Clinical trial NCT02032524
Conditions: Glycogen Storage Disease Type II Pompe Disease
Sponsor: Genzyme, a Sanofi Company
Start date: 2014-02-27; Completion date: 2022-12-12
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary Objective:

Long-term safety and pharmacokinetics (PK) of avalglucosidase alfa

Secondary Objective:

Long-term effect of avalglucosidase alfa on pharmacodynamic variables

Detailed description:
The planned duration of the study for each participant was initially 6 years. Each participant continued with the study until the participant withdrew, the Investigator withdrew the participant, or the Sponsor terminated the study. An additional follow-up phase began after the participant has completed the 6-year study period, and lasted until avalglucosidase alfa was approved in the participant's country, except in the United Kingdom (UK), Germany and Denmark, where the duration of the additional follow-up phase was up to the approval in the country or limited to a maximum of 2 years, whichever occurred first (ie, for participants in the UK, Germany and Denmark, the total study duration per participant was 8 years at the maximum including the initial 6-year period and the additional 2-year follow-up).

Arms: arm 1: administered intravenously every 2 weeks
Interventions: intervention 1: Avalglucosidase Alfa
Intervention descriptions: intervention 1: Pharmaceutical form: lyophilized powder reconstituted for infusion Route of administration: intravenous

Protocol documents:
Prot_000.pdf: 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by amendment 
Date, version 
Amended Clinical Trial Protocol 09 
All 
21 December 2020, version 1 (electronic 9.0) 
Amended Clinical Trial Protocol 08 
Denmark only 
30 September 2020, version 1 (electronic 8.0) 
Amended Clinical Trial Protocol 07 
All 
21 January 2020, version 1 (electronic 7.0) 
Amended Clinical Trial Protocol 06 
All 
06 September 2019, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 05 
France only 
18 July 2018, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 04 
All 
27 November 2017, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 03 
All 
29 January 2016, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02 
All 
25 July 2014, version 1 (electronic 1.0) 
Amended Clinical Trial protocol 01 
All 
09 December 2013, version 1 (electronic 1.0) 
Original Protocol 
 
30 September 2013, version 1 (electronic 1.0) 
Amended protocol 09 (21 December 2020) 
This amended protocol (Amendment 09) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/Ethics Committee (EC) of the European Parliament 
and the Council of the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The overall rationale for this amendment is as follows: 
• To include the recommendations that were developed for the COVID-19 pandemic period 
and were shared with the sites/Investigators. These recommendations will remain 
applicable after the end of the pandemic, especially the information regarding the post-
infusion surveillance period. 
• To revise the text in Sections 12, 13, and 14 as per the current Sanofi protocol template to 
use the updated wordings that are compliant with general guidance, including monitoring 
techniques. 
• To update Section 8.1 for details regarding home infusions to harmonize this text across 
the different studies included in the avalglucosidase alfa development program. 
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Protocol amendment summary of changes table 
Section Number and Name 
Description of Change 
Brief Rationale 
Protocol Amendment Summary of 
Changes Table 
Document formatting revision. 
To update document history and provide 
overall rationale for the amendment. 
Section 8.1 Investigational medicinal 
product 
Requirement for patients to remain in the 
hospital or in the infusion center for the 
observation period related to onset of 
AEs was revised from 2 hours to 1 hour 
and the following text was added: “In 
case the patient does not stay for this 
observation period (eg, as part of 
contingency measures for a regional or 
national emergency that is declared by a 
governmental agency), the Investigator 
(or appropriate designee) will contact the 
patient to ensure that no AEs occurred 
during the observation period.” 
Due to COVID-19 pandemic restrictions, 
the observation period after the infusions 
were performed at the study site or 
infusion center was shortened or 
skipped for patient’s safety reasons. 
Also to lighten this period after the end 
of the pandemic and in order to obtain 
information in case this observation 
period is not performed, the observation 
time after the end of infusion is reduced 
to 1 hour. 
Section 8.1 Investigational medicinal 
product 
Under “Home infusion” subsection, the 
text was updated to harmonize with other 
studies included in the avalglucosidase 
alfa development program. 
The home infusion text is amended to 
allow patients to benefit from home 
infusion sooner in case of an 
unexpected event (ie, after 6 months 
free of IARs instead of 12 months) or to 
resume home infusion sooner after 
interruption for IAR during home 
infusion. Some text is also updated to 
harmonize across the other studies 
included in the avalglucosidase alfa 
development program. 
Section 10.4.3 Instructions for reporting 
serious adverse events 
Text was deleted regarding proactively 
sending the SAE-related reporting 
documents via fax or as photocopy. 
As per recent Sanofi procedures, the 
direct sending of source documents to 
the Sponsor (except to 
Pharmacovigilance department) is no 
more recommended. 
Section 12 Regulatory, ethical, and study 
oversight considerations; Section 13 
Study monitoring; Section 14 Additional 
requirements 
Headings, subsections, and 
corresponding text were fully updated in 
Sections 12, 13, and 14 to reflect current 
practices as outlined in the current 
protocol template, including monitoring 
techniques. 
To align with current protocol template. 
Section 17.2 Appendix 2: Protocol 
amendment history 
Added new Section 17.2.8. 
To incorporate the changes from 
amended protocol 07 to amended 
protocol 08. 
Throughout 
Typos have been corrected where 
necessary. 
Minor editorial and document formatting 
revisions are made. 
To provide clarifications. 
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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
  
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
  
Company: 
Address: 
 
 
Genzyme Corporation 
50 Binney Street 
Cambridge, MA, 02142 
USA 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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CLINICAL TRIAL SUMMARY 
 
COMPOUND: GZ402666 - 
avalglucosidase alfa (neoGAA, 
GZ402666) 
STUDY No.: LTS13769 
TITLE 
An open-label, multicenter, multinational extension study of the 
long-term safety and pharmacokinetics of repeated biweekly infusions 
of avalglucosidase alfa (neoGAA, GZ402666) in patients with Pompe 
disease. 
INVESTIGATOR/TRIAL LOCATION 
Sites that have previously participated, or that are currently 
participating, in an avalglucosidase alfa study. 
STUDY OBJECTIVES 
Primary objective: 
To assess the long-term safety and pharmacokinetics (PK) of 
avalglucosidase alfa in patients with Pompe disease who have 
previously completed an avalglucosidase alfa study. 
Secondary objective: 
To assess the long-term effect of avalglucosidase alfa on 
pharmacodynamic and exploratory efficacy variables to assess if the 
benefits of avalglucosidase alfa are maintained and to assess the time 
course of response. 
STUDY DESIGN 
Open-label, multicenter, multinational extension study of the long-term 
safety and PK of repeated biweekly infusions of avalglucosidase alfa in 
patients with Pompe disease. 
STUDY POPULATION 
 
Main selection criteria 
Inclusion criteria: 
I 01. 
Patients with Pompe disease who previously completed an 
avalglucosidase alfa study. 
I 02. 
The patient and/or their parent/legal guardian is willing and 
able to provide signed informed consent, and the patient, 
if <18 years of age, is willing to provide assent if deemed able 
to do so. 
I 03. 
The patient (and patient’s legal guardian if patient is 
<18 years of age) must have the ability to comply with the 
clinical protocol. 
I 04. 
The patient, if female and of childbearing potential, must have 
a negative pregnancy test [urine beta-human chorionic 
gonadotropin (B-hCG)] at baseline. Note: Sexually active 
female patients of childbearing potential and male patients 
are required to practice true abstinence in line with their 
preferred and usual lifestyle or to use two acceptable effective 
methods of contraception, a barrier method such as a 
condom or occlusive cap (diaphragm or cervical/vault cap) 
with spermicidal foam/gel/film/cream/suppository and an 
established non-barrier method such as oral, injected, 
or implanted hormonal methods, an intrauterine device, 
or intrauterine system for the entire duration of the treatment 
period. 
 
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Exclusion criteria: 
E 01. 
The patient is concurrently participating in another clinical 
study using investigational treatment. 
E 02. 
The patient, in the opinion of the Investigator, is unable to 
adhere to the requirements of the study. 
E 03. 
The patient has clinically significant organic disease (with the 
exception of symptoms relating to Pompe disease), including 
clinically significant cardiovascular, hepatic, pulmonary, 
neurologic, or renal disease, or other medical condition, 
serious intercurrent illness, or extenuating circumstance that, 
in the opinion of the Investigator, precludes participation in the 
study or potentially decreases survival. 
Total expected number of patients 
This is an ongoing extension study, and therefore, the number of 
patients will be determined by enrollment from other avalglucosidase 
alfa studies. 
Expected number of sites 
The number of sites will be determined by enrollment of patients from 
other avalglucosidase alfa studies. 
STUDY TREATMENT 
 
Investigational product 
Avalglucosidase alfa (recombinant human α-glucosidase conjugated 
with synthetic bis-mannose-6-phosphate-Man6 glycan). 
Formulation and route of administration 
Sterile lyophilized powder administered by intravenous (IV) infusion 
following reconstitution and dilution. 
Dose regimen 
20 mg/kg of body weight every other week (qow). 
PRIMARY ENDPOINT 
Primary endpoint: 
Safety: 
Assessment of adverse events (AEs)/treatment-emergent AEs 
(TEAEs), including infusion-associated reactions (IARs) and deaths. 
Physical examination. 
Clinical laboratory evaluations including hematology, biochemistry, and 
urinalysis. 
Vital signs. 
Body weight. 
12-lead electrocardiogram (ECG). 
Immunogenicity assessments. 
SECONDARY AND EXPLORATORY 
ENDPOINTS 
Secondary endpoints: 
Pharmacokinetics 
Estimates for Cmax, AUClast, AUC, t1/2z, CL, and Vd. 
Pharmacodynamics 
Skeletal muscle magnetic resonance imaging (MRI). 
Skeletal muscle needle or open biopsy. 
Urinary Hex4. 
Exploratory plasma and urine biomarkers. 
Pharmacogenetics 
Serum skeletal muscle ribonucleic acid (RNA) expression analysis. 
Plasma circulating microRNA analyses. 
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Exploratory Endpoints: 
Efficacy 
6-minute walk test (6MWT). 
Pulmonary function testing (PFT) endpoints. 
ASSESSMENT SCHEDULE 
Refer to study and period flow charts. 
Medical/surgical history, and Pompe disease history, including GAA 
gene mutations, will be imported from the patient’s prior 
avalglucosidase alfa study file in the database when possible. 
STATISTICAL CONSIDERATIONS 
Out of range laboratory values, vital signs, and ECGs will be flagged by 
the Investigator as clinically significant or non-clinically significant 
abnormalities. The clinically significant abnormalities will be recorded 
as AEs and included in the TEAE counts. 
Treatment-emergent adverse events will be tabulated (counts and 
percentages). 
Infusion-associated reactions and discontinuations due to AEs will be 
summarized. 
Descriptive statistics will be generated by dose level and time points for 
selected parameters of interest. 
In addition, raw data and changes from baseline for selected 
parameters will be summarized by descriptive statistics and/or plots. 
Descriptive statistics for actual values and changes from baseline will 
be generated by time point for selected safety parameters of interest. 
Data may also be plotted. For the purpose of analysis, baseline will be 
prior to the first dose of GZ402666 in any prior avalglucosidase alfa 
study. 
Pharmacokinetics 
Pharmacokinetic parameters will be summarized for each dose level 
and study visit by means of descriptive statistics. 
Pharmacodynamics 
Changes over time in tissue glycogen content in the lower extremity 
muscle will be summarized using descriptive statistics. Evaluation of 
intact muscle and fatty replacement from MRI will be descriptive using 
a grading scale and, if feasible, quantitative using a numeric method of 
determining the degree (%) of overall fatty replacement of muscle from 
the skeletal muscle MRI and an individual (%) measure for the 
quadriceps. A correlative measure comparing the biopsied muscle and 
its MRI counterpart will also be performed. Relationship between 
pharmacodynamic and efficacy endpoints will be explored using 
graphic display or correlational analysis as appropriate. 
Exploratory efficacy 
Observed measurements and changes from baseline will be provided 
for each endpoint: 6MWT and PFT parameters. 
DURATION OF STUDY (per patient) 
The duration of the study for each patient is initially 6 years. Each 
patient will continue with the study until the patient withdraws, the 
Investigator withdraws the patient, or the Sponsor terminates the study. 
An additional follow-up phase will begin after the patient has completed 
the 6-year study period, and will last until avalglucosidase alfa is 
approved in the patient’s country, except in the UK, Germany and 
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Denmark, where the duration of the additional follow-up phase will be 
up to the approval in the country or limited to a maximum of 2 years, 
whichever occurs first (ie, for patients in the UK, Germany and 
Denmark, the total study duration per patient is 8 years at the maximum 
including the initial 6-year period and the additional 2-year follow-up). 
STUDY COMMITTEES 
Steering Committee: No 
Data Monitoring Committee: Yes 
Adjudication Committee: No 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
Baselinea 
• Informed consent 
• Inclusion/exclusion 
criteria 
• Urine pregnancy test 
(females only) 
• ECG 
• Demographics 
• Medical/surgical 
history 
• Pompe disease 
history, including 
GAA mutation 
• ECG, hematology, 
biochemistry and 
urinalysis data prior to 
first avalglucosidase 
alfa infusion 
• Results of MRI 
baseline from 
previous 
avalglucosidase alfa 
study to be obtained 
 
Biweeklyb  
• Infusion of 
avalglucosida
se alfa  
• Vital signs 
 
Monthly  
• Urine pregnancy 
test (females 
only) 
• For first 3 years 
since enrollment: 
Biochemistry 
• For first 
6 months:  
Anti-
avalglucosidase 
alfa antibodies 
and neutralizing 
antibodies in 
ADA-positive 
patients 
 
Quarterly 
• Body weight 
• After first 
6 months: 
Anti-avalglucosida
se alfa antibodies 
and neutralizing 
antibodies in 
ADA-positive 
patients 
• After first 3 years 
since enrollment: 
Biochemistry 
 
Every 6 Months  
• Physical examination 
• ECG 
• Hematology and urinalysis 
• Anti-alglucosidase alfa IgG 
antibodies (only patients 
who were previously treated 
with alglucosidase alfa) 
• 6MWT 
• PFT 
 
At 6 Months, 
Yearly Thereafter 
• avalglucosidase 
alfa plasma 
samples for PK 
analysis 
• Urine Hex4 sample 
collection 
• Exploratory 
biomarker urine 
sample collection 
• Exploratory 
biomarker plasma 
sample collection 
• microRNA plasma 
sample collection 
 
Every 2 Years 
• MRI 
• Skeletal muscle 
needle or open 
biopsyc 
• Serum samples for 
skeletal muscle 
RNA expression 
analysisc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Every Visit: Adverse event and concomitant medication collection 
 
 
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Re-baseline Visit 
 
• Physical examination (within 1 
month) 
• Urine pregnancy test (females 
only) 
• Body weight 
• Vital signs 
• ECG (within 1 month) 
• Hematology and urinalysis 
(within 1 month) 
• Biochemistry 
• Anti-avalglucosidase alfa 
antibodies and neutralizing 
antibodies in ADA-positive 
patients 
• Anti-alglucosidase alfa IgG 
antibodies (only patients who 
were previously treated with 
alglucosidase alfa) 
• avalglucosidase alfa plasma PK 
samples (within 6 months) 
• MRI (within 6 months) 
• Skeletal muscle needle or open 
biopsy (within 6 months)c 
• Urine Hex4 sample collection 
(within 1 month) 
• Exploratory biomarker urine 
sample collection (within 
1 month) 
• Exploratory biomarker plasma 
sample collection (within 
1 month) 
• 6MWT (within 1 month) 
• PFT (within 1 month) 
• microRNA plasma sample 
collection (within 1 month) 
• Serum samples for skeletal muscle 
RNA expression analysis (within 
6 months)c 
 
End of Study Visit  
• Physical examination 
• Urine pregnancy test (females 
only) 
• Body weight 
• Vital signs 
• ECG 
• Hematology and urinalysis 
• Biochemistry 
• Anti-avalglucosidase alfa 
antibodies and neutralizing 
antibodies in ADA-positive 
patients 
• Anti-alglucosidase alfa IgG 
antibodies (only patients who 
were previously treated with 
alglucosidase alfa) 
• avalglucosidase alfa plasma PK 
samples 
• MRI 
• Skeletal muscle needle or open 
biopsy (within 6 months)c 
• Urine Hex4 sample collection 
• Exploratory biomarker urine 
sample collection 
• Exploratory biomarker plasma 
sample collection 
• 6MWT 
• PFT 
• microRNA plasma sample 
collection 
• Serum samples for skeletal muscle 
RNA expression analysis (within 
6 months)c 
• Infusion of avalglucosidase alfa  
 
 
 
 
 
 
 
Follow-up Visit: Adverse event and concomitant medication collection 
 
 
 
Additional Follow-up Phase: An additional follow-up phase will begin after the patient has completed the 6-year study period, and will last until 
avalglucosidase alfa is approved in the patient’s country, except in the UK, Germany and Denmark, where the duration of the additional follow-up phase will 
be up to the approval in the country or limited to a maximum of 2 years, whichever occurs first (ie, for patients in the UK, Germany and Denmark, the total 
study duration per patient is 8 years at the maximum including the initial 6-year period and the additional 2-year follow-up). 
 
