A Multicenter, Multinational, Open-Label Study of the Effects of Aldurazyme® (Laronidase) Treatment on Lactation in Women With Mucopolysaccharidosis I (MPS I) and Their Breastfed Infants
Phase: PHASE4
Conditions: Mucopolysaccharidosis I, Hurler's Syndrome, Hurler-Scheie Syndrome, Scheie
Sponsor: Genzyme, a Sanofi Company

Aldurazyme® (laronidase)  
 
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CLINICAL STUDY PROTOCOL 
 
Study Number ALID01803 
 
A Multicenter, Multinational, Open-Label Study of the Effects of Aldurazyme® 
(laronidase) Treatment on Lactation in Women with Mucopolysaccharidosis I (MPS I) 
and Their Breastfed Infants 
 
Final:  26 June 2003 
Amendment 1: 14 January 2008 
Amendment 2: 05 January 2011 
 
 
 
Sponsor:  
BioMarin/Genzyme LLC 
 
 
500 Kendall Street 
 
 
Cambridge, MA 02142, US 
 
Study Manager: 
 
 
 
 
 
 
 
 
Biostatistician: 
 
  
 
 
 
 
 
 
 
 
 
This protocol was designed and will be conducted, recorded, and reported in accordance with the 
principles of Good Clinical Practice as stated in the International Conference on Harmonisation 
of Technical Requirements for Registration of Pharmaceuticals for Human Use and any 
applicable national and regional laws. 
I have read and agree to abide by the requirements of this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
____ 
Investigator Signature 
Date 
 
____________________________________________________________________________ 
Medical Monitor Signature                                                                                       Date 
 
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Aldurazyme® (laronidase)  
 
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1. SYNOPSIS 
 
NAME OF COMPANY 
BioMarin/Genzyme LLC 
500 Kendall Street 
Cambridge, MA  02142 
NAME OF FINISHED PRODUCT 
Aldurazyme® 
NAME OF ACTIVE 
INGREDIENT 
laronidase  
SUMMARY TABLE 
Referring to Part 
……… 
of the Dossier: 
Volume:                          
Page:                               
Reference:                       
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
TITLE: A Multicenter, Multinational, Open-Label Study of the Effects of Aldurazyme 
(laronidase) Treatment on Lactation in Women with Mucopolysaccharidosis I (MPS I) 
and Their Breastfed Infants 
PROTOCOL NO.: ALID01803 
INVESTIGATOR/STUDY CENTERS: Investigators at up to 10 study centers will 
participate. 
OBJECTIVE:  
The objective of this study is to determine whether Aldurazyme affects lactation in 
women with MPS I disease by: 
a. Determining whether laronidase activity is present in the breast milk of mothers 
with MPS I disease who are being treated with Aldurazyme during lactation. 
b. Determining whether Aldurazyme affects the growth, development, and 
immunologic response of breastfed infants born to mothers with MPS I disease 
who are being treated with Aldurazyme during lactation. 
METHODOLOGY: This is a multicenter, multinational, open-label study of lactation 
in postpartum women receiving Aldurazyme and the effects of Aldurazyme on the 
growth, development, and immunologic response of their breastfed infants. This study 
provides 2 options for participation: (1) full participation by both the mother and the 
infant (Full/Full) and (2) full participation by the mother and only umbilical chord 
blood, urine, and developmental assessments of the infant (Full/Partial). 
 
Mother (Both Participation Options): Eligible women will be enrolled and tested at 
baseline, every 12 weeks (±5 days) thereafter, and at the end of the study to test for the 
formation or continued presence of immunoglobulin G (IgG) antibodies in blood 
and/or urine glycosaminoglycans (uGAG) in urine. Within 1 month after birth, every 
12 weeks thereafter, and at the end of the study, samples of breast milk will be 
collected within 24 hours preceding an Aldurazyme infusion and within 60 minutes of 
completing an infusion of Aldurazyme to determine the presence of laronidase. The 
effects of Aldurazyme on lactation will be assessed through medical history, complete 
physical examinations, and breastfeeding status to determine if the mother is 
successfully breastfeeding.  
 
Infant: 
Full/Full Participation Option: Infants will be enrolled and, at birth, a sample of 
umbilical cord blood will be collected to determine baseline immunoglobulin M (IgM) 

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Proprietary and Confidential 
NAME OF COMPANY 
BioMarin/Genzyme LLC 
500 Kendall Street 
Cambridge, MA  02142 
NAME OF FINISHED PRODUCT 
Aldurazyme® 
NAME OF ACTIVE 
INGREDIENT 
laronidase  
SUMMARY TABLE 
Referring to Part 
……… 
of the Dossier: 
Volume:                          
Page:                               
Reference:                       
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
and IgG titers for the infant. The infant will then be tested every 12 weeks (±5 days) 
and at the end of the study to test for the formation or continued presence of IgG and 
IgM antibodies in blood and for the levels of GAG in urine.  If 2 consecutive blood 
samples 12 weeks apart (not including the baseline blood draw), are negative for IgG 
and IgM antibodies, study participation for mothers and infants will last 12 months; 
otherwise, testing will continue for 18 months. 
 
Full/Partial Participation Option: Infants will be enrolled and, at birth, a sample of 
umbilical cord blood will be collected to determine baseline IgM and IgG titers. Urine 
samples will be collected every 12 weeks (±5 days) and at the end of the study to test 
for the levels of uGAG. The effects of Aldurazyme on lactation will be assessed 
through medical history, complete physical examinations, and development assessment 
using the Denver II Developmental Screening Test, to determine if the infant is 
growing and developing normally. The duration of the study for this option will be 18 
months. 
NUMBER OF SUBJECTS: Up to 10 mothers and their infants (who must be 
receiving breast milk while the mother is receiving Aldurazyme therapy) will be 
enrolled in this study. 
 
DIAGNOSIS/INCLUSION CRITERIA:  
Mothers must meet the following criteria: 
1.   The patient must have a documented α-L-iduronidase deficiency with a 
fibroblast, plasma, serum, leukocyte, or dried blood spot α-L-iduronidase 
enzyme activity assay. 
2.   Be pregnant, planning to breastfeed postpartum, and receiving 
Aldurazyme while breastfeeding. 
3.   Provide signed, written informed consent prior to any protocol-related 
procedures. Consent of a legally authorized guardian is required for 
mothers younger than 18 years of age. If a mother is younger than 18 
years of age and can understand the consent, written informed consent is 
required from both the mother and the authorized guardian.  
4.  Provide signed, written informed consent for their infants to participate as 
study subjects. If a mother is younger than 18 years of age, consent for 
mother and infant will be obtained from the legal guardian. 
 
 
Mothers (and their infants) will be excluded from this study if any of the following 
exclusion criteria are met: 

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1.   Have a medical condition, serious intercurrent illness, or other 
extenuating circumstance that may interfere with study compliance, 
including all prescribed evaluations and follow-up activities. 
2.   Have received an investigational drug within 30 days prior to study 
enrollment. 
DOSE/ROUTE/REGIMEN: Mothers who are receiving Aldurazyme therapy will 
receive Aldurazyme at their prescribed dose and regimen. Each Aldurazyme infusion 
will be prepared as described in the appropriate country labeling for Aldurazyme. 
REFERENCE TREATMENT: No reference treatment will be used in this open-label 
study. 
CRITERIA FOR EVALUATION: 
Mother 
• Laronidase: Breast milk will be collected within 1 month of giving birth, every 
12 weeks (±5 days) thereafter, and at the end of the study to check for the presence 
of laronidase. 
• Breastfeeding Status: Breastfeeding status will be recorded within 1 month 
postpartum, every 12 weeks (±5 days) thereafter, and at the end of the study. 
• Immunoglobulins: Mothers will be tested at baseline, within 1 month postpartum, 
every 12 weeks (±5 days) thereafter, and at the end of the study to test for the 
formation or continued presence of IgG antibodies. 
• uGAG Level: Mothers will be tested at baseline, every 12 weeks (±5 days) 
thereafter, and at the end of the study to determine the level of uGAG.  
• Safety: Adverse events (AEs) and concomitant medications will be summarized at 
each visit.  
Infant 
• Immunoglobulins: At birth, a sample of umbilical cord blood will be collected to 
determine baseline IgM and IgG titers.   
• Breastfeeding Status: Breastfeeding status will be recorded within 1 month 
postpartum, every 12 weeks (±5 days) thereafter, and at the end of the study. 
• uGAG Level: Urine samples will be collected at baseline, every 12 weeks (±5 days) 
thereafter, and at the end of the study to determine the level of uGAG.  
• Development: The infant’s growth and development will be monitored from birth to 
the end of the study through complete physical examinations and the Denver II 
Developmental Screening Test. 
• Safety: AEs and concomitant medications will be summarized at each visit.  
 
