int. 1978 Mar;13(3):223-
35. 
3. Meuwissen SG, Dingemans KP, Strijland A, Tager JM, Ooms BC. Ultrastructural and 
biochemical liver analyses in Fabry’s disease. Hepatology. 1982 Mar-Apr;2(2):263-8. 
4. Aivazian AA, Trofimov IB, Seredniakova NI. Ultrastructural changes in the skin of patients 
with Fabry's angiokeratoma. Arkh Pathol. 1985;47(7):60-3. 
5. Drachenberg CB, Schweitzer EJ, Bartlett ST, Behrens MT, Papadimitriou JC. Polyarteritis 
nodosa-like necrotizing vasculitis in Fabry disease. J Inherit Metab Dis. 1993;16(5):901-2. 
6. Ahlmen J, Hultberg B, Brynger H, Sjoblad S, Svalander C. Clinical and diagnostic 
considerations in Fabry's disease. Acta Med Scand. 1982;211(4):309-12. 
7. Desnick RJ, Astrin KH, Bishop DF. Fabry disease: molecular genetics of the inherited 
nephropathy. Adv Nephrol Necker Hosp. 1989;18:113-27. 
8. Nagan N, Faulkner NE, Curtis C, Schrijver I. Laboratory Guidelines for Detection, 
Interpretation, and Reporting of Maternal Cell Contamination in Prenatal Analyses a report of 
the association for molecular pathology. J Mol Diagn. 2011 Jan;13(1):7-11. doi: 
10.1016/j.jmoldx.2010.11.013. 
9. SAS Institute, Inc. SAS Procedure Guide: Version 6. 4th ed. Cary, NC: SAS Institute 
Inc;1990. 
10. SAS Institute, Inc. SAS/STAT User’s Guide: Vol 1-2, Version 6. Cary NC: SAS Institute, Inc; 
1990. 
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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AGAL02603 Amended Protocol 08

SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning direct 
or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002643 VERSION 7.0 (20-FEB-2019) 
Page 1
STATISTICAL ANALYSIS PLAN 
A Multicenter, Multinational Study of the Effects of Fabrazyme® (agalsidase beta) 
Treatment on Lactation and Infants  
GZ419828-AGAL02603/MSC12868 
STATISTICIAN: 
 