 
a Note that medical/surgical history, and Pompe disease history, including GAA gene mutations will be imported from the patient’s prior avalglucosidase alfa study file in the database when possible. ECG, 
hematology, biochemistry, and urinalysis data from first day of avalglucosidase alfa infusion (ie, prior to first infusion in any prior avalglucosidase alfa study) will be entered by the study site into the database. 
b In case of temporary treatment discontinuation visit and assessment schedules will be adapted to the absence of infusion of avalglucosidase alfa (GZ402666) as outlined in Section 10.1.3.8. 
c Muscle biopsy is not required in patients in whom the prior muscle biopsy, obtained in a prior avalglucosidase alfa study, had a glycogen content <5% unless the patient shows significant clinical decline.  
6MWT = 6-minute walk test; ADA = anti-drug antibody, ECG = electrocardiogram; Hex4 = glucose tetrasaccharide; IgG = immunoglobulin G; MRI = magnetic resonance imaging; PFT = pulmonary function testing; 
PK = pharmacokinetic(s) 
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2 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 09 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE .................................................................. 2 
1 
FLOW CHARTS ............................................................................................................................... 9 
1.1 
GRAPHICAL STUDY DESIGN ........................................................................................................ 9 
1.2 
STUDY FLOW CHART .................................................................................................................. 11 
1.2.1 
Patients receiving same dose as received in a prior avalglucosidase alfa study (inclusive of 
20 mg/kg qow) ................................................................................................................................ 11 
1.2.2 
Patients being switched to avalglucosidase alfa 20 mg/kg qow from previous different dose ...... 13 
1.2.3 
Additional follow-up phase ............................................................................................................. 15 
2 
TABLE OF CONTENTS ................................................................................................................ 17 
2.1 
LIST OF TABLES ........................................................................................................................... 22 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 23 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 25 
4.1 
INTRODUCTION ............................................................................................................................ 25 
4.1.1 
Safety pharmacology and toxicology ............................................................................................. 25 
4.1.2 
Absorption, distribution, metabolism, and excretion data .............................................................. 27 
4.2 
STUDY DESIGN AND RATIONALE OF SPECIFIC PARAMETERS ............................................ 30 
4.2.1 
Study design .................................................................................................................................. 30 
4.2.2 
Specific parameters rationale ........................................................................................................ 30 
4.2.2.1 
Safety ............................................................................................................................................. 30 
4.2.2.2 
Pharmacodynamic and exploratory biomarkers assessments ...................................................... 31 
4.2.2.3 
Exploratory efficacy ........................................................................................................................ 32 
4.2.2.4 
Pharmacogenomics ....................................................................................................................... 32 
5 
STUDY OBJECTIVES ................................................................................................................... 33 
5.1 
PRIMARY ....................................................................................................................................... 33 
5.2 
SECONDARY ................................................................................................................................ 33 
6 
STUDY DESIGN ............................................................................................................................ 34 
6.1 
DESCRIPTION OF THE PROTOCOL ........................................................................................... 34 
6.2 
DURATION OF STUDY PARTICIPATION .................................................................................... 34 
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6.2.1 
Duration of study participation for each patient ............................................................................. 34 
6.2.2 
Determination of end of clinical trial (all patients) .......................................................................... 34 
6.3 
STUDY CONDUCT ........................................................................................................................ 35 
6.3.1 
Data Monitoring Committee ........................................................................................................... 35 
6.3.2 
Allergic Reaction Review ............................................................................................................... 35 
6.3.3 
Guidance for stopping rules ........................................................................................................... 35 
6.3.3.1 
Individual patient stopping criteria .................................................................................................. 35 
6.3.3.2 
Study stopping criteria ................................................................................................................... 36 
7 
SELECTION OF PATIENTS .......................................................................................................... 37 
7.1 
INCLUSION CRITERIA .................................................................................................................. 37 
7.2 
EXCLUSION CRITERIA ................................................................................................................ 37 
8 
STUDY TREATMENTS ................................................................................................................. 38 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS ............................................................................. 38 
8.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS .................................................................... 40 
8.3 
BLINDING PROCEDURES ............................................................................................................ 40 
8.3.1 
Methods of blinding ........................................................................................................................ 40 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 40 
8.5 
PACKAGING AND LABELING ...................................................................................................... 41 
8.6 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 41 
8.7 
RESPONSIBILITIES ...................................................................................................................... 41 
8.7.1 
Treatment accountability and compliance...................................................................................... 42 
8.7.2 
Return and/or destruction of treatments ........................................................................................ 42 
8.8 
CONCOMITANT MEDICATION ..................................................................................................... 42 
8.8.1 
Pretreatment for patients with infusion-associated reactions ........................................................ 43 
8.8.2 
Management of infusion-associated reactions .............................................................................. 43 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 44 
9.1 
PRIMARY ENDPOINT - SAFETY .................................................................................................. 44 
9.1.1 
Adverse events .............................................................................................................................. 44 
9.1.2 
Physical examination ..................................................................................................................... 45 
9.1.3 
Laboratory safety variables ............................................................................................................ 45 
9.1.4 
Vital signs ....................................................................................................................................... 46 
9.1.5 
Body weight .................................................................................................................................... 46 
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9.1.6 
Electrocardiogram variables .......................................................................................................... 46 
9.1.7 
Immunogenicity .............................................................................................................................. 47 
9.2 
PHARMACOKINETICS .................................................................................................................. 47 
9.2.1 
Sampling times ............................................................................................................................... 47 
9.2.2 
Number of pharmacokinetic samples ............................................................................................. 48 
9.2.3 
Sample handling procedure ........................................................................................................... 48 
9.2.4 
Bioanalytical methods .................................................................................................................... 48 
9.2.5 
Pharmacokinetic parameters ......................................................................................................... 48 
9.3 
PHARMACODYNAMIC PARAMETERS ........................................................................................ 49 
9.3.1 
Skeletal muscle magnetic resonance imaging ............................................................................... 49 
9.3.2 
Skeletal muscle biopsy .................................................................................................................. 50 
9.3.3 
Urinary Hex4 .................................................................................................................................. 50 
9.3.4 
Exploratory plasma and urine biomarkers ..................................................................................... 50 
9.4 
EXPLORATORY EFFICACY ASSESSMENTS ............................................................................. 50 
9.4.1 
Six-minute walk test ....................................................................................................................... 50 
9.4.2 
Pulmonary function testing endpoints ............................................................................................ 51 
9.5 
PHARMACOGENETIC ASSESSMENT ......................................................................................... 51 
9.5.1 
Skeletal muscle RNA expression analysis ..................................................................................... 51 
9.5.2 
Circulating microRNA analysis ....................................................................................................... 51 
9.6 
SAMPLED BLOOD VOLUME ........................................................................................................ 51 
9.7 
FUTURE USE OF SAMPLES ........................................................................................................ 51 
10 
STUDY PROCEDURES ................................................................................................................ 53 
10.1 
VISIT SCHEDULE .......................................................................................................................... 53 
10.1.1 
Baseline visit .................................................................................................................................. 53 
10.1.2 
Treatment phase ............................................................................................................................ 53 
10.1.2.1 Biweekly ......................................................................................................................................... 53 
10.1.2.2 Monthly ........................................................................................................................................... 54 
10.1.2.3 Quarterly ........................................................................................................................................ 54 
10.1.2.4 Every 6 months .............................................................................................................................. 54 
10.1.2.5 At 6 months and yearly thereafter .................................................................................................. 54 
10.1.2.6 Every 2 years ................................................................................................................................. 55 
10.1.2.7 Re-baseline visit ............................................................................................................................. 55 
10.1.2.8 Patient temporarily discontinued from study treatment while remaining in the study .................... 56 
10.1.3 
Additional follow-up phase ............................................................................................................. 56 
10.1.3.1 Biweekly ......................................................................................................................................... 56 
10.1.3.2 Monthly ........................................................................................................................................... 57 
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10.1.3.3 Quarterly ........................................................................................................................................ 57 
10.1.3.4 Every 6 months .............................................................................................................................. 57 
10.1.3.5 Yearly ............................................................................................................................................. 57 
10.1.3.6 Every 2 years ................................................................................................................................. 57 
10.1.3.7 End of study visit ............................................................................................................................ 57 
10.1.3.8 Follow-up ........................................................................................................................................ 58 
10.2 
DEFINITION OF SOURCE DATA .................................................................................................. 59 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION ....................................... 60 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ........................... 60 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ........................... 60 
10.3.3 
Criteria for permanent treatment discontinuation ........................................................................... 61 
10.3.4 
Handling of patients after permanent treatment discontinuation ................................................... 61 
10.3.5 
Procedure and consequence for patient withdrawal from study .................................................... 61 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING .......................... 62 
10.4.1 
Definitions of adverse events ......................................................................................................... 62 
10.4.1.1 Adverse event ................................................................................................................................ 62 
10.4.1.2 Serious adverse event ................................................................................................................... 62 
10.4.1.3 Adverse event of special interest ................................................................................................... 62 
10.4.2 
General guidelines for reporting adverse events ........................................................................... 64 
10.4.3 
Instructions for reporting serious adverse events .......................................................................... 64 
10.4.4 
Guidelines for reporting adverse events of special interest ........................................................... 65 
10.4.4.1 Reporting of adverse events of special interest with immediate notification ................................. 65 
10.5 
OBLIGATIONS OF THE SPONSOR ............................................................................................. 66 
10.6 
ADVERSE EVENTS MONITORING .............................................................................................. 66 
11 
STATISTICAL CONSIDERATIONS .............................................................................................. 67 
11.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 67 
11.2 
DISPOSITION OF PATIENTS ....................................................................................................... 67 
11.2.1 
Protocol deviations ......................................................................................................................... 68 
11.3 
ANALYSIS POPULATIONS ........................................................................................................... 68 
11.4 
PATIENT DEMOGRAPHIC AND MEDICAL HISTORY ................................................................. 68 
11.5 
SAFETY ANALYSIS....................................................................................................................... 69 
11.5.1 
Physical examination, vital signs, and body weight ....................................................................... 69 
11.5.2 
Clinical laboratory tests .................................................................................................................. 69 
11.5.3 
Adverse events .............................................................................................................................. 69 
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11.5.4 
Electrocardiogram .......................................................................................................................... 69 
11.5.5 
Anti-avalglucosidase alfa antibodies, neutralizing antibodies, and infusion-associated 
reactions ......................................................................................................................................... 69 
11.6 
ANALYSIS OF PHARMACOKINETIC DATA ................................................................................. 70 
11.6.1 
Pharmacokinetic parameters ......................................................................................................... 70 
11.6.2 
Statistical analysis .......................................................................................................................... 70 
11.7 
PHARMACODYNAMIC AND EXPLORATORY BIOMARKER ANALYSIS ................................... 70 
11.8 
EXPLORATORY EFFICACY ANALYSIS....................................................................................... 71 
11.9 
EXTENT OF STUDY TREATMENT EXPOSURE AND COMPLIANCE ........................................ 71 
11.10 
PRIOR/CONCOMITANT MEDICATION/THERAPY ...................................................................... 71 
11.11 
INTERIM ANALYSIS ...................................................................................................................... 71 
12 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ............................. 72 
12.1 
REGULATORY AND ETHICAL CONSIDERATIONS .................................................................... 72 
12.2 
INFORMED CONSENT PROCESS ............................................................................................... 73 
13 
STUDY MONITORING................................................................................................................... 75 
13.1 
DATA QUALITY ASSURANCE ...................................................................................................... 75 
13.2 
SOURCE DOCUMENTS ............................................................................................................... 75 
14 
ADDITIONAL REQUIREMENTS ................................................................................................... 77 
14.1 
DATA PROTECTION ..................................................................................................................... 77 
14.2 
STUDY AND SITE CLOSURE ....................................................................................................... 79 
14.3 
CLINICAL TRIAL RESULTS AND DISSEMINATION OF CLINICAL STUDY DATA..................... 79 
14.4 
PUBLICATION POLICY ................................................................................................................. 80 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS .......................................................................... 81 
16 
BIBLIOGRAPHIC REFERENCES ................................................................................................. 82 
17 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 83 
17.1 
APPENDIX 1: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 83 
17.2 
APPENDIX 2: PROTOCOL AMENDMENT HISTORY .................................................................. 83 
17.2.1 
Amended protocol 01: 09 December 2013 .................................................................................... 83 
17.2.2 
Amended protocol 02: 25 July 2014 .............................................................................................. 84 
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17.2.3 
Amended protocol 03: 29 January 2016 ........................................................................................ 84 
17.2.4 
Amended protocol 04: 27 November 2017 .................................................................................... 85 
17.2.5 
Amended protocol 05: 18 July 2018 .............................................................................................. 85 
17.2.6 
Amended protocol 06: 06 September 2019 ................................................................................... 86 
17.2.7 
Amended protocol 07: 21 January 2020 ........................................................................................ 89 
17.2.8 
Amended protocol 08: 30 September 2020 ................................................................................... 90 
2.1 
LIST OF TABLES 
 
Table 1 - Toxicokinetic parameters for avalglucosidase alfa following the fourth intravenous dose to CD-1 
mice at a dose of 4, 40, or 120 mg/kg ........................................................................................................... 28 
Table 2 - Toxicokinetic parameters for avalglucosidase alfa following the first and fourth intravenous 
infusion to cynomolgus monkeys at doses of 4, 40, and 120 mg/kg ............................................................. 29 
Table 3 - Toxicokinetic parameters for avalglucosidase alfa following the 1st, 7th, and 13th intravenous 
infusion to cynomolgus monkeys at a dose of 50 and 200 mg/kg ................................................................ 30 
Table 4 - List of pharmacokinetic parameters and definitions ....................................................................... 49 
 
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3 
LIST OF ABBREVIATIONS 
 
6MWT: 
6-minute walk test 
ADA: 
anti-drug antibody 
AE: 
adverse event 
AESI: 
adverse events of special interest 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
AUC: 
area under the concentration curve  
bis-M6P: 
bis-mannose-6-phosphate 
CI: 
confidence interval 
CL: 
clearance 
CPR: 
cardiopulmonary resuscitation 
CRF: 
case report form 
CTCAE: 
common terminology criteria for adverse events 
DMC: 
Data Monitoring Committee 
DPO: 
Data Protection Officer 
EC: 
Ethics Committee 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
ERT: 
enzyme replacement therapy 
EU: 
European Union 
FDA: 
Food and Drug Administration 
FEV1: 
forced expiratory volume in the 1st second of the FVC maneuver  
FVC: 
forced vital capacity 
GAA: 
acid alpha-glucosidase 
GAAKO: 
GAA knockout 
GCP: 
Good Clinical Practice 
GDPR: 
General Data Protection Regulation 
GSD: 
glycogen storage disease 
Hex4: 
glucose tetrasaccharide 
IAR: 
infusion-associated reaction 
IB: 
Investigator’s Brochure 
ICF: 
Informed Consent Form 
ICH: 
International Council for Harmonisation 
IEC: 
Independent Ethics Committee 
IgE: 
immunoglobulin E 
IgG: 
immunoglobulin G 
IMP: 
investigational medicinal product  
IRB: 
Institutional Review Board 
IV: 
intravenous 
M6P: 
mannose-6-phosphate 
MedDRA: 
Medical Dictionary for Regulatory Activities 
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MEP: 
maximal expiratory pressure  
MIP: 
maximal inspiratory pressure  
MRI: 
magnetic resonance imaging 
MUG: 
methylumbelliferyl-α-D-glucoside 
NCI: 
National Cancer Institute 
NOAEL: 
no observed adverse effect level 
PEF: 
peak expiratory flow 
PFT: 
pulmonary function testing 
PI: 
Principal Investigator 
PK: 
pharmacokinetic(s) 
PR: 
interval from the beginning of the P wave until the beginning of the QRS 
complex 
PT: 
preferred term 
qow: 
every other week 
QRS: 
interval from start of the Q wave to the end of the S wave 
QT: 
interval between the start of the Q wave to the end of the T wave 
QTc: 
QT interval corrected for heart rate 
rhGAA: 
recombinant human acid alpha-glucosidase 
RNA: 
ribonucleic acid 
RR: 
interval between the peaks of successive QRS complexes 
SAE: 
serious adverse event 
SD: 
standard deviation 
SOC: 
system organ class 
SUSAR: 
suspected unexpected serious adverse reaction 
t1/2: 
terminal elimination half-life  
TEAE: 
treatment-emergent adverse event  
TK: 
toxicokinetic(s) 
ULN: 
upper limit of normal 
β-HCG: 
beta-human chorionic gonadotropin  
 
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4 
INTRODUCTION AND RATIONALE 
4.1 
INTRODUCTION 
Pompe disease (also known as acid maltase deficiency or glycogen storage disease [GSD] 
Type II) is a rare, autosomal recessive genetic disorder caused by the deficiency of lysosomal acid 
α-glucosidase (GAA), an enzyme that degrades glycogen. Genzyme, a Sanofi company, has 
developed alglucosidase alfa, which contains the active ingredient recombinant human acid 
α-glucosidase (rhGAA), as long-term enzyme replacement therapy (ERT) for patients with a 
confirmed diagnosis of Pompe disease. Alglucosidase alfa treatment is globally approved 
(tradenames: Myozyme® and Lumizyme®) for the treatment of Pompe disease based on its 
efficacy to prolong invasive ventilator-free survival in infants (1) and its ability to improve 
walking distance and to stabilize respiratory function in children 8 years and older and adults (2). 
To achieve these benefits, alglucosidase alfa is administered at high doses (20 mg/kg every other 
week[qow]), relative to other ERTs. Echocardiogram measurements demonstrate that 
alglucosidase alfa works well in cardiac muscle. There is a more variable response to treatment in 
skeletal muscle. This is thought to be, at least in part, due to the relative low level of  
bis-mannose-6-phosphate (bis-M6P) on alglucosidase alfa. Therefore, increasing the level of  
bis-M6P on alglucosidase alfa may provide a mechanism to drive uptake into the skeletal muscle. 
Genzyme is investigating a second generation therapy for Pompe disease called avalglucosidase 
alfa (neoGAA, GZ402666) (rhGAA conjugated with synthetic bis-M6P-Man6 glycan). 
Avalglucosidase alfa is a modification of alglucosidase alfa that results in the conjugation of a 
number of hexamannose structures containing 2 terminal M6P moieties to oxidized sialic acid 
residues on alglucosidase alfa, thereby increasing bis-M6P levels on the compound.  
4.1.1 Safety pharmacology and toxicology 
Four in vivo toxicology studies have been conducted to support the development of 
avalglucosidase alfa. These include 2 repeat dose studies (2 and 4 weeks) conducted in CD-1 
mice, and 2 repeat dose studies (4 weeks and 6 months) conducted in cynomolgus monkeys. A 
safety pharmacology evaluation was also conducted as part of the 6-month toxicity study in 
cynomolgus monkeys. Additionally, a mouse micronuclei assessment was conducted in GAA 
knockout (GAAKO) mice to evaluate the potential genotoxicity of avalglucosidase alfa. 
The toxicity of avalglucosidase alfa was first evaluated in CD-1 mice in a 14-day repeat dose 
study. Doses were administered as an intravenous (IV) bolus at 50 mg/kg every other day for 
14 days. Administration of avalglucosidase alfa at 50 mg/kg was associated with macroscopic 
findings in the male reproductive tract (none of the male reproductive tract tissues were examined 
microscopically). 
In the liver, minimal to mild multifocal necrosis and inflammatory infiltrates were present after 
administration of avalglucosidase alfa at 50 mg/kg, although no correlating serum chemistry 
alterations were observed. Terminal elevations in serum calcium, phosphorus, and potassium were 
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observed in males dosed with 50 mg/kg of avalglucosidase alfa. A definitive relationship of these 
alterations to the test article could not be established because of the possible confounding factor of 
carbon dioxide asphyxiation prior to blood collection in these animals. The above findings were 
further evaluated in the 28-day studies in CD-1 mice and cynomolgus monkeys, and in the 
26-week study in cynomolgus monkeys. 
The toxicity of avalglucosidase alfa was evaluated in 28-day repeat dose toxicity studies in the 
CD-1 mouse and the cynomolgus monkey. In both studies, avalglucosidase alfa was administered 
every week for 28 days (4 doses total) at 0, 4, 40, or 120 mg/kg via IV bolus to mice or via a 
6-hour IV infusion to monkeys. Toxicokinetic data are summarized in Section 4.1.2. 
Results from the study in CD-1 mice demonstrated that repeated administrations of 
avalglucosidase alfa were overall well tolerated. One death was noted and 1 early sacrifice was 
necessary within 1 hour of the fourth avalglucosidase alfa administration in the 4 mg/kg dose 
group. This was likely due to a hypersensitivity reaction following repeated administration of a 
human protein into a mouse. There were no significant changes noted in body weights, clinical 
observations, clinical chemistry and hematology parameters, or in organ weights and organ to 
body weight ratios. Histopathology of all animals at the terminal sacrifice showed no evidence of 
toxicity related to avalglucosidase alfa administration. 
The no observed adverse effect level (NOAEL) was established at ≥120 mg/kg in CD-1 mice. 
Results from the study in cynomolgus monkeys demonstrated that once weekly repeated 
administrations via a 6-hour IV infusion for 4 consecutive weeks was well tolerated by 
cynomolgus monkeys. There were no test article-related clinical signs or changes in body weight, 
body weight change (gain), physical examination findings, clinical pathology parameters, or 
macroscopic/microscopic findings that could be attributed to the administration of avalglucosidase 
alfa. 
The NOAEL was established at ≥120 mg/kg in cynomolgus monkeys. 
As hypersensitivity reactions are likely to occur in mice in long-term repeat dose toxicity 
assessments, and no differences in toxicological findings between species were noted in the 
28-day studies, a 26-week repeat dose toxicity study was conducted in one species, the 
cynomolgus monkey. Avalglucosidase alfa was administered every other week for 26 weeks at 
doses of 0, 50, or 200 mg/kg via a 6-hour IV infusion, followed by a 4-week recovery period. 
Toxicokinetic data are summarized in Section 4.1.2. 
Administration of avalglucosidase alfa was well tolerated and caused no changes in any parameter 
that was measured in this study. There were no test article-related changes in clinical 
observations, body weights, body weight changes, food consumption, ophthalmic evaluations, 
organ weights, or in macroscopic/microscopic evaluations. Furthermore, there were no 
macroscopic or microscopic findings in the male reproductive tract or in the liver. 
There were 2 early sacrifices during the study. One female monkey on study was sacrificed in a 
moribund condition prior to receiving any test article. On Day 168, a second female monkey at 
50 mg/kg was sacrificed in a moribund condition. The most likely cause of the moribund 
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condition was the result of systemic inflammation resulting from contamination of the venous 
access port and unrelated to the test article based on the macroscopic and microscopic findings. 
The following evaluations were conducted as part of this study for evaluation of safety 
pharmacology and the results are as follows: 
• Central nervous system: There were no changes in activity levels considered related to 
avalglucosidase alfa administration when compared to controls. All monkeys were 
observed to be in a normal quiet state (score of 2) to a high arousal state (score of 4) 
during the study. Observations for the presence of muscle fasciculations, facial muscle 
movements, and visual field were all normal. 
• Respiratory rate, heart rate, and core body temperature: There were no changes considered 
related to avalglucosidase alfa administration when compared to controls. 
• Electrocardiograms (ECGs): All monkeys maintained sinus rhythms throughout the study. 
One atrial and 1 ventricular premature depolarization were noted on Day 155. The 
ventricular premature depolarization occurred in a male animal administered vehicle, and 
the atrial premature depolarization was observed in a male monkey treated with 50 mg/kg 
of avalglucosidase alfa. These rhythm disturbances can occur in normal monkeys and were 
not test article related. Intravenous dosing once every 2 weeks with avalglucosidase alfa at 
up to 200 mg/kg/dose did not have any toxicologic effects on recorded ECGs in this study. 
The NOAEL was established at 200 mg/kg in cynomolgus monkeys. 
4.1.2 Absorption, distribution, metabolism, and excretion data 
The pharmacokinetics (PK) of avalglucosidase alfa have been evaluated in a number of preclinical 
studies in the GAAKO mouse model of Pompe disease following administration of 20 mg/kg. 
Additionally, toxicokinetic (TK) evaluations were conducted as part of the 28-day toxicology 
study in CD-1 mice, the 28-day toxicology study in non-human primates, and the 26-week 
toxicology study in non-human primates. 
Average PK parameters in GAAKO mice following a single IV administration at 20 mg/kg of 
avalglucosidase alfa are as follows: the terminal elimination half-life (t1/2), 26.9 minutes; volume 
of distribution, 29.0 mL/kg; area under the concentration curve (AUC), 36.7 minutes*mg/mL; and 
clearance (CL), 0.55 mL/minutes/kg. 
Avalglucosidase alfa TK was evaluated following single and repeat IV administration at dose 
levels of 4, 40, and 120 mg/kg in CD-1 mice (Table 1). Saturation kinetics were observed at the 
dose levels evaluated. This was characterized by increased t1/2, decreased CL, and increased 
AUC/dose as the dose levels increased to 120 mg/kg. No consistent differences in TK parameters 
were noted when comparing the first and fourth dose, suggesting that there were no meaningful 
changes in TK parameters following repeated IV administration in CD-1 mice. 
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Table 1 - Toxicokinetic parameters for avalglucosidase alfa following the fourth intravenous dose 
to CD-1 mice at a dose of 4, 40, or 120 mg/kg 
Parameter 
4 mg/kg 
(n=1) 
40 mg/kg 
(n=6) 
120 mg/kg 
(n=5) 
t1/2 (hr) 
0.315 
0.752 ±0.242 
0.939 ±0.127 
CL (mL/hr) 
80.0 
28.4 ±8.80 
27.0 ±3.83 
Vz (mL) 
36.3 
29.7 ±8.46 
36.2 ±4.10 
Cmax (μg/mL) 
68.8 
949 ±161 
2866 ±656 
AUC0-inf (μg x hr/mL) 
50.0 
1498 ±368 
4513 ±589 
AUC0-inf/Dose (μg x hr/mL/Dose) 
12.5 
37.4 ±9.19 
37.6 ±4.91 
Values represent mean ±SD. 
Toxicokinetic parameters were also determined for avalglucosidase alfa in non-human primates 
following the first and fourth infusion at 40 and 120 mg/kg dose levels in a 28-day toxicology 
study (Table 2). There were limited serum concentration data available for the 4 mg/kg dose level 
at both the first and fourth doses, which did not allow for the estimation of TK parameters. Across 
both infusions analyzed, avalglucosidase alfa elimination was either monophasic or biphasic. 
Toxicokinetic parameters were calculated only from the first phase of elimination, as the second 
phase had limited data points for analysis (many animals had avalglucosidase alfa levels below 
the level of detection at later time points). 
At both the first and fourth infusions of avalglucosidase alfa, saturation kinetics appear to be 
present. While this is only a trend at the first infusion, statistically significant differences occur in 
t1/2 and CL at the fourth infusion. This suggests that saturation kinetics may become more 
prominent between 40 and 120 mg/kg after repeated infusions of avalglucosidase alfa. 
No significant differences were noted for TK parameters between the first and fourth infusions at 
the 40 mg/kg dose level, but significant differences in TK parameters (decreased CL and 
increased AUC0-inf/dose) were noted with repeated administration at the 120 mg/kg dose level. 
This suggests that repeated dosing in the monkey at this dose level affects the TK profile of 
avalglucosidase alfa. For both dose levels and infusions, avalglucosidase alfa TKs did not appear 
to differ between male and female monkeys. 
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Table 2 - Toxicokinetic parameters for avalglucosidase alfa following the first and fourth 
intravenous infusion to cynomolgus monkeys at doses of 4, 40, and 120 mg/kg 
 