For the Full/Full Participation option only: 
• Immunoglobulins:  Blood samples to test for IgM and IgG antibodies to laronidase 
will be taken from the infant every 12 weeks. If 2 consecutive samples 12 weeks 
apart (not including the baseline blood draw) are negative for IgG and IgM 
antibodies, study participation will last 12 months; otherwise, testing will continue 
for 18 months. 
STATISTICAL AND ANALYTICAL PLANS:  
Genzyme Corporation will be responsible for data entry and editing, reviewing all the 
information in the Case Report Forms (CRFs), statistical analysis, and generation of 

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the clinical report. 
Clinical data will be double-entered and validated in an Oracle database using Clintrial 
Version 4.5 on a VAX/VMS computer. 
 
Prior to locking the database, all data editing will be complete and decisions regarding 
the evaluability of all patient data for inclusion in the statistical analysis will be made.  
The rationale for excluding any data from the statistical analyses will be prospectively 
defined, and classification of all or part of a patient's data as nonevaluable will be 
completed and documented before the entire database is locked and before the 
statistical analysis is begun. The statistical analysis will not begin until the entire 
database is locked and signed off, in accordance with the Standard Operating 
Procedures (SOPs) of the Biostatistics Department. 
 
The Genzyme Biostatistics Department will perform the statistical analysis of the data 
derived from this study. The analysis will be performed using the SAS® statistical 
software system (SAS Institute Inc., 2008; SAS Language, Version 9.2). 
 
Study Variables 
The analyses of the data from this study are designed to address the following 
questions: 
• Is laronidase activity present in the breast milk of mothers with MPS I disease 
who are being treated with Aldurazyme during lactation?  
• Does Aldurazyme affect the growth, development, and immunologic response 
of breastfed infants born to mothers with MPS I disease who are being treated 
with Aldurazyme during lactation? 
 
Effects of Aldurazyme on lactation in mothers will be assessed in terms of the 
proportion of lactating women with serum IgG antibodies to laronidase, the levels of 
IgG antibody titers to laronidase, the proportion of women who breastfed, the 
proportion of women who were successful at breastfeeding, the proportion of women 
whose breast milk contained laronidase, the levels of laronidase in the breast milk of 
lactating mothers with MPS I disease, the proportion of women with abnormal uGAG 
levels, the levels of uGAG, and medical history and physical examination findings. 
 
Effects of Aldurazyme on infants will be assessed in terms of the proportion of infants 
with abnormal uGAG levels, the levels of uGAG, medical history and complete 
physical examination findings (including growth), and the developmental assessment 
findings. For the infants participating in the Full/Full option, the effects of Aldurazyme 
will be assessed in terms of the proportion of infants with IgM and IgG antibodies 
present at any time point, the levels of IgG and IgM antibody titers to laronidase, and 
the time to development of IgM and IgG antibodies to laronidase. 
 
Patient Population 
The intent-to-treat (ITT) approach will be the main analysis for this study.  This 
approach will include both mothers and infants of mothers who receive Aldurazyme 
during lactation.  The ITT analysis will be the basis for determination of the effects of 

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Aldurazyme on lactation. 
 
Handling of Dropouts 
For the analyses, summary data for patients who terminate the study early or miss 
study visits (and consequently have missing data) will not be carried forward to the 
next time point.  Hence, the analyses will be performed on an observed-cases basis. 
 
Statistical Methods 
All data collected in this study will be documented using summary tables, graphs, 
figures, and patient data listings. 
 
No hypothesis testing will be performed. 
 
Statistical Methods: Demographics and Baseline Characteristics 
Demographic and baseline characteristics data for the mother and for the infant will be 
summarized descriptively.  For categorical variables, frequencies and percentages will 
be presented.  For continuous variables, descriptive statistics (n’s, means, medians, 
standard deviations, minimums, and maximums) will be presented. 
 
Prior medications will also be summarized descriptively (using frequencies and 
percentages). 
 
Statistical Methods: Patient Accountability 
Data from all patients (mothers and infants) who are enrolled in the study will be 
included in the summary of patient accountability.  The frequency and percentage of 
patients enrolled in the study, attended each visit, are discontinued from the study, or 
complete the study will be summarized. 
 
Statistical Methods: Study Variables 
The following variables will be summarized descriptively: 
 
Mothers 
• The proportion of lactating women with serum IgG antibodies to laronidase 
• Amount of IgG antibody titers to laronidase in lactating women 
• The proportion of women who breastfed 
• The proportion of women who were successful at breastfeeding 
• The proportion of women whose breast milk contains laronidase 
• Amount of laronidase in the breast milk of lactating mothers with MPS I 
disease 
• The proportion of women with abnormal uGAG levels 
• Amount of uGAG in the urine of women 
• Medical history and physical examination findings 
 
 
 
 

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Infants 
• The proportion of infants with abnormal uGAG levels 
• Amount of uGAG in the urine of infants  
• Medical history and physical examination findings (including growth)  
• Developmental assessment findings  
• For the Full/Full Participation option only: 
o The proportion of infants with IgM and IgG antibodies to laronidase present 
at any time point  
o The time to development of IgM and IgG antibodies to laronidase 
o Amount of IgG and IgM antibody titers to laronidase 
 
In addition, the incidence of AEs will be summarized descriptively using the Medical 
Dictionary for Regulatory Activities (MedDRA) coding.  Shifts in physical 
examination results from baseline (last baseline measurement) to the study time points 
will be summarized descriptively. 
 
Sample Size 
This study will enroll up to 10 mothers and their infants. No formal sample size 
calculations were performed. 
 
Interim Analysis 
After 3 infants have completed the study, an interim summary of the data will be 
provided as described above for the main analyses, in order to facilitate discussions 
with the FDA.  As this is an open-label post-marketing study with no formal hypothesis 
testing, the usual adjustments to significance levels will not be required. 
 
 

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2. TABLE OF CONTENTS 
 
1. SYNOPSIS...............................................................................................................................3 
2. TABLE OF CONTENTS .........................................................................................................9 
Table of Tables ...............................................................................................................................9 
3.   ABBREVIATIONS AND TERMS ........................................................................................10 
4.    INTRODUCTION .................................................................................................................11 
5. STUDY OBJECTIVE ............................................................................................................14 
5.1 
Objective ...................................................................................................................14 
6. INVESTIGATIONAL PLAN ................................................................................................15 
6.1 
Study Design .............................................................................................................15 
6.2 
Study Rationale .........................................................................................................16 
7. PATIENT POPULATION AND SELECTION.....................................................................18 
7.1 
Inclusion Criteria.......................................................................................................18 
7.2 
Exclusion Criteria......................................................................................................18 
7.3 
Withdrawal Criteria...................................................................................................18 
8. TREATMENTS......................................................................................................................20 
8.1 
Treatments Administered ..........................................................................................20 
8.2 
Investigational Product..............................................................................................20 
8.3 
Patient Numbering.....................................................................................................20 
8.4 
Packaging and Labeling ............................................................................................20 
8.5 
Prior and Concomitant Medications..........................................................................20 
9. EFFICACY AND SAFETY VARIABLES............................................................................21 
9.1 
Schedule of Study Evaluations..................................................................................21 
9.2 
Tests and Procedures.................................................................................................24 
9.3 
Measurements............................................................................................................27 
9.4 
Adverse Events..........................................................................................................28 
9.5 
Serious Adverse Events.............................................................................................29 
9.6 
Adverse Event and Serious Adverse Event Reporting..............................................30 
10. DATA QUALITY ASSURANCE .........................................................................................32 
11. STATISTICAL METHODS AND PLANNED ANALYSES ...............................................33 
11.1 
Study Variables .........................................................................................................33 
11.2  
Demographics and Baseline Characteristics .............................................................34 
11.3  
Patient Accountability...............................................................................................34 
11.4 
Study Variables .........................................................................................................35 
11.5  
Sample Size...............................................................................................................35 
11.6  
Interim Analysis ........................................................................................................35 
12. SPECIAL REQUIREMENTS AND PROCEDURES ...........................................................36 
       12.1     Institutional and Ethics Review..................................................................................36 
       12.2     Changes to the Conduct of the Study or Protocol ..................................................... 36 
       12.3     Investigator's Responsibilities...................................................................................36 
13.  REFERENCES......................................................................................................................40 
 