DATE OF ISSUE: 09-Apr-2020 
Total number of pages: 
25 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN .................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 4 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................. 5 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 5 
1.2 
OBJECTIVES ................................................................................................................................... 5 
1.2.1 
Primary objectives ............................................................................................................................ 5 
1.2.2 
Secondary objectives ....................................................................................................................... 5 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 5 
1.4 
STUDY PLAN ................................................................................................................................... 6 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .................................. 6 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN........................ 7 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ....................................................................... 8 
2.1 
ANALYSIS ENDPOINTS .................................................................................................................. 8 
2.1.1 
Demographic and baseline characteristics ...................................................................................... 8 
2.1.2 
Prior or concomitant medications ..................................................................................................... 8 
2.1.3 
Efficacy endpoints ............................................................................................................................ 9 
2.1.3.1 
Primary efficacy endpoint(s) ............................................................................................................. 9 
2.1.3.2 
Secondary efficacy endpoint(s) ........................................................................................................ 9 
2.1.4 
Safety endpoints ............................................................................................................................... 9 
2.1.4.1 
Adverse events variables ............................................................................................................... 10 
2.1.4.2 
Deaths ............................................................................................................................................ 11 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 11 
2.1.4.4 
Vital signs variables ........................................................................................................................ 11 
2.1.4.5 
Electrocardiogram variables ........................................................................................................... 11 
2.1.4.6 
Other safety endpoints ................................................................................................................... 11 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 11 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 12 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 12 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 12 
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2.3.1 
Efficacy populations ....................................................................................................................... 13 
2.3.2 
Safety population ............................................................................................................................ 13 
2.4 
STATISTICAL METHODS ............................................................................................................. 13 
2.4.1 
Demographics and baseline characteristics .................................................................................. 13 
2.4.2 
Prior or concomitant medications ................................................................................................... 13 
2.4.3 
Extent of investigational medicinal product exposure and compliance .......................................... 14 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 14 
2.4.3.2 
Compliance .................................................................................................................................... 14 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 14 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ......................................................................................... 14 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 14 
2.4.4.3 
Multiplicity issues ............................................................................................................................ 14 
2.4.4.4 
Additional efficacy analysis(es) ...................................................................................................... 14 
2.4.5 
Analyses of safety data .................................................................................................................. 14 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 15 
2.4.5.2 
Deaths ............................................................................................................................................ 16 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 16 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 16 
2.4.5.5 
Analyses of electrocardiogram variables ....................................................................................... 16 
2.4.5.6 
Analyses of other safety endpoints ................................................................................................ 16 
2.4.6 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 16 
2.5 
DATA HANDLING CONVENTIONS............................................................................................... 16 
2.5.1 
General conventions ...................................................................................................................... 16 
2.5.2 
Data handling conventions for secondary efficacy variables.......................................................... 16 
2.5.3 
Missing data ................................................................................................................................... 16 
2.5.4 
Windows for time points ................................................................................................................. 17 
2.5.5 
Unscheduled visits ......................................................................................................................... 17 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 17 
2.5.7 
Statistical technical issues ............................................................................................................. 18 
3 
INTERIM ANALYSIS ..................................................................................................................... 19 
4 
DATABASE LOCK ........................................................................................................................ 20 
5 
SOFTWARE DOCUMENTATION .................................................................................................. 21 
6 