First Dose 
Fourth Dose 
Parameter 
4 mg/kg 
(n=4) 
40 mg/kg 
(n=4) 
120 mg/kg 
(n=4) 
4 mg/kg 
(n=4) 
40 mg/kg 
(n=4) 
120 mg/kg 
(n=4) 
t1/2 (hr) 
N/A 
0.533 ±0.189 
0.729 ±0.179 
N/A 
0.508 ±0.184 
0.919 ±0.199a 
CL (mL/hr/kg) 
N/A 
53.5 ±21.5 
40.3 ±10.6 
N/A 
43.3 ±8.84 
20.5 ±2.22b, d 
Vz (mL/kg) 
N/A 
38.4 ±10.5 
44.0 ±20.2 
N/A 
33.0 ±18.5 
27.0 ±6.01 
Cmax (μg/mL) 
N/A 
192 ±63.3 
862 ±302 
N/A 
258 ±39.7 
1273 ±214  
AUC0-inf (μg x hr/mL) 
N/A 
824 ±260 
3155 ±911 
N/A 
954 ±202 
5900 ±660e  
AUC0-inf/Dose  
(μg x hr/mL/Dose) 
N/A 
20.6 ±6.49 
26.3 ±7.59 
N/A 
23.9 ±5.05 
49.2 ±5.50c, e 
Values represent mean ±SD. Statistics performed below were unpaired t-tests. 
a p value <0.05, TK parameter significantly different (40 vs 120 mg/kg fourth infusion). 
b p value <0.01, TK parameter significantly different (40 vs 120 mg/kg fourth infusion). 
c p value <0.001, TK parameter significantly different (40 vs 120 mg/kg fourth infusion). 
d p value <0.05, TK parameter significantly different (120 mg/kg first vs fourth infusion). 
e p value <0.01, TK parameter significantly different (120 mg/kg first vs fourth infusion). 
Toxicokinetics were evaluated as part of the 6-month toxicology study in non-human primates. 
Avalglucosidase alfa TK parameters were evaluated following the 1st, 7th, and 13th infusion at 
the 50 and 200 mg/kg dose levels. 
Across all infusions and both doses analyzed, avalglucosidase alfa elimination was biphasic. 
Toxicokinetics parameters were calculated only from the first phase of elimination, as the second 
phase had limited data points for analysis and represented GAA activity at, or very close to, 
background levels observed in vehicle-treated animals. 
At infusion 1, 7, and 13 of avalglucosidase alfa, saturation kinetics were present (Table 3). These 
dose-related TK differences reached statistical significance with all 3 infusions analyzed. This 
strongly suggests that saturation kinetics is occurring between 50 and 200 mg/kg with 
avalglucosidase alfa in monkeys. 
Intradose TK parameters appeared to change with successive infusions (ie, infusion 1, 7, and 13). 
These changes were characterized by increases in Cmax, t1/2, and AUC, and decreases in CL. 
Compared to the first infusion of 50 mg/kg, most TK parameters were significantly different for 
both the 7th and 13th infusions. At 200 mg/kg, compared to the first infusion, most TK 
parameters exhibited a trend for differences at infusion 7 and significant differences at 
infusion 13. Toxicokinetic parameter changes observed between infusion 1, 7, and 13 suggest that 
repeated dosing in the monkey at the dose levels tested affects the TK profile of avalglucosidase 
alfa. 
For both dose levels and infusions, avalglucosidase alfa TK did not appear to differ between male 
and female monkeys. 
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Table 3 - Toxicokinetic parameters for avalglucosidase alfa following the 1st, 7th, and 13th 
intravenous infusion to cynomolgus monkeys at a dose of 50 and 200 mg/kg 
 
50 mg/kg 
200 mg/kg 
Parameter 
1st 
Infusion 
(n=12) 
7th 
Infusion 
(n=11) 
13th 
Infusion 
(n=10) 
1st 
Infusion 
(n=12) 
7th 
Infusion 
(n=11) 
13th 
Infusion 
(n=8) 
t1/2 (hr) 
0.525 ±0.092 
0.577 ±0.114 
0.737 ±0.228b 
1.40 ±0.209a 
1.72 ±0.100a, b 
1.99 ±0.240a, b, c  
Cl (mL/hr/kg) 
22.3 ±6.83 
15.7 ±3.82b 
14.4 ±4.29b 
10.9 ±1.59a 
9.33 ±1.75a 
7.88 ±2.44a, b  
Vz (mL/kg) 
16.3 ±3.12 
12.7 ±2.33b 
14.6 ±3.16 
21.8 ±3.38a 
23.0 ±4.01a 
22.2 ±5.84a 
Cmax (μg/mL) 
566 ±157 
818 ±177b 
861 ±189b 
3892 ±506 
4347 ±894 
5284 ±1440b 
AUC0-inf 
(μg X hr/mL) 
2423 ±682 
3341 ±748b 
3712 ±977b 
18728 ±2866 
22463 ±6268 
28162 ±10694b 
AUC0-inf/Dose 
(μg X hr/mL/Dose) 
48.5 ±13.6 
66.8 ±15.0b 
74.2 ±19.5b 
93.6 ±14.3a 
112 ±31.3a 
141 ±53.5a, b   
a p<0.05 TK parameter significantly different (50 vs 200 mg/kg). 
b p <0.05, TK parameter significantly different (compared to first infusion at the same dose). 
c p <0.05, TK parameter significantly different (compared to seventh infusion at the same dose). 
Biodistribution studies were also conducted with avalglucosidase alfa to evaluate the tissue 
distribution in GAAKO mice following a single 20 mg/kg dose. Results indicate that the majority 
of avalglucosidase alfa (~60% of injected dose) was detected in the liver, while less than 2% and 
1% of injected dose was present in the heart and skeletal muscle, respectively. 
More detailed information on the compound is provided in the Investigator’s Brochure (IB). 
4.2 
STUDY DESIGN AND RATIONALE OF SPECIFIC PARAMETERS 
4.2.1 Study design 
LTS13769 is an open-label, multicenter, multinational extension study with repeated IV infusions 
of avalglucosidase alfa Safety, pharmacokinetic, pharmacodynamic, pharmacogenetic, and 
exploratory efficacy data will be collected during this long-term study. The population will be 
patients with Pompe disease who have completed an avalglucosidase alfa study. 
4.2.2 Specific parameters rationale 
4.2.2.1 Safety 
Safety parameters include adverse event (AE) collection, physical examination, urine pregnancy 
test for women of childbearing potential, body weight, vital signs, hematology, biochemistry, 
urinalysis, and ECG. 
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Patients will receive an IV infusion of avalglucosidase alfa every other week (qow). Prior to each 
infusion, the patient should be assessed by the Investigator or appropriate designee to determine if 
the patient is free of acute illness and is clinically stable to receive the infusion. Detailed infusion 
administration procedures can be found in the pharmacy manual. 
The follow-up observation period for the end-of-study visit and for treatment-emergent adverse 
events (TEAE) is anticipated to be approximately 4 weeks after the last administration of 
avalglucosidase alfa considering the long tissue half-life of ERTs used to treat lysosomal storage 
diseases. 
An immune reaction against an exogenously administered recombinant protein plays a critical role 
in the safety of the compound. Therefore, safety assessments will include blood samples for  
anti-avalglucosidase alfa antibodies, neutralizing antibody formation in anti-drug antibody (ADA) 
seropositive patients, and anti-alglucosidase alfa immunoglobulin G (IgG) antibodies (only 
patients who were previously treated with alglucosidase alfa). 
Additional exploratory safety assessments will be conducted when clinically indicated. In the 
event that a patient experiences a moderate, severe, or recurrent mild infusion-associated reactions 
(IARs) suggestive of hypersensitivity reactions, additional blood samples will be collected for the 
evaluation of: 
• Circulating immune complex detection; and 
• Immunoglobulin E (IgE), serum tryptase, and complement activation. 
Additionally, skin testing may be performed, as appropriate, in patients who experience an IAR 
that meets the following criteria: 
• Infusion-associated reaction is suggestive of IgE-mediated 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 the Sponsor. 
Skin testing may be another predictor of IgE-mediated reaction and may be suggested for 
confirmation of the IgE results. 
4.2.2.2 Pharmacodynamic and exploratory biomarkers assessments 
Glucose tetrasaccharide (Hex4), a tetraglucose oligomer, has been shown to be elevated in the 
urine of patients with Pompe disease. Hence, determination of fasted Hex4 levels may be a means 
by which the efficacy of treatments may be monitored. 
Fasted plasma samples and fasted urine samples will be taken for exploration of potential 
biomarkers of disease severity or response to avalglucosidase alfa. 
Skeletal muscle magnetic resonance imaging (MRI) will be taken to guide site selection for 
muscle needle or open biopsies and to explore the effects of therapy on muscle pathology. When a 
muscle biopsy is available pharmacodynamic activity of avalglucosidase alfa will be assessed 
through tissue glycogen measurements from biopsies of the lower extremity (quadriceps). 
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Glycogen content will be measured by histomorphometric analysis or severity grading to 
determine how effectively avalglucosidase alfa is able to remove glycogen from muscle. 
4.2.2.3 Exploratory efficacy 
Exploratory avalglucosidase alfa efficacy will be evaluated in terms of functional capacity using 
the 6-minute walk test (6MWT) distance walked and pulmonary function testing (PFT; including 
the assessment of forced vital capacity [FVC], forced expiratory volume in the 1st second of the 
FVC maneuver [FEV1], maximal inspiratory pressure [MIP], maximal expiratory pressure 
[MEP], and peak expiratory flow [PEF] in the upright and supine positions). 
4.2.2.4 Pharmacogenomics 
Previous studies in Pompe muscle biopsies have shown a number of RNA species whose 
expression is correlated with disease progression. Measurements of circulating muscle creatine 
kinase indicate that muscle cell contents can be observed in the blood of patients with Pompe 
disease, suggesting the possibility of measuring muscle derived RNAs among the cell-free RNA 
in the blood, as has been done in cancer and for prenatal diagnosis. If feasible, circulating RNA 
measurement could provide a minimally invasive biomarker for disease progression and severity. 
Therefore, plasma samples will also be collected and assessed for circulating microRNA 
concentrations on both the whole-genome and individual gene levels.  
When a muscle biopsy is available, skeletal muscle tissue samples, taken by needle or open 
biopsy, will be evaluated for exploratory RNA expression. Such data will be used to evaluate if 
transcriptional changes are predictive of disease course and if the pattern indicates response to 
treatment. An additional serum sample will be collected in connection with this analysis. This 
serum sample will be used to assess whether any of the targets that are identified in muscle are 
expressed in serum and therefore could be assessed as a serum-based marker of Pompe disease. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective is to assess the long-term safety and PK of avalglucosidase alfa in patients 
with Pompe disease who have previously completed an avalglucosidase alfa study. 
5.2 
SECONDARY 
The secondary objective is to assess the long-term effect of avalglucosidase alfa on 
pharmacodynamic and exploratory efficacy variables to assess if the benefits of avalglucosidase 
alfa are maintained and to assess the time course of response. 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
LTS13769 is an open-label, multicenter, multinational extension study with repeated IV infusions 
of avalglucosidase alfa (neoGAA, GZ402666). Safety, pharmacokinetic, pharmacodynamic, 
pharmacogenetic, and exploratory efficacy data will be collected during this long-term study. The 
population will be patients with Pompe disease who have completed an avalglucosidase alfa 
study. The graphical design and study flow charts are presented in Section 1. 
Patients who have provided signed written informed consent and have met all of the inclusion 
criteria and have not met the exclusion criterion will be enrolled in the study. 
Safety, pharmacokinetic, pharmacodynamic, pharmacogenetic, and efficacy assessments will be 
performed at scheduled visits throughout the extension study. Adverse events and concomitant 
medications will be collected continuously throughout the study. 
An independent Data Monitoring Committee (DMC) will review safety information during 
periodic bi-annual safety reviews, as well as on an ad hoc basis as outlined in the DMC charter, 
which is maintained separately from the study protocol. An immunologist will be consulted, when 
necessary, to review information and provide treatment recommendations for IARs. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The duration of the study for each patient is initially 6 years. Each patient will continue with the 
study until the patient withdraws, the Investigator withdraws the patient, or the Sponsor 
terminates the study. An additional follow-up phase will begin after the patient has completed the 
6-year study period, and will last until avalglucosidase alfa is approved in the patient’s country, 
except in the UK, Germany and Denmark, where the duration of the additional follow-up phase 
will be up to the approval in the country or limited to a maximum of 2 years, whichever occurs 
first (ie, for patients in the UK, Germany and Denmark, the total study duration per patient is 
8 years at the maximum including the initial 6-year period and the additional 2-year follow-up) 
(refer to Appendix 1 [Section 17.1] for definition applicable for patients in the UK, Germany and 
Denmark). 
6.2.2 Determination of end of clinical trial (all patients) 
The clinical trial will end when the last patient completes the last follow-up visit. 
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6.3 
STUDY CONDUCT 
6.3.1 Data Monitoring Committee 
An independent DMC, appointed by the Sponsor, will review the protocol and will thereafter 
provide medical and ethical guidance related to the conduct of this study. The DMC will review 
safety information as outlined in the DMC charter, which is maintained separately from the study 
protocol. 
During the course of the study bi-annual periodic reviews of safety data will be performed by the 
DMC. In addition, the DMC will review safety data on an ad hoc basis if any AE meets the 
individual patient or study stopping criteria as discussed in Section 6.3.3.1 and Section 6.3.3.2, or 
if any AE that, in the opinion of the Investigator or Sponsor, raises significant concerns regarding 
the safety of the avalglucosidase alfa administered dose. Should any major safety issues arise, 
final decisions regarding the study will be made by the Sponsor’s Chief Medical Officer and 
Global Safety Officer, taking into consideration the DMC opinion (as applicable). 
6.3.2 Allergic Reaction Review  
Infusion-associated reactions and other events which could require consultation of an 
allergist/immunologist will be reviewed by an immunologist. 
Should any major safety issues arise, final decisions regarding the study will be made by the 
Sponsor’s Chief Medical Officer and Global Safety Officer, taking into consideration the 
immunologist opinion (as applicable). 
6.3.3 Guidance for stopping rules 
For the purpose of this study, the following criteria should be considered as guidance for the 
decision to stop avalglucosidase alfa administration to a patient or to stop the trial. 
6.3.3.1 Individual patient stopping criteria 
If any of the following AEs occur, dosing will be temporarily stopped for the specific patient who 
experienced the AE, pending ad hoc DMC review and recommendations: 
• Any life-threatening Grade 4 AE as graded by the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE, v4.03) not related to the 
patient’s underlying condition. 
• More than 1 AE of CTCAE Grade 3 or greater, not related to the patient’s underlying 
condition, for which the relationship to treatment cannot be reasonably excluded. 
• Any increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total 
bilirubin, or alkaline phosphatase >3x the baseline value, ie, prior to the first dose of 
GZ402666 in any prior avalglucosidase alfa study. 
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• Any increase in ALT or AST >3x the upper limit of normal, in the presence of total 
bilirubin >2x the upper limit of normal. 
• Any AE that, in the opinion of the Investigator or Sponsor, raises significant concerns 
regarding the safety of avalglucosidase alfa administered dose. 
6.3.3.2 Study stopping criteria 
If either of the following events occurs, an ad hoc DMC review will be requested immediately: 
• Two patients develop the same life-threatening AE (eg, anaphylactic reaction), not related 
to their underlying condition. 
• Any avalglucosidase alfa-related death. 
After consideration of DMC recommendations, final decisions for discontinuation of study drug 
for all or selected clinical trial patients will be made by the Sponsor. 
In the event a significant safety concern arises, the Sponsor may immediately decide to 
discontinue study drug dosing in all clinical trial patients, prior to receipt of DMC 
recommendation. Investigational sites will be notified within 24 hours of the Sponsor’s 
notification of the event(s). 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Patients with Pompe disease who previously completed an avalglucosidase alfa study. 
I 02. The patient and/or their parent/legal guardian is willing and able to provide signed 
informed consent, and the patient, if <18 years of age, is willing to provide assent if 
deemed able to do so. 
I 03. The patient (and patient’s legal guardian if patient is <18 years of age) must have the 
ability to comply with the clinical protocol. 
I 04. The patient, if female and of childbearing potential, must have a negative pregnancy test 
(urine beta-human chorionic gonadotropin [β-HCG]) at baseline. Note: Sexually active 
female patients of childbearing potential and male patients are required to practice true 
abstinence in line with their preferred and usual lifestyle or to use two acceptable effective 
methods of contraception, a barrier method such as a condom or occlusive cap (diaphragm 
or cervical/vault cap) with spermicidal foam/gel/film/cream/suppository and an established 
non-barrier method such as oral, injected, or implanted hormonal methods, an intrauterine 
device, or intrauterine system for the entire duration of the treatment period. 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria: 
E 01. The patient is concurrently participating in another clinical study using investigational 
treatment. 
E 02. The patient, in the opinion of the Investigator, is unable to adhere to the requirements of 
the study. 
E 03. The patient has clinically significant organic disease (with the exception of symptoms 
relating to Pompe disease), including clinically significant cardiovascular, hepatic, 
pulmonary, neurologic, or renal disease, or other medical condition, serious intercurrent 
illness, or extenuating circumstance that, in the opinion of the Investigator, precludes 
participation in the study or potentially decreases survival. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS 
Avalglucosidase alfa, the investigational medicinal product (IMP), will be supplied as a sterile, 
nonpyrogenic, lyophilized product in single-use 20 mL vials containing approximately 100 mg 
of avalglucosidase alfa in 10 mM histidine, 2% glycine, 2% mannitol, and 0.01% polysorbate 80, 
with a pH of 6.2. 
Avalglucosidase alfa will be administered by IV infusion following reconstitution and dilution at 
a dose of 20 mg/kg body weight qow. 
The total amount of investigational product administered may be adjusted as needed to account 
for changes in body weight. Most recent body weight should be used for dose calculation. Each 
avalglucosidase alfa IV infusion will be administered in a step-wise manner. The rate will begin at 
a slow initial rate and will be gradually increased if there are no signs of IARs, until a maximum 
rate is reached. The infusion length will be dependent on the dose. Specific details pertaining to 
the infusion volumes and rates as well as dose calculation can be found in the pharmacy manual. 
Prior to each infusion, the patient should be assessed by the Investigator or appropriate designee 
(ie, qualified physician with the exception of patients who receive home infusion of 
avalglucosidase alfa as outlined below under the subsection “Home infusion”) to determine if the 
patient is free of acute illness and is clinically stable to receive the infusion. Infusions will be 
postponed (see Section 8.7.1) if the patient is acutely ill on the scheduled day of infusion. Any 
modification to the dose and/or frequency of dosing is not permitted unless it is due to an AE, in 
which case it is not a protocol violation, but the Investigator must consult with the Sponsor in the 
event of a dose change. No dose increase above the maximum recommended dose of 20 mg/kg 
qow will be allowed for any patients.  
Patients will be required to remain in the hospital or the infusion center for observation of AEs for 
1 hour after each infusion; see below for the patients receiving home infusion. Patients may be 
required to stay for a longer observation period at the Investigator’s discretion. In case the patient 
does not stay for this observation period (eg, as part of contingency measures for a regional or 
national emergency that is declared by a governmental agency), the Investigator (or appropriate 
designee) will contact the patient to ensure that no adverse event occurred during the 
observational period. 
Home infusion 
Home infusion may be possible, where permitted by national and local regulations. Patients must 
meet the eligibility requirements outlined below. In addition, the Investigator and the Sponsor 
must agree that home infusion is appropriate. Patient’s underlying co-morbidities and ability to 
adhere to the requirements of the study need to be taken into account when evaluating patients for 
eligibility to receive home infusion. Any identified risk of noncompliance to monitoring of study 
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requirements or potential for loss to follow-up should lead to this patient not being eligible for 
home infusion. 
The following criteria must be documented in the patient’s medical record: 
• The Investigator must agree in writing that home infusion is appropriate for the patient.  
• The patient must be willing and able to comply with home infusion procedures. 
• The patient has been trained on home infusion process. 
• The patient must, in the Investigator’s (or designee’s) opinion, have been clinically stable 
with no history of moderate or severe IARs for at least 12 months, and must be on a stable 
avalglucosidase alfa dose. In case of unexpected event that prevent infusions to be 
performed at site for a prolonged period, (eg, as part of contingency measures for a 
regional or national emergency that is declared by a governmental agency), with DMC 
agreement, the required period of 12 months with no history of moderate or severe IAR 
may be reduced to 6 months, to allow home infusion to be resumed sooner. 
• If this reduced period from 12 months to at least 6 months, is considered safe and after 
confirmation with the DMC (which will be documented in Trial Master File), it will be 
considered as a permanent criterion after the unexpected event is resolved (eg, 
contingency measures for a regional or national emergency that is declared by a 
governmental agency are terminated). 
• No infusion rate increases will be allowed while a patient is receiving home infusions. 
• The patient must have no ongoing (not yet recovered) SAEs that, in the opinion of the 
Investigator, may affect the patient’s ability to tolerate the infusion. 
• Home infusion infrastructure, resources, and procedures must be established and available 
according to applicable regional regulations (see Section 17.1 for regulations applicable 
specifically in France disallowing the option for home infusion). In exceptional 
circumstances, the Investigator may require a local vendor for home infusion services. In 
such circumstances, the Investigator will attest that this vendor meets the requirements to 
properly manage the home infusion of avalglucosidase alfa, including available resources 
and procedures. 
• Patients experiencing a moderate or severe IAR while being infused at home will return to 
the study site for their following infusion and will continue to receive infusions at the site 
until the Investigator feels it is safe for the patient to resume home infusion. 
• If recurrent IARs or hypersensitivity/anaphylactic reactions have occurred prior to start of 
home infusions or occur during home infusions, the Investigator should assess whether or 
not it is safe for the patient to start or to continue to be treated via home infusion. 
• The Sponsor should be notified about all IARs and consulted (as needed) if the patient 
experiences IARs suggestive of hypersensitivity reactions (refer to Section 8.8.2). 
• In the event of manufacturing scale change, the patient will be required to receive the first 
infusion at the site. All criteria for return to home infusion will apply. 
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• Prior to beginning home infusions, the home infusion agency staff, including new staff 
members, must have been trained by the site on proper procedures to administer infusions, 
monitor patients, document procedures, and report to site on a timely basis. Any new staff 
member must be trained by the site prior to resuming home infusions. The site must 
confirm that the home infusion agency staff has received training at least equivalent to that 
provided to new staff members. 
• Because of the possibility of anaphylactic reactions, medical personnel competent in 
recognizing and treating adverse reactions (including anaphylactic reactions) should be 
readily available throughout the home infusion. 
• The home infusion agency staff should remain at the patient’s home for the duration of the 
infusion and through the post-infusion observation period, which is required to be at least 
2 hours.  
• The home infusion agency staff must be trained in basic life support (cardiopulmonary 
resuscitation [CPR]), and should have a process for requesting additional emergency 
services, if needed. 
• 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 the Sponsor and agree to be monitored. 
The Principal Investigator (PI) is responsible for approving a patient’s initiation with home 
infusions and is still responsible for all study procedures and patient’s safety even when 
delegating infusion responsibilities to the home care company during this clinical study.  
It is the PI’s responsibility to guide staff on the clinical management of the patient in case of IARs 
or hypersensitivity or anaphylactic reactions. The PI will be the point of contact for home infusion 
agency staff in case of questions or emergency situations. 
Infusions given in the home setting versus in the clinic will be captured through the electronic 
case report form (eCRF) forms for AEs and exposure. 
8.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS 
Not applicable. 
8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
This study is an open-label design. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
This is an open-label study without randomization. Patients who comply with all 
inclusion/exclusion criteria will be enrolled in the study. Each patient will receive 20 mg/kg qow. 
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The patient will retain the same patient number from the initial study. 
8.5 
PACKAGING AND LABELING 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (ie, pharmacists or designees) are responsible for storing 
IMP provided by the Sponsor in a secure and safe place in accordance with local regulations, 
labeling specifications, policies, and procedures. 
Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the compound should be managed 
according to the rules provided by the Sponsor. 
It is recommended that the reconstituted product be used immediately after reconstitution. 
Additional stability data are provided in the pharmacy manual. 
8.7 
RESPONSIBILITIES 
The Investigator, the clinical site pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMP will be dispensed in accordance with the Investigator's prescription, and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (eg, deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date) should be promptly notified to 
the Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP provided by the Sponsor to a third party, 
allow the IMP provided by the Sponsor to be used other than as directed by this clinical trial 
protocol, or dispose of IMP provided by the Sponsor in any other manner. 
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8.7.1 Treatment accountability and compliance 
Administration of the IMP is performed in collaboration with qualified study personnel, and under 
the responsibility of the Investigator or the subinvestigator. 
• IMP accountability: 
- 
The person responsible for drug dispensing is required to maintain adequate records of 
the IMP. These records include the date and number of treatment units received from 
the Sponsor, dispensed for patient, and destroyed or returned to the Sponsor, 
- 
The person responsible for drug administration to the patient will record precisely the 
date, time of the drug administration, and number of treatment units used for 
administration, 
- 
The Investigator records the dosing information on the appropriate page(s) of the 
eCRF, 
- 
The monitor in charge of the study then checks the eCRF data by comparing them with 
the IMP which he/she has retrieved and IMP records. 
The patient’s compliance with the treatment regimen will be monitored in terms of the patient 
receiving the study drug infusion every other week within a ±7-day window from the previous 
infusion date. Missed, delayed, or incomplete infusions will be clearly documented and 
considered in the analysis. Missed doses of study treatment due to sickness, safety concerns, or for 
medical reasons are not protocol deviations, but must be documented for analysis and potential 
impact on the study results. 
8.7.2 Return and/or destruction of treatments 
Reconciliation of the IMP must be performed at the site by the Investigator and the monitoring 
team using the appropriate accountability log and documented on the appropriate accountability 
log countersigned by the Investigator and the monitoring team. 
A written authorization for destruction will be given by the Sponsor once the reconciliation is 
achieved. This destruction can be performed at the site depending on local requirements; 
alternatively, the IMP can be returned to the Sponsor for destruction. 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to any IMP. 
Medications and therapies taken by the patient during the period between the end of the prior 
avalglucosidase alfa study until prior to providing informed consent for the extension study, and 
during the course of the study, will be recorded in the eCRF. Similarly, pre-infusion medications 
(if allowed; see Section 8.8.1 and Section 8.8.2) and assistive devices will be recorded in the 
eCRF. 
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Patients are restricted from participating in other concurrent investigational protocols that are not 
restricted to data and/or sample collection for patient demographic, disease, and/or 
avalglucosidase alfa treatment purposes. 
8.8.1 Pretreatment for patients with infusion-associated reactions 
In clinical trials with alglucosidase alfa, some patients were pretreated with antihistamines, 
antipyretics, and/or corticosteroids. Infusion-associated reactions occurred in some patients after 
receiving antipyretics, antihistamines, or corticosteroids. 
In general, the use of pretreatment in this study is at the discretion of the Investigator. The routine 
use of pretreatment is not recommended, especially in patients with previous IgE-mediated 
hypersensitivity reaction. Antihistamines can mask early symptoms of a hypersensitivity reaction 
(skin reaction), making it difficult for the infusion staff to recognize the initial signs of distress 
and the need to decrease the infusion rate and/or otherwise intervene. 
8.8.2 Management of infusion-associated reactions 
For management of mild IARs, infusion rate reductions (ie, reduced to half the rate) or temporary 
interruptions may mitigate the reaction. 
Testing for moderate, severe, and recurrent mild IARs will include, if clinically indicated: 
• Assessments for circulating immune complex detection; and IgE, serum tryptase, and 
complement activation, following moderate, severe, or recurrent mild IARs suggestive of 
hypersensitivity reactions. 
• Skin testing if IARs are suggestive of a Type I hypersensitivity reaction (IgE-mediated) as 
appropriate. 
For moderate to severe or recurrent IARs, the Investigator may consider the use of pretreatment 
medications (ie, antihistamines, antipyretics, and/or glucocorticoids), in addition to infusion rate 
reductions, interruptions, or even discontinuation, if necessary. Please refer to the Investigator 
Brochure for further guidance on the management of infusion-associated reactions. 
If severe hypersensitivity or anaphylactic reactions occur, immediate discontinuation of the 
infusion should be considered, and appropriate medical treatment should be initiated. Severe 
reactions are generally managed with infusion interruption, administration of antihistamines, 
corticosteroids, IV fluids, and/or oxygen, when clinically indicated. In some cases of anaphylaxis, 
epinephrine has been administered. Because of the potential for severe infusion reactions, 
appropriate medical support measures, including CPR equipment especially for patients with 
cardiac hypertrophy and patients with significantly compromised respiratory function, should be 
readily available. 
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. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
Baseline demographic characteristics will consist of: 
1. Age (years). 
2. Gender. 
3. Race. 
4. Ethnicity. 
5. Pompe disease history including GAA mutations and aspects of disability. 
6. ECG, hematology, biochemistry, and urinalysis data from first day of avalglucosidase alfa 
infusion (ie, prior to first infusion in any prior avalglucosidase alfa study). 
9.1 
PRIMARY ENDPOINT - SAFETY 
The primary endpoint of this study is safety. The following safety assessments will be collected 
and analyzed: 
• Assessment of AEs/TEAEs, including IARs and deaths. 
• Physical examination. 
• Clinical laboratory evaluations, including hematology, biochemistry, and urinalysis. 
• Vital signs. 
• Body weight. 
• 12-lead ECG. 
• Immunogenicity assessments. 
A β-hCG urine test will be administered to females of child bearing potential at baseline and 
monthly thereafter throughout the duration of the study. 
9.1.1 Adverse events 
Adverse events, spontaneously reported by the patient or observed by the Investigator, will be 
monitored throughout the study. This includes the monitoring and reporting of IARs. The safety 
profile will be based on incidence, severity, and cumulative nature of TEAEs. 
Treatment-emergent adverse events are defined as AEs that develop or worsen during the 
on-treatment period. For this study, the on-treatment period will be defined as the period from the 
time of first dose of IMP to at least 4 weeks after the last administration of the IMP. The 
on-treatment period may end earlier (ie, 2 weeks after the last administration of IMP) if the patient 
enrolls in another study or receives commercially available ERT. For the purposes of the study, 
status of ongoing and new AEs will be assessed 4 weeks after the last study infusion, or for 
patients who discontinue early, after their last completed study visit (Section 10.1.3.8). Any new 
AE or serious AE (SAE) that occurs during the 4-week follow-up period and is assessed as related 
to the drug or study procedures will be reported/collected in the clinical database. 
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Definitions of AEs, SAEs, and AEs of special interest (AESIs), including reporting procedures, 
can be found in Section 10.4 to Section 10.6. 
At each study visit, patients will be evaluated for new AEs and the status of existing AEs. The 
Investigator may elicit symptoms using an open-ended question, followed by appropriate 
questions that clarify the patient’s verbatim description of AEs or change in concomitant 
medications. 
Adverse events will be summarized with respect to the type, frequency, severity, seriousness, and 
relatedness. Pretreatment and TEAEs will be coded to a “Preferred Term (PT)” and associated 
primary “System Organ Class (SOC)” using the Medical Dictionary for Regulatory Activities 
(MedDRA). All events will be managed and reported in compliance with all applicable 
regulations, and included in the final clinical study report. 
9.1.2 Physical examination 
Physical examination will include, at a minimum, an assessment of the patient’s general 
appearance; skin; head, eyes, ears, nose, and throat; examinations of lymph nodes, abdomen, 
extremities/joints, neurological and mental status; heart and respiratory auscultation; peripheral 
arterial pulse; and pupil, knee, Achilles, and plantar reflexes. 
9.1.3 Laboratory safety variables 
The clinical laboratory data consist of blood analysis (including hematology and biochemistry) 
and urinalysis. Clinical laboratory values will be analyzed by a central laboratory. These values 
will be analyzed after conversion into standard international units, and international units will be 
used in all listings and tables. 
Blood samples should be drawn in fasting conditions for: 
• Hematology: red blood cell count, hematocrit, hemoglobin, white blood cell count with 
differential count (neutrophils, eosinophils, basophils, monocytes, and lymphocytes), 
platelets. 
• Biochemistry: 
- 
Plasma/serum electrolytes: sodium, potassium, chloride, calcium, 
- 
Liver function: AST, ALT, alkaline phosphatase, gamma-glutamyl transferase, total 
and conjugated bilirubin, 
- 
Renal function: creatinine, blood urea nitrogen, uric acid, 
- 
Metabolic panel: glucose, albumin, total proteins, total cholesterol, triglycerides, 
- 
Potential muscle toxicity: creatine kinase, creatine kinase with MB fraction, lactate 
dehydrogenase. 
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Urinalysis will include urine color, appearance, specific gravity, proteins, glucose, erythrocytes, 
leucocytes, ketone bodies, and pH to be assessed: 
• Qualitatively: A dipstick is to be performed on a freshly voided specimen for qualitative 
detection using a reagent strip. 
• Quantitatively: A quantitative measurement for protein, erythrocytes, and leukocytes count 
will be required in the event that the urine sample test is positive for any of the above 
parameters by urine dipstick (eg, to confirm any positive dipstick parameter by a 
quantitative measurement). 
9.1.4 Vital signs 
Vital signs will include heart rate, systolic and diastolic blood pressure, respiratory rate, 
temperature, and oxygen saturation. Vital signs are to be assessed prior to infusion, with each 
infusion rate change, at the end of the infusion and at the end of the post-infusion observation 
period. Collection windows are ±15 minutes. 
9.1.5 Body weight 
Body weight will be measured in kilograms and collected in the eCRFs every 3 months 
throughout the duration of the study, as well as at the “end of study visit”. More frequent weight 
may be obtained at the discretion of the Investigator.  
9.1.6 Electrocardiogram variables 
Standard 12-lead ECGs are recorded after at least 15 minutes in the supine position using an 
electrocardiographic device. The following will be assessed: heart rate, rhythm, interval between 
the peaks of successive QRS complexes (RR), interval from the beginning of the P wave until the 
beginning of the QRS complex (PR), interval from start of the Q wave to the end of the S wave 
(QRS), interval between the start of the Q wave and the end of the T wave (QT), QT interval 
corrected for heart rate (QTc) automatic correction evaluation (by the ECG device), QRS axis, 
R voltage V6, voltage V1, left ventricular hypertrophy criteria, right ventricular hypertrophy 
criteria, repolarization charges, and overall cardiac impression for each patient. 
Each ECG consists of a 10-second recording of the 12 leads simultaneously, leading to: 
• A single 12-lead ECG (25 mm/s, 10 mm/mV) printout including date, time, initials, and 
number of the patient, signature of the research physician, and at least 3 complexes for 
each lead. The study site cardiologist’s medical opinion and automatic values will be 
recorded in the eCRF. This printout will be retained at the site. 
• A single digital file will be stored which enables manual reading when it is necessary 
(centralized reading of computerized ECGs); each digital file will be identified by 
theoretical time (day and time), real date and real time (recorder time), and patient number 
(eg, 3 digits) and initials (eg, 3 digits). The digital recording, data storage, and 
transmission (whenever requested) need to comply with all applicable regulatory 
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requirements (ie, US Food and Drug Administration [FDA] Code of Federal Regulations, 
Title 21, Part 11). 
The qualified Investigator or appropriate designee (qualified physician) should review the ECGs 
in a timely manner to determine if there are any safety concerns and for clinical management of 
the patient. In the event of any clinically significant abnormal findings that meet the definition of 
an AE (see Section 10.4.1 for definitions and reporting), 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. 
In case of abnormal findings by the qualified Investigator, the ECG should be provided to the 
study site cardiologist for further confirmation and description of findings. 
All ECGs will also be collected and read centrally by a third-party independent reviewer. 
9.1.7 Immunogenicity 
Immunogenicity assessments will include the following: 
• Samples will be collected from patients and evaluated for anti-avalglucosidase alfa 
antibodies every month during the first 6 months and then every 3 months throughout the 
duration of the study. ADA seropositive patient serum will be assessed for neutralizing 
antibodies to avalglucosidase alfa which may include inhibition of enzyme activity and 
uptake. 
• Samples will be collected from patients who were previously treated with alglucosidase 
alfa and evaluated for anti-alglucosidase alfa IgG antibodies every 6 months for up to the 
first 6 years of the study. 
• Samples will be collected from patients and evaluated for IgE, complement activation, 
serum tryptase following moderate, severe, or recurrent mild IARs suggestive of 
hypersensitivity reactions (Section 8.8.2). 
• In the event a patient exhibits signs or symptoms suggestive of systemic immune-mediated 
reactions involving skin and other organs while receiving alglucosidase alfa, serum 
samples are obtained for the evaluation of circulating immune complexes. 
• Leftover antibody samples will be stored for further analysis as needed. 
• See the study-specific laboratory manual as well as the Study Operations Manual (SOM) 
for guidelines on the collection and shipment of antibody and IAR samples and circulating 
immune complex samples. 
9.2 
PHARMACOKINETICS 
9.2.1 Sampling times 
Blood samples for evaluation of avalglucosidase alfa PK will be collected before, during, and 
after avalglucosidase alfa infusions at 6 months and then yearly thereafter for the first 6 years. 
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Sampling times are as follows: pre-dose (prior to infusion), at the end of the infusion, and at 1, 4, 
8, 12, and 24 hours after infusion. The following PK blood samples are to be collected within 
15 minutes of scheduled time: pre-dose and all samples immediately following the end of the 
infusion through 8 hours post infusion. Pharmacokinetic samples collected 12 hours through 
24 hours post infusion are to be collected ±2 hours of the scheduled time. 
9.2.2 Number of pharmacokinetic samples 
The number of PK samples will vary by patient depending on the length of the patient’s 
participation in the extension study. 
9.2.3 Sample handling procedure 
Special procedures for collection, storage, and shipment will be provided in the study- specific 
laboratory manual. 
9.2.4 Bioanalytical methods 
Plasma samples will be analyzed using validated, sensitive and specific bioanalytical methods, 
namely, a fluorometric assay using a 4-methylumbelliferyl-α-D-glucoside (4-MUG) substrate to 
detect avalglucosidase alfa activity. 
9.2.5 Pharmacokinetic parameters 
The following PK parameters will be calculated, using noncompartmental methods from plasma 
avalglucosidase alfa concentrations obtained after single and repeat dose administration. The 
parameters will include, but may not be limited to the following list in Table 4. 
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Table 4 - List of pharmacokinetic parameters and definitions 
Parameters 
Drug/Analyte 
Matrix 
Definition/Calculation 
Cmax 
avalglucosidase 
alfa  
Plasma 
Maximum plasma concentration observed 
AUClast 
avalglucosidase 
alfa  
Plasma 
Area under the plasma concentration versus time curve calculated using the 
trapezoidal method from time zero to the real time 
AUC 
avalglucosidase 
alfa  
Plasma 
Area under the plasma concentration versus time curve extrapolated to 
infinity according to the following equation: 
z
C
AUC
AUC
last
last