TABLE OF TABLES 
Table 9-1 Schedule of Study Evaluations - Mother (Full Participation) and Infant (Full 
Participation)........................................................................................................................... 22 
Table 9-2 Schedule of Study Evaluations - Mother (Full Participation) and Infant (Partial 
Participation)........................................................................................................................... 23 

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3.  ABBREVIATIONS AND TERMS 
AE 
adverse event 
CRF 
case report form 
FDA 
Food and Drug Administration 
GAG 
glycosaminoglycan 
GCP 
Good Clinical Practice 
GPS&RM 
Global Patient Safety & Risk Management 
IAR 
infusion-associated reaction 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
 
IRB 
Institutional Review Board 
ITT 
intent-to-treat population 
LLC 
Limited Liability Company 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPS I 
mucopolysaccharidosis I 
SAE 
serious adverse event 
SOP 
Standard Operating Procedures 
uGAG 
urinary glycosaminoglycans 

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4.     INTRODUCTION  
Mucopolysaccharidosis I (MPS I) is a progressive and life-threatening lysosomal storage 
disorder caused by a deficiency of the lysosomal enzyme α-L-iduronidase (Neufeld, 
2001, The Metabolic and Molecular Bases of Inherited Disease).  Patients with MPS I 
disease accumulate excessive amounts of the glycosaminoglycans (GAG) heparan sulfate 
and dermatan sulfate in all organs and tissues of the body.  Historically, patients with 
MPS I disease have been broadly categorized as Hurler, Hurler/Scheie, and Scheie, 
representing the most severe, intermediate, and less severe clinical phenotypes, 
respectively.  These classifications are arbitrary categorizations of points on a spectrum 
of patient phenotypes and MPS I disease.  Although the degree of severity may vary 
between patients, MPS I is always a serious disease.  While the pathophysiologic basis 
for MPS I disease is clear, the diverse combination of medical problems and the rate of 
progression of specific clinical symptoms varies greatly between patients, and there is 
significant patient-to-patient heterogeneity.  Clinical symptoms begin in infancy to late 
childhood, progress over a period of years, and ultimately lead to death during the first or 
second decade of life in most patients.  Despite this heterogeneity, MPS I disease is 
characterized by enlargement of the liver and spleen and excessive levels of urinary GAG 
(uGAG) excretion.  Additionally, cardiopulmonary and functional effects are consistently 
among the most important clinical manifestations of the disease (Neufeld, 2001, The 
Metabolic and Molecular Bases of Inherited Disease). 
 
Lysosomal storage in MPS I disease is most clearly manifested clinically by enlargement 
of the liver and spleen due to engorgement of macrophages, as well as parenchymal cells, 
with GAG (Neufeld, 2001, The Metabolic and Molecular Bases of Inherited Disease).  
Enlargement of the liver and spleen may have a number of clinical consequences, 
including limitation of diaphragmatic excursion causing shortness of breath, early satiety, 
abdominal discomfort, poor self-image, and difficulty bending over.  In addition, the 
excessive storage within the kidney, and particularly the collecting tubules, leads to the 
excretion of excessive amounts of uGAG.  For this reason, uGAG levels are commonly 
used in the diagnosis of suspected MPS I disease.  The storage of GAG is present in 
every tissue and nearly every cell type, as might be expected for a widespread 
macromolecule such as GAG.  Stored GAG substrate also leads to coarsened facial 
features, abnormal bones, large tongue, and stiffened joints, in part due to synovial 
engorgement with GAG. 
 
The functional capacity of patients with MPS I disease is also profoundly affected by 
GAG storage in a variety of tissues.  Decreased cardiopulmonary function contributes to 
reduced physical ability (Semenza, 1988, Medicine), and direct accumulation of GAG 
within connective tissues affects mobility in patients with MPS I disease (Neufeld, 2001, 
The Metabolic and Molecular Bases of Inherited Disease).  Joint stiffness, decreased 
range of motion, and pain often limit the usual activities of daily living, including 
walking.  Skeletal storage causes short stature and skeletal deformities, which can also 
affect mobility.  Ocular abnormalities include decreased visual acuity, corneal clouding, 
and glaucoma, which also affect daily activities (Kakkis, 1996, Principles of Child 

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Neurology).  In patients with severe disease, mental retardation and neurodegeneration 
begin early in life.  In all patients with MPS I disease, the continued progression of 
disease leads to diminished physical activity and functional status, resulting in immobility 
and, often, a bedridden state. 
Patients with MPS I disease exhibit severe progressive airway obstruction due to 
lysosomal GAG storage in the lymphoid and soft tissues of the pharynx and airway itself.  
Patients have decreased pulmonary function due to a restrictive-type abnormality caused 
by the small immobile thorax, hepatomegaly limiting diaphragmatic excursion, and, to 
some extent, storage in the lung itself.  The combination of upper airway obstruction and 
decreased pulmonary function makes patients more susceptible to obstructive sleep 
apnea, with clinical features that may include fatigue, daytime somnolence, pulmonary 
hypertension, and cor pulmonale (Mahowald, 1989, Sleep Res; Ruckenstein, 1991, J 
Otolaryngol; Bredenkamp, 1992, Ann Otol Rhinol Laryngol).  Upper airway obstruction 
also poses high anesthesia risks because of difficulty with intubation during the myriad of 
procedures these patients must endure, such as hernia repair, spinal fusion surgery, open-
heart surgery, and ventriculoperitoneal shunt placement.  Many patients have died or 
required tracheostomies following airway problems during anesthesia (Belani, 1993, J 
Pediatr Surg).  The pulmonary problems are further compounded by frequent pulmonary 
and upper respiratory tract infections that produce excessive thick secretions and chronic 
changes in the respiratory tract (Semenza, 1988, Medicine).  In addition, primary cardiac 
problems, including endocardial fibroelastosis, cardiomyopathy, pulmonary hypertension, 
and valvular disease, can lead to poor cardiac function that exacerbates the respiratory 
dysfunction due to pulmonary edema and poor cardiac output (Dangel, 1998, Eur J 
Pediatr).  Most patients with MPS I disease die between late childhood and early 
adulthood from pulmonary or cardiac causes. 
 
While the storage of GAG is the fundamental pathophysiology of MPS I disease, an 
effective and safe therapeutic for MPS I disease must treat the underlying lysosomal 
storage disorder in addition to the impairments in respiratory and physical function 
experienced by MPS I patients. 
 
On 30 April 2003, the U.S. Food and Drug Administration (FDA) granted a marketing 
approval for Aldurazyme (laronidase) for the treatment of MPS I in patients with Hurler 
and Hurler-Scheie syndromes as well as patients with moderate to severe symptoms of 
Scheie syndrome (Aldurazyme® United States Product Information, 2010, 
BioMarin/Genzyme LLC).    
 
On 10 June 2003, the European Commission granted a Marketing Authorization for 
Aldurazyme in the European Union.  Aldurazyme (laronidase) is indicated for long-term 
enzyme replacement therapy in patients with a confirmed diagnosis of MPS I to treat the 
non-neurological manifestations of the disease (Aldurazyme® Summary of Product 
Characteristics, 2010, Genzyme Europe B.V., 2010).   

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4.1 
Summary of Risks and Benefits 
 
For further details concerning efficacy, warnings, precautions, and 
contraindications, the Investigator should refer to the appropriate section of the 
approved country product label. 
 
 
 

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5. STUDY OBJECTIVE 
 
5.1 Objective 
 
The objective of this study is to determine whether Aldurazyme affects lactation in 
women with MPS I disease by: 
 
a. Determining whether laronidase activity is present in the breast milk of 
mothers with MPS I disease who are being treated with Aldurazyme during 
lactation. 
 
b. Determining whether Aldurazyme affects the growth, development, and 
immunologic response of breastfed infants born to mothers with MPS I 
disease who are being treated with Aldurazyme during lactation. 

