A Long-term Study to Evaluate Growth and Development Outcomes in Patients With Infantile-Onset Pompe Disease Who Are Receiving Alglucosidase Alfa
Phase: PHASE4
Conditions: Pompe Disease, Glycogen Storage Disease Type II (GSD-II), Acid Maltase Deficiency Disease
Sponsor: Genzyme, a Sanofi Company



Alglucosidase Alfa 
2 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
1. SYNOPSIS 
NAME OF COMPANY 
Genzyme Corporation, a Sanofi Company 
500 Kendall Street 
Cambridge, MA  02142 
NAME OF FINISHED PRODUCT 
Myozyme® / Lumizyme® (alglucosidase alfa) 
NAME OF ACTIVE INGREDIENT 
alglucosidase alfa 
SUMMARY TABLE 
Referring to Part …… 
of the Dossier: 
Volume:                       
Page:                            
Reference:                   
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
TITLE: 
A Long-term Study to Evaluate Growth and Development Outcomes in Patients with Infantile-Onset 
Pompe Disease Who Are Receiving Alglucosidase Alfa 
INVESTIGATOR STUDY CENTERS: 
The number of study centers will not be limited prospectively. 
OBJECTIVES: 
The overall objective is to evaluate long-term growth and development of patients with infantile-onset 
Pompe disease who begin treatment with alglucosidase alfa before 1 year of age.  Patients will be 
followed for a 10-year period.  An additional objective is to collect long-term safety data on patients 
with infantile-onset Pompe disease.  As an exploratory objective, the effect of alglucosidase alfa 
treatment on urinary oligosaccharides (Hex4) will be evaluated.  For research purposes only, cross-
reacting immunologic material (CRIM) status and GAA mutation analysis will be evaluated. 
METHODOLOGY: 
This is a multicenter study of patients with infantile-onset Pompe disease who begin alglucosidase alfa 
treatment prior to 1 year of age.  Patients with a confirmed diagnosis of Pompe disease who begin  
alglucosidase alfa treatment prior to their first birthday will be followed in this study for 10 years.   
The patient’s legal guardian(s) must sign the informed consent form prior to performance of any of the 
study assessments outlined in Table 9-1.   
An independent Data Safety Monitoring Board (DSMB) will review safety information on an ad hoc 
basis as outlined in the DSMB charter, which is maintained separately from the study protocol. 
An independent Allergic Reaction Review Board (ARRB) will be consulted on an ad hoc basis as 
outlined in the ARRB charter, which is also maintained separately from this protocol. 
NUMBER OF SUBJECTS: 
The number of patients followed in this study will not be limited prospectively.   
DIAGNOSIS/INCLUSION CRITERIA: 
Inclusion Criteria: 
(1) the patient’s legal guardian(s) must provide written informed consent prior to study assessments 
being performed; (2) the patient must have a confirmed diagnosis of Pompe disease as determined by 
deficient endogenous GAA activity or GAA mutation analysis; and (3) the patient must be <1 year of 
age at time of study enrollment (and receive  alglucosidase alfa treatment before 1 year of age), or the 
patient must be between 1 year and 24 months of age and must have initiated alglucosidase alfa 
treatment prior to turning 1 year of age. 
Exclusion Criteria: 
(1) the patient is participating in another clinical study using alglucosidase alfa or any investigational 
therapy. 
DOSE/ROUTE/REGIMEN: 
 
(electronic 
 
 
 
2.0)

Alglucosidase Alfa 
3 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
NAME OF COMPANY 
Genzyme Corporation, a Sanofi Company 
500 Kendall Street 
Cambridge, MA  02142 
NAME OF FINISHED PRODUCT 
Myozyme® / Lumizyme® (alglucosidase alfa) 
NAME OF ACTIVE INGREDIENT 
alglucosidase alfa 
SUMMARY TABLE 
Referring to Part …… 
of the Dossier: 
Volume:                       
Page:                            
Reference:                   
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
 Alglucosidase alfa will be administered at 20 mg/kg body weight as prescribed by the treating physician 
every 2 weeks as an intravenous infusion.  If clinically feasible, all patients will continue at the same 
dose throughout the study.  Any modification to the dose and/or frequency of dosing is not permitted 
unless it is due to disease progression or to an adverse event (AE), in which case it is not a protocol 
deviation, but the Investigator must consult with the Sponsor’s Medical Monitor and Global Safety 
Officer in the event of a dose change.  The dosing change and the reasons for it will be documented on 
the appropriate case report forms.  
It is recommended that the reconstitution and administration instructions in the current prescribing 
information be followed. 
Patients who meet specific criteria may have the option for home infusions.  Because of the possibility of 
anaphylactic reactions, personnel competent in recognizing and treating adverse reactions (including 
anaphylactic reactions) should be readily available throughout the home infusion.  The following criteria 
must be documented in the patient’s medical record: 
o 
The patient must be clinically stable with no history of moderate or severe IARs within 
6 months prior to planned transition to home infusion. 
o 
The patient must have no ongoing serious adverse events (SAEs) that, in the opinion of the 
Investigator, may impact the patient’s ability to tolerate infusion. 
o 
The home infusion agency staff must be trained by the Investigator prior to beginning home 
infusions.  Any new staff member must be trained by the Investigator prior to beginning home 
infusions. 
o 
The home infusion agency staff must have access to and be trained on proper safety equipment, 
including but not limited to cardiopulmonary resuscitation equipment. 
o 
If recurrent IARs or hypersensitivity/anaphylactic reactions occur, the Investigator should 
assess whether or not it is safe for the patient to continue to be treated via home infusion. 
Genzyme should be notified about all IARs and consulted (as needed) if the patient experiences 
IARs suggestive of hypersensitivity reactions (refer to Section 9.5.2). 
o 
Home Infusion Agency must keep source documentation of the infusion, including 
documentation of any AEs.  Home Infusion Agency must be amenable to providing specific 
source documentation to Genzyme and agree to be monitored.  The Principal Investigator is still 
responsible for all study procedures and patient’s safety even when delegating infusion 
responsibilities to the home care company. 
The Principal Investigator is responsible for approving a patient’s initiation with home infusions and is 
ultimately responsible for the safety of the patient during this clinical study.  Refer to the Study Manual 
and Home Infusion Manual for further details regarding home infusions. 
REFERENCE TREATMENT: 
There will be no comparator treatment or placebo in this study. 
CRITERIA FOR EVALUATION: 
Efficacy: The following efficacy assessments will be performed at scheduled visits during the study: 
• 
Growth as measured by recumbent length/height, weight and head circumference  
 
(electronic 
 
 
 
2.0)

Alglucosidase Alfa 
4 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
NAME OF COMPANY 
Genzyme Corporation, a Sanofi Company 
500 Kendall Street 
Cambridge, MA  02142 
NAME OF FINISHED PRODUCT 
Myozyme® / Lumizyme® (alglucosidase alfa) 
NAME OF ACTIVE INGREDIENT 
alglucosidase alfa 
SUMMARY TABLE 
Referring to Part …… 
of the Dossier: 
Volume:                       
Page:                            
Reference:                   
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
• 
Motor development and function, as measured by changes in the motor subscale of the Bayley 
Scales of Infant and Toddler Development (Bayley-III) (up to 42 months of age), Gross Motor 
Function Measure (GMFM-88) and Pompe Pediatric Evaluation of Disability Inventory (Pompe 
PEDI) 
• 
Cognitive Development, as measured by the cognitive and language subscales of the Bayley 
Scales of Infant and Toddler Development (Bayley-III) (up to 42 months of age), change in the 
Brief IQ score of the Leiter International Performance Scale – Revised (Leiter-R) and/or the 
change in the Nonverbal IQ score of the Leiter International Performance Scale - 3rd Edition 
(Leiter-3) (starting at the final assessment of the Bayley-III before 42 months of age). 
For patients treated with alglucosidase alfa prior to age 1 (prior to study entry), available retrospective 
growth and development data will be collected.  Parameters for retrospective data collection will include 
available standard-of-care growth (height, weight, head circumference) and motor milestone information 
(e.g. head support, sitting, standing, and walking ability) from the time of treatment initiation. 
Safety: The following safety assessments will be performed during the study: AE monitoring, laboratory 
tests (clinical chemistry, hematology and urinalysis), anti-rhGAA antibody (immunoglobulin G [IgG]) 
collection, neuroimaging (at the discretion of the Investigator), vital signs (blood pressure, heart rate, 
respiratory rate, and temperature), physical examinations, electrocardiograms (ECGs), hearing testing 
and visual screening. 
Additional safety evaluations will include the assessment of: (1) immunoglobulin E (IgE), serum 
tryptase, complement activation and skin testing, when clinically indicated following moderate, severe, 
or recurrent IARs suggestive of hypersensitivity; and (2) circulating immune complex detection when 
clinically indicated by symptoms suggestive of immune complex disease. 
Inhibitory antibody (activity and uptake) will be assessed when clinically indicated (e.g., requirement for 
new invasive ventilator use, plateau or decline in response in the presence of adequate dosing). 
EXPLORATORY: 
The effect of alglucosidase alfa treatment on urinary oligosaccharides (Hex4) will be evaluated. 
RESEARCH PURPOSES ONLY: 
The potential effect of CRIM status and GAA mutation on efficacy outcomes will be analyzed. 
STATISTICAL METHODS: 
The statistical analysis of all growth and development parameters and other efficacy outcomes and safety 
measurements will be conducted on all patients who receive alglucosidase alfa.  All data collected in this 
study will be documented using summary tables, figures and patient data listings.  For categorical 
variables, frequencies and percentages will be presented.  For continuous variables, descriptive statistics 
(n, mean, median, standard deviation, minimum, and maximum) will be presented.   
Analyses will be performed using the SAS® statistical software system.  Detailed descriptions of the 
analyses will be provided in a Statistical Analysis Plan. 
STATISTICAL METHODS: 
The statistical analysis of all growth and development parameters and other efficacy outcomes and safety 
measurements will be conducted on all patients who receive alglucosidase alfa.  All data collected in this 
study will be documented using summary tables, figures and patient data listings.  For categorical 
 
(electronic 
 
 
 
2.0)

Alglucosidase Alfa 
5 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
NAME OF COMPANY 
Genzyme Corporation, a Sanofi Company 
500 Kendall Street 
Cambridge, MA  02142 
NAME OF FINISHED PRODUCT 
Myozyme® / Lumizyme® (alglucosidase alfa) 
NAME OF ACTIVE INGREDIENT 
alglucosidase alfa 
SUMMARY TABLE 
Referring to Part …… 
of the Dossier: 
Volume:                       
Page:                            
Reference:                   
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
variables, frequencies and percentages will be presented.  For continuous variables, descriptive statistics 
(n, mean, median, standard deviation, minimum, and maximum) will be presented.   
Analyses will be performed using the SAS® statistical software system.  Detailed descriptions of the 
analyses will be provided in a Statistical Analysis Plan. 
Baseline demographic and background variables will be summarized for the patients enrolled in the 
study using descriptive statistics. 
In addition to descriptive statistics by visit, longitudinal repeated measures modeling will be used to 
analyze the trends in key growth and development parameters over time. 
Analyses of key variables may be stratified by relevant baseline factors. 
Besides standard safety analyses of the incidence of AEs and SAEs, additional analyses will be carried 
out to examine the trends in incidence and prevalence of AEs, SAEs and other relevant safety parameters 
over time.  Key safety analyses will be also carried out by gender. 
EXPLORATORY: 
The effect of alglucosidase alfa treatment on urinary oligosaccharides (Hex4) will be evaluated. 
RESEARCH PURPOSES ONLY: 
The potential effect of CRIM status and GAA mutation on efficacy outcomes will be analyzed. 
 