+
=
 
Values with a percentage of extrapolation >20% will not be taken into 
account in the descriptive statistics 
tlast 
avalglucosidase 
alfa  
Plasma 
Time corresponding to the last concentration above the limit of quantification, 
Clast 
t1/2z 
avalglucosidase 
alfa  
Plasma 
Terminal half-life associated with the terminal slope (λz) determined 
according to the following equation: 
z
1/2Z
0.693
 
t

=
 
where λz is the slope of the regression line of the terminal phase of the 
plasma concentration versus time curve, in semi-logarithmic scale. Half-life is 
calculated by taking the regression of at least 3 points. 
CL 
avalglucosidase 
alfa  
Plasma 
Apparent total body clearance of a drug from the plasma calculated using the 
following equation: 
AUC
D
 
CL
ose
=
 
Vd 
avalglucosidase 
alfa  
Plasma 
Apparent Volume of Distribution during the terminal (λz) phase calculated 
using the following equation: 
z
z
CL
 
V

=
 
 
9.3 
PHARMACODYNAMIC PARAMETERS 
9.3.1 Skeletal muscle magnetic resonance imaging 
Skeletal muscle MRI will be performed prior to the muscle needle or open biopsy procedure. 
Skeletal muscle MRI images obtained within LTS13769 study will be analyzed using muscle MRI 
images obtained as baseline from previous study. Magnetic resonance imaging will be processed 
and analyzed centrally. A protocol for MRI acquisition and analysis will be provided in the study- 
specific manual. 
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9.3.2 Skeletal muscle biopsy 
Muscle biopsy is not required in patients in whom the prior muscle biopsy, obtained in a prior 
avalglucosidase alfa study, had a glycogen content <5% unless the patient shows significant 
clinical decline. Needle or open biopsy of the lower extremity (quadriceps) muscle will be 
performed following the skeletal muscle MRI. The MRI appearance of the muscle will be used to 
determine the level (axial slice position) that the biopsy procedure should target (avoiding fatty 
replaced tissue). Glycogen content will be measured by histomorphometric analysis or severity 
grading to determine how effectively avalglucosidase alfa is able to remove glycogen from 
muscle. 
Further instructions regarding the biopsy sampling and the collection and shipment of biopsy 
samples will be provided in the study-specific laboratory manual. 
9.3.3 Urinary Hex4 
Fasted urine samples for the assessment of urinary Hex4 concentrations will be collected prior to 
IMP infusion. Procedures for the collection, handling, and shipment of all urine samples will be 
included in the study-specific laboratory manual. 
9.3.4 Exploratory plasma and urine biomarkers 
Fasted plasma and urine samples will be collected prior to IMP infusion for the assessment of 
exploratory biomarkers. Procedures for the collection, handling, and shipment of all samples will 
be included in the study-specific laboratory manual. Results will be used to inform on biomarker 
targets for future studies and will not be reported in the CSR. 
9.4 
EXPLORATORY EFFICACY ASSESSMENTS 
Avalglucosidase alfa efficacy will be evaluated in terms of functional capacity using the 6MWT 
and PFT. 
9.4.1 Six-minute walk test 
The 6MWT will be performed to assess ambulatory capacity in the study population. During the 
treatment period, the assessment will be completed before IMP infusion. See the study-specific 
laboratory manual for further details. 
The measurement is the distance walked in 6 minutes, measured in meters; the percent of 
predicted distance and the amount of time walked (3) to quantify endurance (as all patients may 
not complete the full 6-minute walk) will also be recorded. In addition, data will be collected for 
pre- versus post-test changes in heart rate. Testing equipment and administration techniques will 
be standardized among investigational sites. The distance (in meters) will be recorded and the 
corresponding percent predicted value will be calculated. 
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9.4.2 Pulmonary function testing endpoints 
Pulmonary function testing will be completed before IMP infusion. 
The PFT administration protocol is standardized across sites in accordance with American 
Thoracic Society guidelines (4). Pulmonary function testing will include the assessment of FVC, 
FEV1, MIP, MEP, and PEF in the upright and supine positions. 
9.5 
PHARMACOGENETIC ASSESSMENT 
Fasted pharmacogenetic samples will be collected. Refer to the study-specific laboratory manual 
for guidelines on the collection and shipment of whole blood samples. 
9.5.1 Skeletal muscle RNA expression analysis 
In patients in whom the prior muscle biopsy, obtained in a prior avalglucosidase alfa study, had a 
glycogen content >5% or who show significant clinical decline, muscle tissue samples will be 
taken via biopsy of the lower extremity (quadriceps) muscle, as indicated in Section 9.3.2. An 
additional serum sample will be collected in connection with this analysis. These serum samples 
will be used to assess whether proteins for any of the mRNA targets that are identified in muscle 
are expressed in serum and therefore could be assessed as a serum-based marker of Pompe 
disease. Results will be used to inform on biomarker targets for future studies and will not be 
reported in the CSR. 
9.5.2 Circulating microRNA analysis 
Plasma samples will be collected and assessed for circulating microRNA concentrations on both 
the whole-genome and individual gene levels. Results will be used to inform on biomarker targets 
for future studies and will not be reported in the CSR. 
9.6 
SAMPLED BLOOD VOLUME 
The total volume of sampled blood will vary depending on the patient’s length of participation in 
this extension study. 
9.7 
FUTURE USE OF SAMPLES 
Not all of the samples collected during this study may be required for the tests planned in this 
clinical trial. For subjects who have consented to it, the samples that are unused or left over after 
testing may be used for other research purposes (excluding genetic analysis) related to Pompe 
disease and other diseases than those defined in the present protocol. 
These other research analyses will help to understand either disease subtypes or drug response, or 
to develop and/or validate a bioassay method, or to identify new drug targets or biomarkers. 
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Some samples may remain labeled with the same identifiers as the one used during the study 
(ie, subject ID). They may be transferred to a Sanofi site (or a subcontractor site) which can be 
located outside of the country where the study is conducted. The Sponsor has included safeguards 
for protecting subject confidentiality and personal data (see Section 14.1). 
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10 
STUDY PROCEDURES 
Section 1.2 summarizes the schedule of study events for all patients enrolled into this study. 
Specific details on the timing of study assessments are provided below. The individual evaluations 
are described in Section 9. 
Medical/surgical history, and Pompe disease history, including GAA gene mutations, will be 
imported from the patient’s prior avalglucosidase alfa study file in the database when possible.  
Adverse event and concomitant medication collection will be performed at every visit throughout 
the study. 
10.1 
VISIT SCHEDULE 
10.1.1 Baseline visit 
Patients enrolled in the study will have the following procedures performed at baseline. 
The patient will receive information on the study objectives and procedures from the Investigator. 
The patient will have to sign the informed consent prior to any action related to the study. 
Patients who meet all the inclusion criteria and none of the exclusion criteria will be eligible for 
inclusion in the study. Final inclusion will be performed just before the IMP administration at the 
first treatment visit. 
• Informed consent. 
• Inclusion/exclusion criteria. 
• Urine pregnancy test (females only). 
• ECG. 
• Demographics. 
• Medical/Surgical history. 
• Pompe disease history, inclusive of GAA mutation and aspects of disability. 
• ECG, hematology, biochemistry, and urinalysis data from first day of avalglucosidase alfa 
infusion (ie, prior to first infusion in any prior avalglucosidase alfa study). 
• Results of MRI baseline from previous avalglucosidase alfa study to be obtained. 
10.1.2 Treatment phase 
10.1.2.1 Biweekly 
The following will be performed every 2 weeks starting at the date of the first infusion: 
• Vital signs. 
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• Infusion of avalglucosidase alfa. 
Information regarding the infusion of the IMP can be found in the pharmacy manual. 
10.1.2.2 Monthly 
The following assessments will be performed on a monthly basis:  
• Urine pregnancy test (females only). 
• Biochemistry (for first 3 years since enrollment). 
• Anti-avalglucosidase alfa antibodies and neutralizing antibodies in antidrug-antibody 
(ADA) positive patients (for first 6 months). 
10.1.2.3 Quarterly   
The following assessments will be performed on a quarterly basis:  
• Anti-avalglucosidase alfa antibodies and neutralizing antibodies in ADA-positive patients 
(after the first 6 months). 
• Body weight. 
• Biochemistry (after first 3 years since enrollment). 
10.1.2.4 Every 6 months  
The following assessments will be performed every 6 months: 
• Physical examination. 
• ECG. 
• Hematology and urinalysis. 
• 6MWT. 
• PFT. 
• Anti-alglucosidase alfa IgG antibodies (only patients who were previously treated with 
alglucosidase alfa). 
10.1.2.5 At 6 months and yearly thereafter  
The following assessments will be performed at 6 months and yearly thereafter: 
• Avalglucosidase alfa PK plasma sample collection. 
• Urine Hex4 sample collection. 
• Exploratory biomarker urine sample collection. 
• Exploratory biomarker plasma sample collection. 
• Plasma sample collection for microRNA analyses. 
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10.1.2.6 Every 2 years  
The following assessments will be performed every 2 years: 
• MRI. 
• Skeletal muscle biopsy (not required in patients in whom the prior muscle biopsy, obtained 
in a prior avalglucosidase alfa study, had a glycogen content <5% unless the patient shows 
significant clinical decline). 
• Serum sample collection for skeletal muscle RNA expression analyses (not required in 
patients in whom the prior muscle biopsy, obtained in a prior avalglucosidase alfa study, 
had a glycogen content <5% unless the patient shows significant clinical decline). 
10.1.2.7 Re-baseline visit  
The following assessments will be performed at the re-baseline visit after having obtained 
informed consent and before receiving the higher dose. 
The “Re-baseline” will only apply to patients who have switched from 5 or 10 to 20 mg/kg. If the 
patient changes dose from 5 or 10 mg/kg to 20 mg/kg qow dose, the visit dates need to be adapted 
accordingly (see Section 1.2). 
Results from selected previous assessments may be used and the assessment does not need to be 
repeated at the re-baseline visit depending on the last available assessment date: 
• Physical examination (within 1 month). 
• Urine pregnancy test (females only). 
• Body weight. 
• Vital signs. 
• ECG (within 1 month). 
• Hematology and urinalysis (within 1 month). 
• Biochemistry. 
• Anti-avalglucosidase alfa antibodies and neutralizing antibodies in ADA-positive patients. 
• Anti-alglucosidase alfa IgG antibodies (only patients who were previously treated with 
alglucosidase alfa). 
• Avalglucosidase alfa PK plasma sample collection (within 6 months). 
• MRI (within 6 months). 
• In patients in whom the prior muscle biopsy, obtained in a prior avalglucosidase alfa 
study, had a glycogen content >5% or who show significant clinical decline: 
- 
Skeletal muscle needle or open biopsy (within 6 months), 
- 
Serum sample collection for skeletal muscle RNA expression analyses (within 
6 months). 
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• Urine Hex4 sample collection (within 1 month). 
• Exploratory biomarker urine sample collection (within 1 month). 
• Exploratory biomarker plasma sample collection (within 1 month). 
• 6MWT (within 1 month). 
• PFT (within 1 month). 
• Plasma sample collection for microRNA analyses (within 1 month). 
10.1.2.8 
Patient temporarily discontinued from study treatment while remaining in the 
study 
• In case of temporary treatment discontinuation of study drug the visits and assessments 
will be adapted to the absence of infusion of avalglucosidase alfa until the patient resumes 
treatment within the study: 
- 
Study visits can be adapted to every 4 weeks or when laboratory and/or clinical testing 
are scheduled, as long as the assessment time windows in the study protocol are 
respected. Patients should adhere to original target infusion and visit schedule based on 
first infusion in LTS13769 or first infusion of 20 mg/kg in the LTS13769 study. 
- 
As no infusion of IMP will be performed, no assessment of infusion-associated vital 
signs, as well as no PK sampling is required while the participant is temporarily 
withdrawn from treatment. 
• Reinitiation of treatment with IMP will be offered to the patient at the discretion of the 
Investigator and in agreement with the study participant, under close and appropriate 
clinical and/or laboratory monitoring. 
10.1.3 Additional follow-up phase 
An additional follow-up phase will begin after the patient has completed the 6-year study period, 
and will last until avalglucosidase alfa is approved in the patient’s country, except in the UK, 
Germany and Denmark, where the duration of the additional follow-up phase will be up to the 
approval in the country or limited to a maximum of 2 years, whichever occurs first (ie, for patients 
in the UK, Germany and Denmark, the total study duration per patient is 8 years at the maximum 
including the initial 6-year and the additional 2-year follow-up) (refer to Appendix 1  
[Section 17.1] for definition applicable for patients in the UK, Germany and Denmark). 
10.1.3.1 Biweekly 
The following will be performed every 2 weeks: 
• Vital signs. 
• Infusion of avalglucosidase alfa. 
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Information regarding the infusion of the IMP can be found in the pharmacy manual. 
10.1.3.2 Monthly 
The following assessments will be performed on a monthly basis:  
• Urine pregnancy test (females only). 
10.1.3.3 Quarterly 
The following assessments will be performed on a quarterly basis:  
• Body weight. 
10.1.3.4 Every 6 months  
The following assessments will be performed every 6 months: 
• Physical examination. 
• ECG. 
• Hematology and urinalysis. 
• Biochemistry. 
• Anti-avalglucosidase alfa antibodies and neutralizing antibodies in ADA-positive patients. 
• 6MWT. 
• PFT. 
10.1.3.5 Yearly 
The following assessments will be performed at 6 months and yearly thereafter: 
• Exploratory biomarker urine sample collection. 
• Exploratory biomarker plasma sample collection. 
• Plasma sample collection for microRNA analyses. 
10.1.3.6 Every 2 years 
The following assessments will be performed every 2 years: 
• MRI. 
10.1.3.7 End of study visit 
The following will be performed at the end of study visit: 
• Physical examination. 
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• Urine pregnancy test (females only). 
• Body weight. 
• Vital signs. 
• ECG. 
• Hematology and urinalysis. 
• Biochemistry. 
• Anti-avalglucosidase alfa antibodies and neutralizing antibodies in ADA-positive patients. 
• MRI. 
• In patients in whom the prior muscle biopsy, obtained in a prior avalglucosidase alfa 
study, had a glycogen content >5%, or who show significant clinical decline: 
- 
Skeletal muscle needle or open biopsy (within 6 months), 
• Urine Hex4 sample collection. 
• Exploratory biomarker urine sample collection. 
• Exploratory biomarker plasma sample collection. 
• 6MWT. 
• PFT. 
• Plasma sample collection for microRNA analyses. 
• Infusion of avalglucosidase alfa. 
10.1.3.8 Follow-up 
• The Investigator should take all appropriate measures to ensure the safety of the patients, 
notably he/she should follow-up the outcome of any AEs (eg, clinical signs, laboratory 
values or other) until the return to normal or consolidation of the patient's condition. 
• All AEs documented at a previous visit/contact that are designated as ongoing will be 
reviewed by the Investigator at subsequent visits/contacts. 
• In case of any SAE, the patient must be followed up until clinical recovery is complete and 
laboratory results have returned to normal, or until outcome has been stabilized. This may 
imply that follow-up may continue after the patient has left the clinical trial and that 
additional investigations may be requested by the monitoring team. The Investigator will 
ensure that follow-up includes further investigations consistent with appropriate medical 
management and patient consent to elucidate the nature and/or causality of the AE. 
• In case of any SAE or non-serious AE brought to the attention of the Investigator at any 
time after cessation of the IMP and considered by him/her to be caused by the IMP with a 
reasonable possibility, this should be reported to the monitoring team. 
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• The Investigator will provide follow-up information for any SAE to the Sponsor as soon as 
it is available. The Sponsor or regulatory authorities may request additional information 
regarding an SAE. 
• For this study, the on-treatment period will be defined as the period from the time of first 
dose of IMP to at least 4 weeks after the last administration of the IMP. The on-treatment 
period may end earlier (ie, 2 weeks after the last administration of IMP) if the patient 
enrolls in another study or receives commercially available ERT. In this case the follow-up 
period may be reduced from 4 to 2 weeks. For the purposes of the study, status of ongoing 
and new AEs will be assessed 4 weeks after the last infusion, or for patients who 
discontinue early, after their last completed study visit. Any new AE or SAE that occurs 
during the 4-week follow-up period and is assessed as related to the drug or study 
procedures will be reported/collected in the clinical database. 
10.2 
DEFINITION OF SOURCE DATA 
All evaluations that are reported in the eCRF must be supported by appropriately identified source 
documentation. The results of certain examinations or evaluations recorded in the eCRF may be 
considered to be source data. 
The Investigator must provide the Sponsor or its designee direct access to each patient’s source 
documents. Source documents may include, but are not limited to, the following original 
documents, data, and records where information was first recorded: 
• Hospital records. 
• Medical histories and narrative statements relating to the patient’s progress. 
• Clinical and office charts. 
• Operative reports. 
• Laboratory notes/reports. 
• Memoranda and telephone notes/records. 
• Patients’ evaluation checklists. 
• Pharmacy dispensing records. 
• Recorded data from automated instruments. 
• Copies of transcriptions certified after verification as being accurate copies. 
• Project-specific worksheets (eg, for study visits), including all worksheets developed 
specifically for this study. 
• X-ray images and corresponding reports. 
• ECG readings and corresponding reports. 
• MRI image sets and corresponding reports. 
• Video recordings of surgery. 
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10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION 
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the eCRF. In any case, the 
patient should remain in the study as long as possible. 
The following may be justifiable reasons for the Investigator or Sponsor to discontinue a patient 
from treatment: 
• The patient was erroneously included in the study (ie, was found to not have met the 
inclusion/exclusion criterion). 
• The patient experiences an intolerable or unacceptable AE. 
• The patient is unable to comply with the requirements of the protocol. 
• The patient participates in another investigational study without the prior written 
authorization of the Sponsor. 
• The patient becomes pregnant. 
• The patient becomes lost to follow-up. 
The Investigator or the Sponsor (see Section 14.2) terminates the study. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs or if the patient becomes pregnant. Reinitiation of treatment with the IMP will be done under 
close and appropriate clinical/and or laboratory monitoring once the Investigator will have 
considered according to his/her best medical judgment that the responsibility of the IMP in the 
occurrence of the concerned event was unlikely and if the selection criteria for the study are still 
met (refer to Section 7.1 and Section 7.2). 
For all temporary treatment discontinuations, duration should be recorded by the Investigator in 
the appropriate screens of the eCRF when considered as confirmed. Visit and assessment 
schedules will be adapted to the absence of infusion of IMP (refer to Section 1.2 and 
Section 10.1.2.8). 
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time. 
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10.3.3 Criteria for permanent treatment discontinuation 
At patient request, ie, withdrawal of the consent for treatment, the patients may withdraw from 
treatment with the IMP if they decide to do so, at any time and irrespective of the reason, or this 
may be the Investigator’s decision. All efforts should be made to document the reasons for 
treatment discontinuation and this should be documented in the eCRF. 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation before making a decision of permanent discontinuation of the IMP for the concerned 
patient. 
10.3.4 Handling of patients after permanent treatment discontinuation 
Patients will be followed-up according to the study procedures as specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedure normally planned for the last dosing day with the IMP. 
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate screens of the eCRF when considered as confirmed. 
10.3.5 Procedure and consequence for patient withdrawal from study 
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. Withdrawal of consent for treatment should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for non-patient 
contact follow-up, eg, medical records check. If possible, the patients should be assessed using the 
procedures defined above. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing. 
If possible, the patients are assessed using the procedure normally planned for the end of study 
visit. 
For patients who fail to return to the site, the Investigator should make the best effort to recontact 
the patient (eg, contacting patient’s family or private physician, reviewing available registries or 
health care databases), and to determine his/her health status, including at least his/her vital status. 
Attempts to contact such patients must be documented in the patient’s records (eg, times and dates 
of attempted telephone contact, receipt for sending a registered letter). 
The statistical analysis plan will specify how these patients lost to follow-up for their primary 
endpoints will be considered. 
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Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused. 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events 
10.4.1.1 Adverse event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
10.4.1.2 Serious adverse event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death, or 
• Is life-threatening, or: 
- 
Note: The term “life-threatening” in the definition of “serious” refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect. 
• Is a medically important event: 
- 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or non-serious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor may be appropriate. Such events may require further investigation in 
order to characterize and understand them. AESIs may be added or removed during a study by 
protocol amendment. 
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AESIs will include: 
• Infusion-associated reactions: 
- 
IARs are defined as AESIs that occur during either the infusion or the observation 
period following the infusion which are deemed to be related or possibly related to the 
IMP. At the discretion of the Investigator, AEs occurring after completion of the  
post-infusion observation period that are assessed as related may also be considered 
IARs. Refer to Section 8.8.2 for additional testing in the event a patient experiences a 
moderate, severe, or recurrent IAR suggestive of hypersensitivity reactions and for 
suggested guidelines for the management of IARs. 
• Pregnancy: 
- 
Pregnancy occurring in a female patient included in the clinical trial. Pregnancy will be 
recorded as an AESI with immediate notification in all cases. It will be qualified as an 
SAE only if it fulfills the SAE criteria. 
- 
Male patients will be instructed to notify the Investigator immediately if they discover 
that their sexual partner is pregnant. 
- 
In the event of pregnancy in a female participant, IMP should be discontinued. 
- 
Follow-up of the pregnancy is mandatory in a female participant or in a female partner 
of a male participant, until the outcome has been determined. 
• Overdose: 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the patient and defined as at least twice the 
intended dose within the intended therapeutic interval, adjusted according to the tested 
drug. 
• Clinical laboratory (change from baseline, ie, prior to the first dose of GZ402666 in any 
prior avalglucosidase alfa study): 
- 
ALT or AST increase of ≥3 x the upper limit of normal (ULN) if baseline is <ULN, or 
ALT or AST increase ≥2 x the baseline value if baseline is ≥ULN, 
- 
A maximum ALT value of ≥400 IU/L or AST value of ≥500 IU/L or an increase in 