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6. INVESTIGATIONAL PLAN 
 
6.1 Study Design 
 
This is a multicenter, multinational, open-label study in breastfeeding women 
receiving Aldurazyme during lactation and its effects on lactation and the growth, 
development, and immunologic response of their breastfed infants.  This study 
provides 2 options for participation: (1) full participation by the mother and the infant 
(Full/Full) and (2) full participation by the mother and only umbilical chord blood, 
urine, and developmental assessments of the infant (Full/Partial). 
Pregnant women may enroll in this study at any time after a confirmed diagnosis of 
pregnancy and prior to the birth of their infants. The effects of Aldurazyme on 
lactation will be assessed at each visit through medical history and complete physical 
examinations to determine if the mother is successfully breastfeeding and if the infant 
is growing and developing normally.  An eligible mother and her infant will be 
considered separate study subjects and each will be assigned a 6-digit identification 
number once signed written consent is secured.  Subsequently, mothers and infants 
will undergo a baseline visit to confirm study eligibility and to determine baseline 
measurements of several clinical parameters. 
 
For mothers, samples of breast milk will be collected within 24 hours preceding an 
Aldurazyme infusion and within 60 minutes of completing an infusion of Aldurazyme 
within 1 month after birth and every 12 weeks (±5 days) thereafter to determine 
presence of laronidase. Mothers will be tested at baseline, every 12 weeks (±5 days) 
thereafter, and at the end of the study for immunoglobulin G (IgG) antibodies to 
laronidase in blood and/or GAG in urine. 
 
For infants in both participation groups, a sample of umbilical cord blood will be 
collected at birth to determine baseline immunoglobulin M (IgM) and IgG titers. 
Urine samples will be collected at baseline, every 12 weeks (±5 days) thereafter, and 
at the end of the study to test uGAG levels. In addition, growth and development will 
be measured during complete physical examinations and by utilizing the Denver II 
Developmental Screening Test. 
 
For infants in the Full/Full participation option, infants will be tested every 12 weeks 
(±5 days) for IgG and IgM antibodies to laronidase in blood. 
 
Concomitant medications and adverse events (AEs) will be collected and summarized 
for both mothers and infants. 
 
Mothers and infants will be evaluated for 18 months unless 1 of the following 
conditions occurs: (a) if 2 consecutive infant samples 12 weeks apart (not including 
the baseline blood draw, if performed) are negative for IgG and IgM antibodies, study 
participation for mothers and infants will last 12 months, (b) the mother withdraws 

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consent and discontinues study participation, (c) the mother or infant is discontinued 
from the study by the Investigator (refer to Section 7.3.1 for details), or (d) the study 
is terminated (Section 12.3.5). If the mother is no longer lactating, the mother will 
discontinue this study.  The infant will be followed for urine and development only 
for the remainder of the study. 
 
6.2 Study Rationale 
 
In the past, pregnancies in females with MPS I disease have been rare. However, it is 
anticipated that with enzyme replacement therapy becoming widely available, more 
affected females will be able to become pregnant and to deliver viable infants.  It is 
not known whether Aldurazyme is excreted in human milk, and there are limited data 
involving infants of mothers receiving Aldurazyme during lactation.  This clinical 
study is being conducted to evaluate the effects of treatment with Aldurazyme on 
lactation in female patients with MPS I disease.  This study will also examine the 
growth, development, and immunologic response of breastfed infants whose mothers 
are receiving Aldurazyme infusions during lactation.  Antibody formation to 
laronidase in mothers and their infants will be monitored postpartum throughout the 
study; if 2 consecutive infant samples 12 weeks apart (not including the baseline 
blood draw, if performed) are negative for IgG and IgM antibodies, study 
participation for mothers and infants will last 12 months; otherwise, testing will 
continue for mothers and infants for 18 months. This study will also present the 
uGAG levels for the mothers and their infants. 
 
Concomitant medications and AEs for both mother and infant will be collected at 
each visit and summarized using the Medical Dictionary of Regulatory Activities 
(MedDRA) coding. 
 
6.2.1 Dosing Regimen 
Mothers will receive Aldurazyme at their prescribed dose and regimen.  The 
Aldurazyme infusion will be prepared as described in the appropriate country 
labeling for Aldurazyme at each study site. 
6.2.2 Study Duration 
For the Full/Full participation option: Mothers and infants will participate in this 
study for 12 months if 2 consecutive infant samples 12 weeks apart (not including 
the baseline blood draw, if performed) are negative for IgG and IgM antibodies; 
otherwise, testing will continue for mothers and infants for 18 months. 
 
For the Full/Partial participation option: The study duration will be 18 months. 
 
6.2.3 Study Population 
Mothers treated with Aldurazyme who intend to breastfeed their infants while 
receiving Aldurazyme will be eligible for enrollment into this study.  Mothers being 
treated with Aldurazyme infusion during lactation will have to provide signed 

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written informed consent for themselves and their infants prior to any protocol-
related procedures being performed.  Consent for all infants enrolled in the study 
will be obtained from the infant’s legally authorized guardian.  If a mother is 
younger than 18 years of age, consent for mother and infant will be obtained from 
the legal guardian. 
 
 

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7. PATIENT POPULATION AND SELECTION 
 
Up to 10 mothers and their infants will be enrolled in this study, at up to 10 study centers. 
 
7.1 Inclusion Criteria 
 
Mothers must meet the following criteria to be enrolled in this study: 
 
1.   The patient must have a documented α-L-iduronidase deficiency with a 
fibroblast, plasma, serum, leukocyte, or dried blood spot α-L-iduronidase 
enzyme activity assay. 
 
2.  Be pregnant, planning to breastfeed postpartum, and receiving Aldurazyme 
while breastfeeding. 
 
3.   Provide signed, written informed consent prior to any protocol-related 
procedure.  Consent of a legally authorized guardian is required for mothers 
younger than 18 years of age.  If a mother is younger than 18 years of age and 
can understand the consent, written informed consent is required from both the 
mother and the legally authorized guardian.  
 
4.  Provide signed, written informed consent for their infants to participate as study 
subjects.  If a mother is younger than 18 years of age, consent for mother and 
infant will be obtained from the legally authorized guardian. 
 
7.2 Exclusion Criteria 
 
Mothers (and their infants) will be excluded from this study if any of the following 
exclusion criteria are met: 
 
1. Have a medical condition, serious intercurrent illness, or other extenuating 
circumstance that may interfere with study compliance including all prescribed 
evaluations and follow-up activities. 
 
2.  Have received an investigational drug within 30 days prior to study enrollment. 
 
7.3 Withdrawal Criteria 
 
7.3.1 Patient Withdrawal 
 
A mother (or the legal guardian of a mother younger than 18 years of age) is 
free to withdraw consent and discontinue her participation, as well as her 
infant’s participation, in the study at any time, without prejudice to further 
treatment.  Study participation of an infant and mother may be discontinued 
at any time at the Investigator’s discretion. If the mother is no longer 

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lactating, the mother will discontinue this study; the infant will be followed 
for only urine and developmental assessments for the remainder of the 
study. 
 
If the mother and/or the infant discontinue(s) participation in the study, or 
their participation is discontinued by the Investigator, the Patient 
Completion/Discontinuation Case Report Form (CRF) describing the reason 
for discontinuation must be completed. Any AEs experienced by the mother 
or infant up to the point of discontinuation must be documented on the AE 
CRF.  
Whenever possible the mother and/or infant should return to the study site 
for the final clinical assessments as specified in Section 9 Efficacy and 
Safety Variables (Table 9-1 and Table 9-2), as appropriate. The Study 
Investigator will describe the reason for discontinuation on the appropriate 
CRF.   
 
If AEs are present at the time of study discontinuation and these events are 
deemed related to Aldurazyme, the relevant patient (mother or infant) will 
be re-evaluated if, in the opinion of the Investigator upon consultation with 
the Sponsor, follow-up is clinically warranted or relevant to the evaluation 
of safety of the trial treatment; results of re-evaluation will be recorded on 
the CRF.  Serious adverse events (SAEs) will be followed until resolution. If 
the patient withdraws consent, the Investigator may not be able to obtain this 
data. 
  