(electronic 
 
 
 
2.0)

Alglucosidase Alfa 
6 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
2. TABLE OF CONTENTS 
1. 
SYNOPSIS.......................................................................................................................2 
2. 
TABLE OF CONTENTS ...............................................................................................6 
3. 
ABBREVIATIONS AND TERMS................................................................................9 
4. 
INTRODUCTION.........................................................................................................11 
4.1 
Summary of Potential Risks ...............................................................................13 
4.2 
Summary of Potential Benefits...........................................................................13 
5. 
STUDY OBJECTIVES.................................................................................................13 
6. 
INVESTIGATIONAL PLAN ......................................................................................14 
6.1 
Study Design.......................................................................................................14 
7. 
PATIENT POPULATION AND SELECTION.........................................................15 
7.1 
Inclusion Criteria ................................................................................................15 
7.2 
Exclusion Criteria ...............................................................................................15 
7.3 
Patient Withdrawal .............................................................................................15 
7.4 
Study or Site Termination...................................................................................16 
8. 
TREATMENTS.............................................................................................................17 
8.1 
Treatments Administered....................................................................................17 
8.2 
Prior and Concomitant Medications/Therapies ..................................................18 
8.3 
Treatment Compliance........................................................................................18 
9. 
EFFICACY, SAFETY, AND EXPLORATORY VARIABLES...............................18 
9.1 
Schedule of Assessments....................................................................................18 
9.1.1 
Baseline.............................................................................................21 
9.1.2 
First Infusion (Day 0) and Every Other Week..................................21 
9.1.3 
Every 3 Months (Months 3, 6, 9, 12, 15, 18, 21, 24, etc.)................22 
9.1.4 
Every 6 Months (Months 6, 12, 18, 24, etc.)....................................22 
9.1.5 
Every 12 Months (Or on Withdrawal from the Study).....................22 
9.2 
Efficacy and Additional Exploratory Efficacy Assessments..............................22 
9.2.1 
Physical Growth................................................................................22 
9.2.2 
Cognitive Function and Motor Development Assessments..............23 
9.2.2.1 
Bayley Scales of Infant and Toddler 
Development (Bayley-III) ...........................................23 
9.2.2.2 
Leiter International Performance Scale-Revised 
(Leiter-R) & Leiter International Performance 
Scale-Updated (Leiter-3) .............................................24 
9.2.2.3 
Gross Motor Function Measure (GMFM-88)..............25 
9.2.2.4 
Pompe Pediatric Evaluation of Disability 
Inventory (Pompe PEDI).............................................26 
9.2.3 
Urinary Oligosaccharide (Hex4) Levels...........................................26 
9.2.4 
CRIM Status .....................................................................................26 
9.2.5 
GAA Mutation Analysis...................................................................27 
9.3 
Safety Assessments.............................................................................................27 
9.3.1 
Neuroimaging Assessment ...............................................................27 
9.3.2 
Hearing Testing.................................................................................27 
9.3.3 
Visual Screening...............................................................................28 
9.3.4 
Electrocardiogram.............................................................................29 
9.3.5 
Safety Laboratory Assessments........................................................29 
 
(electronic 
 
 
 
2.0)

Alglucosidase Alfa 
7 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
9.3.6 
Vital Signs.........................................................................................30 
9.3.7 
Immunologic Testing........................................................................30 
9.3.7.1 
Routine Anti-rhGAA IgG Antibody Testing...............30 
9.3.7.2 
Inhibitory Antibody Testing ........................................30 
9.3.7.3 
Additional Testing for Moderate or Severe or 
Recurrent IARs............................................................30 
9.3.7.4 
Circulating Immune Complexes..................................32 
9.4 
Other Assessments..............................................................................................32 
9.4.1 
Concomitant Medications/Therapies ................................................32 
9.5 
Adverse Events ...................................................................................................32 
9.5.1 
Serious Adverse Events ....................................................................33 
9.5.1.1 
Autopsy and Post-Mortem Biopsy...............................34 
9.5.2 
Infusion-Associated Reactions .........................................................34 
9.5.3 
Adverse Experience and Serious Adverse Experience 
Reporting ..........................................................................................34 
10. DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT.........36 
10.1 
Recording of Data...............................................................................................36 
10.2 
Data Quality Assurance ......................................................................................36 
10.3 
Data Management...............................................................................................36 
11. STATISTICAL METHODS AND PLANNED ANALYSES....................................36 
12. SPECIAL REQUIREMENTS AND PROCEDURES...............................................38 
12.1 
Data Safety Monitoring Board (DSMB).............................................................38 
12.2 
Allergic Reaction Review Board........................................................................39 
12.3 
Institutional and Ethical Review.........................................................................39 
12.4 
Changes to the Conduct of the Study or Protocol...............................................39 
12.5 
Investigator's Responsibilities ............................................................................39 
12.5.1 
Patient Informed Consent .................................................................39 
12.5.2 
Case Report Forms............................................................................40 
12.5.3 
Record Retention ..............................................................................40 
12.5.4 
Monitoring ........................................................................................40 
12.5.5 
Warnings, Precautions, Contraindications........................................40 
12.5.6 
Disclosure of Data ............................................................................41 
13. REFERENCES..............................................................................................................42 
 
(electronic 
 
 
 
2.0)

Alglucosidase Alfa 
8 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
LIST OF IN-TEXT TABLES 
Table 9-1 
Schedule of Assessments....................................................................................19 
Table 9-2 
Hearing Assessments Appropriate for Age ........................................................28 
 
 
(electronic 
 
 
 
2.0)

Alglucosidase Alfa 
9 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
3. ABBREVIATIONS AND TERMS 
 
AE 
Adverse event 
AM Battery 
Attention and Memory Battery 
ARRB 
Allergic Reaction Review Board 
BAB 
Butyl-p-aminobenzoate 
BAER 
Brainstem-auditory evoked response 
Bayley-III 
Bayley Scales of Infant and Toddler Development 
BUN 
Blood urea nitrogen 
°C 
Degrees centigrade 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations (USA) 
CK 
Creatine kinase 
CK-MB 
Creatine kinase muscle, brain isoform 
CRF 
Case report form 
CRIM 
Cross-reacting immunologic material 
CS 
Clinically significant 
CSSF 
Clinical Supply Shipment Form 
DSMB 
Data Safety Monitoring Board 
DUMC 
Duke University Medical Center 
EC 
European Community 
ECG 
Electrocardiogram 
EMEA 
European Medicines Agency 
ERT 
Enzyme replacement therapy 
EU 
European Union 
FDA 
Food and Drug Administration 
FVC 
Forced Vital Capacity 
GAA 
Acid α-glucosidase 
GCP 
Good Clinical Practice 
Glc4 (Hex4) 
Glcα1-6Glcα1-4Glcα1-4Glc (a tetraglucose oligomer) 
GMFM-88 
Gross Motor Function Measure-88 
H 
Out of range high (on laboratory reports) 
HPLC 
High pressure liquid chromatography 
IAR 
Infusion-associated reaction 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IQ 
Intelligence quotient 
IRB 
Institutional Review Board 
kg 
Kilogram 
L 
Out of range low (on laboratory reports) 
 
(electronic 
 
 
 
2.0)

Alglucosidase Alfa 
10 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
Leiter-3 
Leiter-R 
Leiter International Performance Scale- 3rd Edition 
Leiter International Performance Scale–Revised 
LVH 
Left ventricular hypertrophy 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MRI 
Magnetic resonance imaging 
MS 
Mass spectrometry 
NCS 
Not clinically significant 
OAE 
Oto-acoustic emission 
PEDI 
Pediatric evaluation of disability inventory 
PI 
Principal Investigator 
rhGAA 
Recombinant human acid α-glucosidase 
RVH 
Right ventricular hypertrophy 
SAE 
Serious adverse event 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SM 
Study Manual 
US/USA 
United States of America 
UV 
Ultraviolet 
VR Battery 
Visualization and Reasoning Battery 
WHO 
World Health Organization 
 
(electronic 
 
 
 
2.0)

Alglucosidase Alfa 
11 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
4. INTRODUCTION 
Pompe disease is a rare autosomal recessive metabolic muscle disease caused by the deficiency 
of acid α glucosidase (GAA), an enzyme that degrades lysosomal glycogen. As opposed to the 
exclusively cytoplasmic accumulation of glycogen that occurs in other glycogen storage 
disorders, Pompe disease is characterized by organelle bound (lysosomal) and extra-lysosomal 
accumulation of glycogen in many body tissues, ultimately leading to multisystemic pathology. 
Historically, Pompe disease has been arbitrarily classified into different subtypes based on the 
age at onset of symptoms, extent of organ involvement, and rate of progression to death.  
Essentially, there is a broad spectrum of disease ranging from a rapidly progressive form 
(infantile-onset) to a more slowly progressive form (late-onset) with considerable variability and 
overlap existing between these extremes (Chen, 2000, Mol Med Today; Hirschhorn, 2001, The 
Metabolic and Molecular Bases of Inherited Disease; van den Hout, 2003, Pediatrics).  It is 
important to note that all presentations of Pompe disease share a common underlying pathology; 
i.e., deficiency of GAA with subsequent accumulation of glycogen. 
At the most rapidly progressive end of the disease spectrum are patients with the infantile-onset 
form of Pompe disease.  These patients typically present with symptoms within the first 
12 months of life.  A massive deposition of glycogen in the heart and skeletal muscle results in 
rapidly progressive cardiomyopathy and generalized muscle weakness and hypotonia.  
Moreover, motor development is often completely arrested, or if motor milestones are achieved, 
they are subsequently lost.  Death from cardiac and/or respiratory failure generally occurs before 
most patients reach 1 year of age (Hirschhorn, 2001, The Metabolic and Molecular Bases of 
Inherited Disease).  Patients presenting with this typical disease course have been described in 
the literature as having ‘classical’ infantile-onset Pompe disease.  A subset of patients with 
infantile-onset Pompe disease that survive beyond 1 year has been described by Slonim and 
colleagues (Slonim, 2000, J Pediatr).  The clinical course of disease in these patients is 
characterized by a slower progression of cardiomyopathy and longer survival, with patients 
generally developing respiratory failure between 1 and 2 years of age.  Although some patients 
die before 1 year of age, others may survive beyond 2 years. 
The late-onset form of Pompe disease progresses less rapidly than the infantile-onset form.  
Symptoms appear during childhood or as late as the sixth decade of life.  Patients present with 
progressive myopathy, predominantly of the proximal muscles in the pelvic and shoulder girdles, 
and a variable progression of respiratory involvement.  Typically these patients develop minimal 
or no cardiomyopathy (Chen, 2000, Mol Med Today; Laforêt, 2000, Neurology; Hirschhorn, 
2001, The Metabolic and Molecular Bases of Inherited Disease).  The course of late-onset 
Pompe disease is less predictable than the infantile form, with some patients experiencing a rapid 
deterioration in skeletal and respiratory muscle function leading to loss of ambulation and 
 
(electronic 
 
 
 
2.0)