direct, indirect, or total bilirubin of ≥2 x ULN, 
- 
Serum creatinine increase of >1.5 x the baseline value (and final serum creatinine 
value is >ULN). 
In the event of an AESI, the Sponsor will be informed immediately (ie, within 24 hours), using the 
AE form together with the SAE complementary form to be entered in the eCRF. 
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10.4.2 General guidelines for reporting adverse events 
• All AEs, regardless of seriousness or relationship to IMP, spanning from the signature of 
the informed consent form until the end of the study as defined by the protocol for that 
patient, are to be recorded on the corresponding screen(s) of the eCRF. 
• When a safety event is categorized as a primary outcome, the event will be reported as an 
AE but will be waived from reporting to health authorities providing an agreement has 
been reached with them. 
• Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP. 
- 
There is one exception to this rule. In instances where a patient experiences an IAR 
(refer to Section 8.8.2), allergic, or anaphylactic reaction, either during infusion or post 
observation period, each of the individual signs and/or symptoms comprising the 
reaction should be captured as individual AE terms. 
• The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
• When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
• Laboratory, vital signs, or ECG abnormalities are to be recorded as AEs only if: 
- 
Symptomatic and/or, 
- 
Requiring either corrective treatment or consultation, and/or, 
- 
Leading to IMP discontinuation or modification of dosing, and/or, 
- 
Fulfilling a seriousness criterion, and/or, 
- 
Defined as an AESI. 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator must immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the eCRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the eCRF or after a standard delay. 
• All further data updates should be recorded in the eCRF as appropriate within 24 hours of 
knowledge. In addition, every effort should be made to further document any SAE that is 
fatal or life-threatening within a week (7 days) of the initial notification. 
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• A back-up plan (using a paper case report form (CRF) process) is available and should be 
used when the eCRF system does not work. Please refer to the Study Operations Manual 
for further guidance. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.4 Guidelines for reporting adverse events of special interest 
The needs for specific monitoring, documentation, and management of AESIs are described in 
this section. 
For each defined AESI, consider carefully the need to collect additional specific information that 
would impact the study and/or the eCRF design, such as: 
• Pre-existing related condition or lifestyle of interest for the AE (eg, habits, cardiovascular 
risk factor). 
• Expected list of associated signs and symptoms. 
• Corrective actions (eg, treatment discontinuation, concomitant treatment). 
• Diagnostic actions (eg, test[s] or procedure[s] results). 
• Additional descriptive factors. 
• Sequelae. 
• IARs: 
- 
Any pre-infusion medication(s) administered, 
- 
Infusion rate at which the IAR occurred, 
- 
Time to onset of IAR, 
- 
Any adjustments to infusion rate made, 
- 
Any medications and/or therapies administered, 
- 
Time to IAR resolution (de-challenge), 
- 
Re-challenge, 
- 
Relevant vital signs (including pre-infusion vital signs). 
10.4.4.1 Reporting of adverse events of special interest with immediate notification 
For AESIs with immediate notification, the Sponsor will be informed immediately (ie, within 
24 hours), as per the SAE notification instructions described in Section 10.4.3, even if not 
fulfilling a seriousness criterion, using the corresponding pages in the eCRF. 
• ALT increase. 
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• IARs. 
• Pregnancy. 
• Overdose. 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to the IMP (suspected 
unexpected serious adverse reaction [SUSAR]), to the health authorities, institutional 
review boards (IRBs)/independent ethics committees (IECs) as appropriate, and to the 
Investigators. 
• All SAEs that are expected and at least reasonably related to the IMPs to the health 
authorities, according to local regulations. 
In this study, some AEs are considered related to the underlying condition. Any AE not listed as 
an expected event in the Investigator’s Brochure or in this protocol will be considered unexpected. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.6 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations and 
included in the final clinical study report. 
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11 
STATISTICAL CONSIDERATIONS 
The Sponsor will be responsible for data collection and editing, reviewing, and validating all the 
information in the eCRFs, statistical analysis, and generation of the clinical report. 
Prior to locking the database, all data editing will be complete and decisions regarding the 
evaluability of all patient data for inclusion in the statistical analysis will be made. The rationale 
for excluding any data from the statistical analyses will be prospectively defined, and 
classification of all or part of a patient’s data as non-evaluable will be completed and documented 
before the entire database is locked. 
All data collected in this study will be documented using summary tables, figures, and patient data 
listings. 
All summary statistics will be computed and displayed overall and by treatment group and 
scheduled assessment time point. Summary statistics for continuous variables will include n, 
mean, standard deviation, minimum, median, and maximum. For categorical variables, 
frequencies and percentages will be presented. Graphical displays will be provided as appropriate. 
Any changes to the statistical analysis will be delineated in the statistical analysis plan. 
11.1 
DETERMINATION OF SAMPLE SIZE 
This is an ongoing extension study, and therefore, the number of patients will be determined by 
enrollment from other avalglucosidase alfa studies. Thus, no formal sample size calculations have 
been performed. 
11.2 
DISPOSITION OF PATIENTS 
Disposition of patients will be depicted by intended dose level for both the patient study status and 
also for the patient analysis populations. For patient study status, the total number of patients for 
each one of the following categories will be presented in the clinical study report: 
• Registered patients are patients who signed the informed consent and who are planned to 
receive the IMP. 
• All treated population. 
• Patients who completed the study treatment period as per protocol. 
• Patients who discontinued study treatment and reasons for discontinuation. 
• Pharmacokinetic population. 
• Pharmacodynamic population. 
• Efficacy population. 
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For all categories of patients, percentages will be calculated using the number of exposed patients 
(all treated population). Reasons for treatment discontinuation will be supplied in tables giving 
numbers and percentages by dose level. 
Additionally, the analysis populations for safety, PK, pharmacodynamics, and efficacy will be 
summarized in a table by patient counts on the registered population. 
11.2.1  Protocol deviations 
During the review of the database, compliance with the protocol will be examined with regard to 
inclusion and exclusion criteria, treatment compliance, prohibited therapies, and timing and 
availability of planned assessments. Protocol deviations will be identified by the study team 
before database lock and documented as appropriate, including missing data and IMP 
discontinuations, and classified as minor, major, or critical. Protocol deviations discovered during 
the data reconciliation process will be tracked by the Sponsor or its designee. 
Individual deviations to inclusion and exclusion criteria as reported by the Investigator will be 
listed. 
If any, other deviations will be listed by patient and/or described in the body of the clinical study 
report. 
11.3 
ANALYSIS POPULATIONS 
• Full Analysis Set: This analysis set consists of all patients who received at least 
1 complete infusion of IMP. 
• Safety Analysis Set: This analysis set consists of all patients who received any amount of 
IMP and will be used as the basis for all safety analyses. 
• PK/Pharmacodynamics/Efficacy Analysis Set: All patients without any critical 
deviations related to IMP administration, and for whom any 
PK/pharmacodynamic/efficacy data are available, will be included in the 
PK/pharmacodynamic/efficacy population. 
11.4 
PATIENT DEMOGRAPHIC AND MEDICAL HISTORY 
Medical/surgical history, and Pompe disease history, including GAA gene mutations, will be 
imported from the patient’s prior avalglucosidase alfa study file in the database when possible. 
ECG, hematology, biochemistry, and urinalysis data from first day of avalglucosidase alfa 
infusion (ie, prior to first infusion in any prior avalglucosidase alfa study) will be entered by the 
study site into the database. These data will be summarized using summary statistics for 
continuous variables and frequency distribution for categorical variables. All data will be 
presented in by-patient listings. 
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11.5 
SAFETY ANALYSIS 
Descriptive statistics for actual values and changes from baseline will be generated by time point 
for selected safety parameters of interest. Data may also be plotted. For the purpose of analysis, 
baseline will be prior to the first dose of GZ402666 in a prior avalglucosidase alfa study. 
11.5.1 Physical examination, vital signs, and body weight 
Observed measurements and changes from baseline to study time points in physical examination 
findings, vital signs (including but not limited to blood pressure, heart rate, respiratory rate, and 
temperature), and body weights will be summarized. Listings of abnormal findings/values will be 
presented. 
11.5.2 Clinical laboratory tests 
Observed measurements and changes from baseline to study time points in hematology, 
biochemistry, and urinalysis will be descriptively summarized. All laboratory values will be 
classified as normal, above normal, or below normal based on normal ranges provided by the 
laboratory. All data will be presented in listings along with individual listings of patients with 
clinically significant abnormal laboratory values. 
11.5.3 Adverse events 
All AEs, SAEs, and IARs will be coded using MedDRA and summarized by primary SOC and 
PT. Detailed listings of patients who experience AEs, SAEs, and IARs will be presented. The 
incidence of TEAEs, IARs, and SAEs will be tabulated (frequencies and percentages) by dosing, 
by severity, and by relationship to treatment. In tabulating severity of AEs on a per-patient basis, 
the greatest severity will be assigned to a patient should there be more than one occurrence of the 
same AE with different reported severities. Relationships of the AE to treatment will be 
categorized as not related, unlikely related, possibly related, or related. The highest level of 
association will be reported in patients with differing relationships for the same AE. Listings of 
AEs, SAEs, and IARs for all patients will be provided, which will include severity and 
relationship to treatment, as well as actions taken regarding treatment and patient outcome. A 
separate listing for patients who withdraw from the study due to AEs will be provided. The 
incidence of AEs leading to study discontinuations will also be summarized. 
11.5.4 Electrocardiogram 
Observed measurements and changes from baseline to study time points in ECG results (QTc, PR 
interval, etc) will be summarized. Listings of abnormal findings/values will be presented for each 
patient. 
11.5.5 Anti-avalglucosidase alfa antibodies, neutralizing antibodies, and 
infusion-associated reactions 
Percentage of patients who seroconverted to avalglucosidase alfa, time to seroconversion and 
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peak anti-avalglucosidase alfa antibody titer will be summarized using summary statistics. For 
patients who were previously treated with alglucosidase alfa only, the percentage of patients 
testing positive to alglucosidase alfa and IgG antibody titer data to alglucosidase alfa will be 
summarized using summary statistics as well. Antibody titer values will be summarized using 
summary statistics at each study visit. All data will be presented in listings for each patient. By-
patient listings will also display results of neutralizing antibody. 
For patients who have an IAR, by-patient listings will also display results of circulating immune 
complex, anti-avalglucosidase alfa IgE antibody, serum tryptase activity, complement activation, 
and skin testing performed. 
Descriptive summaries may also be provided as appropriate. 
11.6 
ANALYSIS OF PHARMACOKINETIC DATA 
11.6.1 Pharmacokinetic parameters 
The list of PK parameters is listed in Section 9.2.5. 
11.6.2 Statistical analysis 
Individual assessments and descriptive statistics (mean, standard deviation [SD], median, 
minimum, maximum, geometric mean, and percent coefficient of variation) will be presented for 
plasma concentration time data and PK parameters for each dose level and visit. Individual and 
mean (SD) plasma concentration time profile will be presented graphically for each visit. 
To evaluate the effect of immunogenicity on the PK of avalglucosidase alfa, pre-dose ADA and 
neutralizing antibody titers for each patient will be analyzed graphically with respect to clearance 
at 6 months and then yearly thereafter. If relationships are apparent, further quantitative/statistical 
analysis may be performed (eg, statistical significance, correlation coefficients). 
11.7 
PHARMACODYNAMIC AND EXPLORATORY BIOMARKER ANALYSIS 
Pharmacodynamic endpoints as described in Section 9.3 will be summarized using descriptive 
statistics at each scheduled study visit. Observed measurements, as well as change from baseline, 
will be summarized. If a linear trend in the change of a pharmacodynamic endpoint is observed, 
longitudinal model may be employed to model change from baseline over time. In addition, 
95% confidence intervals (CI) of changes will be presented. 
Evaluation of intact muscle and fatty replacement from MRI will be descriptive using a grading 
scale and, if feasible, quantitative using a numeric method of determining the degree (%) of 
overall fatty replacement of muscle from the skeletal muscle MRI and an individual (%) measure 
for the quadriceps. A correlative measure comparing the biopsied muscle and its MRI counterpart 
will also be performed. 
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Urine Hex4 levels will be summarized using descriptive statistics at each scheduled study visit. 
Observed measurements, as well as change from baseline, will be summarized. If a linear trend in 
the change of urine Hex4 levels is observed, a longitudinal model may be employed to model 
change from baseline over time. In addition, 95% CIs of changes will be presented. Due to the 
small number of patients, nonlinear relationship will not be formally characterized. 
To explore the relationship between PK endpoints and urine Hex4 levels, scatter plots and linear 
mixed model may be used as appropriate. 
To explore the relationship between glycogen content and biomarkers, correlational statistics 
(Spearman or Pearson) at each scheduled study visit will be used. In addition, scatter plots and 
linear regression analysis will be used to describe the relationship between glycogen content and 
each biomarker. 
Similar analyses will be carried out to explore the relationship between other pharmacodynamic 
endpoints, exploratory biomarkers, and exploratory efficacy assessments. 
11.8 
EXPLORATORY EFFICACY ANALYSIS 
Observed measurements and changes from baseline to each study time point in 6MWT distance 
walked and PFT parameters (% predicted sitting and supine FVC, FEV1, MIP, MEP, and PEF) 
will be summarized using summary statistics. In addition, 95% CIs will be used to estimate the 
change from baseline at each study visit. Graphical displays showing data over time will be 
presented. 
11.9 
EXTENT OF STUDY TREATMENT EXPOSURE AND COMPLIANCE 
Number of weeks in the study, the number of study infusions, and the dose received by patients 
will be summarized using summary statistics. Frequency and percentage of patients remaining on 
treatment will be summarized quarterly. 
Data from all patients who are enrolled in the study will be included in the summary of patient 
accountability. The frequency and percentage of patients who are enrolled in the study, 
discontinued from the study, and completed the study, along with reasons for discontinuation, will 
be summarized. 
11.10 PRIOR/CONCOMITANT MEDICATION/THERAPY 
Concomitant medication/therapy data will be coded using the World Health Organization Drug 
dictionary. Number and percentages of patients receiving each concomitant medication/therapy 
will be tabulated. 
11.11 INTERIM ANALYSIS 
A clinical study report will be produced at study completion. An interim report will also be 
produced if a sub-study analysis of data is performed to support regional regulatory requirements. 
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12 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
12.1 
REGULATORY AND ETHICAL CONSIDERATIONS 
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. 
- 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation (GDPR)). 
• The protocol, protocol amendments, Informed Consent Form (ICF), IB , and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants. 
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
- 
Determining whether an incidental finding (as per Sanofi policy) should be returned to 
a participant and, if it meets the appropriate criteria, to ensure the finding is returned 
(an incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding: 
- 
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity. 
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- 
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted 
out of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
- 
In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), European Medical Device Regulation 2017/745 for 
clinical device research (if applicable), and all other applicable local regulations. 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the European Union (EU) Member States and/or 
Ethics Committees, as appropriate, for any amendments to the clinical trial that are deemed as 
“substantial” (ie, changes which are likely to have a significant impact on the safety or physical or 
mental integrity of the clinical trial participants or on the scientific value of the trial) prior to their 
implementation. 
12.2 
INFORMED CONSENT PROCESS 
• The Investigator or his/her representative will explain the nature of the study to the 
participants or their legally authorized representative, and answer all questions regarding 
the study, including what happens to the participant when his/her participation ends (post-
trial access strategy for the study).  
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative [defined as parent(s) or guardian(s)] will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Privacy and Data Protection requirements including those of 
the GDPR and of the French law, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• In case of ICF amendment while the participants are still included in the study, they must 
be re-consented to the most current version of the ICF(s).Where participants are not in the 
study anymore, teams in charge of the amendment must define if those participants must 
or not re-consent or be informed of the amendment (eg, if the processing of personal data 
is modified, if the Sponsor changes, etc). 
• A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative.  
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Participants who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples or 
new extra samples for optional exploratory research. The Investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Participants will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. A separate consent will be required to document a participant's 
agreement to allow any remaining specimens to be used for exploratory research. Participants who 
decline to participate in this optional research will not provide this separate consent. 
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13 
STUDY MONITORING 
13.1 
DATA QUALITY ASSURANCE 
• All participant data relating to the study will be recorded on printed or eCRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• Guidance on completion of CRFs will be provided in the CRF completion instructions. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
13.2 
SOURCE DOCUMENTS 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Source documents include (but are not limited to): participant’s medical file, appointment 
books, original laboratory records, functional outcome assessment source document. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
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• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
DATA PROTECTION 
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy and Data Protection laws and regulations, including the 
GDPR. The study Sponsor is the Sanofi company responsible for ensuring compliance with this 
matter, when processing data from any individual who may be included in the Sanofi databases, 
including Investigators, nurses, experts, service providers, Ethics Committee members, etc. 
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
Protection of participant data 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Patient race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Not Reported) or ethnicity (Hispanic or Latino, Not 
Hispanic or Latino, Not Reported, Unknown) will be collected in this study because these data are 
required by several regulatory authorities. In addition, it is unknown if race or ethnicity may have 
an impact on the Pompe disease ERT. It is now recognized that some drug metabolism are 
impacted by race (eg, warfarin [5]) and/or ethnicity (various drugs [6]). 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor.  
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
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Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or pre-
contractual relationship. They may be communicated to any company of the Sanofi group 
(“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (DPO) (link 
available at Sanofi.com). 
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients: 
- 
Personnel within Sanofi or partners or service providers involved in the study.  
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency. 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers. 
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
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their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project.  
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
14.2 
STUDY AND SITE CLOSURE 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio. 
- 
Discontinuation of further study intervention development. 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator. 
- 
Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
14.3 
CLINICAL TRIAL RESULTS AND DISSEMINATION OF CLINICAL STUDY DATA 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
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A Coordinating Investigator will be designated to review and sign the completed clinical study 
report.  
Analysis of DBS, plasma and urine biomarkers, pharmacogenetic biomarkers, exploratory 
immunogenicity assessments, exploratory muscle biopsy and PK not included in the study report 
will be included in separate technical reports. 
Study participants 
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable datasets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
Professionals involved in the study or in the drug development program 
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organisations”. 
14.4 
PUBLICATION POLICY 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor or prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the Investigator and by the Sponsor and the signed amendment will be filed with this 
clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC written approval/favorable opinion concerning the revised 
informed consent form prior to implementation of the change and patient signature should be 
re-collected if necessary. 
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16 
BIBLIOGRAPHIC REFERENCES 
1. Kishnani PS, Corzo D, Nicolino M, Byrne B, Mandel H, Hwu WL, et al. Recombinant human 
acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology. 
2007;68:99-109. 
2. van der Ploeg AT, Clemens PR, Corzo D, Escolar DM, Florence J, Groeneveld GJ, et al. A 
randomized study of alglucosidase alfa in late-onset Pompe’s disease. N Engl J Med. 
2010;362:1396-406. 
3. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS 
statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166:111-
7. 
4. American Thoracic Society/European Respiratory Society. ATS/ERS Statement on respiratory 
muscle testing. Am J Respir Crit Care Med. 2002;166:518-624. 
5. Schelleman H, Chen J, Chen Z, Christie J, Newcomb CW, Brensinger CM, et al. Dosing 
Algorithms to Predict Warfarin Maintenance Dose in Caucasians and African Americans. Clin 
Pharmacol Ther. 2008;84:332-9. 
6. Yasuda SU, Zhang L, Huang SM. The Role of Ethnicity in Variability in Response to Drugs: 
Focus on Clinical Pharmacology Studies. Clin Pharmacol Ther. 2008;84:417-3. 
 