REFERENCES ............................................................................................................................... 22 
7 
LIST OF APPENDICES ................................................................................................................. 23 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
AE: 
Adverse Event 
MCC: 
Maternal Cell Contamination 
NA: 
Not Applicable 
PK: 
Pharmacokinetic 
 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION  
This is a phase 4, multicenter, multinational study of the potential effects of Fabrazyme on 
lactation and on the growth, development, and immunologic response of infants born to mothers 
with Fabry disease who are treated with Fabrazyme during lactation. The mothers will receive 
Fabrazyme treatment as part of the standard of care of Fabry disease and will be followed through 
the Fabry Registry. 
Pregnant women who received Fabrazyme at any point during their pregnancy can be enrolled in 
the study. The mothers will receive Fabrazyme treatment (commercially available) at their 
currently prescribed dosage regimen as determined by their treating physician. If an enrolling 
woman is not receiving treatment with Fabrazyme at the Baseline visit, she should start treatment 
with Fabrazyme between the delivery and Month 1 visit. 
Approximately 10 mothers and up to 10 infants will be enrolled in this study. 
1.2 
OBJECTIVES  
1.2.1 Primary objectives  
The primary objectives of this study are: 
1. To determine whether αGAL activity is present in the breast milk of mothers with Fabry 
disease who are being treated with Fabrazyme during lactation. 
2. To measure breast milk production and composition (volume, protein and fat content) in 
women with Fabry disease who receive Fabrazyme during lactation. 
3. To determine whether Fabrazyme affects the growth, development, and immunologic response 
of infants born to mothers with Fabry disease who receive Fabrazyme during lactation. 
1.2.2 Secondary objectives  
NA 
1.3 
DETERMINATION OF SAMPLE SIZE  
No formal statistical sample size calculations were performed for this study. The sample size of 
approximately 10 mothers and up to 10 infants is based upon 1) the availability of mothers to 
study lactation in this rare disease and 2) the availability of infants whose parents or legal 
guardians consent to their participation in this study. 
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1.4 
STUDY PLAN  
This study will evaluate the effects of Fabrazyme on lactation and on the growth, development, 
and immunologic response of infants born to mothers with Fabry disease who are treated with 
Fabrazyme during lactation. There are 3 participation scenarios: mother/infant full participation, 
mother full participation/infant development only, and mother full participation/infant no 
participation (see protocol Section 9.1). 
Whether or not the mother continues to lactate will be assessed at each visit. Breast milk will be 
collected at Months 1, 3, and 6 immediately prior to Fabrazyme infusion, just after the end of the 
infusion, and 2 hours after the end of the infusion. Breast milk samples will be analyzed for 
volume, presence of αGAL activity, total fat content, and total protein concentration. Blood 
samples from the mother will be drawn for pharmacokinetic (PK) analysis prior to each breast 
milk collection. If infant genotyping is performed on the umbilical blood cord sample collected at 
Baseline visit, a buccal cell sample will be obtained from the mother to rule out contamination of 
the cord blood sample with maternal DNA. 
If the parent(s)/legal guardian(s) consent to infant participation, the infant’s growth and 
development will be assessed. The infant may also be tested for the formation or continued 
presence of serum IgG and IgM antibodies to r-hαGAL and for genotype. 
For the purposes of this study, the mother and the infant will each be considered a study patient. 
The mother must be enrolled in the Fabry Registry and will be followed using the Fabry Registry 
assessment schedule and CRFs as well as this study’s CRF. During this study, infants will be 
evaluated, ie, the infant may be tested for IgG and IgM antibodies to r-hαGAL at birth and Months 
2, 6, and 12 and will be tested developmentally at each visit for 24 months, or until the 
parent(s)/legal guardian(s) withdraws consent and discontinues the infant’s study participation, the 
infant is discontinued from the study by the Investigator (see Section 7.3.1), or the study is 
terminated (see Section 7.3.2). 
If the mother is no longer lactating, the mother will discontinue this study but continue to be 
followed in the Fabry Registry. The infant will be followed for development only for the 
remainder of this 24-month study. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
The statistical section of the protocol was never changed in an amendment. 
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The first patient was enrolled on August 29, 2006. After 5 mothers have contributed breast milk 
samples to this study, an interim analysis of αGAL activity in the breast milk will be performed. In 
addition, the status of this study will be summarized annually as part of the Fabry Registry 
Program Annual Report and the Fabrazyme Post-Marketing Commitment Annual Report.. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN  
NA 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES  
2.1 
ANALYSIS ENDPOINTS  
2.1.1 Demographic and baseline characteristics  
The baseline value is defined as within 1 month prior to delivery (mother) and at birth (infant).  
All baseline safety parameters are presented along with the on-treatment summary statistics in the 
safety sections (Section 2.4.5 and Section 2.4.4). 
Demographic characteristics 
Demographic variables are gender (Male, Female), race (white, Black, Asian, American Indian or 
Alaska Native, Native Hawaiian or other Pacific Island), age in years (quantitative), ethnicity 
(Hispanic or Latino, non-Hispanic or Latino). 
Lactation Status 
The mother’s lactation status will be provided: Is the mother providing milk for the protocol? 
(Yes, No); Is the mother planning on breast feeding the infant(s)? (Yes, No).  
Maternal cell contamination (MCC) analysis 
If umbilical cord blood sample was collected and MCC analysis was performed, the results 
(Maternal Cell Contamination detected, No Maternal Cell Contamination detected) will be 
collected. 
Medical history 
Medical history (including Fabrazyme status during pregnancy) will be collected through the 
Registry.  
This information will be coded using the version of Medical Dictionary for Regulatory Activities 
(MedDRA) currently in effect at Sanofi at the time of database lock. 
Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5.  
2.1.2 Prior or concomitant medications  
All medications taken from the time of signing the informed consent through study completion are 
to be reported in the case report form pages. 
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All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints  
NA 
2.1.3.1 Primary efficacy endpoint(s)  
NA 
2.1.3.2 Secondary efficacy endpoint(s)  
NA 
2.1.4 Safety endpoints  
The safety analysis will be based on the reported adverse events (AEs) and other safety 
information, such as physical examinations, etc. 
 