Alglucosidase Alfa 
12 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
respiratory failure, others progressing less rapidly, and yet others with dissociation in the 
progression of skeletal and respiratory muscle involvement (Laforêt, 2000, Neurology).  
Eventually, most patients become wheelchair-bound, require ventilator support and ultimately 
succumb to respiratory failure (Chen, 2000, Mol Med Today; Hirschhorn, 2001, The Metabolic 
and Molecular Bases of Inherited Disease). 
Genzyme Corporation has been involved in development of enzyme replacement therapy (ERT) 
for the treatment of Pompe disease since 1998.  Initially, the clinical development program 
focused primarily on demonstration of safety and efficacy in patients with the infantile-onset 
form of Pompe disease.  Based on the findings of the clinical trials, Myozyme received 
marketing approval in the United States (US), European Union (EU) and Canada in 2006 for 
long-term ERT in patients with a confirmed diagnosis of Pompe disease while research to 
establish the benefit of alglucosidase alfa in late-onset Pompe disease continued.  Lumizyme 
received marketing approval in the United States (US) in 2010 for use in late-onset Pompe 
disease patients 8 years of age and older. In 2014, the indication was expanded for Lumizyme to 
include all patients with a confirmed diagnosis of Pompe disease, irrespective of age or 
phenotype. The recommended dosage regimen of alglucosidase alfa is 20 mg/kg of body weight 
administered once every 2 weeks as an intravenous solution.  A brief overview of results of ERT 
in Pompe disease is provided below. 
In the infantile-onset patients, alglucosidase alfa markedly extended survival as compared to an 
untreated historical cohort (Kishnani, 2007, Neurology).  ERT with alglucosidase alfa also 
reversed indices of cardiomyopathy and improved cardiac function in the vast majority of 
patients.  Moreover, consistent gains in motor function were observed, with a subset of patients 
achieving independent ambulation.  These findings contrast sharply to the severe and unremitting 
clinical deterioration observed in virtually all untreated patients with infantile-onset Pompe 
disease (van den Hout, 2003, Pediatrics). 
In patients with late-onset Pompe disease, alglucosidase alfa was associated with maintenance or 
improvements in pulmonary function, muscle strength, gross motor function, and functional 
status/disability.  In a study of 5 pediatric patients with late-onset Pompe disease, improvement 
in Forced Vital Capacity (FVC) and Six Minute Walk Test (6MWT) results were observed after 
26 weeks of treatment with alglucosidase alfa in 3 patients.  While all 5 patients were 
symptomatic at Baseline, they were still ambulatory and ventilator-free during daytime hours, 
suggesting significant residual muscle function prior to initiation of alglucosidase alfa.  It is 
likely that such preservation of muscle function contributed to their response to treatment.  In 
contrast, published data on the use of ERT in patients with advanced late-onset Pompe disease 
have reported major clinical improvements in a patient after years rather than weeks of treatment 
(Winkel, 2004, Ann Neurol).  Given the severity of illness in these patients and the progressive 
 
(electronic 
 
 
 
2.0)

Alglucosidase Alfa 
13 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
nature of late-onset Pompe disease (Laforêt, 2000, Neurology), lack of deterioration in treated 
patients could represent clinical stabilization of the disease by ERT with alglucosidase alfa. 
4.1 
Summary of Potential Risks 
Identified safety risks of alglucosidase alfa treatment include development of infusion-associated 
reactions (IARs) including hypersensitivity and life-threatening anaphylactic shock and/or 
cardiac arrest; immune-mediated reactions, immunologic response and acute cardiorespiratory 
failure associated with fluid overload.  Patients in this study will be closely monitored for IARs 
and other adverse reactions.  As with all ongoing clinical studies of alglucosidase alfa, an 
independent Data Safety Monitoring Board (DSMB) appointed by Genzyme will review safety 
data on an ad hoc basis and an independent Allergic Reaction Review Board (ARRB) appointed 
by Genzyme Corporation will also be consulted, when necessary, to review information and 
provide treatment recommendations for IARs.   
For further details concerning warnings, precautions, and contraindications, the Investigator 
should refer to the appropriate section of the Investigator’s Brochure (IB). 
4.2 
Summary of Potential Benefits 
Alglucosidase alfa is a lysosomal glycogen-specific enzyme indicated for patients with Pompe 
disease (GAA deficiency) and is an element of the standard of care.  Enzyme replacement 
therapy with alglucosidase alfa has shown positive effects on survival, invasive ventilator-free 
survival, and motor development in patients with infantile-onset Pompe disease.   
The treatment administered and assessments performed during this study are not expected to 
provide a direct benefit to the individual patient beyond the standard of care, other than to 
evaluate the long-term growth and development outcomes in patients with infantile-onset Pompe 
disease who are receiving ERT with alglucosidase alfa. The data obtained in this study are 
expected to benefit the population of patients with Pompe disease as a whole through collection 
of long-term safety data. 
 
5. STUDY OBJECTIVES 
The overall objective is to evaluate long-term growth and development of patients with infantile-
onset Pompe disease who begin treatment with alglucosidase alfa before 1 year of age.  Patients 
will be followed for a 10-year period.  An additional objective is to collect long-term safety data 
on patients with infantile-onset Pompe disease.  As an exploratory objective, the effect of 
alglucosidase alfa treatment on urinary oligosaccharides (Hex4) will be evaluated.  For research 
purposes only, cross-reacting immunologic material (CRIM) status and GAA mutation analysis 
will be evaluated. 
 
(electronic 
 
 
 
2.0)

Alglucosidase Alfa 
14 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
6. INVESTIGATIONAL PLAN 
6.1 Study Design 
This is a multicenter study of patients with infantile-onset Pompe disease who begin 
alglucosidase alfa treatment prior to 1 year of age.  Patients with a confirmed diagnosis of Pompe 
disease who begin alglucosidase alfa treatment prior to their first birthday will be followed in 
this study for 10 years.  The number of patients followed in this study will not be limited 
prospectively. 
The patient’s legal guardian(s) must sign the informed consent form prior to performance of any 
of the study assessments outlined in Table 9-1. 
An independent Data Safety Monitoring Board (DSMB) will review safety information on an ad 
hoc basis as outlined in the DSMB Charter, which is maintained separately from the study 
protocol. 
An independent Allergic Reaction Review Board (ARRB) will be consulted on an ad hoc basis 
as outlined in the ARRB Charter, which is also maintained separately from this protocol. 
Efficacy will be evaluated in terms of physical growth, as measured by changes in recumbent 
length/height, weight and head circumference; motor development and function, as measured by 
changes in the motor subscale of the Bayley Scales of Infant and Toddler Development (Bayley-
III) (up to 42 months of age), Gross Motor Function Measure (GMFM-88) and Pompe Pediatric 
Evaluation of Disability Inventory (Pompe PEDI); and cognitive development, as measured by 
changes in the cognitive and language subscales of the Bayley Scales of Infant and Toddler 
Development (Bayley-III) (up to 42 months of age), change in the Brief IQ score of the Leiter 
International Performance Scale – Revised (Leiter-R) and/or the change in the Nonverbal IQ 
score of the Leiter International Performance Scale – 3rd Edition (Leiter-3)  (starting at the final 
assessment of the Bayley-III before 42 months of age).  As an exploratory objective, the effect of 
alglucosidase alfa treatment on urinary oligosaccharides (Hex4) will be evaluated.  For research 
purposes only, cross-reacting immunologic material (CRIM) status and GAA mutation will be 
evaluated. 
For patients treated with alglucosidase alfa prior to age 1 (prior to study entry), available 
retrospective growth and development data will be collected.  Parameters for retrospective data 
collection will include available standard-of-care growth (height, weight, head circumference) 
and motor milestone information (e.g. head support, sitting, standing, and walking ability) from 
the time of treatment initiation. 
Safety will be evaluated in terms of AE monitoring, laboratory tests (clinical chemistry, 
hematology, and urinalysis), anti-rhGAA antibody (IgG) formation, neuroimaging (at the 
discretion of the Investigator), vital signs (blood pressure, heart rate, respiratory rate, and 
 
(electronic 
 
 
 
2.0)

Alglucosidase Alfa 
15 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
temperature), physical examinations, electrocardiograms (ECGs), hearing testing and visual 
screening. 
Additional safety evaluations will include the assessment of: (1) IgE, serum tryptase, 
complement activation and skin testing, when clinically indicated following moderate, severe, or 
recurrent IARs suggestive of hypersensitivity; and (2) circulating immune complex detection 
when clinically indicated by symptoms suggestive of immune complex disease.  Inhibitory 
antibody activity and uptake will be assessed when clinically indicated (e.g., requirement for new 
invasive ventilator use, plateau or decline in response in the presence of adequate dosing). 
7. PATIENT POPULATION AND SELECTION 
Male and female patients with Pompe disease may participate. 
 
7.1 Inclusion Criteria 
Patients must meet the following criteria to be enrolled in this study: 
1. The patient’s legal guardian(s) must provide written informed consent prior to study 
assessments being performed; 
2. The patient must have a confirmed diagnosis of Pompe disease as determined by 
deficient endogenous GAA activity or GAA mutation analysis; and 
3. The patient must be <1 year of age at time of study enrollment (and receive  
alglucosidase alfa treatment before 1 year of age), or the patient must be between 1 
year and 24 months of age and must have initiated  alglucosidase alfa treatment prior 
to turning 1 year of age. 
7.2 Exclusion Criteria 
A patient will be excluded from this study if the following criterion is met: 
1. The patient is participating in another clinical study using alglucosidase alfa or any 
investigational therapy. 
7.3 Patient Withdrawal 
A patient’s legal guardian(s) is free to withdraw authorization and discontinue participation in 
the study at any time, and without prejudice to further alternate treatment.  If a patient’s legal 
guardian(s) decides to discontinue participation in the study, the Investigator should immediately 
contact the patient’s legal guardian in order to obtain information about the reason(s) for 
discontinuation.  The Investigator should collect information pertaining to current AEs and 
follow-up ongoing AEs.  All patients should have final clinical assessments conducted. 
All AEs ongoing at the time of withdrawal or study termination require a 30-day follow up.  The 
Investigator will be asked to follow all SAEs that were ongoing at the time of withdrawal or 
study completion until resolution, until follow-up is deemed no longer medically necessary or 
 
(electronic 
 
 
 
2.0)

Alglucosidase Alfa 
16 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
until the patient is lost to follow-up.  The Investigator will provide an explanation on the case 
report form (CRF) describing the reason for discontinuation. 
In the event that a patient dies, permission will be sought (through a separate informed consent 
form) from the patient’s legal guardian(s) for a research autopsy or post-mortem research biopsy.  
Samples collected from this procedure will be used for research purposes only and data will not 
be provided to the Investigator or be included in any study analyses.  Refer to the Study Manual 
(SM) for research autopsy and post-mortem research biopsy procedural guidelines. 
A patient'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: 
• The patient and/or patient’s legal guardian(s) is uncooperative, including failure to appear 
at study visits. 
• The patient was erroneously included in the study. 
• The patient develops an exclusion criterion or suffers an unmanageable AE. 
• The study is terminated by the Sponsor. 
• The patient and/or patient’s legal guardian(s) refuses alglucosidase alfa administration. 
• Participation in an investigational study without the prior authorization of Genzyme. 
To facilitate long-term data collection, patients will be encouraged to enroll in the Pompe 
Disease Registry via their treating physician after study completion or discontinuation. 
7.4 Study or Site Termination 
If the Sponsor, an Investigator, a clinical monitor, or national regulatory authority official 
discover conditions during the study that indicate the study or a study site should be terminated, 
this action may be taken after appropriate consultation between the Sponsor, the Investigator, the 
clinical monitor, and the DSMB, as appropriate.  Conditions that may warrant termination of the 
study or a 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 Genzyme Corporation to end the study. 
• Failure of the Investigator to comply with pertinent regulatory authorities. 
• Submission of knowingly false information from the research facility to the Sponsor, the 
clinical monitor, or regulatory authorities. 
• Insufficient adherence to protocol requirements. 
Study termination and follow-up will be performed in compliance with the conditions set forth in 
21 CFR 312. 
 