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17 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
17.1 
APPENDIX 1: COUNTRY-SPECIFIC REQUIREMENTS 
France 
The Sponsor is required by the French health authority to state in the protocol that the option for 
home infusion added in LTS13769 protocol amendment 04 does not apply in France, consistent 
with their position disallowing home infusion for all enzyme replacement therapies (ERT). 
United Kingdom, Germany and Denmark 
In order to comply with the UK, German and Danish Health Authority position regarding the 
protocol language, the duration of the additional follow-up phase will be defined as “up to the 
approval in the country or limited to a maximum of 2 years whichever occurs first (ie, for patients 
in the UK, Germany and Denmark, the total study duration per patient is 8 years at the maximum 
including the initial 6-year period and the additional 2-year follow-up).” 
17.2 
APPENDIX 2: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly after the cover page. 
17.2.1 Amended protocol 01: 09 December 2013 
This amended protocol (Amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it significantly impacts either the safety or physical/mental integrity of 
participants or the scientific value of the study. 
Overall Rationale for the Amendment 
Change inclusion criteria to specific acceptable contraceptive methods 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary, 7.1 Inclusion 
criteria 
Change to inclusion criteria 
To add contraceptive methods to I04 
Clinical Trial Summary, 6.2.1 Duration 
of study participation for each patient, 
6.2.2 Determination of end of clinical 
trial (all patients) 
Change to study duration 
Clarification 
11.11 Interim analysis 
Change to interim analysis 
Clarification 
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17.2.2 Amended protocol 02: 25 July 2014 
This amended protocol (Amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it significantly impacts either the safety or physical/mental integrity of 
participants or the scientific value of the study. 
Overall Rationale for the Amendment 
Change to frequency and timing of assessments 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Graphical study design, 1.2 Study 
flow chart, 9.1.7 Immunogenicity, 
10.1.2.2 Monthly, 10.1.2.3 Monthly for 
first 6 months and Quarterly visits 
thereafter and 10.1.2.4 Every 6 months  
Change to frequency of antibody 
testing 
To simplify by reducing frequency of sampling 
for antibody testing 
1.2 Study flow chart 
Addition of time window for study 
assessments and IP administration 
To specify accepted time window for study 
assessments and IP administration from 
previous assessment date and previous IP 
administration date 
1.1 Graphical study design, 1.2 Study 
flow chart, 9.1.5 Body weight, 10.1.2.3 
Monthly for first 6 months and 
Quarterly visits thereafter and 10.1.2.4 
Every 6 months  
Change to the frequency of 
assessment of body weight 
To harmonize frequency of assessment of 
body weight with recommendations from the 
Pharmacy Manual 
Throughout 
Clarifications 
Not summarized 
17.2.3 Amended protocol 03: 29 January 2016 
This amended protocol (Amendment 03) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it significantly impacts either the safety or physical/mental integrity of 
participants or the scientific value of the study. 
Overall Rationale for the Amendment 
Change the dose regimen for all patients to 20 mg/kg qow and change to the visit schedule for 
patients switching from 5 mg/kg qow or 10 mg/kg qow to 20 mg/kg qow 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary, 
8.1 Investigational 
medicinal products and 
8.4 Methods of assigning 
patients to treatment group  
20 mg/kg body weight qow was selected as the 
final avalglucosidase alfa dose for the extension 
study. 
Avalglucosidase alfa was generally safe and 
well tolerated at all dose levels in TDR12857. 
The doses were differentiated by improvement 
in FVC with avalglucosidase alfa 20 mg/kg 
qow in the treatment naïve patients (Group 1) 
versus stabilization with 5 mg/kg. 
1.1 Graphical study design, 
1.2 Study flow chart and 
10.1.2.7 Re-baseline visit   
Change to the visit schedule for patients 
switching from 5 mg/kg qow or 10 mg/kg qow to 
20 mg/kg qow 
To include a re-baseline visit for assessments 
before receiving the higher dose, from which 
point forward the patient will follow the new 
visit schedule 
Throughout 
Minor editorial and document formatting revisions 
Minor, therefore have not been summarized 
17.2.4 Amended protocol 04: 27 November 2017 
This amended protocol (Amendment 04) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it significantly impacts either the safety or physical/mental integrity of 
participants or the scientific value of the study. 
Overall Rationale for the Amendment 
Added option for home infusion of IMP 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
8.1 Investigational 
medicinal products 
Added option of home infusion of IMP for patients 
meeting all eligibility requirements in regions 
where home infusion is deemed appropriate 
To allow collection of data on home infusion of 
IMP in a clinical setting under GCP and to 
enhance patient retention and collection of 
long-term safety data 
Throughout 
Minor editorial and document formatting revisions 
Minor, therefore have not been summarized 
17.2.5 Amended protocol 05: 18 July 2018 
This amended protocol (amendment 05) is considered to be nonsubstantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union because it neither significantly impacts the safety or physical/mental integrity 
of participants nor the scientific value of the study. 
Overall Rationale for the Amendment 
To comply with the requirement of the French health authority to state in the protocol that the 
option for home infusion added in LTS13769 protocol amendment 04 does not apply in France, 
consistent with their position disallowing home infusion for all enzyme replacement therapies 
(ERT). 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
PROTOCOL AMENDMENT SUMMARY 
OF CHANGES TABLE 
Document formatting revision 
To combine the protocol amendment 
into a consolidated amended protocol 
8.1 Investigational medicinal products 
Added reference to Section 17.1 specific 
for France 
Provide detail on regional requirements 
for home infusion in France 
17 Supporting documentation and 
operational considerations 
Document formatting revision 
Add a new section for appendices 
17.1 Appendix 1: Country-specific 
requirements 
Added requirement specific for France 
Home infusion of ERT is not allowed in 
France 
17.2 Appendix 2: Protocol amendment 
history 
Document formatting revision 
To provide a summary of all changes to 
original protocol in one place 
17.2.6 Amended protocol 06: 06 September 2019 
This amended protocol (amendment 06) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it significantly impacts either the safety or physical/mental integrity of 
participants or the scientific value of the study. 
Overall Rationale for the Amendment 
The overall rationale for this amendment is as follows: 
• To comply with the DMC recommendation with regards to home infusions. 
• To reference the Investigator’s Brochure (IB) in the protocol. 
• To extend the additional follow-up period until avalglucosidase alfa is approved in the 
patient’s country. 
• To comply with the United Kingdom (UK) position regarding the protocol language with 
regards to the study follow-up period duration. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
PROTOCOL AMENDMENT SUMMARY 
OF CHANGES TABLE 
Document formatting revision 
To combine the protocol amendment 
into a consolidated amended protocol 
Clinical trial summary (Duration of study) 
Text added regarding an additional 
follow-up phase for all patients and UK 
patients. 
 
 
 
 
mRNA analysis was removed from the 
pharmacogenetics endpoints 
To extend the additional follow-up period 
until avalglucosidase alfa is approved in 
the patient’s country. 
To comply with the UK position 
regarding the protocol language with 
regards to study follow-up period 
duration. 
This test will no longer be performed. 
1.1 Graphical study design 
Text added regarding follow-up phase  
for all patients and UK patients 
 
 
 
 
 
mRNA analysis was removed from the 
“At 6 months”, “Re-baseline”, and “EOS” 
visits. 
To extend the additional follow-up period 
until avalglucosidase alfa is approved in 
the patient’s country. 
To comply with the UK position 
regarding the protocol language with 
regards to study follow-up period 
duration. 
 
This test will no longer be performed. 
1.2.1 and 1.2.2 Study flow charts 
End of study visit and follow-up visit 
deleted and the columns for these visits 
and the procedures were moved to the 
new study flow chart in Section 1.2.3; 
footnote “b” updated 
 
mRNA analysis removed from 
pharmacogenetics assessments 
To extend the additional follow-up period 
until avalglucosidase alfa is approved in 
the patient’s country. 
 
 
 
This test will no longer be performed. 
1.2.3 Study flow chart 
Added study flow chart for additional 
follow-up phase 
To extend the additional follow-up period 
until avalglucosidase alfa is approved in 
the patient’s country. The study flow 
chart was added to denote the study 
procedures required for the additional 
follow-up period. 
4.1.2 Absorption, distribution, 
metabolism, and excretion data 
Added reference to the Investigator’s 
Brochure 
To reference the IB in the protocol. 
4.2.2.4 Pharmacogenomics 
Text deleted/updated; sampling for 
mRNA was removed. 
To reflect the amendment-specific 
changes 
6.2.1 Duration of study participation for 
each patient 
Text updated regarding study duration 
and text added regarding the follow-up 
phase for all patients and reference 
added to Appendix 1, Section 17.1 
specific for the UK 
To extend the additional follow-up period 
until avalglucosidase alfa is approved in 
the patient’s country. 
To comply with the UK position 
regarding the protocol language with 
regards to the study follow-up period 
duration. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.1 Investigational medicinal products 
(Home infusion) 
Deleted the requirement for a signed 
“Patient Registration Form”. 
Clarification for home infusion personnel 
regarding training of basic life support 
To comply with the DMC 
recommendation with regards to the 
home infusions procedure. 
9.1.7 Immunogenicity 
Text updated for the sample collection 
period for patients who were previously 
treated with alglucosidase alfa 
Text updated to specify IAR and 
circulating immune complex samples 
must be collected and shipped per the 
study-specific laboratory manual and the 
Study Operations Manual 
Clarification. 
9.2.1 Sampling times 
Text updated for the blood sample 
collection period 
Clarification. 
9.3.4 Exploratory plasma and urine 
biomarkers 
Text added regarding biomarker results 
and reporting 
Clarification. 
9.5.1 Skeletal muscle RNA expression 
analysis 
Text added regarding biomarker results 
and reporting 
Clarification. 
9.5.2 Circulating microRNA analysis 
Heading updated (sampling for mRNA 
was removed) and text added regarding 
biomarker results and reporting 
Clarification. 
10.1.2.5 At 6 months and yearly 
thereafter 
Plasma sample collection for mRNA 
analysis removed 
This test will no longer be performed. 
10.1.2.7 Re-baseline visit 
Plasma sample collection for mRNA 
analysis removed 
This test will no longer be performed. 
10.1.3 Additional follow-up phase 
New section and subsections 
(Sections 10.1.3.1 through 10.1.3.6) with 
corresponding text added regarding 
procedures in the additional follow-up 
phase 
To extend the additional follow-up period 
until avalglucosidase alfa is approved in 
the patient’s country. 
10.1.3.7 End of study visit 
Restructured EOS visit section (this 
section was previously Section 10.1.2.8) 
and deleted the following assessments: 
 
Anti-alglucosidase alfa IgG antibodies 
(only patients who were previously 
treated with alglucosidase alfa). 
 
 
NeoGAA PK plasma sample collection. 
 
Serum sample collection for skeletal 
muscle RNA expression analyses (within 
6 months). 
 
mRNA assessment. 
 
 
 
 
As patients have not received 
alglucosidase for 6 years, anti-GAA ADA 
assessments are not performed during 
the additional follow-up phase. 
 
This test will no longer be performed. 
 
 
This test will no longer be performed. 
 
 
This test will no longer be performed. 
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Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
“neoGAA” replaced with “avalglucosidase 
alfa” 
To align with other protocols and overall 
development plan 
17.1 Appendix 1: Country-specific 
requirements 
Added requirements specific for the UK 
To comply with the UK position 
regarding the protocol language with 
regards to study follow-up period 
duration. 
17.2.7 Amended protocol 07: 21 January 2020 
This amended protocol (amendment 07) is considered to be nonsubstantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union because it neither significantly impacts the safety or physical/mental integrity 
of participants nor the scientific value of the study. 
Overall Rationale for the Amendment 
The overall rationale for this amendment is as follows: 
• To clarify that study duration for each patient is initially 6 years to align protocol wording 
with other study documents (ICF in particular) and align between different sections of the 
protocol. 
• To modify the wording on duration of the additional follow-up period after the 6-year 
study for patients in the UK and Germany as follows: the duration of the additional follow 
up period will be up to the approval in the country or limited to a maximum of 2 years, 
whichever occurs first (ie, for UK and German patients, the total study duration per patient 
is 8 years at the maximum including the initial 6-year and the additional 2-year follow-up). 
• To correct typographical errors in the table footnote references in Section 1.2.3.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
PROTOCOL AMENDMENT SUMMARY 
OF CHANGES TABLE 
Document formatting revision 
To update document history and provide 
overall rationale for the amendment 
Clinical trial summary (Duration of study) 
Clarification that study duration for each 
patient is initially 6 years.  
Revised wording for study follow-up 
period duration specific for the UK and  
German patients. 
 
To align protocol wording with other 
study documents (ICF in particular) and 
align between different sections of the 
protocol. 
To comply with the UK and German 
Health Authority position regarding the 
protocol language with regards to study 
follow-up period duration. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Graphical study design 
Revised wording for study follow-up 
period duration specific for the UK and  
German patients. 
 
To comply with the UK and German 
Health Authority position regarding the 
protocol language with regards to study 
follow-up period duration. 
1.2 Study flow chart 
Deleted specifics regarding neutralizing 
antibody testing. 
Corrected footnote references. 
Details are provided in Section 9.1.7 
Immunogenicity. 
To correct typographical errors in the 
study flow chart for the additional follow-
up period. 
6.2.1 Duration of study participation for 
each patient 
Clarification that study duration for each 
patient is initially 6 years.  
Revised wording for study follow-up 
period duration specific for the UK and  
German patients. 
 