The following study variables will be summarized as appropriate for the mothers (items marked 
with * will be collected through the Registry): 
 
Medical history (including Fabrazyme status during pregnancy)* 
 
Genotyping* 
 
Pregnancy outcome* 
 
IgG antibody status* 
 
Lactation status 
 
Plasma and breast milk PK testing 
 
The level of αGAL, volume, and fat and protein content in breast milk samples 
 
Frequency of AEs 
 
Frequency of concomitant medications 
 
The following study variables will be summarized as appropriate for the infants: 
 
Medical history 
 
Physical examination 
 
Gender 
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 
Genotype 
 
Apgar score at 1 minute and 5 minutes after birth 
 
Denver II Developmental Screening Test 
 
IgM antibodies to r-hαGAL – presence, time to development, level of titers present 
 
IgG antibodies to r-hαGAL – presence, time to development, level of titers present 
 
Frequency of AEs 
 
Frequency of concomitant medications 
Observation period  
The on-study observation period is defined as the time from the signing of the informed consent 
until the end of the study (defined as last protocol planned patient contact by telephone 
approximately 28 days after the final study procedures are completed).  
2.1.4.1 Adverse events variables  
All AEs ongoing at the time of withdrawal, study termination, or study completion require a 
follow up at approximately 28 days after discontinuation of study participation. The Investigator 
will be asked to follow-up on all SAEs that were ongoing at the time of withdrawal, termination or 
completion until resolution, until both the sponsor and investigator agree follow-up is deemed no 
longer medically necessary or until the patient is lost to follow-up. 
If any new SAEs are identified during the course of this follow-up of ongoing SAEs, additional 
follow-up of these new SAEs may be performed. The Investigator and sponsor will determine if 
the follow-up is clinically warranted and relevant to the evaluation of the safety of the trial 
treatment or until patient is lost to follow up. The investigator must follow patients with AEs until 
their condition resolves or stabilizes. Certain conditions that are not expected to resolve, such as 
metastatic cancer, need not be followed indefinitely by the investigator. 
All adverse events (including serious adverse events) will be coded to a lower-level term (LLT), 
preferred term (PT), high-level term (HLT), high-level group term (HLGT), and associated 
primary system organ class (SOC) using the version of Medical Dictionary for Regulatory 
Activities (MedDRA) currently in effect at Sanofi at the time of database lock. 
All occurrences of adverse events (including serious adverse) from the time of signed informed 
consent until the end of the study will be recorded. 
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2.1.4.2 Deaths  
The deaths from the signing of the informed consent through the completion of the study will be 
recorded.  
2.1.4.3 Laboratory safety variables  
NA 
2.1.4.4 Vital signs variables  
NA 
2.1.4.5 Electrocardiogram variables  
NA 
2.1.5 Pharmacokinetic variables  
Pharmacokinetic Sampling 
αGAL concentrations will be measured form Blood and breast milk samples taken from the 
mothers. Blood samples will be taken from the mother at Months 1, 3, and 6 for PK testing (if 
mother is lactating at the time of the evaluation and is receiving Fabrazyme therapy).  
Bioanalytical Method 
Plasma and milk αGAL concentrations will be quantified by measuring enzyme activity using a 
fluorometric assay with a lower limit of quantification of 1.38 ng/mL. The assay does not 
differentiate between endogenous αGAL and Fabrazyme. 
Pharmacokinetic parameters 
The following pharmacokinetic parameters will be calculated, using noncompartmental methods 
from plasma αGAL concentrations and milk αGAL concentrations 
 
maximum plasma concentration observed (Cmax) in plasma and milk 
 
area under the plasma αGAL concentration versus time curve calculated using the 
trapezoidal method from 0 to 2 hours post end of infusion (AUC0-2 plasma). 
 
the amount of αGAL in milk calculated as the product of αGAL activity times the milk 
volume 
 
area under the milk αGAL concentration versus time curve calculated using the trapezoidal 
method from 0 to 2 hours post end of infusion (AUC0-2 milk). 
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 
lactation clearance determined in the 0-2 hours interval, according to the following 
equation: amount of αGAL excreted over the sampling period divided by the AUC during 
the sampling period 
The milk to plasma ratio for AUC0-2 will also be computed. 
2.2 
DISPOSITION OF PATIENTS  
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patient who met the inclusion criteria and signed the 
informed consent. Enrolled patients are defined as any patient who signed the informed consent 
and participated in at least one study visit. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary table: 
 