 
(electronic 
 
 
 
2.0)

Alglucosidase Alfa 
17 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
8. TREATMENTS 
 
8.1 Treatments Administered 
Alglucosidase alfa will be administered at 20 mg/kg body weight as prescribed by the treating 
physician every 2 weeks as an intravenous infusion.  If clinically feasible, all patients will 
continue at the same dose throughout the study.  Any modification to the dose and/or frequency 
of dosing is not permitted unless it is due to disease progression or to an AE, in which case it is 
not a protocol deviation, but the Investigator must consult with the Sponsor’s Medical Monitor 
and Global Safety Officer in the event of a dose change.  The dosing change and the reasons for 
it will be documented on the appropriate CRFs. 
It is recommended that the reconstitution and administration instructions in the current 
prescribing information be followed. 
Patients who meet specific criteria may have the option for home infusions.  Because of the 
possibility of anaphylactic reactions, personnel competent in recognizing and treating adverse 
reactions (including anaphylactic reactions) should be readily available throughout the home 
infusion.  The following criteria must be documented in the patient’s medical record: 
o The patient must be clinically stable with no history of moderate or severe IARs within 6 
months prior to planned transition to home infusion. 
o The patient must have no ongoing SAEs that, in the opinion of the Investigator, may 
impact the patient’s ability to tolerate infusion. 
o The home infusion agency staff must be trained by the Investigator prior to beginning 
home infusions.  Any new staff member must be trained by the Investigator prior to 
beginning home infusions. 
o The home infusion agency staff must have access to and be trained on proper safety 
equipment, including but not limited to cardiopulmonary resuscitation equipment. 
o If recurrent IARs or hypersensitivity/anaphylactic reactions occur, the Investigator should 
assess whether or not it is safe for the patient to continue to be treated via home infusion. 
Genzyme should be notified about all IARs and consulted (as needed) if the patient 
experiences IARs suggestive of hypersensitivity reactions (refer to Section 9.5.2). 
o Home Infusion Agency must keep source documentation of the infusion, including 
documentation of any AEs.  Home Infusion Agency must be amenable to providing 
specific source documentation to Genzyme and agree to be monitored.  The Principal 
Investigator is still responsible for all study procedures and patient’s safety even when 
delegating infusion responsibilities to the home care company. 
The Principal Investigator (PI) is responsible for approving a patient’s initiation with home 
infusions and is ultimately responsible for the safety of the patient during this clinical study.  
Refer to SM and Home Infusion Manual for further details regarding home infusions. 
 
(electronic 
 
 
 
2.0)

Alglucosidase Alfa 
18 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
8.2 Prior and Concomitant Medications/Therapies 
From the time informed consent is obtained through study completion, all medications taken by 
the patient for AEs, pre-infusion medications and medications for long-term disease management 
will be recorded in the Concomitant Medication CRF.  Concomitant therapies and assistive 
devices will be recorded in the Concomitant Therapies CRF. 
8.3 Treatment Compliance 
The patient’s compliance with the treatment regimen will be monitored in terms of the patient 
receiving the alglucosidase alfa infusion on a regular basis.  Missed or incomplete infusions will 
be clearly documented and considered in the statistical analyses. 
9. EFFICACY, SAFETY, AND EXPLORATORY VARIABLES 
 
9.1 Schedule of Assessments 
The study will be conducted in conjunction with the patient’s standard of care as outlined in the 
following sections.  Table 9-1 summarizes the Schedule of Assessments at each visit period for 
patients enrolled into this study.  With the exception of the Baseline, Day 0 and biweekly study 
assessments, all other assessments have a window of +/- 60 days.  Any assessments conducted as 
standard of care 30 days before start of first study infusion may be utilized for baseline 
assessment provided all required information is captured.  Infusions received after signing of the 
informed consent form and before completion of baseline assessments will be captured as a 
Concomitant Medication on CRF.  Details of the assessments are provided in the SM. 
 
(electronic 
 
 
 
2.0)

Alglucosidase alfa 
19 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL: 02 DECEMBER 2014 
Table 9-1 
Schedule of Assessments 
 
 
Baseline  
(Prior to Initiation of 
Study Infusion) 
First Infusion (Day 0) 
and Every Other 
Week 
Every 3 
Months 
Every 6 Months 
Every 12 Months 
(or on withdrawal) 
Informed Consent1 
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
Demography 
X 
 
 
 
 
Medical/Surgical History2 
X 
 
 
 
 
Recumbent length/height, weight 
and head circumference3 
X 
 
AGE < 3 
YEARS 
AGES 3 TO 5 
YEARS 
AGE ≥ 5 YEARS 
Bayley-III4,5, 6 
X 
 
 
AGES 1 MONTH 
to 42 MONTHS 
 
Leiter-R or 
updated Leiter-3 Scale6 
  
 
 
 
FROM FINAL Bayley-III 
assessment <42 MONTHS OF 
AGE 
GMFM-885 
X 
 
 
AGE < 5 YEARS 
AGE ≥ 5 YEARS 
Pompe PEDI5 
X 
 
 
AGE < 5 YEARS 
AGE ≥ 5 YEARS 
Oligosaccharide (Hex4) levels in 
urine7 
X 
 
 
TO STUDY 
MONTH 24 
FROM STUDY MONTH 24  
Skin Biopsy for CRIM status 
assay8 
X 
 
 
 
 
GAA mutation analysis9 
X 
 
 
 
 
Chemistry, hematology and 
urinalysis 
X 
 
 
 
X 
Serum IgG collection10 
X (collected just prior 
to first study infusion) 
 
TO STUDY 
MONTH 24 
 
FROM STUDY MONTH 24 
Neuroimaging (at the discretion of 
the Investigator)11 
X 
 
 
 
X 
Vital Signs12 
X 
X 
 
 
 
Physical examination 
X 
 
 
 
X 
ECG 
X 
 
 
 
X 
Audiometry Exam 
X 
 
 
 
X 
Visual Assessment 
X 
 
 
 
X 
Alglucosidase alfa Infusion13 
 
ONGOING ADMINISTRATION 
Adverse Event/Concomitant 
Medications/Therapies 
←  CONTINUOUS MONITORING → 
 
(electronic 
 
 
2.0)

Alglucosidase alfa 
20 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL: 02 DECEMBER 2014 
The Schedule of Study Assessments will be repeated in 12 month modules (e.g. Year 1, Year 2, etc.).  With the exception of the Baseline, Day 0 and biweekly 
study assessments, all other assessments have a window of +/- 60 days. 
1 Informed consent must be obtained prior to enrollment into the study. 
2 Available retrospective growth and development data including motor milestone information (e.g., head support, sitting, standing and walking ability) for those 
patients treated with  alglucosidase alfa prior to study entry will be collected to summarize clinical status information for each patient at the time of initiation of 
treatment with  alglucosidase alfa to allow for assessment of changes in growth and development over time with treatment with  alglucosidase alfa for all 
patients enrolled. 
3 At each time point, growth measurements (recumbent length or height, weight and head circumference) will be measured 3 times in a row and averaged.  All 
measurements should be recorded to the nearest tenth of a centimeter.  The measurement of recumbent length or height, weight and head circumference should 
be performed by an individual, who does not have access to the records of the patient’s earlier measurements in the study and, as far as possible, by the same 
individual at each patient visit.   
4 Bayley-III is to be discontinued when the patient reaches 42 months of age.  The Bayley-III will be administered to patients from 1 month of age until the 
maximum score on each of the 3 administered scales has been obtained.  Once the maximum score for a scale has been achieved, only the remaining scales will 
be administered. 
5 Additional anti-alglucosidase alfa IgG antibody testing should be performed upon determination of any notable deterioration in a patient’s motor function. 
6 Modified Leiter-R Scale or updated Leiter-3 Scale assessment is to be performed at the last assessment of the Bayley-III Cognitive and Language Scales prior 
to the patient reaching 42 months of age and annually thereafter until the patient reaches the end of the follow up period. If previous assessments have been 
performed using Leiter-R and switch to Leiter-3 Scale is planned, then both assessments need to be performed at the same time of the initial administration of 
the Leiter-3, in order to create a baseline. The dates of the two tests should be recorded appropriately in the CRFs and the scores recorded on the appropriate 
test score sheets. 
7 Oligosaccharide (Hex4) testing will be performed every 6 months until the 24th month and then yearly.   
8 Genzyme Corporation or their designee will perform the CRIM analysis in skin biopsies.  CRIM will be conducted only if written results are not available. 
9 GAA mutation analysis is to be conducted only if written results are not available.   
10 To be collected every 3 months up to Study Month 24 (3, 6, 9, 12, 15, 18, 21 and 24) and annually thereafter.  Additional testing should be performed upon 
determination of any notable deterioration in a patient’s motor function.  Serum IgG samples should always be collected pre-infusion at each time point. 
11 Serial brain magnetic resonance imaging (MRI) will be performed at the discretion of the Investigator. 
12 In addition to a Baseline vital sign measurement, vital signs will be monitored prior to the start of each infusion, at the end of each infusion, and upon the 
occurrence of any IARs. 
13 Prior to each infusion, the patient should be assessed by the PI or appropriate designee to determine if the patient is free of acute illness and clinically stable to 
receive the infusion. 
(electronic 
 
 
2.0)