To align protocol wording with other 
study documents (ICF in particular) and 
align between different sections of the 
protocol. 
To comply with the UK and German 
Health Authority position regarding the 
protocol language with regards to study 
follow-up period duration. 
9.1.7 Immunogenicity 
Corrected typographical error regarding 
antibody testing. 
Modified wording regarding the type of 
testing for neutralizing antibodies to 
avalglucosidase alfa 
Modified wording regarding duration of 
testing for anti-alglucosidase alfa IgG 
antibodies. 
To specify testing to be done for anti-
avalglucosidase alfa antibodies. 
To allow flexibility in case approval is 
obtained to end testing of inhibition of 
enzyme activity. 
To allow testing of anti-alglucosidase 
alfa IgG antibodies to be stopped earlier 
than 6 years. 
10.1.3 Additional follow-up phase 
Revised wording for study follow-up 
period duration specific for the UK and  
German patients. 
 
To comply with the UK and German 
Health Authority position regarding the 
protocol language with regards to study 
follow-up period duration. 
17.1 Appendix 1: Country-specific 
requirements 
Revised wording for study follow-up 
period duration specific for the UK and  
German patients. 
To comply with the UK and German 
Health Authority position regarding the 
protocol language with regards to study 
follow-up period duration. 
17.2.6 Appendix 2: Protocol amendment 
history 
Added new section. 
To incorporate the changes from 
amended protocol 05 to amended 
protocol 06. 
17.2.8 Amended protocol 08: 30 September 2020 
This amended protocol (Amendment 08) is considered to be nonsubstantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union because it does not significantly impact either the safety or physical/mental 
integrity of participants or the scientific value of the study. 
Overall Rationale for the Amendment 
The overall rationale for this amendment is as follows: 
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• To comply with the Danish Medicines Agency (DKMA) position regarding the protocol 
language with regards to the study follow-up period duration. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
PROTOCOL AMENDMENT SUMMARY 
OF CHANGES TABLE 
Document formatting revision 
To update document history and provide 
overall rationale for the amendment 
Clinical trial summary (Duration of study) 
Revised wording for study follow-up 
period duration specific for patients in the 
UK, Germany and Denmark. 
 
To comply with the DKMA position 
regarding the protocol language with 
regards to study follow-up period 
duration. 
1.1 Graphical study design (Additional 
Follow-up Phase) 
Revised wording for study follow-up 
period duration specific for patients in the 
UK, Germany and Denmark. 
 
To comply with the DKMA position 
regarding the protocol language with 
regards to study follow-up period 
duration. 
6.2.1 Duration of study participation for 
each patient 
Revised wording for study follow-up 
period duration specific for patients in the 
UK, Germany and Denmark. 
 
To comply with the DKMA position 
regarding the protocol language with 
regards to study follow-up period 
duration. 
10.1.3 Additional follow-up phase 
Revised wording for study follow-up 
period duration specific for patients in the 
UK, Germany and Denmark. 
 
To comply with the DKMA position 
regarding the protocol language with 
regards to study follow-up period 
duration. 
17.1 Appendix 1: Country-specific 
requirements 
Revised wording for study follow-up 
period duration specific for patients in the 
UK, Germany and Denmark. 
 
To comply with the DKMA position 
regarding the protocol language with 
regards to study follow-up period 
duration. 
17.2.6 Appendix 2: Protocol amendment 
history 
Correction to description of amended 
protocol 06 changes consistent with 
designation as a substantial amended 
protocol. 
To correct typographical error 
17.2.7 Appendix 2: Protocol amendment 
history 
Added new section. 
To incorporate the changes from 
amended protocol 06 to amended 
protocol 07. 
 
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Amended Clinical Trial Protocol 09 Erratum  
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Page 2 
REASON FOR ERRATUM: 
 
In the Clinical Trial Summary table (page 5) and in section 5.2 (page 33), exploratory efficacy 
variables are wrongly listed as secondary endpoints. 
In the LTS13769 study protocol (Amended Clinical Trial Protocol 09, page 6), exploratory 
plasma and urine biomarkers and pharmacogenetics assessments are wrongly listed as secondary 
endpoints. These assessments are clearly exploratory in nature and are not reported in the Clinical 
Study Report, as also described in the study protocol: 
• 
Amended Clinical Trial Protocol 09, page 50 
9.3.4 Exploratory plasma and urine biomarkers 
Fasted plasma and urine samples will be collected prior to IMP infusion for the assessment of 
exploratory biomarkers. Procedures for the collection, handling, and shipment of all samples will 
be included in the study-specific laboratory manual. Results will be used to inform on biomarker 
targets for future studies and will not be reported in the CSR. 
• 
Amended Clinical Trial Protocol 09, page 51 
9.5 
Pharmacogenetic assessment 
Fasted pharmacogenetic samples will be collected. Refer to the study-specific laboratory manual 
for guidelines on the collection and shipment of whole blood samples. 
9.5.1 Skeletal muscle RNA expression analysis 
In patients in whom the prior muscle biopsy, obtained in a prior avalglucosidase alfa study, had a 
glycogen content >5% or who show significant clinical decline, muscle tissue samples will be 
taken via biopsy of the lower extremity (quadriceps) muscle, as indicated in Section 9.3.2. An 
additional serum sample will be collected in connection with this analysis. These serum samples 
will be used to assess whether proteins for any of the mRNA targets that are identified in muscle 
are expressed in serum and therefore could be assessed as a serum-based marker of Pompe 
disease. Results will be used to inform on biomarker targets for future studies and will not be 
reported in the CSR. 
9.5.2 Circulating microRNA analysis 
Plasma samples will be collected and assessed for circulating microRNA concentrations on both 
the whole-genome and individual gene levels. Results will be used to inform on biomarker targets 
for future studies and will not be reported in the CSR. 
 
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DESCRIPTION OF CHANGE AND WHAT IS BEING CHANGED: 
CLINICAL TRIAL SUMMARY 
The following text on page 5: 
STUDY OBJECTIVES 
Primary objective: 
To assess the long-term safety and pharmacokinetics (PK) of 
avalglucosidase alfa in patients with Pompe disease who have 
previously completed an avalglucosidase alfa study. 
Secondary objective: 
To assess the long-term effect of avalglucosidase alfa on 
pharmacodynamic and exploratory efficacy variables to assess if the 
benefits of avalglucosidase alfa are maintained and to assess the time 
course of response. 
Is replaced with: 
STUDY OBJECTIVES 
Primary objective: 
To assess the long-term safety and pharmacokinetics (PK) of 
avalglucosidase alfa in patients with Pompe disease who have 
previously completed an avalglucosidase alfa study. 
Secondary objective: 
To assess the long-term effect of avalglucosidase alfa on 
pharmacodynamic and exploratory efficacy variables to assess if the 
benefits of avalglucosidase alfa are maintained and to assess the time 
course of response. 
The following text beginning on page 6: 
SECONDARY AND EXPLORATORY 
ENDPOINTS 
Secondary endpoints: 
Pharmacokinetics 
Estimates for Cmax, AUClast, AUC, t1/2z, CL, and Vd. 
Pharmacodynamics 
Skeletal muscle magnetic resonance imaging (MRI). 
Skeletal muscle needle or open biopsy. 
Urinary Hex4. 
Exploratory plasma and urine biomarkers. 
Pharmacogenetics 
Serum skeletal muscle ribonucleic acid (RNA) expression analysis. 
Plasma circulating microRNA analyses. 
Exploratory Endpoints: 
Efficacy 
6-minute walk test (6MWT). 
Pulmonary function testing (PFT) endpoints. 
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Is replaced with: 
SECONDARY AND EXPLORATORY 
ENDPOINTS 
Secondary endpoints: 
Pharmacokinetics 
Estimates for Cmax, AUClast, AUC, t1/2z, CL, and Vd. 
Pharmacodynamics 
Skeletal muscle magnetic resonance imaging (MRI). 
Skeletal muscle needle or open biopsy. 
Urinary Hex4. 
Exploratory plasma and urine biomarkers. 
Pharmacogenetics 
Serum skeletal muscle ribonucleic acid (RNA) expression analysis. 
Plasma circulating microRNA analyses. 
Exploratory Endpoints: 
Efficacy 
6-minute walk test (6MWT). 
Pulmonary function testing (PFT) endpoints. 
Pharmacodynamics 
Exploratory plasma and urine biomarkers. 
Pharmacogenetics 
Serum skeletal muscle ribonucleic acid (RNA) expression analysis. 
Plasma circulating microRNA analyses. 
 
5.2 SECONDARY 
The following text on page 33: 
The secondary objective is to assess the long-term effect of avalglucosidase alfa on 
pharmacodynamic and exploratory efficacy variables to assess if the benefits of avalglucosidase 
alfa are maintained and to assess the time course of response. 
Is replaced with: 
The secondary objective is to assess the long-term effect of avalglucosidase alfa on 
pharmacodynamic and exploratory efficacy variables to assess if the benefits of avalglucosidase 
alfa are maintained and to assess the time course of response. 
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
An open-label, multicenter, multinational extension study of the long-term safety 
and pharmacokinetics of repeated biweekly infusions of neoGAA in patients with 
Pompe disease
Compound: Avalglucosidase alfa (GZ402666) 
Sanofi Protocol Number: LTS13769
STATISTICIAN: [Name], PhD
Statistical Project Leader: [Name], PhD, [Contact] 
DATE OF ISSUE: 25-Mar-2020
Total number of pages: 
60 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning direct 
or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) 
Page 1
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN .................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................. 6 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 6 
1.2 
OBJECTIVES ................................................................................................................................... 6 
1.2.1 
Primary objectives ............................................................................................................................ 6 
1.2.2 
Secondary objectives ....................................................................................................................... 6 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 6 
1.4 
STUDY PLAN ................................................................................................................................... 6 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .................................. 7 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN........................ 7 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ....................................................................... 8 
2.1 
ANALYSIS ENDPOINTS .................................................................................................................. 8 
2.1.1 
Demographic and baseline characteristics ...................................................................................... 8 
2.1.2 
Prior and concomitant medication/therapy ....................................................................................... 9 
2.1.3 
Efficacy endpoints ............................................................................................................................ 9 
2.1.3.1 
Primary efficacy endpoint(s) ............................................................................................................. 9 
2.1.3.2 
Secondary efficacy endpoint(s) ........................................................................................................ 9 
2.1.4 
Safety endpoints ............................................................................................................................. 12 
2.1.4.1 
Adverse events variables ............................................................................................................... 13 
2.1.4.2 
Deaths ............................................................................................................................................ 14 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 15 
2.1.4.4 
Vital signs variables ........................................................................................................................ 15 
2.1.4.5 
Electrocardiogram variables ........................................................................................................... 15 
2.1.4.6 
Anti-drug antibody and neutralizing antibody endpoints ................................................................. 16 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 17 
2.1.6 
Pharmacodynamic endpoints ......................................................................................................... 17 
2.1.7 
Pharmacogenetics ......................................................................................................................... 18 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 19 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 20 
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2.3 
ANALYSIS POPULATIONS ........................................................................................................... 20 
2.3.1 
Full analysis (FA) set ...................................................................................................................... 20 
2.3.2 
Safety analysis set ......................................................................................................................... 20 
2.3.3 
Pharmacokinetics/pharmacodynamics/efficacy analysis Set ......................................................... 20 
2.3.4 
ADA evaluable set .......................................................................................................................... 21 
2.4 
STATISTICAL METHODS ............................................................................................................. 21 
2.4.1 
Demographics and baseline characteristics .................................................................................. 21 
2.4.2 
Prior or concomitant medications ................................................................................................... 21 
2.4.3 
Extent of investigational medicinal product exposure and compliance .......................................... 21 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 21 
2.4.3.2 
Compliance .................................................................................................................................... 22 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 22 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ......................................................................................... 22 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 22 
2.4.4.3 
Multiplicity issues ............................................................................................................................ 22 
2.4.4.4 
Additional efficacy analysis(es) ...................................................................................................... 23 
2.4.5 
Analyses of safety data .................................................................................................................. 23 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 24 
2.4.5.2 
Deaths ............................................................................................................................................ 27 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 28 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 29 
2.4.5.5 
Analyses of electrocardiogram variables ....................................................................................... 29 
2.4.5.6 
Analyses of Immunogenicity........................................................................................................... 29 
2.4.5.7 
Analyses of physical examination variables ................................................................................... 31 
2.4.6 
Analyses of pharmacokinetic variables .......................................................................................... 31 
2.4.7 
Analyses of pharmacodynamic variables ....................................................................................... 32 
2.4.8 
Pharmacogenetics ......................................................................................................................... 33 
2.4.9 
Analyses of quality of life/health economics variables ................................................................... 33 
2.5 
DATA HANDLING CONVENTIONS............................................................................................... 33 
2.5.1 
General conventions ...................................................................................................................... 33 
2.5.2 
Data handling conventions for secondary efficacy variables.......................................................... 33 
2.5.3 
Missing data ................................................................................................................................... 34 
2.5.4 
Windows for time points ................................................................................................................. 35 
2.5.5 
Unscheduled visits ......................................................................................................................... 35 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 36 
2.5.7 
Statistical technical issues ............................................................................................................. 36 
3 
INTERIM ANALYSIS ..................................................................................................................... 37 
4 
DATABASE LOCK ........................................................................................................................ 38 
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5 
SOFTWARE DOCUMENTATION .................................................................................................. 39 
6 
REFERENCES ............................................................................................................................... 40 
7 
LIST OF APPENDICES ................................................................................................................. 41 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ....................... 42 
APPENDIX B 
VISIT WINDOWS ................................................................................................................ 50 
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Page 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ATC: 
anatomic category class 
BMS: 
biomedical system 
ENT: 
ear, nose, throat 
GLI: 
global lung initiative 
ITT: 
intent to treat 
IV: 
intravenous 
LTS-switch: 
patients switched to the 20 mg/kg dose after entering LTS13769 
MRD: 
minimal required dilution 
neoGAA: 
avalglucosidase alfa 
PD: 
pharmacodynamic 
qow: 
every other week 
SD: 
standard deviation 
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Page 6 
1 
OVERVIEW AND INVESTIGATIONAL PLAN 
1.1 
STUDY DESIGN AND RANDOMIZATION 
LTS13769 is an open-label, multicenter, and multinational extension study with repeated IV 
infusions of avalglucosidase alfa. Safety, pharmacokinetic, pharmacodynamic, pharmacogenetic, and 
exploratory efficacy data will be collected during this long-term study. The population will be 
patients with Pompe disease who have completed study avalglucosidase alfa TDR12857. Patients 
who received avalglucosidase alfa intravenous (IV) infusion 20 mg/kg of body weight every other 
week (qow) in the TDR12857 study will continue to receive the same dose in the extension study, 
while patients who previously received the 5 or 10 mg/kg qow dose will first continue on the same 
dose that they received in the TDR12857 study, and then provide consent to switch to the 20 mg/kg 
qow regimen for the remaining duration of the LTS13769 study (henceforth called the LTS-switch 
group in this document). 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objectives of the LTS13769 study are to assess the long-term safety and 
pharmacokinetics (PK) of avalglucosidase alfa in patients with Pompe disease who have previously 
completed an avalglucosidase alfa study.  
1.2.2 Secondary objectives 
The secondary objectives of the LTS13769 study are to assess if the benefits of avalglucosidase alfa 
are maintained and the time course of response, by examining the long-term effect of avalglucosidase 
alfa on pharmacodynamic (PD) and exploratory efficacy variables. 
1.3 
DETERMINATION OF SAMPLE SIZE 
Sample size for the TDR12857 study was based upon empirical considerations. LTS13769 is the 
extension study of TDR12857; therefore, the number of patients in LTS13769 was determined by the 
subgroup of TDR12857 patients who consented to continue in the extension study. Thus, no formal 
sample size calculations have been performed for the TDR12857 or the LTS13769 study. 
1.4 
STUDY PLAN 
The following diagram is a flowchart of the study: more detailed graphical design and study flow 
charts are presented in Section 1 of study protocol. 
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1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL 
The statistical section of the protocol was never changed in an amendment. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
The following main modifications have been made in this version of SAP: 

Added Global Lung Initiative (GLI) 2012 reference equations to calculate FVC % predicted
values

Updated immunogenicity analysis. Some revisions of immunogenicity analysis are made to
be consistent with integrated immunogenicity analysis plan.

Added the second equations for calculating reference value for percentage of predicted total
distance walked in 6MWT

Added Algorithm-defined IARs to be consistent with integrated safety analysis plan

Updated drug compliance definition to be consistent with COMET and mini-COMET studies

Added K-M analysis for treatment-emergent adverse events

The Appendix on Potentially Clinically Significant Abnormalities Criteria was updated
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
The statistical analysis and reporting will be based on all data from study TDR12857 and its 
extension study, LTS13769. The baseline value is defined as the last non missing value prior to first 
TDR12857 treatment, unless otherwise specified.  The rebaseline values will be the last non-missing 
assessment before patients switch to 20 mg/kg dose for LTS-switch patients. 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
Demographic information, Pome disease history, gene mutations (GAA and ACE genotyping), 
and aspects of disability will be imported from the TDR12857 study database. Medical/surgical 
history information will be taken from LTS13769 study. 
Demographic characteristics 
Demographic variables are  

Gender (Male, Female)

Race (Caucasian/white, Black, Asian/Oriental, American Indian or Alaska Native, Native
Hawaiian or other Pacific Island, other)

Ethnicity (Hispanic, nonHispanic)

Age in years at TDR12857 study enrollment

Height (cm)

Weight (kg)

BMI (kg/m2)
Medical / Surgical History 
Collected data regarding any past and/or concomitant diseases or past surgeries include: 

Site/system, eg, Infectious Disease, Allergic, Metabolic/Endocrine/Nutritional, etc.

Description of diagnosis, symptoms, conditions, or surgeries

Date started/ended

Ongoing or not
Pompe Disease Characteristics 
Pompe disease history includes: 

Age at first symptoms of  Pompe disease

Age at diagnosis of Pompe disease
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
Pompe medical history: cardiovascular, ENT (ear, nose, throat), gastrointestinal, respiratory,
and musculoskeletal characteristics

Family Pompe disease history: number of family members with confirmed Pompe disease in
categories of relationship (siblings, parents, cousins, and children)
2.1.2 Prior and concomitant medication/therapy 
All medications taken within 28 days before the TDR12857 screening/baseline evaluation visit, 
during the study periods of both TDR12857 and LTS13769, as well as during the period between 
the end of TDR12857 and the signing of the informed consent for the extension study, until the 
end of the LTS13769 study are to be reported in the case report form (CRF) pages. 

Prior medications are those the patient used prior (including 28 days before the
screening/baseline visit of the TDR12857 study) to first investigational medicinal product
(IMP) intake. Prior medications can be discontinued before first administration or can be
ongoing during the treatment phase. Prior medications that continue to be administered
during the treatment phase will be classified as both prior and concomitant medications.

Concomitant medications are any treatments received by the patient concomitantly to IMP,
from first study treatment in the TDR12857 study to the end of treatment + 28 days. As
mentioned above, a given medication can be classified as both a prior medication and a
concomitant medication if a patient receives the medication before and after the first
administration of the study drug. Concomitant medications do not include medications started
during the posttreatment period.
All medications will be coded using the version of WHO Drug Dictionary Enhanced extended 
with the Herbal Dictionary (WHO DDE+HD) in effect at Sanofi at the time of database lock. 
2.1.3 Efficacy endpoints 
As the primary objective of this study is to assess the long-term safety and pharmacokinetics (PK) 
of avalglucosidase alfa (neoGAA) in patients with Pompe disease who have previously completed 
TDR12857, a neoGAA study, there is no primary efficacy for this extension study. However, as 
part of the secondary objective, exploratory efficacy endpoints will be assessed to see if the benefits 
of neoGAA are maintained. 
2.1.3.1 Primary efficacy endpoint(s) 
Not applicable. 
2.1.3.2 Secondary efficacy endpoint(s) 
The exploratory efficacy endpoints include the six-minute walk test (6MWT) and the pulmonary 
function testing (PFT). These assessments were performed at baseline, Week 13, and Week 25 in 
the TDR12857 study, at the baseline for roll over to LTS 13769, and performed every 6 months, 
at the rebaseline visit (for patients previously in the 5 and 10 mg/kg dose groups only; see 
Section 1.4), and at the end of study visit in the LTS13769 study. 
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Six-minute walk test (6MWT) 
The 6MWT assessments include: the distance walked in 6 minutes, measured in meters; the 
percentage of predicted distance; and the amount of time walked to quantify endurance (as all 
patients may not complete the full 6-minute walk). In addition, data will be collected for pretest 
versus posttest changes in heart rate and assistive device use. The distance (in meters) will be 
recorded and the corresponding percentage of predicted value will be calculated. The percentage of 
predicted distance walked will be calculated based on the normal reference equation in Table 1. For 
analysis purposes, the age at each assessment will be calculated based on (assessment date - birth 
date + 1)/365.25. 
Table 1 - Equations for calculating reference value for percentage of predicted total distance walked in 
6MWT (1) 
Age at baseline 
Gender 
Equation 
≥18 years 
Male and Female 
868.8 - 2.99 * age - 74.7 * sex 
Age in years; sex = 0 if male and sex = 1 if female. 
In order to compare the percent predicted values with studies using several percent predicted 
equations, the percentage of predicted distance walked will be calculated based on the normal 
reference equation in Table 2. For analysis purposes, the age at each assessment will be calculated 
based on (assessment date - birth date + 1)/365.25, weight is collected at the time of the assessment 
and height will be baseline height for the study. 
Table 2 - Equations for calculating reference value for percentage of predicted total distance walked in 
6MWT (2) 
Gender 
Equation 
Male 
7.57*height (cm)-5.02*age (year)-1.76*weight 
(kg)-309 
Female 
2.11*height (cm)-5.78*age (year)-2.29*weight 
(kg)+667 
Additional supportive analysis of 6MWT based on subjects who completed the full 6 minute walk by 
excluding subjects that walked less than 6 minutes will be provided. 
Pulmonary function test  
Pulmonary Function Testing (PFT) will include the assessments of forced vital capacity (FVC), 
forced expiratory volume in the first second of the FVC maneuver (FEV1), maximal inspiratory 
pressure (MIP), maximal expiratory pressure (MEP), and peak expiratory flow (PEF) in the supine 
and standing positions. 
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Predicted values for MIP and MEP are derived using the formulas below (3): 
Male: 
MIP (predicted) = 120 – (0.41 x age) 
MEP (predicted) = 174 – (0.83 x age) 
Female: 
MIP (predicted) = 108 – (0.61 x age) 
MEP (predicted) = 131 – (0.86 x age) 
Predicted values for FVC, FEV1, and PEF are derived using the formulas below (4): 
ht 
patient height (cm) at baseline 
age 
patient age (years) at the time of the assessment 
Male (20 years or older): 
FEV1 (predicted) = 0.5536 – (0.01303 x age) – (0.000172 x age2) + (0.00014098 x ht2) 
PEF (predicted) = 1.0523 + (0.08272 x age) – (0.001031 x age2) + (0.00024962 x ht2) 
Female (20 years or older): 
FEV1 (predicted) = 0.4333 – (0.00361 x age) – (0.000194 x age2) + (0.00011496 x ht2) 
 PEF (predicted) = 0.9267 + (0.06929 x age) – (0.001031 x age2) + (0.00018623 x ht2) 
FVC will be reported in absolute value in liters, as well as the percent of predicted normal values 
based on Global Lung Initiative (GLI) 2012 reference equations (5). The FVC percent of predicted 
values will be calculated based on FVC in liters, gender, race (classified as Caucasian, Asian and 
African-American, and Other/Mixed), age (at least one decimal place in years), and height (in cm) at 
baseline and will be reported centrally from Biomedical Systems (BMS), following pulmonary 
software specification and user requirement (6).   
The FVC percent predicted value is calculated as: 
(actual FVC measurement/predicted value of FVC) * 100. 
The GLI-2012 regression equations and lookup tables are used to calculate predicted values of FVC 
(1). FVC is predicted according to the following equation:  
M = exp(a0 + a1·ln(Height) + a2·ln(Age) + a3·black + a4·NEAsia + a5·SEAsia + a6·Other + 
Mspline) 
Where 
black = 1 if a subject is African American, otherwise = 0 
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NEAsia = 1 if a subject is from North East Asia, otherwise = 0 
SEAsia = 1 if a subject is from South East Asia, otherwise = 0 
Other = 1 if subject is ‘other ethnic group’ or mixed ethnicity, otherwise = 0 
Coefficients a(n) depend on sex and are given by lookup table 
Mspline is age-varying coefficients, given by lookup table for each type of sex 
For the analysis purpose, the age will be calculated based on (assessment date - birth 
date + 1)/365.25. 
2.1.4 Safety endpoints 
The safety analysis will be based on the reported adverse events (AEs) and other safety information, 
such as clinical laboratory data, vital signs, ECG, etc. 
Observation period 
The observation period will be divided into the following epochs: 

The screening epoch is defined as the study period preceding treatment, starting from the
signed informed consent date (TDR12857) up to the first administration of IMP. (Note:
medications known to have been taken by the patients within 28 days of the TDR12857
screening/baseline visit will be recorded in the CRF as well.)