A follow-up safety call will be made 1 month (28 days) after any AE or 
SAE following discontinuation or withdrawal from the study. If any new AE 
or SAE is identified during the course of this follow-up of ongoing AEs, 
additional follow-up of these new AEs/SAEs may be performed if, in the 
opinion of the Investigator (upon consultation with the Sponsor), the follow-
up is clinically warranted and relevant to the evaluation of the safety of the 
trial treatment. 
 

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8. TREATMENTS 
 
8.1  
Treatmnts Administered 
Mothers will receive Aldurazyme treatment at their currently defined dosing 
regimen as determined by their treating physician. The Aldurazyme infusion will 
be prepared as described in the appropriate country labeling for Aldurazyme at 
each study site.  
 
8.2 
Investigational Product   
Mothers enrolled in this study will receive commercially available Aldurazyme.  
Refer to appropriate country labeling information. 
 
8.3 
Patient Numbering  
After signing the written informed consent, each mother will be assigned a 6-digit 
identification number. Each infant will be assigned a separate 6-digit identification 
number. 
 
8.4 
Packaging and Labeling 
Refer to appropriate country labeling information for packaging and labeling 
information for Aldurazyme. 
 
8.5 
Prior and Concomitant Medications 
All medications taken by mothers and infants from the time the Informed Consent 
Form is signed until the end of study participation will be recorded in the 
Concomitant Medication CRF.   
 
 
 
 
 
 

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9. EFFICACY AND SAFETY VARIABLES 
 
Efficacy will not be measured in this study. 
 
9.1 
Schedule of Study Evaluations 
After obtaining signed, written informed consent for both mother and infant, the 
study will be conducted as outlined in the following sections.  Table 9-1 
summarizes the schedule of study events at each visit for mothers and infants 
enrolled in the Full/Full participation option of the study.  Table 9-2 summarizes 
the schedule of study events at each visit for mothers and infants enrolled in the 
Full/Partial participation option of the study. Refer to the Study Operations 
Manual for guidelines regarding test assessments and procedures for 
handling/shipment of all central laboratory samples. 
The timing of study procedures will be based on calendar weeks starting with 
Week 1 (week of baseline assessments).  The study procedures and assessments 
are scheduled so that the maximum time a mother or infant participates in the 
study is approximately 18 months. 

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Table 9-1 Schedule of Study Evaluations - Mother (Full Participation) and Infant (Full 
Participation) 
Evaluation 
Baseline1 
Within 1 Month 
Postpartum 
Every 12 Weeks 
(±5 days) 
End of 
Study2 
Mother 
 
 
 
 
Entry criteria 
X 
 
 
 
Written informed consent3 
X 
 
 
 
Medical history and complete physical 
examination 
X 
X 
X 
X 
IgG antibody4 
  X 
 
X 
X 
uGAG  
X 
 
X 
X 
Laronidase in breast milk5 
 
X 
X 
X 
Breastfeeding status 
 
X 
X 
X 
Concomitant medications 
Continuous Monitoring 
Adverse events 
Continuous Monitoring 
Infant 
 
Written informed consent 
(provided by parent[s]/legal guardian[s])3 
X 
 
 
 
Medical history and complete physical 
examination 
X6 
X 
X 
X 
IgG and IgM antibodies  
  X7 
 
X 
X 
Breastfeeding status 
 
X 
X 
X 
uGAG  
X8 
 
X 
X 
Development assessment9 
 
 
X 
X 
Concomitant medications 
Continuous Monitoring 
Adverse events 
Continuous Monitoring 
IgG, immunoglobulin G; IgM, immunoglobulin M; uGAG, urinary glycosaminoglycans 
1 Baseline is defined as birth (infant) and within 1 month prior to birth (mother). 
2 Mother and infant will participate in this study for 12 months if 2 consecutive infant samples 12 weeks apart, 
not including the baseline blood draw, are negative for IgG and IgM antibodies; otherwise, testing will continue 
for mother and infant for 18 months. 
3 Written informed consent may be given by mother (or legal guardian if mother is younger than 18 years of 
age) during pregnancy or after delivery. 
4 Blood samples must be drawn before breast milk samples are collected. 
5 Breast milk samples will be collected within 24 hours prior to Aldurazyme infusion and within 60 minutes 
after completion of Aldurazyme infusion. 
6 The baseline medical history and physical examination for the infant must be performed within the first week 
after birth. 
7 Baseline IgG and IgM are obtained from umbilical cord blood immediately after birth. 
8 Baseline urine sample in infants must be obtained within 72 hours of birth and prior to the next infusion of the 
mother. 
9 Infant development (personal-social, fine motor, language, and gross motor) is assessed with the Denver II 
Developmental Screening Test.  
 
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Table 9-2 Schedule of Study Evaluations - Mother (Full Participation) and Infant 
(Partial Participation) 
Evaluation 
Baseline1 
Within 1 Month 
Postpartum 
Every 12 Weeks 
(±5 days) 
End of 
Study2 
Mother 
 
 
 
 
Entry criteria 
X 
 
 
 
Written informed consent3 
X 
 
 
 
Medical history and complete physical 
examination 
X 
X 
X 
X 
IgG antibody4 
  X 
 
X 
X 
uGAG 
X 
 
X 
X 
Laronidase in breast milk5 
 
X 
X 
X 
Breastfeeding status 
 
X 
X 
X 
Concomitant medications 
Continuous Monitoring 
Adverse events 
Continuous Monitoring 
Infant 
 
Written informed consent 
(provided by parent[s]/legal guardian[s])3 
X 
 
 
 
Medical history and complete physical 
examination 
X6 
X 
X 
X 
Umbilical cord blood sample for IgG and 
IgM antibodies 
  X7 
 
 
 
Breastfeeding status 
 
X 
X 
X 
uGAG 
X8 
 
X 
X 
Development assessment9 
 
 
X 
X 
Concomitant medications 
Continuous Monitoring 
Adverse events 
Continuous Monitoring 
IgG, immunoglobulin G; IgM, immunoglobulin M; uGAG, urinary glycosaminoglycans 
1 Baseline is defined as birth (infant) and within 1 month prior to birth (mother). 
2 Mother and infant will participate in this study for 18 months. 
3 Written informed consent may be given by mother (or legal guardian if mother is younger than 18 years of 
age) during pregnancy or after delivery. 
4 Blood samples must be drawn before breast milk samples are collected. 
5 Breast milk samples are collected within 24 hours prior to Aldurazyme infusion and within 60 minutes after 
completion of Aldurazyme infusion. 
6 The baseline medical history and physical examination for the infant must be performed within the first week 
after birth. 
7Baseline IgG and IgM are obtained from umbilical cord blood immediately after birth. 
8 Baseline urine samples in infants must be obtained within 72 hours of birth and prior to the next infusion of the 
mother. 
9 Infant development (personal-social, fine motor, language, and gross motor) is assessed with the Denver II 
Developmental Screening Test.  
 
 

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9.2  Tests and Procedures  
 
Mothers may enroll in this study any time after pregnancy is documented and prior 
to the birth of their infants. After entry criteria have been met and the mother or the 
mother’s legal guardian has provided written informed consent for both mother and 
infant for study participation, mothers and infants will undergo the following 
assessments: 
9.2.1 Tests and Procedures for Mother and Infant (Full/Full Participation) 
9.2.1.1 Baseline 
Mother (within 1 month prior to infant’s birth): 
• Written informed consent for mother and infant 
• Medical history and complete physical examination  
• Blood samples for IgG antibody testing to laronidase 
• Urine samples for uGAG testing 
• Concomitant medications and AEs  
Infant (at birth): 
• Parent(s)/legal guardian(s) provide signed written informed consent for the 
infant. (May be collected/provided prior to birth.) 
• Medical history and complete physical examination (within the first week) 
• Umbilical cord blood sample from infant for IgG and IgM antibody testing 
to laronidase (immediately after birth) 
• Urine samples for uGAG  testing (within 72 hours of birth and prior to next 
infusion) 
• Concomitant medications and AEs (prior to discharge) 
 
9.2.1.2 Within 1 Month Postpartum: 
Mother: 
•     Medical history and complete physical examination 
•     Breast milk samples to test for the presence of laronidase (To be collected 
within 24 hours prior to Aldurazyme infusion and within 60 minutes after 
completion of Aldurazyme infusion.) 
• 
Breastfeeding status 
• Concomitant medications and AEs  
Infant: 
• Medical history and complete physical examination 
• Breastfeeding status 
• Concomitant medications and AEs  
 