Aalglucosidase Alfa 
21 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
9.1.1 Baseline 
The following procedures will be performed. 
• Informed consent 
• Inclusion/exclusion criteria 
• Demography 
• Medical/Surgical history (including available major motor milestone information (e.g., head 
support, sitting, standing and walking ability) 
• Recumbent length/height, weight and head circumference 
• Bayley-III 
• GMFM-88 
• Pompe PEDI 
• Oligosaccharide (Hex4) levels in urine 
• Skin biopsy for CRIM assay 
• GAA mutation analysis 
• Chemistry, hematology and urinalysis 
• Serum IgG collection (collected just prior to first study infusion) 
• Neuroimaging (at the discretion of the Investigator) 
• Vital signs 
• Physical examination 
• ECG 
• Audiometry exam 
• Visual assessment 
• Adverse event/concomitant medications/therapies 
Upon confirmation that the patient meets all eligibility criteria and signing of the informed 
consent form, eligible patients will then be assigned a Patient Identification number. 
9.1.2 First Infusion (Day 0) and Every Other Week 
Following the Baseline procedures, 
• Alglucosidase alfa infusions are to be administered per the Investigator.  Prior to each 
infusion, the patient should be assessed by the PI or appropriate designee to determine if the 
patient is free of acute illness and clinically stable to receive the infusion. 
• Vital signs monitored prior to the start of each infusion, at the end of each infusion and upon 
the occurrence of any IARs 
• Continuous adverse event/concomitant medications/therapies monitoring 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
22 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
9.1.3 Every 3 Months (Months 3, 6, 9, 12, 15, 18, 21, 24, etc.) 
The following procedures will be performed: 
• Recumbent length/height, weight and head circumference (up to 3 years of age) 
• Serum IgG collection (up to Study Month 24) 
9.1.4 Every 6 Months (Months 6, 12, 18, 24, etc.) 
The following procedures will be performed: 
• Recumbent length/height, weight and head circumference (ages 3 to 5 years) 
• Bayley-III (to be discontinued when the patient reaches 42 months of age) 
• GMFM-88 (performed every 6 months until 5 years of age, at which point assessment will be 
performed yearly) 
• Pompe PEDI (performed every 6 months until 5 years of age, at which point assessment will 
be performed yearly) 
• Oligosaccharide (Hex4) levels in urine (performed every 6 months up to Study Month 24, 
after which point assessment will be performed yearly) 
9.1.5 Every 12 Months (Or on Withdrawal from the Study) 
The following procedures will be performed: 
• Recumbent length/height, weight and head circumference (yearly once patient reaches age ≥ 
5 years) 
• Leiter-R Brief IQ scale and/or updated Leiter-3 Nonverbal IQ scale (to begin concurrent with 
the last assessment of the Bayley-III Cognitive and Language Scales prior to the patient 
reaching 42 months of age) 
• GMFM-88 (yearly once patient reaches age ≥ 5 years) 
• Pompe PEDI (yearly once patient reaches age ≥ 5 years) 
• Oligosaccharide (Hex4) levels in urine (yearly after Study Month 24) 
• Chemistry, hematology and urinalysis 
• Serum IgG collection (after Month 24) 
• Neuroimaging (at the discretion of the Investigator) 
• Physical examination 
• ECG 
• Audiometry exam 
• Visual assessment 
• Adverse event/concomitant medications/therapies 
9.2 Efficacy and Additional Exploratory Efficacy Assessments 
9.2.1 Physical Growth 
Physical growth will be assessed at the times specified in Table 9-1. 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
23 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
Recumbent length will be measured in young children (generally those less than 3 years of age) 
using a firm box with an inflexible board that accommodates the head on one side and has a 
movable slab on the other side that can be pressed against the soles of the feet with the legs fully 
extended.  Standing height will be measured in older children using a stadiometer that has been 
calibrated immediately prior to measurement of height if it has not been calibrated in the 
previous 4 hours.  Weight will be measured with the patient unclothed.  Head circumference will 
be measured using a measuring tape that is placed over the mid forehead and that is extended 
circumferentially to include the most prominent portion of the occiput so that the greatest volume 
of the cranium is measured.  Head circumference will be measured beyond 2 years of age to rule 
out the potential concern of glycogen deposition in the central nervous system with resultant 
macroencephaly. 
Length/height, weight, and head circumference will each be performed 3 times in a row and the 
average of these 3 measurements (refer to the SM for additional instructions) will be entered in 
the CRF for the appropriate measurement.  All measurements should be recorded to the nearest 
tenth of a centimeter.  To the extent possible, the individual performing the measurements of 
recumbent length, height, weight and head circumference should not have access to records of 
the patient’s earlier measurements.  As far as possible, these measurements will be performed by 
the same individual at each patient visit. 
9.2.2 Cognitive Function and Motor Development Assessments 
9.2.2.1 Bayley Scales of Infant and Toddler Development (Bayley-III) 
The Bayley-III (Bayley, 2005, Bayley Scales of Infant and Toddler Development, Third Edition) 
will be administered by a trained clinician to assess cognitive language and motor development.  
The Bayley-III consists of three administered scales (cognitive, language and motor) with 5 
subtests (cognitive, receptive language, expressive language, fine motor and gross motor).  The 
Cognitive Scale assesses how a child thinks, responds and learns about the world.  The Language 
Scale assesses how well a child can communicate using gestures, sounds and words in the 
Expressive Communication subscale, and how well a child recognizes sounds and understands 
instructions and spoken language in the Receptive Communication subscale.  The Motor Scale 
assesses how well a child can use his or her hands and fingers to perform activities in the Fine 
Motor subscale, and how well a child can move his or her body in the Gross Motor subscale.  
Normative data is available for the Bayley-III from 1 month to 42 months of age and was derived 
from a sample of US infants and children in 2004.  Data was also collected from 668 children 
with specific clinical diagnoses, including Down syndrome, prematurity, cerebral palsy, 
language impairment, pervasive developmental disorder and fetal alcohol exposure.  Raw scores, 
scaled scores, and composite scores with percentile rank and confidence intervals will be 
reported for each of the three administered scales for patients from 1 month to 42 months of age. 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
24 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
All clinicians administering the Bayley-III will be provided with a training video and instruction 
manual.  The Bayley-III will be administered to patients from 1 month of age up to 42 months of 
age or until the maximum score on each of the 3 administered scales has been obtained according 
to the times specified in Table 9-1.  Once the maximum score for a scale has been achieved, only 
the remaining scales will be administered.  Test administration takes approximately 90 minutes. 
Test results will be centrally scored by a trained clinician. 
9.2.2.2 Leiter International Performance Scale-Revised (Leiter-R) & Leiter International 
Performance Scale-Updated (Leiter-3) 
The Leiter-R Scale (Roid, 1997, Leiter International Performance Scale-Revised) and/or the 
updated Leiter-3 Scale (Roid, 2013, Leiter International Performance Scale- 3rd Edition (Leiter 
3)) will be administered by a trained clinician to assess intellectual ability.  The Leiter Scale was 
designed as a nonverbal measure of intellectual function, memory and attention for individuals 
who could not be validly assessed with standard intelligence tests.  Special populations for whom 
the Leiter Scale was intended include those with communication disorders, hearing impairments, 
motor impairments, and certain types of learning disabilities.  
The Leiter-R Scale consists of two groups of subtests, the Visualization and Reasoning Battery 
(VR Battery) and the Attention and Memory Battery (AM Battery).  Four subtests of the VR 
Battery have been assembled into a Brief Scale IQ test for the estimation of intellectual ability.  
The subtests in the Leiter-R are Figure Ground, Form Completion, Sequential Order and 
Repeated Patterns. The Brief Scale IQ test will be administered in this study to estimate global 
intellectual ability.  Raw and scaled scores will be reported for each of the administered subtests 
in addition to the Brief Scale IQ Composite score.   
The Leiter-3, published in 2013, is an updated version of the Leiter-R.  The Leiter-3 consists of 
two groups of subtests, the Cognitive Battery and the Attention/Memory Battery.  Nonverbal 
Intelligence will be used in this study to estimate global intellectual ability.  The first four 
subtests of the Cognitive Battery are compiled to assess Nonverbal Intelligence. These subtests 
are: Figure Ground, Form Completion, Sequential Order, and Classification-Analogies.  The fifth 
subtest (Visual Patterns) is an optional subtest, which may be administered if one of the four 
subtests is compromised.  Raw and scaled scores will be reported for each administered subtest 
in addition to the Nonverbal IQ Composite score. 
All clinicians administering the Leiter-R and /or the Leiter-3 will be provided with a training 
video and instruction manual.  The Leiter-R and/or the Leiter-3 will be administered to patients 
starting at the last assessment of the Bayley-III Cognitive and Language Scales prior to the 
patient reaching 42 months of age and annually thereafter until the patient reaches the end of the 
follow up period, as specified in Table 9-1. If previous assessments have been performed using 
Leiter-R and switch to Leiter-3 Scale is planned, then both assessments need to be performed at 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
25 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
the same time of the initial administration of the Leiter-3 in order to create a baseline. The dates 
of the two tests should be recorded appropriately in the CRFs and the scores recorded on the 
appropriate test score sheets. Test administration takes approximately 60 minutes.  Test results 
will be centrally scored by a trained clinician. 
9.2.2.3 Gross Motor Function Measure (GMFM-88) 
The GMFM-88 was designed to measure gross motor function in children with cerebral palsy.  
The GMFM-88 was developed specifically to detect quantitative changes in gross motor 
function.  There is no age cut-off for the GMFM-88. 
The GMFM-88 consists of 88 items organized into 5 dimensions: 
o lying and rolling 
o sitting 
o crawling and kneeling 
o standing 
o walking, running and jumping 
Items were selected to represent motor functions typically performed by children without motor 
impairments by age of 5 years. 
Each item is scored on a 4-point Likert scale (i.e., 0 = cannot do; 1 = initiates [< 10% of the 
task]; 2 = partially completes [10 to < 100 % of the task]; 3 = task completion).  The score for 
each dimension is expressed as a percentage of the maximum score for that dimension.  The total 
score is obtained by adding the percentage scores for each dimension and dividing the sum by 
the total number of dimensions.  Therefore, each dimension contributes equally to the total score.  
Test results will be centrally scored by a trained clinician. 
Validity and reliability has been shown in patients with cerebral palsy.  The GMFM-88 was 
validated on 136 children with cerebral palsy, 25 children with acute head injuries and 
34 children without motor delays who ranged in age from 1 month to 4.3 years.  The subjects 
were measured twice over a period of 6 months.  Change scores were correlated with the ratings 
of change by independent physical therapists from videotapes on the initial and 6-month test in 
random order.  The correlation made between the GMFM-88 change scores and the ratings made 
from the videotapes was 0.82. 
In addition, the GMFM-88 has been validated in children with Down syndrome.  One hundred 
twenty-three children were assessed twice over a period of 6 months using the GMFM-88 and 
the Modified Bayley Scales of Infant Development II.  Test-retest and inter-rater variability were 
all > 0.90 (Russell, 1989, Dev Med Child Neurol).  While not originally validated for children 
with diagnoses other than cerebral palsy, the GMFM-88 has been used for other children with 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
26 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
motor difficulties including children with osteogenesis imperfecta (Ruck-Gibis, 2001, Pediatr 
Phys Ther), and acute lymphoblastic leukemia (Wright, 1998, Med Pediatr Oncol). 
9.2.2.4 Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) 
A disease-specific version of the PEDI was developed to assess functional capabilities and 
performance in children with Pompe disease from 2 months through adolescence (Haley, 2005, 
Dev Med Child Neurol; Haley, 2004, Pediatr Neurol; Haley, 2003, Pediatr Rehabil; Haley, 
2003, Dev Med Child Neurol).  All patients will be administered the Pompe PEDI, regardless of 
age.  The Pompe PEDI includes all items from the original PEDI, as well as additional items in 
the Functional Skills Mobility and Self-Care domains to reflect clinically relevant functional 
skills for children with Pompe disease.  Norm-based scoring was developed for these new items 
and scoring algorithms for the PEDI have been adjusted to reflect the additional normative data 
collected for the Pompe PEDI.  A trained clinician will administer the Pompe PEDI with input 
from the patient or patients’ legal guardian.  Test administration requires approximately 
60 minutes.  The Pompe PEDI will be centrally scored.  Results are reported as raw score, 
normative standard score (with standard error) and scaled score (with standard error). 
9.2.3 Urinary Oligosaccharide (Hex4) Levels 
As an exploratory measure, collection of urine for oligosaccharide levels will be performed at the 
times specified in Table 9-1.  A tetraglucose oligomer, Glcα1-6Glcα1-4Glcα1-4Glc, designated 
Glc4 (Hex4), has been shown to be elevated in the urine (Hallgren, 1974, Eur J Clin Invest; 
Chester, 1983, Lancet; Peelen, 1994, Clin Chem; An, 2000, Anal Biochem; An, 2005, Mol Genet 
Metab) in patients with Pompe disease.  Hence determination of Hex4 may be a means by which 
the efficacy of treatments may be monitored.  HPLC-UV (An, 2000, Anal Biochem) and stable 
isotope dilution ESI-MS/MS (Young, 2003, Anal Biochem) are two different methods available 
for the analysis of Hex4 in biological fluids as the butyl-p-aminobenzoate (BAB) derivative.  
Oligosaccharide levels in urine will be measured by a central laboratory, and additional 
information for the collection and handling of these samples can be found in the SM. 
9.2.4 CRIM Status 
The potential effect of CRIM status will be investigated for research purposes only. 
The GAA Western blot will be used to assess CRIM status in baseline skin biopsy samples from 
patients with Pompe disease.  The CRIM Western blot assay was developed to detect the major 
protein forms of GAA known to exist in the cell, including 110, 95, 76, or 70 kDa forms.  A 
patient is considered CRIM positive if the presence of any bands corresponding to the apparent 
molecular weight of these forms of GAA is detected in samples prepared from patient fibroblasts 
in the Western blot assay. 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
27 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
CRIM status testing will be performed by Genzyme Corporation or their designee using an assay 
that recognizes both recombinant and native GAA.  Information for the collection and handling 
of these samples can be found in the SM. 
9.2.5 GAA Mutation Analysis 
Deoxyribonucleic acid (DNA) will be isolated from peripheral blood samples obtained from 
enrolled patients using established methods.  DNA sequencing will be performed on these 
samples to fully characterize both deleterious mutations and background variation within the 
GAA gene.    GAA mutation analysis is to be conducted only if written results are not available. 
 