Screened patients 
 
Screen failure patients and reasons for screen failure 
 
Patients who did not complete the study treatment period as per protocol 
 
Patients who discontinued study treatment by main reason for permanent treatment 
discontinuation 
 
Status at last study contact  
For all categories of patients (except for the screened and nonrandomized categories) percentages 
will be calculated using the number of enrolled patients as the denominator.  Reasons for 
treatment discontinuation will be supplied in tables giving numbers and percentages by treatment 
group.   
A patient is considered lost to follow-up at the end of the study if he/she is not assessed at the last 
protocol planned visit.  
2.2.1 Randomization and drug dispensing irregularities  
NA  
2.3 
ANALYSIS POPULATIONS  
All patients enrolled will be included in the safety population. Patients who signed the informed 
consent but did not participate in any study visit are not considered enrolled in the study.   
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2.3.1 Efficacy populations  
NA 
2.3.2 Safety population  
The safety population is defined as all patients who enrolled, i.e. signed the informed consent and 
participated in at least 1 study visit.  
2.4 
STATISTICAL METHODS  
The descriptions of analysis below assume that a sufficient number of patients will be enrolled in 
the study such that summary statistics of the data will be meaningful to the reviewers. In case of 
sparse data (less than 5 mothers and/or 5 infants enrolled), the collected data will be presented in 
patient listings. 
2.4.1 Demographics and baseline characteristics  
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, and maximum for each treatment group.  Categorical and 
ordinal data will be summarized using the number and percentage of patients in each treatment 
group.  
Parameters described in Section 2.1.1 will be summarized by mother and infant groups using 
descriptive statistics.  
Medical history as collected in the Registry will be presented according to the preprinted case 
report form history responses. 
2.4.2 Prior or concomitant medications  
The concomitant medications will be presented for the enrolled population.  
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomic category (ATC) class (anatomic category) and the first 3 
digits of the ATC class (therapeutic category).  All ATC codes corresponding to a medication will 
be summarized, and patients will be counted once in each ATC category (anatomic or therapeutic) 
linked to the medication. Consequently, patients may be counted several time for the same 
medication.  
The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence across treatment groups.  In case of equal 
frequency regarding ATCs, alphabetical order will be used. 
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The tables for concomitant medications will be sorted by decreasing frequency of ATC followed 
by all other therapeutic classes based on the incidence. In case of equal frequency regarding ATCs, 
alphabetical order will be used.  
2.4.3 Extent of investigational medicinal product exposure and compliance  
The enrolled mothers will receive Fabrazyme treatment (commercially available) at their currently 
prescribed dosage regimen as determined by their treating physician. Therefore, the extent of IMP 
exposure and compliance will not be assessed nor summarized. 
2.4.3.1 Extent of investigational medicinal product exposure  
 
The data collected for Fabrazyme infusions received by the mother will be presented in a listing. 
2.4.3.2 Compliance  
NA 
2.4.4 Analyses of efficacy endpoints  
2.4.4.1 Analysis of primary efficacy endpoint(s)  
NA 
2.4.4.2 Analyses of secondary efficacy endpoints  
NA 
2.4.4.3 Multiplicity issues  
NA 
2.4.4.4 Additional efficacy analysis(es)  
NA 
2.4.5 Analyses of safety data  
The summary of safety results will be presented by mother and infant groups.  
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2. In case 
of sparse data, the results will be presented in patient listings. 
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2.4.5.1 Analyses of adverse events  
Generalities 
All adverse events (AEs) reported from signing of informed consent through completion of the 
study will be presented. 
Adverse event incidence tables will present by SOC and PT, sorted in alphabetical order for each 
group (mother, infant), the number (n) and percentage (%) of patients experiencing an adverse 
event.  Multiple occurrences of the same event in the same patient will be counted only once in the 
tables within the study period.  The denominator for computation of percentages is the safety 
population within each group (mother, infant). 
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period.  For that purpose, the table of all adverse events presented by SOC and PT 
sorted by the internationally agreed SOC order and decreasing frequency of PTs within SOCs will 
define the presentation order for all other tables unless otherwise specified.  
Analysis of all adverse events 
The following adverse event summaries will be generated for the safety population. 
 