 
 

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9.2.1.3 Every 12 Weeks (±5 days): 
Mother: 
• Medical history and complete physical examination  
• Blood samples for IgG antibody testing to laronidase 
• Urine samples for uGAG testing 
• Breast milk samples to test for the presence of laronidase (To be collected 
within 24 hours prior to Aldurazyme infusion and within 60 minutes after 
completion of Aldurazyme infusion.) 
• Breastfeeding status 
• Concomitant medications and AEs  
Infant: 
• Medical history and complete physical examination 
• Blood sample for IgG and IgM antibody testing to laronidase  
• Breastfeeding status 
• Urine samples for uGAG testing 
• Development assessment using the Denver II Developmental Screening Test 
• Concomitant medications and AEs 
 
9.2.1.4 End of Study: 
Mother: 
• Medical history and complete physical examination  
• Blood samples for IgG antibody testing to laronidase 
• Urine samples for uGAG testing 
• Breast milk samples to test for the presence of laronidase (To be collected 
within 24 hours prior to Aldurazyme infusion and within 60 minutes after 
completion of Aldurazyme infusion.) 
• Breastfeeding status 
• Concomitant medications and AEs  
Infant: 
• Medical history and complete physical examination 
• Blood samples for IgG and IgM antibody testing to laronidase  
• Breastfeeding status 
• Urine samples for uGAG testing 
• Development assessment using the Denver II Developmental Screening Test 
• Concomitant medications and AEs 
9.2.2 Tests and Procedures for Mother and Infant (Full/Partial Participation) 
9.2.2.1  Baseline 
Mother (within 1 month prior to infant’s birth): 
• Written informed consent for mother and infant 
• Medical history and complete physical examination  
• Blood sample for IgG antibody testing to laronidase 

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• Urine samples for uGAG testing 
• Concomitant medications and AEs  
Infant (at birth): 
• Parent(s)/legal guardian(s) provide signed written informed consent for the 
infant. (May be collected/provided prior to birth.) 
• Medical history and complete physical examination (within the first week) 
• Umbilical cord blood sample from infant for IgG and IgM antibody testing 
to laronidase (immediately after birth) 
• Urine samples for uGAG  testing (within 72 hours of birth and prior to next 
infusion) 
• Concomitant medications and AEs (prior to discharge) 
 
9.2.1.2  Within 1 Month Postpartum: 
Mother: 
•     Medical history and complete physical examination 
•     Breast milk samples to test for the presence of laronidase (To be collected 
within 24 hours prior to Aldurazyme infusion and within 60 minutes after 
completion of Aldurazyme infusion.) 
• 
Breastfeeding status 
• Concomitant medications and AEs 
Infant: 
• Medical history and complete physical examination 
• Breastfeeding status 
• Concomitant medications and AEs 
 
9.2.2.3  Every 12 Weeks (±5 days): 
Mother: 
• Medical history and complete physical examination  
• Blood samples for IgG antibody testing to laronidase 
• Urine samples for uGAG testing 
• Breast milk samples to test for the presence of laronidase (To be collected 
within 24 hours prior to Aldurazyme infusion and within 60 minutes after 
completion of Aldurazyme infusion.) 
• Breastfeeding status 
• Concomitant medications and AEs  
Infant: 
• Medical history and complete physical examination 
• Breastfeeding status 
• Urine samples for uGAG testing 
• Development assessment using the Denver II Developmental Screening Test 
• Concomitant medications and AEs 

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9.2.2.4 End of Study: 
Mother: 
• Medical history and complete physical examination  
• Blood samples for IgG antibody testing to laronidase 
• Urine samples for uGAG testing 
• Breast milk samples to test for the presence of laronidase (To be collected 
within 24 hours prior to Aldurazyme infusion and within 60 minutes after 
completion of Aldurazyme infusion.) 
• Breastfeeding status 
• Concomitant medications and AEs 
Infant: 
• Medical history and complete physical examination 
• Breastfeeding status 
• Urine samples for uGAG testing 
• Development assessment using the Denver II Developmental Screening Test 
• Concomitant medications and AEs 
 
9.3 Measurements 
The effects of Aldurazyme treatment on lactation in women with MPS I disease 
and their breastfed infants will be monitored continuously throughout study 
participation and will be assessed in terms of incidence of AEs, physical 
examination results, vital signs, and immunogenicity testing.  Refer to Tables 9-1 
and 9-2 for the schedule of these assessments and to the Study Operations Manual 
for details. 
 
9.3.1 Physical
 
Examination 
 
Each physical examination will include the following physical observations: 
General Appearance, Skin, Head, Ears, Eyes, Nose, and Throat, Lymph 
Nodes, Heart, Lungs, Abdomen, Extremities/Joints, Neurological, Mental 
Status, and the following, if appropriate, Breasts, External Genitalia, Pelvic, 
Rectal, Vital Signs, and Height/Weight.  
 
If clinically significant worsening from baseline of the physical examination 
assessments is noted, the change will be documented as an AE on the AE 
CRF and will be followed as an AE consistent with the procedure outlined 
in Section 9.6.  Clinical significance is defined as any variation in physical 
findings that has medical relevance resulting in an alteration in medical care. 
 
9.3.2 Immunogenicity Testing   
Blood samples for anti-laronidase IgG (mother and infant) and IgM (infant) 
antibody testing will be obtained at baseline and every 12 weeks thereafter 
throughout the study for the Full/Full participation option only. If 2 

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consecutive infant samples 12 weeks apart (not including the baseline blood 
draw) are negative for IgG and IgM antibodies, study participation for the 
mother and infant will last 12 months; otherwise, testing will continue for 
the mother and infant for 18 months. 
 
9.4 Adverse Events 
 
An AE is any untoward medical occurrence in a clinical investigation patient, which 
does not necessarily have a causal relationship with the product (active or placebo 
drug, biologic, or device).  An AE can, therefore, be any unfavorable and unintended 
symptom, sign, disease or condition, or test abnormality whether or not considered 
related to the product. 
 
Adverse events include: 
• 
Symptoms described by the patient or signs observed by the Investigator or 
medical staff. 
• 
Test abnormalities (laboratory tests, electrocardiogram, X-rays, etc.) that 
result in an alteration in medical care (diagnostic or therapeutic). 
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 
re-occur after the patient has recovered from the pre-existing condition or they 
represent an exacerbation in intensity or frequency. 
Any AEs experienced by the mother or infant from the time of signing the Informed 
Consent Form through the completion of study participation, will be reported as 
described in Section 9.6 and recorded on the CRF.  If AEs are present when the 
patient completes study participation or discontinues the study prematurely and 
these events are deemed related to Aldurazyme, the relevant patient (mother or 
infant) will be re-evaluated if, in the opinion of the Investigator (upon consultation 
with the Sponsor), the follow-up is clinically warranted and relevant to the 
evaluation of the safety of the trial treatment; results of re-evaluation will be 
recorded on the CRF.  SAEs will be followed until resolution. 
If any new AE or SAE is identified during the course of this follow-up of ongoing 
AEs, additional follow-up of these new AEs/SAEs may be performed if, in the 
opinion of the Investigator (upon consultation with the Sponsor), the follow-up is 
clinically warranted and relevant to the evaluation of the safety of the trial 
treatment. 
 
9.4.1  Infusion-Associated Reactions 
An infusion-associated reaction (IAR) is defined as an AE that occurs 
during the infusion or observation period following the infusion and 
assessed as causally related to laronidase. Related events occurring after the 
post-infusion period may be considered infusion reactions at the discretion 
of the reporter. 

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9.5 
Serious Adverse Events 
A SAE 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 
 
Death:  The patient died as the result of the event. 
 
Life-threatening event:  Any AE that places the patient, in the view of the 
Investigator, at immediate risk of death from the AE as it occurred, i.e., does not 
include an AE that had it occurred in a more severe form, might have caused death. 
 
Required or prolonged inpatient hospitalization:  The AE resulted in an initial 
inpatient hospitalization or prolonged an existing hospitalization of the patient.  If a 
patient is hospitalized as part of the clinical use of the product, a period of normal 
hospitalization will be outlined in the protocol or by the judgment of the 
Investigator.  Hospitalizations longer than this period will be prolonged 
hospitalizations. 
 
Persistent or significant disability/incapacity:  An AE that results in a substantial 
disruption of a person’s ability to conduct normal life functions. 
 