9.3 Safety Assessments 
9.3.1 Neuroimaging Assessment 
In previous clinical trials, a small number of patients with infantile-onset Pompe disease have 
been found to have a pattern of delayed myelination and/or white matter signal abnormalities in 
the brain, as evaluated by neuroimaging assessments conducted prior to and following the onset 
of treatment with alglucosidase alfa.  Consequently, serial brain MRIs will be conducted at the 
discretion of the Investigator as sedation for this procedure may be required for young patients 
and may pose an unacceptable risk in patients who have cardiopulmonary involvement.  MRIs 
will be conducted according to standard procedures (specified in the SM) at the times specified 
in Table 9-1 in order to evaluate possible changes in brain structures over time. 
If clinically significant changes in neuroimaging findings as compared to Baseline results are 
noted, the changes will be documented as AEs on the AE CRF.  Clinical significance is defined 
as any variation in neuroimaging findings that has medical relevance and may result in an 
alteration in medical care.  The Investigator will continue to monitor the patient until the 
parameter returns to Baseline or until the Investigator determines that follow-up is no longer 
medically necessary. 
9.3.2 Hearing Testing 
Hearing loss has been reported in patients with glycogen storage disorders (Galton, 1976, Acta 
Paediatr Scand; Jurecka, 1985, Arch Dermatol).  Furthermore, cochlear involvement has been 
demonstrated in a mouse model of Pompe disease, and hearing loss found in patients with 
infantile-onset Pompe disease (Kamphoven, 2004, Neurobiol Dis). 
Hearing will be assessed at the times specified in Table 9-1 using an age-appropriate method of 
hearing assessment, as determined by the Investigator.  Refer to Table 9-2 for a list of commonly 
available hearing tests appropriate for infants and children of various ages.  Abnormal hearing 
tests should be confirmed by more than 1 method, and should be correlated with the presence or 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
28 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
absence of middle ear effusion.  Results of the hearing testing will be recorded on the CRF.  
Refer to the SM for specific details on hearing testing procedures. 
 
Table 9-2 
Hearing Assessments Appropriate for Age 
Auditory test 
Developmental age of child 
Conditioned-oriented responses 
9 months to 2.5 years 
Visual reinforcement audiometry 
9 months to 2.5 years 
Play audiometry 
2.5 years to 4 years 
Conventional audiometry 
4 years and older 
Otoacoustic emission testing 
All ages 
Brainstem auditory evoked response * 
Birth to 9 months of age 
Source: (Cunningham, 2003, Pediatrics) 
*BAER should only be performed if the results of other hearing testing are inconclusive as BAER may require 
sedation in young children which could pose unacceptable risks to patients who have significant cardiopulmonary 
compromise.  BAER should only be performed at the discretion of the investigator. 
If clinically significant changes in hearing as compared to Baseline results are noted, the changes 
will be documented as AEs on the AE CRF.  Clinical significance is defined as any variation in 
hearing tests that has medical relevance and may result in an alteration in medical care.  The 
Investigator will continue to monitor the patient until the parameter returns to Baseline or until 
the Investigator determines that follow-up is no longer medically necessary. 
9.3.3 Visual Screening 
As visual impairment may impact the patient’s ability to perform developmental tests, vision 
testing is being performed in this study to help in the interpretation of developmental testing.  
Ophthalmologic evaluation is to be performed by the Investigator in accordance with the 
guidelines described by the American Association of Pediatrics (AAP, 1996, Pediatrics).  The 
type of visual screening will be determined by the patient’s age at the time of the assessment.  
All patients will have an exam of the eye, test ocular motility and the red reflex exam.  Patients 
3 years of age and over will have the same assessments described previously plus a visual acuity 
test.  Patients 4 years of age and over will have each of the previously described assessments plus 
fundoscopy.  In accordance with AAP guidelines for vision screening, abnormal vision screening 
results should be followed with evaluation by an ophthalmology specialist and follow up should 
include slit lamp examination, if deemed necessary.  Testing will occur at the times specified in 
Table 9-1. 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
29 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
If clinically significant changes in vision as compared to Baseline results are noted, the changes 
will be documented as AEs on the AE CRF.  Clinical significance is defined as any variation that 
has medical relevance and may result in an alteration in medical care.  The Investigator will 
continue to monitor the patient until the parameter returns to Baseline or until the Investigator 
determines that follow-up is no longer medically necessary. 
9.3.4 Electrocardiogram 
A standard 12-lead ECG will be conducted at the times specified in Table 9-1.  The following 
will be assessed: heart rate, rhythm, RR, PR, QRS, QT, QTc, QRS axis, R voltage V6, S voltage 
V1, LVH criteria, RVH criteria, and repolarization changes. 
The ECG should be reviewed by a site cardiologist, preferably a pediatric cardiologist, in a 
timely manner for derivation of study data and clinical management of the patient.  Interpretation 
will include an assessment of heart rate, cardiac rhythm, intervals, axis, conduction defects, and 
overall cardiac impression for each patient.  QTc should be analyzed using both the Fridericia 
and Bazett’s correction formulae in accordance with the FDA’s Guidance for Industry E14 
Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-
Antiarrhythmic Drugs and Questions and Answers (R1); references to these documents can be 
found in the SM.   
If clinically significant ECG changes from Baseline are noted, the changes will be documented 
as AEs on the AE CRF.  Clinical significance is defined as any variation in ECG parameters that 
has medical relevance resulting in an alteration in medical care.  The Investigator will continue 
to monitor the patient with additional ECGs until the ECG returns to Baseline or the Investigator 
determines that follow-up is no longer necessary. 
9.3.5 Safety Laboratory Assessments 
Safety laboratory assessments will be performed pre-infusion at the times specified in Table 9-1.  
The following chemistry and urinalysis variables will be measured: 
• Blood urea nitrogen (BUN), creatinine, glucose, uric acid, calcium, phosphorus, albumin, 
total protein, sodium, potassium, chloride, bicarbonate, serum glutamic oxaloacetic 
transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase, 
total bilirubin, creatine kinase (CK), and creatine kinase muscle, brain isoform (CK-MB). 
• Complete blood count with differential. 
• Urine appearance, specific gravity, pH, protein, glucose, ketones, bilirubin, and blood.  
Microscopy will be performed if clinically indicated. 
Analysis of blood and urine samples will be conducted and reported by each participating site’s 
laboratory.  The Investigator should review lab reports in a timely manner. 
The Investigator must indicate if out of range laboratory values are either clinically significant 
(CS), or not clinically significant (NCS).  It is anticipated that some laboratory values may be 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
30 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
outside of the normal value range due to the underlying disease.  As in routine practice the 
Investigators should use their clinical judgment when considering clinical significance.  Clinical 
significance is defined as any variation in laboratory parameters, which has medical relevance 
and may result in an alteration in medical care.  If CS laboratory changes from Baseline are 
noted, the changes will be documented on the AE CRF.  The Investigator will also assess the 
relationship of all clinically significant out of range values to alglucosidase alfa as being not 
related, remote/unlikely, possible, probable, or definite.  The Investigator will continue to 
monitor the patient with additional laboratory assessments until (1) values have reached normal 
range and/or Baseline, or, (2) in the judgment of the Investigator, out of range values are not 
related to the administration of alglucosidase alfa or other protocol-specific procedures. 
9.3.6 Vital Signs 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be recorded at 
baseline, prior to the start of each infusion, at the end of each infusion, and if the patient 
experiences an IAR, as specified in Table 9-1.  All IARs should be captured on the SAE/IAR 
page and submitted to Global Pharmacovigilance and Epidemiology per Section 9.5.2. 
9.3.7 Immunologic Testing 
9.3.7.1 Routine Anti-rhGAA IgG Antibody Testing 
Serum samples for anti-rhGAA IgG antibody testing will be obtained pre-infusion at the times 
specified in Table 9-1.  Additional anti-glucosidase IgG antibody testing should be performed 
upon determination of any notable deterioration in a patient’s motor function.  Refer to the SM 
for guidelines on the collection and shipment of serum samples. 
9.3.7.2 Inhibitory Antibody Testing 
Inhibitory antibody (activity and uptake) will be assessed when clinically indicated (e.g., plateau 
or decline in response in the presence of adequate dosing).  Refer to the SM for guidelines on the 
collection and shipment of serum samples. 
9.3.7.3 Additional Testing for Moderate or Severe or Recurrent IARs 
In the event that a patient experiences a moderate, severe, or recurrent IAR, additional blood 
samples should be collected as described in Sections 9.3.7.3.1 to 9.3.7.3.3.  At the request of 
Genzyme, after consultation with the Investigator, additional blood samples may be collected for 
recurrent IARs suggestive of a hypersensitivity reaction.  Refer to the SM for guidelines on the 
collection and shipment of samples.  Global Pharmacovigilance and Epidemiology should be 
apprised of sample shipments.  Testing is conducted for research purposes to gain additional 
information as to individuals’ responses to alglucosidase alfa, and is not intended as the sole 
means of clinical management of patients.  Skin testing may also be performed, if clinically 
indicated, as described in Section 9.3.7.3.4.  Suggested guidelines for the management of IARs 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
31 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
during the event and pretreatment guidelines are summarized in the current version of the 
Investigator’s Brochure.   
9.3.7.3.1 
Complement Activation Testing 
In the event that a patient experiences a moderate, severe, or recurrent IAR, a plasma sample 
should be drawn within 1 to 3 hours of the event for complement activation testing, when 
clinically indicated. 
At the request of Genzyme, after consultation with the Investigator, a plasma sample for 
complement activation testing may also be collected for patients with recurrent IARs suggestive 
of a hypersensitivity reaction. 
9.3.7.3.2 
Serum Tryptase Testing 
In the event that a patient experiences a moderate, severe, or recurrent IAR, a serum sample 
should be drawn within 1 to 3 hours of the event for serum tryptase testing, when clinically 
indicated. 
At the request of Genzyme, after consultation with the Investigator, a serum sample for tryptase 
testing may also be collected for patients with recurrent IARs suggestive of a hypersensitivity 
reaction. 
9.3.7.3.3 
Serum IgE Antibody Testing 
In the event that a patient experiences a moderate, severe, or recurrent IAR, the patient should 
return to the study center at least 72 hours after the infusion ends to draw a serum sample that 
will be tested for IgE antibodies, when clinically indicated.  For patients on home infusion, 
whole blood for testing of IgE antibodies may be drawn at home at least 72 hours after the 
infusion ends. 
At the request of Genzyme, after consultation with the Investigator, a serum sample for IgE 
testing may also be collected for patients with recurrent IARs suggestive of a hypersensitivity 
reaction. 
9.3.7.3.4 
Skin Testing 
Skin testing may be performed following consultation with the Investigator, Sponsor, and ARRB 
in patients who experience an IAR that meets the following criteria: 
 IAR is assessed as moderate or severe in intensity by the Investigator or recurrent 
IAR AND 
 IAR is suggestive of an IgE-mediated acute-type hypersensitivity reaction, with 
persistent symptoms of bronchospasm, hypotension and/or urticaria requiring 
intervention OR any other signs or symptoms at the discretion of the Investigator 
or Genzyme. 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
32 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
9.3.7.4 Circulating Immune Complexes 
In the event that patients exhibit evidence of symptoms suggestive of Immune Complex Disease 
(e.g., proteinuria), serum samples will be obtained for the evaluation of circulating immune 
complexes.  Immune complex results will be used as a tool to assist in the clinical evaluation of 
the patient and clinical management will not be dependent solely on these results.  The patient 
will continue to be monitored for immune complex symptomatology, and serum samples will 
continue to be obtained for the evaluation of circulating immune complexes, as appropriate.  
Consideration for further evaluation of possible immune complex disease (i.e., renal biopsy) will 
be at the discretion of the Investigator.  Refer to the SM for guidelines on the collection and 
shipment of serum samples. 
9.4 Other Assessments 
9.4.1 Concomitant Medications/Therapies 
From the time of informed consent through study completion, all medications and therapies (e.g., 
tube feeds) taken by the patient to treat AEs and any long-term disease management will be 
recorded on the CRFs. 
9.5 Adverse Events 
AEs will be assessed at screening/baseline.  At every infusion visit the patient’s legal guardian(s) 
will be asked “Since your last questioning or visit, has the patient experienced any health 
problems?” 
An AE is defined as any undesirable physical, psychological or behavioral effect experienced by 
a patient or subject during their participation in an investigational study, in conjunction with the 
use of the drug or biologic, whether or not product-related.  This includes any untoward signs or 
symptoms experienced by the patient 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 offered by the patient or subject and/or 
observed by the Investigator or medical staff 
• Findings at physical examinations 
• Laboratory abnormalities of clinical significance 
Disease signs, symptoms, and/or laboratory abnormalities already existing prior to the use of the 
product (i.e., prior to participation in the AGLU03606 study) are not considered AEs after 
treatment unless they recur after the patient has recovered from the preexisting condition or in 
the opinion of the Investigator they represent a clinically significant exacerbation in intensity or 
frequency. 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
33 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
Any signs and symptoms experienced by the patient from the time of signing of the informed 
consent through the final study visit will be recorded on the CRF. 
If clinically significant worsening from Baseline is noted, the changes will be documented as 
AEs on the AE CRF.  Clinical significance is defined as any variation in signs, symptoms, or 
testing that has medical relevance and may result in an alteration in medical care.  The 
Investigator will continue to monitor the patient until the parameter returns to Baseline or until 
the Investigator determines that follow-up is no longer medically necessary. 
9.5.1 Serious Adverse Events 
An SAE is 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 
• Important medical events that may jeopardize the patient or subject and may require medical 
or surgical intervention to prevent one 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, i.e., does not include an AE that had 
it occurred in a more severe form, might have caused death. 
Persistent or significant disability/incapacity: Any AE that resulted in a substantial 
disruption of a person’s ability to conduct normal life functions. 
Important medical events that may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed above: AEs that 
may not result in death, be life-threatening, or require hospitalization may be considered 
an SAE when, based upon appropriate medical judgment, they may jeopardize the patient 
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 experience 
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 type 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). 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
34 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
• 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. 
Severity is not equivalent to seriousness. 
9.5.1.1 Autopsy and Post-Mortem Biopsy 
In the event that a patient dies, permission will be sought (through a separate informed consent 
form) from the patient’s legal guardian(s) for a research autopsy or post-mortem research biopsy.  
If consented, samples collected from this procedure will be sent to Genzyme Corporation and 
used for research purposes only; data will not be provided to the Investigator or be included in 
any analyses.  Refer to the SM for research autopsy and post-mortem research biopsy procedural 
guidelines. 
9.5.2 Infusion-Associated Reactions 
Infusion-associated reactions are defined as AEs that occur during the infusion or within up to 24 
hours after the start of infusion and are considered as related or possibly related to the ERT by 
the Investigator or the Sponsor. An event occurring ≥24 hours after the start of an infusion may 
be judged an IAR if a delayed reaction is considered possible by the Investigator or the Sponsor.  
These events should be reported to Global Pharmacovigilance and Epidemiology within 24 hours 
of the Investigator’s first knowledge of the event.  Refer to Section 9.3.7.3 for additional testing 
in the event a patient experiences a moderate, severe, or recurrent IAR.  Suggested guidelines for 
the management of IARs are summarized in the current version of the Investigator’s Brochure. 
9.5.3 Adverse Experience and Serious Adverse Experience Reporting 
The necessity and time requirements for reporting of AEs to Genzyme or designee and/or 
regulatory agencies are as follows: 
• All SAEs and IARs (non-serious and serious) should be reported within 24 hours of the 
Investigator’s first knowledge of the event, even if the experience does not appear to be 
related to alglucosidase alfa.  Such communications are to be directed to:  
Global Pharmacovigilance and Epidemiology 
Fax: +33 160-49-70-70  
E-mail: CL-CPV-receipt@sanofi.com  
 