Overview of adverse events, summarizing number (%) of patients with any 
- 
adverse event 
- 
serious adverse event 
- 
adverse event leading to death 
- 
adverse event leading to permanent treatment discontinuation 
 
All adverse events by primary SOC and PT, showing the number (%) of patients with at 
least 1 adverse event, sorted by the internationally agreed SOC order and by decreasing 
incidence of PTs within each SOC.  This sorting order will be applied to all other tables, 
unless otherwise specified 
 
All adverse events regardless of relationship and related to IMP, by primary SOC and PT, 
showing the number (%) of patients with at least 1 adverse event 
 
All adverse events by maximal severity, presented by primary SOC and PT, showing the 
number (%) of patients with at least 1 adverse event by severity (ie, mild, moderate, or 
severe) 
Analysis of all treatment emergent serious adverse event(s) 
 
All serious adverse events by primary SOC and PT, showing the number (%) of patients 
with at least 1 serious adverse event 
 
All serious adverse events regardless of relationship and related to IMP, by primary SOC 
and PT, showing the number (%) of patients with at least 1 serious adverse event 
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 
All serious adverse events by maximal severity, presented by primary SOC and PT, 
showing the number (%) of patients with at least 1 serious adverse event by severity (ie, 
mild, moderate, or severe) 
Analysis of all adverse event(s) leading to treatment discontinuation 
 
A listing of all adverse events leading to treatment discontinuation will be presented 
2.4.5.2 Deaths  
A listing of adverse events leading to death (death as an outcome on the adverse event case report 
form page as reported by the Investigator) will be presented.  
2.4.5.3 Analyses of laboratory variables  
NA  
2.4.5.4 Analyses of vital sign variables  
NA  
2.4.5.5 Analyses of electrocardiogram variables  
NA  
2.4.5.6 Analyses of other safety endpoints  
2.4.6 Analyses of pharmacokinetic and pharmacodynamic variables  
Descriptive statistics of pharmacokinetic (PK) parameters by visit and by mother and infant 
groups will be provided. However, in case of sparse data, a by patient listing will be provided. 
2.5 
DATA HANDLING CONVENTIONS  
2.5.1 General conventions  
None. 
2.5.2 Data handling conventions for secondary efficacy variables  
NA 
2.5.3 Missing data  
For categorical variables, patients with missing data are not included in calculations of 
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percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a concomitant medication. 
Handling of adverse events with missing or partial date/time of onset 
Missing or partial adverse event onset dates and times will not be imputed.  No imputation of 
adverse event end dates/times will be performed.  No imputation is planned for date/time of 
adverse event resolution. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. No imputation of relationship 
will be presented in the listings. 
Handling of missing severity of adverse events 
If the severity is missing for 1 of the occurrences of an adverse event, the maximal severity on the 
remaining occurrences will be considered.  If the severity is missing for all the occurrences, a 
“missing” category will be added in the summary table. 
2.5.4 Windows for time points  
None 
2.5.5 Unscheduled visits  
Unscheduled visit measurements will not be presented in by-visit summaries but will be presented 
in listings. 
2.5.6 Pooling of centers for statistical analyses  
All analyses will be performed on the safety population. 
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2.5.7 Statistical technical issues  
None 
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3 
INTERIM ANALYSIS  
After 5 mothers have contributed breast milk samples to this study, an interim analysis of αGAL 
activity in the breast milk will be performed.  
In addition, the status of this study will be summarized annually as part of the Fabry Registry 
Program Annual Report and the Fabrazyme Post-Marketing Commitment Annual Report. 
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4 
DATABASE LOCK  
The database is planned to be locked at 60 days after last patient last visit. 
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5 
SOFTWARE DOCUMENTATION  
All summaries and statistical analyses will be generated using SAS version 9.4 or higher. 
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6 
REFERENCES  
None 
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7 
LIST OF APPENDICES  
None 
 
 
 
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