Congenital anomaly/birth defect:  A congenital anomaly/birth defect that occurs in 
the offspring of a patient exposed to the investigational product. 
 
Important medical events:  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, the event may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
• Patient hospitalization for a pre-planned Cesarean Section will not be 
deemed an SAE unless complications occur that result in prolonged 
hospitalization.  
 
 

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Severity Grading 
The Investigator will assess the severity of all AEs/SAEs as Mild, Moderate, or 
Severe, based on the following definitions (developed from CDISC SDTM 
standard terminology v3.1.1). 
 
Definitions 
• Mild:  A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention.  The event does not generally 
interfere with usual activities of daily living. 
• Moderate:  A type of AE that is usually alleviated with additional specific 
therapeutic intervention.  The event interferes with usual activities of daily 
living, causing discomfort, but poses no significant or permanent risk of 
harm to the research participant. 
• Severe:  A type of AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention. 
 
9.6 
Adverse Event and Serious Adverse Event Reporting 
The necessity and time requirements for reporting SAEs to the Sponsor or designee 
and/or regulatory agencies are as follows: 
• All SAEs will be reported within 24 hours of the Investigator’s first 
knowledge of the event, even if the event does not appear to be related to the 
study drug.  Such communications are to be directed to: 
 
Genzyme Global Patient Safety and  
Risk Management 
Fax:  1-617-761-8506 (Global Triage) 
E-mail:  pharmacovigilancesafety@genzyme.com 
 
(See Study Operations Manual for pharmacovigilance study contacts during 
business hours.) 
• All IARs (non-serious and serious) will be reported within 24 hours of the 
Investigator’s first knowledge of the event.  Such communications are to be 
directed to the office listed above. 
• All SAEs will include a detailed written description of the event(s).  Copies 
of relevant patient records, autopsy reports, and other documents may be 
requested by and will be sent to the Global Patient Safety & Risk 
Management (GPS&RM) Department. 
Additionally, Institutional Review Boards (IRB) or Institutional Ethics Committees 
(IEC) must be notified in writing of any expedited SAEs (those AEs that are 
serious, unexpected, and related to study drug).  It is the responsibility of the 

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Investigator to notify the IRB or IEC.  All expedited SAEs associated with the use 
of the study drug will be reported by the Sponsor to appropriate regulatory agencies 
as per the required timelines. 
All AEs and SAEs will be documented on the study CRF, with a full description 
including the nature, date and time of onset and resolution, determination of 
seriousness, severity, corrective treatment, outcome, and relationship to study drug. 
If AEs or SAEs are ongoing when the patient completes or prematurely 
discontinues the study, and these events are deemed related to Aldurazyme, 
additional follow-up will be performed if, in the opinion of the Investigator (upon 
consultation with the Sponsor), the follow-up is clinically warranted and relevant to 
the evaluation of the safety of the trial treatment.  SAEs will be followed until 
resolution. 
If any new AE or SAE is identified during the course of this follow-up of ongoing 
AEs, additional follow-up of these new AEs/SAEs may be performed if, in the 
opinion of the Investigator (upon consultation with the Sponsor), the follow-up is 
clinically warranted and relevant to the evaluation of the safety of the trial 
treatment. 

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10. DATA QUALITY ASSURANCE 
 
All required data will be recorded in the CRF provided by Genzyme Corporation in 
accordance with Section 12.3.2.   
 
The CRFs will be reviewed manually at the study site for completeness by a clinical monitor 
from Genzyme Corporation or a designee, and returned to Genzyme Corporation or its 
designee, for data management and analysis.  If necessary, the study site will be contacted for 
corrections and/or clarifications.  All data will be entered into a study database for analysis 
and reporting.  Any data captured electronically (e.g., laboratory data) will be electronically 
transferred to the database.  Upon completion of data entry, the database will receive a 
quality assurance check to ensure acceptable accuracy and completeness. 

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11. STATISTICAL METHODS AND PLANNED ANALYSES 
Genzyme Corporation 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 
Version 4.5. 
 
Prior to locking the database, all data editing will be complete and decisions regarding the 
evaluability of all patient data for inclusion in the statistical analysis will be made.  The 
rationale for excluding any data from the statistical analyses will be prospectively defined, 
and classification of all or part of a patient’s data as nonevaluable will be completed and 
documented before the entire database is locked and before the statistical analysis is begun.  
The statistical analysis will not begin until the entire database is locked and signed off, in 
accordance with the Standard Operating Procedures of the Biostatistics Department. 
 
The Genzyme Biostatistics Department will perform the statistical analysis of the data 
derived from this study.  The analysis will be performed using the SAS® statistical software 
system (SAS Institute Inc., 2008; SAS Language, Version 9.2). 
 
11.1 Study Variables 
 
The analyses of the data from this study are designed to address the following questions: 
 
• 
Is laronidase activity present in the breast milk of mothers with MPS I disease 
who are being treated with Aldurazyme during lactation?  
• 
Does Aldurazyme affect the growth, development, and immunologic response 
of breastfed infants born to mothers with MPS I disease who are being treated 
with Aldurazyme during lactation? 
 
Effects of Aldurazyme on lactation in mothers will be assessed in terms of the proportion of 
lactating women with serum IgG antibodies to laronidase, the levels of IgG antibody titers to 
laronidase, the proportion of women who breastfed, the proportion of women who were 
successful at breastfeeding, the proportion of women whose breast milk contained laronidase, 
the levels of laronidase in the breast milk of lactating mothers with MPS I disease, the 
proportion of women with abnormal uGAG levels, the levels of uGAG, and medical history 
and physical examination findings. 
 
Effects of Aldurazyme on infants will be assessed in terms of the proportion of infants with 
abnormal uGAG levels, the levels of uGAG, medical history and complete physical 
examination findings (including growth), and the developmental assessment findings. For the 
infants participating in the Full/Full option, the effects of Aldurazyme will be assessed in 
terms of the proportion of infants with IgM and IgG antibodies present at any time point, the 
levels of IgG and IgM antibody titers to laronidase, and the time to development of IgM and 
IgG antibodies to laronidase. 

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11.1.1 Patient Populations 
 
The intent-to-treat (ITT) approach will be the main analysis for this study.  This 
approach will include both mothers and infants of mothers who will receive 
Aldurazyme during lactation.  The ITT analysis will be the basis for determination 
of the effects of Aldurazyme on lactation. 
 
11.1.2 Handling of Dropouts 
 
For the analyses, summary data for patients who terminate the study early or miss 
study visits (and consequently have missing data) will not be carried forward to the 
next time point.  Hence, the analyses will be performed on an observed-cases basis. 
 
11.1.3 Statistical Methods 
 
All data collected in this study will be documented using summary tables, graphs, 
figures, and patient data listings. 
 
No hypothesis testing will be performed. 
 
11.2  Demographics and Baseline Characteristics 
 
Demographic and baseline characteristics data for the mother and for the infant will 
be summarized descriptively. For categorical variables, frequencies and percentages 
will be presented.  For continuous variables, descriptive statistics (n’s, means, 
medians, standard deviations, minimums, and maximums) will be presented.  
 
Prior medications will also be summarized descriptively (using frequencies and 
percentages). 
 
11.3  Patient Accountability 
 
Data from all patients (mothers and infants) 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, or complete the study will be summarized. 

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11.4 Study 
Variables 
 
The following variables will be summarized descriptively:  
 
Mothers 
• The proportion of lactating women with serum IgG antibodies to laronidase 
• Amount of IgG antibody titers to laronidase in lactating women 
• The proportion of women who breastfed  
• The proportion of women who were successful at breastfeeding 
• The proportion of women whose breast milk contains laronidase 
• Amount of laronidase in the breast milk of lactating mothers with MPS I disease  
• The proportion of women with abnormal uGAG levels 
• Amount of uGAG in the urine of women 
• Medical history and physical examination findings 
 
Infants 
• The proportion of infants with abnormal uGAG levels  
• Amount of uGAG in the urine of infants 
• Medical history and complete physical examination (including growth)  
• Developmental assessment findings 
• For the Full/Full Participation option only: 
o The proportion of infants with IgM and IgG antibodies to laronidase present at 
any time point  
o The time to development of IgM and IgG antibodies to laronidase 
o Amount of IgG and IgM antibody titers to laronidase 
 
In addition, the incidence of AEs will be summarized descriptively by using 
MedDRA coding.  Shifts in physical examination results from baseline (last 
baseline measurement) to the study time points will be summarized descriptively. 
 