• All SAEs will include a detailed description of the event(s).  Copies of relevant patient 
records, autopsy reports, and other documents may be requested by and will be sent to Global 
Pharmacovigilance and Epidemiology Department. 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
35 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
Additionally, the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) must 
be notified in writing of any expedited SAEs.  It is the responsibility of the Investigator to notify 
the IRB/IEC.  All unexpected SAEs associated with the use of alglucosidase alfa should be 
immediately reported to appropriate regulatory agencies by Genzyme Corporation if there is a 
reasonable possibility that the drug caused the adverse experience. 
Any AEs or SAEs experienced by the patient from the time of signing of the informed consent 
through completion of the final study assessments must be reported as described and recorded on 
the CRF.   
After completion of the final study assessments, all patients must be followed an additional 30 
days.  At the follow-up assessment, outcome for ongoing AEs and SAEs should be documented 
in the CRF as not yet recovered.  Ongoing SAEs should, however, continue to be followed (and 
information reported to Global Pharmacovigilance and Epidemiology) until resolution, until the 
Investigator deems follow-up is no longer medically necessary or until the patient is lost to 
follow-up. 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
36 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
10. DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT 
10.1 Recording of Data 
All required data will be recorded on the CRF provided by Genzyme Corporation. Copies of 
score sheets for cognitive function and motor development assessments will be sent to a central 
Genzyme representative for centralized scoring.  All missing data will be explained.  Clinical 
data that are not recorded on the CRF will be captured and transferred to Genzyme's Department 
of Biostatistics.  
10.2 Data Quality Assurance 
Data entered on the CRF must be verifiable against source documents at the investigational site.  
A clinical monitor from Genzyme Corporation or a representative of Genzyme Corporation will 
manually review the CRFs against the source documents at the investigational site for validity 
and completeness.  All data captured in the CRFs will be made available to Genzyme or its 
designee for data management and analysis.  If necessary, the study site will be contacted for 
corrections and/or clarifications of the data. 
10.3 Data Management 
Genzyme will be responsible for: 
• Database creation and validation 
• Data entry and editing 
• CRF review and data validation 
• Locking the final database 
Prior to finalizing and locking the database, all decisions concerning the inclusion or exclusion 
of data for each subject will be determined by appropriate medical and statistical personnel.  Any 
and all exclusions related to either safety or efficacy will be documented in patient listings. 
11. STATISTICAL METHODS AND PLANNED ANALYSES 
Prior to data analysis, 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 prior to 
commencing with statistical analysis, as part of the Statistical Analysis Plan. 
The Genzyme Department of Biostatistics will perform the statistical analysis of the data derived 
from this study.  Details of the statistical analysis will be specified in the Statistical Analysis 
Plan.  Analyses will be performed using the SAS® statistical software system. 
All enrolled patients who receive at least one infusion (complete or partial) of alglucosidase alfa 
in this study will comprise the analysis population for the efficacy and safety analyses.  
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
37 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
All data collected will be presented in the form of individual patient listings.  Provided the data 
are not too sparse, summary tables will be created for the efficacy and safety variables. 
Continuous variables will be summarized using descriptive statistics (n, mean, median, standard 
deviation, minimum and maximum).  Categorical variables will be summarized using 
frequencies and percentages. 
Baseline demographic and background variables will be summarized and also presented in 
patient listings.  Efficacy endpoints include physical growth, development, and cognitive 
function. 
Physical growth is assessed by body height/length, weight and head circumference.  Changes 
from baseline to study time points will be summarized descriptively for body height/length, 
weight and head circumference.  Changes in Z-scores (standardized age and gender adjusted 
values) for height/length, weight and head circumference with reference to Center for Disease 
Control (CDC) Growth Charts will also be summarized descriptively.   
The Bayley-III consists of 3 administered scales – cognitive, language and motor and will be 
administered to patients from 1 month to 42 months of age.  Changes from baseline to study time 
points in the raw scores, scaled scores and composite scores reported for each of the 3 
administered scales will be summarized descriptively. 
Cognitive function is assessed by the Leiter-R and/or the updated Leiter-3 instrument for patients 
42 months of age and older.  The Brief Scale IQ (Leiter-R) and/or Nonverbal IQ Scale (Leiter-3) 
that will be administered each consist of 4 subtests. All data collected will be presented in the 
patient listings.  The changes from baseline to study time points in the raw and scaled scores for 
the 4 subtests may be summarized descriptively. 
The GMFM-88 will be used to measure the change over time in the gross motor abilities of the 
patients.  Change from baseline to study time points in the total score and dimension scores will 
be summarized descriptively. 
The Pompe PEDI was developed to assess functional capabilities and performance in children 
with Pompe disease. Changes from baseline to study time points in the raw scores, normative 
standard scores and scaled scores for the Functional Skills Mobility and Self-Care domains will 
be summarized descriptively. 
The potential effect of urinary oligosaccharide levels, CRIM status, and GAA mutation on 
efficacy outcomes may be analyzed. 
Safety assessments include neuroimaging, hearing testing, visual screening, ECG, laboratory 
assessments, immunologic testing.  All data from safety assessments will be presented in patient 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
38 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
listings.  For laboratory assessments, summary statistics will be presented for change in 
laboratory parameters from baseline to analysis time points. 
Concomitant medication will be coded using the WHO drug dictionary.  Concomitant 
medications and concomitant therapies will be listed by patient.  Summary tables giving the 
frequencies and percentages of the concomitant medications used will be provided. 
AEs, SAEs and IARs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  All AEs, SAEs and IARs will be presented in patient listings.  Summary tables 
showing the frequencies and percentages of patients with AEs, SAEs and IARs will be presented.  
The frequencies and percentages of AEs, SAEs and IARs will also be presented. 
In addition, longitudinal repeated measures modeling will be used to analyze trends in key 
growth and development parameters over time.  The impact of patient discontinuation prior to 
study completion will be assessed.  Analyses of key variables may be stratified by relevant 
baseline/demographic factors. 
No formal statistical sample size calculations were performed. 
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) regulations.  These requirements are stated in federal 
regulations as well as “Guidance for Good Clinical Practice,” International Conference on 
Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human 
Use. 
12.1 Data Safety Monitoring Board (DSMB) 
An independent DSMB appointed by Genzyme Corporation will review the protocol and will 
thereafter provide medical and ethical guidance related to the conduct of this study on an ad hoc 
basis to assist in determining if AEs should preclude continued treatment with alglucosidase alfa.  
The ad hoc reviews will be performed in accordance with procedures outlined in the DSMB 
charter, which is maintained separately from the study protocol.  This committee will be 
comprised of 4 physicians who are knowledgeable in aspects of Pompe disease, and who have no 
direct relationship with the study.  One physician will also have expertise in the field of 
allergy/immunology.  Each DSMB member will be required to sign a contract agreement, which 
includes a confidentiality and financial disclosure statement, assuring no conflicts of interests as 
a condition for membership on the board.  These documents, along with all members’ curricula 
vitae, will be filed centrally at the end of the study within the protocol study files at Genzyme 
Corporation, Cambridge, MA (USA). 
Should any major safety issues arise, final decisions regarding the study will be made by the 
Genzyme Corporation Chief Medical Officer, Global Safety Officer, and the DSMB. 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
39 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
12.2 Allergic Reaction Review Board 
An independent ARRB, appointed by Genzyme Corporation, may review information pertaining 
to IARs.  The ARRB responsibilities will serve in a consultancy manner and will provide 
guidance on IAR management as outlined in the ARRB Charter, maintained separately from the 
study protocol.  Communication with the board should be directed to members of the Global 
Pharmacovigilance and Epidemiology group. 
The ARRB will consist of at least 1 Allergist/Immunologist.  Each member of the ARRB will be 
a physician and will not be directly involved in the study.  Each ARRB member will be required 
to sign a contract agreement, which includes a confidentiality and financial disclosure statement, 
assuring no conflicts of interests as a condition for membership on the board.  These documents, 
along with all members’ curricula vitae, will be filed centrally at the end of the study within the 
protocol study files at Genzyme Corporation, Cambridge, MA. 
Should any major safety issues arise, final decisions regarding the study will be made by the 
Genzyme Corporation Chief Medical Officer, Global Safety Officer, and the ARRB. 
12.3 Institutional and Ethical Review 
This protocol and patient authorization form must be reviewed and approved by an IRB or IEC 
complying with the requirements of 21 CFR 56 and the ICH before enrollment of patients.  The 
letter or certificate of approval from the IRB or IEC must be received by Genzyme prior to 
delivery of clinical supplies.   
12.4 Changes to the Conduct of the Study or Protocol 
No change in the study procedures shall be effected without the mutual agreement of the 
Investigator and Genzyme.  All protocol amendments will be issued by Genzyme and must be 
signed by the Investigator.  If changes are made that affect the design of the study, the 
amendment must be submitted to, and approved by the IRB/IEC.  In addition, Genzyme will 
submit protocol amendments to the regulatory authorities as appropriate. 
12.5 Investigator's Responsibilities 
12.5.1 Patient Informed Consent 
Written informed consent is required prior to enrollment in the study.  It is the responsibility of 
the Investigator to obtain such consent.  Investigators must comply with the Declaration of 
Helsinki and local guidelines and regulations when developing the patient informed consent. 
The Investigator must furnish Genzyme with a photocopy of the proposed consent form prior to 
submitting to the IRB/IEC so that Genzyme may ensure that all appropriate elements are 
incorporated into the document.  Upon approval by the IRB/IEC, the Investigator must furnish:  
(1) a photocopy of the approved informed consent, and (2) the letter stating that formal approval 
has been granted by the institution, prior to collecting any data on the patient. 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
40 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
12.5.2 Case Report Forms 
Data will be entered onto CRFs at each site. 
Copies of pertinent records in connection with the study, including patient charts, laboratory 
data, etc. will be made available to Genzyme on request in a timely manner throughout the 
course of the study, with due precaution towards protecting the privacy of the patient. 
12.5.3 Record Retention 
The Investigator must retain paper copies of study records as required by the applicable 
regulatory requirements.  The Investigator should take measures to prevent accidental or 
premature destruction of these documents.  The study records should be retained until at least 2 
years after the last approval of a marketing application in the US or an ICH region and until there 
are no pending or contemplated marketing applications in the US or an ICH region or at least 2 
years have elapsed since the formal discontinuation of clinical development of the investigational 
product.  The Investigator must retain patient identification codes for at least 15 years after the 
completion or discontinuation of the study.  Patient files and other source data must be kept for 
the maximum period of time permitted by the hospital, institution or private practice, but not less 
than 15 years.  Should Investigators be unable to continue maintenance of patient files for the 
full 15 years, Genzyme will assist in this regard. 
12.5.4 Monitoring 
A representative of Genzyme will visit the Investigator periodically for the purpose of 
monitoring the progress of this study in accordance with GCP regulations.  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. 
An audit may be performed at any time during or after completion of the clinical study by 
Genzyme Corporation personnel or their designee.  All study-related documentation must be 
made available to the designated auditor. 
In addition, a representative of the FDA or other regulatory agency may choose to inspect a 
study center at any time prior to, during, or after completion of the clinical study.  A Genzyme 
Corporation 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. 
12.5.5 Warnings, Precautions, Contraindications 
For more specific information concerning warnings, precautions, and contraindications, the 
Investigator is asked to refer to the appropriate section of the Investigator's Brochure as well as 
the full prescribing information for alglucosidase alfa.  Because of the possibility of AEs, proper 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
41 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
safety equipment, including but not limited to cardiopulmonary resuscitation equipment, and 
personnel competent in recognizing and treating adverse reactions of all types should be readily 
available. 
12.5.6 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 established 
and presented to the Investigator previously by Genzyme.  Submission to Genzyme Corporation 
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. 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
42 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
 
13. REFERENCES 
 
AAP. Eye Examination and Vision Screening in Infants, Children and Young Adults. Pediatrics. 
1996; 98(1): 153-157. 
An Y, Young S, Hillman S, van Hove J, Chen Y, Millington D. Liquid chromatography assay for a 
glucose tetrasaccharide, a putative biomarker for the diagnosis of Pompe Disease. Anal 
Biochem. 2000;287:136-143. 
An Y, Young SP, Kishnani PS, Millington DS, Amalfitano A, Corzo D, Chen YT. Glucose 
tetrasaccharide as a biomarker for monitoring the therapeutic response to enzyme 
replacement therapy for Pompe disease. Mol Genet Metab. 2005; 85:247-254. 
Bayley N. Bayley Scales of Infant and Toddler Development. Third ed: Harcourt Assessment, Inc.; 
2005. 
Chen YT and Amalfitano A. Towards a molecular therapy for glycogen storage disease type II 
(Pompe disease). Mol Med Today. 2000;6(6):245-251. 
Chester MA, Lundblad A, Hager A, Sjoblad S, Loonen C, Tager JM, Zopf D. Increased urinary 
excretion of a glycogen-derived tetrasaccharide in heterozygotes with glycogen storage 
diseases type II and III. Lancet1983;1:994-995. 
Cunningham MD and Cox EO. Hearing Assessment in Infants and Children: Recommendations 
Beyond Neonatal Screening. Pediatrics. 2003;111:436-440. 
Galton DJ, Reckless JP & Taitz LS.  Triglyceride storage disease.  A report of two affected 
children associated with neurological abnormalities.  Acta Paediatr Scand. 1976;65:761-
768. 
Haley SM, Dumas HM, Rabin JP, Ni P. Early recovery of walking in children and youths after 
traumatic brain injury. Dev Med Child Neurol. 2003;45:671-675. 
Haley SM, Fragala MA, Aseltine R, Ni P, Skrinar AM. Development of a disease-specific 
disability instrument for Pompe disease. Pediatr Rehabil. 2003;6:77-84. 
Haley SM, Fragala-Pinkham MA, Ni PS, Skrinar AM, Kaye EM. Pediatric physical functioning 
reference curves. Pediatr Neurol. 2004;31:333-341. 
Haley SM, Ni P, Fragala-Pinkham MA, Skrinar AM, Corzo D. A computer adaptive testing 
approach for assessing physical functioning in children and adolescents. Dev Med Child 
Neurol. 2005;47:113-120. 
Hallgren P, Hansson G, Henriksson KG, Hager A, Lundblad A, Svensson S. Increased excretion 
of a glucose-containing tetrasaccharide in the urine of a patient with glycogen storage 
disease type II (Pompe's disease). Eur J Clin Invest. 1974; 4:429-433. 
Hirschhorn R, Reuser A. Glycogen Storage Disease Type II:  Acid Alpha-Glucosidase (Acid 
Maltase) Deficiency. In: Scriver C, Beaudet A, Sly W, Valle D, eds. The Metabolic and 
Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001:3389-3419. 
Ing RJ, Ryan Cook D, Bengur RA, et al. Anaesthetic management of infants with glycogen 
storage disease type II: a physiological approach. Paediatr Anaesth. 2004;14(6):514-519. 
Jurecka W, Aberer E, Mainitz M, Jurgensen O. Keratitis, ichthyosis, and deafness syndrome with 
glycogen storage. Arch Dermatol. 1985(121):799-801. 
Kamphoven JH, de Ruiter MM, Winkel LP, et al. Hearing loss in infantile Pompe's disease and 
determination of underlying pathology in the knockout mouse. Neurobiol Dis. 
2004;16(1):14-20. 
 
(electronic 
 
 
 
2.0)

Aalglucosidase Alfa 
43 (43) 
Clinical Protocol Number AGLU03606/LTS12869 
 
 
GENZYME CORPORATION, A SANOFI COMPANY 
 
PROPRIETARY AND CONFIDENTIAL  
AMENDMENT 7 FINAL:  02 DECEMBER 2014 
Kishnani P, Corzo D, Nicolino M, et al. Recombinant human acid {alpha}-glucosidase. Major 
clinical benefits in infantile-onset Pompe disease.  Neurology. 2007; 68:99-109. 
Laforêt P, Nicolino M, Eymard B, et al. Juvenile and adult-onset acid maltase deficiency in 
France: genotype-phenotype correlation. Neurology. 2000;55(8):1122-1128. 
Peelen GO, de Jong JG, Wevers RA. HPLC analysis of oligosaccharides in urine from 
oligosaccharidosis patients. Clin Chem. Jun 1994;40(6):914-921. 
Roid GH, Miller LJ. Leiter International Performance Scale - Revised: Examiner's Manual. In: GH 
Roid, LJ Miller eds. Leiter International Performance Scale -Revised. Wood Dale, IL: 
Stoelting Co;1997. 
Roid GH, Miller LJ, Poplun M, Koch C. Leiter International Performance Scale- 3rd Edition 
(Leiter3). Wood Dale, IL: Stoelting; 2013. 
Ruck-Gibis J, Plotkin H, Hanley J, Wood-Dauphinee S. Reliability of the gross motor function 
measure for children with osteogenesis imperfecta. Pediatr Phys Ther. 2001;13(1): 10-7. 
Russell DJ, Rosenbaum PL, Cadman DT, Gowland C, Hardy S, Jarvis S. The gross motor 
function measure: a means to evaluate the effects of physical therapy. Dev Med Child 
Neurol. 1989;31(3):341-352. 
Slonim AE, Bulone L, Ritz S, Goldberg T, Chen A et al. Identification of two subtypes of 
infantile acid maltase deficiency. J Pediatr. 2000;137(2):283-285. 
Van den Hout HM, Hop W, van Diggelen OP, et al. The natural course of infantile Pompe's 
disease: 20 original cases compared with 133 cases from the literature. Pediatrics. 
2003;112(2):332-340. 
Winkel LP, Van den Hout JM, Kamphoven JH, et al. Enzyme replacement therapy in late-onset 
Pompe's disease: a three-year follow-up. Ann Neurol. 2004;55(4):495-502. 
Wright MJ, Halton JM, Martin RF, Barr RD. Long-term gross motor performance following 
treatment for acute lymphoblastic leukemia. Med Pediatr Oncol. 1998;31(2): 86-90. 
Young SP, Stevens RD, An Y, Chen YT, Millington DS. Analysis of a Glucose Tetrasaccharide 
Elevated in Pompe Disease by Stable Isotope Dilution-Electrospray Tandem Mass 
Spectrometry. Anal Biochem. May 15 2003;316(2):175-180. 
 
 
 
(electronic 
 
 
 
2.0)