11.5 Sample Size 
 
This study will enroll up to 10 mothers and their infants. No formal sample size 
calculations were performed. 
 
11.6  Interim Analysis 
 
After 3 infants have completed the study, an interim summary of the data will be 
provided as described above for the main analyses, in order to facilitate discussions 
with the FDA.  As this is an open-label post-marketing study with no formal 
hypothesis testing, the usual adjustments to significance levels will not be required. 
 

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12. SPECIAL REQUIREMENTS AND PROCEDURES 
This protocol was designed and will be conducted, recorded, and reported in compliance with 
the International Conference on Harmonisation (ICH)/ Good Clinical Practice (GCP) 
guideline.  These requirements are stated in the ICH Guideline Topic E6 entitled “Guideline 
for Good Clinical Practice.” 
 
12.1 
Institutional and Ethics Review 
 
This protocol and patient informed consent form must be reviewed and approved by 
an IRB/IEC before enrollment of patients and release of investigational product.  
Documentation of IRB/IEC and the approved consent form must be received by 
Genzyme Corporation or its designee prior to obtaining the patient’s informed 
consent.  
  
12.2 
Changes to the Conduct of the Study or Protocol 
 
Any changes in the study protocol, such as changes in the study design, objectives 
or endpoints, inclusion and exclusion criteria, and/or procedures (except to 
eliminate an immediate hazard) will be implemented only after the mutual 
agreement of the Investigator and BioMarin/Genzyme LLC.  All protocol changes 
must be documented in protocol amendment(s).  Protocol amendment(s) must be 
signed by the Investigator and approved by the IRB/IEC prior to implementation.  
Any changes in study conduct that result from a pending amendment will be 
considered protocol deviations until IRB/IEC approval is granted.  Documentation 
of IRB/IEC approval must be returned to Genzyme Corporation or its designee.   
 
12.3 
Investigator's Responsibilities  
 
12.3.1 Patient Informed Consent  
 
Investigators must adhere to GCP, which includes ethical principles that 
have their origin in the Declaration of Helsinki, when developing the patient 
informed consent form and when obtaining consent from the patient.  
Written informed consent is required prior to enrollment in the study.  It is 
the responsibility of the Investigator to document the consent process within 
the source documents and obtain consent using an IRB/IEC approved 
consent form.   
 

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12.3.2 Case Report Forms  
 
Copies of pertinent records in connection with the study, including all 
source documents, will be made available to Genzyme Corporation or its 
designee on request with due precaution towards protecting the privacy of 
the mother and infant. 
 
Case report forms will be filled out legibly and completely.  Unless 
explicitly directed, blank data fields are not acceptable.  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.  Writing in the 
margins of the CRFs is not permitted.  The original CRFs will be provided 
to Genzyme Corporation or its designee.  A copy of the CRFs will be 
maintained in the Investigator’s site file.  Illegible or incomplete entries or 
entries needing additional explanation will be returned or queried to the 
Investigator for clarification.   
  
12.3.3 Record Retention 
 
The Investigator is responsible for oversight and maintenance of the study 
records and patient source documents.  These records must be readily 
available for audit or inspection. 
 
The Investigator must retain study records for at least 2 years after the last 
marketing approval has been granted, or at least 2 years have elapsed since 
the formal discontinuation of clinical program.  However, these documents 
should be retained for a longer period, if required by other applicable 
requirements (e.g., applicable local regulatory requirement) or by an 
agreement with the BioMarin/Genzyme LLC or its designee.  The 
Investigator should contact the BioMarin/Genzyme LLC or its designee 
prior to any record destruction.   
 
Patient records or other source data must be kept for the maximum period of 
time mandated by the hospital, institution, or private practice, but not less 
than 15 years.   
 
If off-site archiving is used, all records should be retrieved and made 
available for review at the time of an audit or regulatory authority 
inspection.   
 
12.3.4 Monitoring  
A representative of BioMarin/Genzyme LLC or its designee will visit the 
Investigator periodically for the purpose of monitoring the progress of this 
study in accordance with the protocol, GCP, and local regulations.  
Noncompliance with the protocol, GCP, and local regulations will be 
documented and corrective actions implemented, as necessary.  It is the 

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responsibility of the Investigator to be present or available for consultation 
during 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. 
 
At any time prior to, during, or after completion of the clinical study, an 
audit may be performed by BioMarin/Genzyme LLC or its designee or a 
representative of a national regulatory agency may choose to inspect a study 
site.  Investigators should notify BioMarin/Genzyme LLC or its designee 
upon notification of inspection by a representative of a national regulatory 
agency.  A BioMarin/Genzyme LLC or designee representative will be 
available to assist in the preparation for study site inspections.  All pertinent 
study data should be made available for verification, audit, or inspection 
purposes. 
 
12.3.5 Study or Site Termination  
 
If BioMarin/Genzyme LLC, the Investigator, or regulatory authorities 
discover any conditions during the study that indicate that the study or study 
site should be terminated, this action may be taken after appropriate 
consultation between BioMarin/Genzyme LLC and the Investigator.  
BioMarin/Genzyme LLC has the right to terminate the participation of 
either an individual site or the study at any time, for any reason which may 
include the following: 
 
 The incidence and severity of AEs in this or other studies indicates a 
potential health hazard to patients. 
 Patient enrollment is unsatisfactory. 
 Data recording is inaccurate or incomplete. 
 Investigator(s) do(es) not adhere to the protocol or applicable 
regulatory guidelines in conducting this study. 
 Submission of knowingly false information from the study site to 
BioMarin/Genzyme LLC or regulatory authorities. 
 Results of a planned interim analysis support terminating the study.   
 
In the event that the study is terminated early, BioMarin/Genzyme LLC will 
provide specific guidance to investigational sites regarding the end-of-study 
procedures.   
 
12.3.6 Investigational Product Control  
 
There will be no clinical trial supplies provided for this study. 

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12.3.7 Disclosure of Data  
 
All details related to the disclosure and publication of study data will be 
addressed in the Investigator’s study contract.   
 
12.3.8 Clinical Study Report 
The Investigator will review and sign the completed clinical study report.   
  

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13.  
REFERENCES 
 
Aldurazyme® (laronidase) Prescribing Information. Novato, CA: BioMarin Pharmaceutical 
Inc. and Cambridge, MA: Genzyme Corporation; 2010.  
 
Aldurazyme® (laronidase) (EU/1//01/253/001-003) Summary of Product Characteristics, 
2010. 
 
Belani KG, Krivit W, Carpenter BL, et al. Children with mucopolysaccharidosis: 
perioperative care, morbidity, mortality and new findings. J Pediatr Surg. 1993;28(3):403-10. 
 
Bredenkamp JK, Smith ME, Dudley JP, Williams JC, Crumley RL, Crockett DM. 
Otolaryngologic manifestations of the mucopolysaccharidoses. Ann Otol Rhinol Laryngol. 
1992; 101(6):472-8. 
 
Dangel JH. Cardiovascular changes in children with mucopolysaccharide storage diseases 
and related disorders–clinical and echocardiographic findings in 64 patients. Eur J Pediatr. 
1998; 157(7):534-8. 
 
Kakkis ED, Neufeld E. The Mucopolysaccharidoses. In: Berg BO, editor. Principles of Child 
Neurology. McGraw-Hill; 1996:1141-65. 
 
Mahowald MW, Iber C, Rosen GM, et al. Sleep disordered breathing in the 
mucopolysaccharidoses. Sleep Res. 1989;18:348 (abstract). 
 
Neufeld E, Muenzer J. The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, 
Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease.  McGraw-Hill; 
2001:3421-52.  
 
Ruckenstein MJ, Macdonald RE, Clarke JT, Forte V. The management of otolaryngological 
problems in the mucopolysaccharidoses: a retrospective review. J Otolaryngol. 
1991;20(3):177-83. 
 
SAS Institute Inc. SAS Language, Version 9.2.  Cary, NC: SAS Institute Inc.; 2008. 
 
Semenza GL, Pyeritz RE. Respiratory complications of mucopolysaccharide storage 
disorders. Medicine (Baltimore). 1988;67(4):209-19.