The treatment epoch is defined as the time from the start of the first administration of the
IMP in the TDR12857 through the completion of the last administration of the IMP.
-
Before- and after-rebaseline periods within the treatment epoch will be used for select
analyses

The residual treatment epoch is defined as the time subsequent to the treatment epoch, from
the completion of the last administration of the IMP through the last administration of the
IMP + 28 days or the end of the protocol-defined follow-up period, whichever is earlier.
The treatment-emergent adverse event (TEAE) period will include both treatment and residual 
treatment epochs. 

The posttreatment epoch is defined as the period of time starting the day after the end of the
treatment-emergent adverse event period up through the end of the study.
The on-study observation period is defined as the time from start of treatment in the TDR12857 until 
the end of the LTS13769 study (defined as the last follow-up visit as defined in LTS13769 protocol 
Section 10.1.2.9). 
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2.1.4.1 Adverse events variables 
Adverse event observation period  

Pretreatment adverse events are adverse events that developed or worsened or became serious
during the screening epoch

Treatment-emergent adverse events are adverse events that developed or worsened or became
serious during the treatment-emergent adverse event period

Posttreatment adverse events are adverse events that developed or worsened or became
serious during the posttreatment period
All adverse events (including serious adverse events (SAE) and adverse events of special interest 
[AESI]) will be coded to a lowest level term (LLT), preferred term (PT), high-level term (HLT), 
high-level group term (HLGT), and associated primary system organ class (SOC) using the 
version of Medical Dictionary for Regulatory Activities (MedDRA) in effect at Sanofi at the time 
of database lock. 
Recording of the occurrence of adverse events (including SAEs and AESIs) will be from the time 
of signed informed consent of the TDR12857 study until the end of the patient’s participation in 
the TDR12857 or LTS13769 study. 
Adverse event of special interest (AESI) 
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. 
AESIs will include the following: 
Infusion-associated reactions (IAR): 
Two definitions will be used in the analysis of IARs: 

Protocol-defined IARs: As defined in the protocol, IARs are defined as AEs that occur during
either the infusion or the post-infusion observation period (ie, up to 2 hours or longer
following the infusion as per the Investigator’s discretion) which are deemed to be related or
possibly related to the IMP. At the discretion of the Investigator, AEs occurring after the
completion of the post-infusion observation period that are assessed as related may also be
considered IARs by the Investigator.

Algorithm-defined IARs: an alternative definition of IAR is defined as any treatment-
emergent AEs meeting one of the following criteria:
a) Event occurs from the start of infusion to the end of infusion plus 24 hours window, and
considered related to study drug;
b) If AE start date is non-missing but time component is missing, compare AE Start date
with infusion start date (date component only) and infusion end date (date component
only).  If AE Start date is between infusion start date and infusion end date plus one day,
consider such AE as algorithm-defined IAR if AE is related to study drug.
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Pregnancy 

Pregnancy occurring in a female patient will be recorded as an AESI with immediate
notification in all cases, and follow-up is mandatory until the outcome has been determined.
It will be qualified as an SAE only if it fulfills the SAE criteria. IMP should be discontinued.

Pregnancy occurring in a sexual partner of a male patient will be considered as an AESI and
the patient will be instructed to notify the Investigator immediately. Follow-up of the
pregnancy is mandatory until the outcome has been determined.
Overdose 
An overdose (accidental or intentional) with the IMP is an event suspected by the Investigator or 
spontaneously notified by the patient and defined as at least twice the intended dose within the 
intended therapeutic interval. 
Clinical laboratory (change from baseline, ie, prior to the first dose in TDR12857) 

ALT or AST increase of ≥3 x the upper limit of normal (ULN) if baseline is <ULN, or ALT
or AST increase ≥2 x the baseline value if baseline is ≥ULN

A maximum ALT value of ≥400 IU/L or AST value of ≥500 IU/L or an increase in direct,
indirect, or total bilirubin of ≥2 x ULN

Serum creatinine increase of >1.5 x the baseline value (and final serum creatinine value is
>ULN)
Severe cutaneous and immune-mediated reactions 
A listing of potential immune mediated reactions will be provided using the search criteria.  Search 
criteria will include but not be limited to the MedDRA PTs of glomerulonephritis, nephrotic 
syndrome, proteinuria, haematuria, vasculitis SMQ, serositis, myocarditis, severe cutaneous adverse 
reactions SMQ, skin lesion, skin necrosis, arthralgia, arthritis, myalgia, arthropathy, 
lymphadenopathy, serum sickness, type III immune complex mediated reaction and influenza like 
illness.  A medical review of these cases will be performed. 
Note that the preferred terms utilized for case identification at the time of analysis will be based on 
the MedDRA version in effect at Sanofi at the time of database lock. A medical review will be 
performed by Global Pharmacovigilance (GPV) to determine whether the selected AEs meet the 
definitions for severe cutaneous and immune-mediated reactions. 
2.1.4.2 Deaths 
The deaths observation period are per the observation periods defined above. 

Death on-study:  deaths occurring during the on-study observation period

Death on-treatment:  deaths occurring during the treatment-emergent adverse event period

Death posttreatment: deaths occurring during the posttreatment period

Death poststudy:  deaths occurring after the end of the study
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2.1.4.3 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology and clinical chemistry, 
and urinalysis. Clinical laboratory values after conversion will be analyzed into standard 
international units and international units will be used in all listings, tables, and figures. 
Blood samples for clinical laboratories will be taken as specified in the study protocol. The 
laboratory parameters will be classified as follows: 

Hematology: red blood cell count, hematocrit, hemoglobin, white blood cell count with
differential count (neutrophils, eosinophils, basophils, monocytes, and lymphocytes),
platelets,

Biochemistry
-
Plasma/serum electrolytes: sodium, potassium, chloride, calcium
-
Liver function: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline
phosphatase, gamma-glutamyl transferase, total, direct and indirect bilirubin,
-
Renal function: creatinine, blood urea nitrogen, uric acid,
-
Metabolic panel: glucose, albumin, total proteins, total cholesterol, triglycerides,
-
Potential muscle toxicity: creatine kinase, creatine kinase with MB fraction, lactate
dehydrogenase,
Urinalysis will include urine color, appearance, specific gravity, proteins, glucose, erythrocytes, 
leukocytes, ketone bodies, and pH to be assessed: 

Qualitatively: A dipstick is to be performed on a freshly voided specimen for qualitative
detection using a reagent strip.

Quantitatively: A quantitative measurement for protein, erythrocytes, and leukocytes count
will be required in the event that the urine sample test is positive for any of the above
parameters by urine dipstick (eg, to confirm any positive dipstick parameter by a quantitative
measurement)
2.1.4.4 Vital signs variables 
Vital signs include heart rate, systolic and diastolic blood pressure, respiratory rate, temperature, 
and oxygen saturation. Vital signs are to be assessed prior to infusion, with each infusion rate 
change, at the end of the infusion, and at the end of postinfusion observation period. Collection 
windows are ±15 minutes. 
2.1.4.5 Electrocardiogram variables 
Standard 12-lead ECG parameters will be recorded after at least 15 minutes in the supine position, 
including heart rate, rhythm, interval between the peaks of successive QRS complexes (RR), 
intervals from the beginning of the P wave until the beginning of the QRS complex (PR), interval 
from the start of the Q wave to the end of the S wave (QRS), interval between the start of the Q 
wave and the end of the T wave (QT), QT interval corrected for heart rate (QTC) automatic 
evaluation (by the ECG device), QRS axis, R voltage V6, voltage V1, left ventricular hypertrophy 
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criteria, right ventricular hypertrophy criteria, repolarization charges, and overall cardiac 
impression for each patient. 
2.1.4.6 Anti-drug antibody and neutralizing antibody endpoints 
Patients will be tested for anti-avalglucosidase alfa antibodies. Samples will be collected from 
patients for evaluation of ADA. ADA seropositive patient serum will be assessed for neutralizing 
antibodies to avalglucosidase alfa, including inhibition of enzyme activity and uptake. 
The qualitative sample status of the ADA will be assessed and be categorized into the following 
classes: 

ADA-negative sample: a sample is considered negative if ADAs are not detected (ie, negative
in screening assay or reactive in screening but negative in confirmatory assay).

ADA-positive sample: sample in which ADA is detected, ie, sample generates an assay signal
equal to or greater than the cut-point in the screening assay and is tested positive in the
confirmatory assay.
The ADA titer of the positive samples will also be assessed. A titer represents a 
quasi-quantitative information on the level of ADA present in a sample. Confirmed positive 
samples are serially diluted until a negative result is achieved. The titer is subsequently defined 
as the reciprocal of the last dilution that tests positive. The minimal required dilution (MRD) will 
be incorporated in the final calculation. 
The ADA attributes will be determined by the following conditions : 

Pre-existing ADAs: antibodies reactive with the study drug present in subjects before
treatment.

Treatment induced ADAs: ADAs developed de novo (seroconversion) following
administration of the study drug. If the baseline ADA sample is missing or non-reportable
and at least one reportable on-treatment ADA sample is available, the baseline sample will be
considered as “negative”.

Treatment boosted ADAs: Pre-existing ADAs that were boosted at least two titer steps from
baseline (i.e., 4 fold increase in titers) following administration of the study drug (any time
after the first drug administration).
The following kinetics of the ADAs will be analyzed: 

Onset of ADA is defined as the time period (in weeks) between the first study drug
administration and the first instance of treatment induced ADAs.

Duration of ADA will be calculated as the date of last treatment induced ADA sample minus
date of first treatment induced ADA sample + 1.
The following ADA response classifications will be used: 
1. Treatment-induced ADA- patients are ADA negative at baseline and have developed an ADA
response
a)
Transient ADA response is defined as: 1) Treatment-inducted ADA detected only at one
sampling timepoint post-baseline (excluding the last sampling time point); or 2)
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Treatment-inducted ADA detected at two or more sampling time points post-baseline, 
where the first and the last ADA-positive samples (irrespective of any negative samples 
in between) are separated by a period of less than 16 weeks, and the subject’s last 
sampling time point is ADA-negative  
b) Persistent ADA response is defined as: 1) Treatment-inducted ADA detected at two or
more sampling time points post-baseline, where the first and the last ADA-positive on-
treatment sample (irrespective of any negative samples in between) are separated by at
least 16 weeks; or 2) Treatment-inducted ADA detected in the last two sampling time
points, irrespective of the time period in between.
The following subclassifications for persistent ADA response will be considered as well. 

Low response – if a patient peak titer ≤800 and positive at final assessment.
This represents the first titer that is greater than a 4-fold increase from the
assay minimum required dilution (MRD).  Titers within this range would be
considered as Low response.

Intermediate response – if a patient was persistently seropositive but peak titer
is 1600-6400 and is positive at final assessment.

High response – if a patient was persistently seropositive and peak titer is
≥12800 and is positive at final assessment.
c) Tolerized – if a patient was persistently seropositive, but negative at the final assessment.
Time to tolerization is defined as (date of tolerization - date of initial seroconversion)/7
Tolerization date = date of the first negative values followed by all subsequent values
negative.
d) Indeterminate ADA response – if the patient developed ADA at the last time point and all
previous samples are ADA negative, therefore cannot determine whether the response
will be transient or persistent in duration.  Other timing that does not comply with
transient or persistent definitions.
2. Treatment-boosted ADA – patients who have pre-existing ADA (positive at baseline) and
have ADA titers boosted to a higher level by a greater than or equal to 4-fold increase (i.e., by
greater than at least twice the 2-fold dilution level).
3. Treatment emergent ADA- combination of treatment induced and treatment boosted
2.1.5 Pharmacokinetic variables 
The blood samples for evaluation of avalglucosidase alfa PK were/will be collected according to 
TDR12857 protocol section 9.3 and LTS13769 protocol section 9.2. PK parameters: including but 
not be limited to Cmax, AUClast, AUC, tlast, t1/2z, CL, and Vd will be calculated by PKDM, using 
noncompartmental methods from plasma avalglucosidase alfa concentrations obtained after single 
and repeat dose administration. 
2.1.6 Pharmacodynamic endpoints 
Skeletal muscle MRI 
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Skeletal muscle magnetic resonance imaging (MRI), aiming to assess disease severity and detect 
treatment effects, will be performed prior to the muscle needle or open biopsy procedure, using 
both qualitative (T1) and quantitative (T2, Dixon) modalities. The images will be read and 
analyzed centrally. 
T1 weighted axial data will be analyzed using the Mercuri scale, which determines degree of 
intact muscle and fatty replacement, providing a qualitative measure of overall disease severity. 
The Mercuri scale (grade 1-4) is as follows: (1) normal appearance, (2) mild involvement, (3) 
moderate involvement, and (4) severe involvement. 
Volumetry: trophicity changes will be evaluated for 5 muscle groups, including the upper leg 
muscles (quadriceps, hamstring) and the lower leg muscles (triceps, extensors, fibularis). The 
measured area of each muscle group, cross-sectional area (CSA), will be provided (in mm2). 
T2: multi-slice multi-spin echo (MSME) and B1 mapping will provide a quantitative measure of 
disease activity (edema, inflammation) within muscles, measured in milliseconds (ms) (abnormal 
value defined as >39 ms). 
Three-point Dixon imaging will provide quantification of fat content in muscles (fat fraction 
[FF], described in percentages). The fat fraction will also be combined with the CSA 
measurements trophicity) to provide an Index of Real Muscle Mass (IRMM) in mm2 (IRMM = 
CSA * [1 – FF]). 
Skeletal muscle needle or open biopsy 
Skeletal muscle needle or open biopsy will be performed on the lower extremity (quadriceps) 
muscle to assess glycogen content. The MRI appearance of the muscle will be used to determine the 
level (axial slice position) that the biopsy procedure should target (avoiding fatty replaced tissue). 
Glycogen content will be measured by histomorphometric analysis or severity grading to determine 
how effectively avalglucosidase alfa is able to remove glycogen from muscle. 
Urinary Hex4 level 
Assessment of urinary Hex4 concentrations will be assessed from fasted urine samples. 
Exploratory urine and plasma biomarkers 
Fasted plasma and urine samples will be collected prior to IMP infusion for the assessment of 
exploratory biomarkers. The analysis of biomarkers will be planned and reported separately. 
2.1.7 Pharmacogenetics 
Serum skeletal muscle RNA expression analysis 
Patients qualified for the muscle biopsy procedures will have additional serum samples taken 
to assess whether any of the mRNA targets identified in muscle are expressed in serum, which 
could subsequently be assessed as a serum-based marker of Pompe disease. The analysis of 
novel serum biomarkers will be planned and reported separately. 
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Plasma circulating microRNA analyses 
Plasma samples will be collected and assessed for circulating microRNA concentrations on 
both the whole-genome and individual gene levels. The analysis of microRNA targets will be 
planned and reported separately. 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patients who met the inclusion criteria and signed the 
informed consent. Patients who enrolled in the extension study, LTS13769, must have signed 
informed consent for the extension study, and met the additional inclusion/exclusion criteria, with 
one of the criteria being the completion of the TDR12857 study. 
For patient study status, information in the following categories for either TDR12857 or 
LTS13769 will be presented in the clinical study report: 

Screened patients

Screen failure patients

Treated patients

Completed TDR12857 study

Patients who entered the LTS13769 study

Completed LTS13769 study

Patients who did not complete the study treatment (either in TDR12857 or LTS13769) by
main reason
Number and percentage of patients treated in TDR12857 that fall into each category will be 
presented in a summary table. Percentages will not be calculated for the screened patients and 
screen failures. Reasons for treatment discontinuation will be supplied in table(s) giving numbers 
and percentages by study, dose, and patient groups. 
A patient is considered lost to follow-up at the end of the study if he/she is not assessed at the last 
protocol planned visit and if the time from the last successful contact to the last protocol planned 
visit is greater than 30 days. 
All critical or major deviations will be summarized in tables giving numbers and percentages of 
deviations by patient group. 
Additionally, the analysis populations for safety, pharmacokinetics (PK), pharmacodynamics, and 
efficacy will be summarized by number of patients enrolled in the TDR12857 study: 

Full Analysis (FA) Set

Safety Analysis Set

PK/Pharmacodynamics/Efficacy Analysis Set
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2.2.1 Randomization and drug dispensing irregularities 
Neither the TDR12857 nor the LTS13769 study was randomized. 
Drug-dispensing irregularities will be monitored throughout the study and reviewed on an ongoing 
basis. 
All drug-dispensing irregularities will be documented in the clinical study report. Whether any of 
these constitute a major protocol deviation is deferred to the decision by the clinical team before 
the database lock. 
Drug-dispensing irregularities to be prospectively identified include but are not limited to: 
Table 3 - Drug allocation irregularities 
Drug allocation irregularities 
Erroneous kit dispensation 
Kit not available 
Patient switched to another site 
2.3 
ANALYSIS POPULATIONS 
Neither the TDR12857 nor the LTS13769 study was randomized. Patients will be analyzed 
according to the treatment they actually received instead of the intent to treat (ITT) approach.  
2.3.1 Full analysis (FA) set 
The FA set consists of all patients who received at least 1 complete infusion of IMP. It will be used 
for efficacy analysis. 
2.3.2 Safety analysis set 
The safety analysis set consists of all patients who received at least 1 complete infusion of IMP. It 
will be used as the basis for all safety analyses. 
2.3.3 Pharmacokinetics/pharmacodynamics/efficacy analysis Set 
Enrolled patients without any critical deviations related to IMP administration, and for whom any 
pharmacokinetics/pharmacodynamics/efficacy data are available, will be included for the analyses of 
PK, PD, and/or efficacy data, respectively. 
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2.3.4 ADA evaluable set 
All enrolled patients who received at least 1 infusion (partial or completed) of avalglucosidase alfa 
and had at least one ADA sample taken post-baseline after avalglucosidase alfa infusion that is 
appropriate for ADA testing with a reportable result. 
2.4 
STATISTICAL METHODS 
2.4.1 Demographics and baseline characteristics 
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, and maximum for each dose and patient group.  Categorical and 
ordinal data will be summarized using the number and percentage of patients in each dose and 
patient group.  
Parameters described in Section 2.1.1 will be summarized by dose and patient group using 
descriptive statistics.  
P-values on demographic and baseline characteristic data will not be calculated.
No specific description of the safety/efficacy parameters will be provided at baseline.  If relevant, the 
baseline values will be described along with each safety/efficacy analysis. 
2.4.2 Prior or concomitant medications 
The prior and concomitant medications will be presented for all patients enrolled in TDR12857, 
whether or not they continued in the extension study LTS13769.   
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomic category class (ATC) and the first 3 digits of the ATC class 
(therapeutic category).  All ATC codes corresponding to a medication will be summarized, and 
patients will be counted once in each ATC category (anatomic or therapeutic) linked to the 
medication. Therefore patients may be counted several times for the same medication.  
The table for prior and concomitant medications will be sorted by decreasing frequency of ATC 
followed by all other therapeutic classes based on the overall incidence. In case of equal frequency 
regarding ATCs within each category, alphabetical order will be used. 
2.4.3 Extent of investigational medicinal product exposure and compliance 
2.4.3.1 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by the duration of IMP exposure, number of 
infusions, and amount of dose received. The extent of IMP exposure will be summarized in safety 
population. 
Duration of IMP exposure is defined as last dose date – first dose date + 14 day, regardless of 
unplanned intermittent discontinuations (see Section 2.5.3 for calculation in case of missing or 
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incomplete data). Duration of IMP exposure will be summarized descriptively as a quantitative 
variable (number, mean, SD, median, minimum, and maximum). In addition, duration of treatment 
exposure will also be summarized categorically by numbers and percentages for each of the 
following categories and cumulatively according to these categories: <6 months, 6 months to <1 
year, 1 to <2 years, 2 to <3 years, 3 to <4 years, 4 to <5 years, 5 to <6 years, and ≥6 years. 
The cumulative dose information will be assessed by the total number of infusions received. These 
data will be summarized descriptively. 
2.4.3.2 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned dose 
(eg, missed dose, overdose, or underdose) of treatment as required by the protocol.  No imputation 
will be made for patients with missing or incomplete data.  
Compliance is calculated as the total amount of drug actually taken by a patient divided by the total 
amount of drug expected to be taken multiplied by 100. The number and percentage of patients with 
noncompliance (missed 2 or more consecutive infusions, or missed ≥20% of total doses in the 
treatment or extension period) will be provided. 
Treatment compliance will be summarized descriptively as quantitative variables (number, mean, 
SD, median, minimum, and maximum). The percentage of patients whose compliance is <80% will 
be summarized.  
Additional dose related non-compliance will be summarized as protocol deviations. 
2.4.4 Analyses of efficacy endpoints 
2.4.4.1 Analysis of primary efficacy endpoint(s) 
Not applicable. 
2.4.4.2 Analyses of secondary efficacy endpoints 
Efficacy endpoints will be summarized with both the FA set and the efficacy analysis set. Observed 
measurements, changes from baseline, and changes from rebaseline (LTS-switch patients only) to 
each applicable study time point in 6MWT distance walked (actual and % predicted based on both 
Enright and Gibbons equations)  and PFT parameters (actual and % predicted, supine and standing 
FVC, FEV1, MIP, MEP, and PEF) will be summarized using summary statistics. 95% CIs will be 
used to estimate the change from baseline at each study visit. Missing data will not be imputed. 
Spaghetti plots showing patient data over time will be presented. A listing of assistive device use 
during the 6MWT will be provided. 
2.4.4.3 Multiplicity issues 
Not applicable. 
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2.4.4.4 Additional efficacy analysis(es) 
Not applicable. 
2.4.5 Analyses of safety data 
The summary of safety results will be presented by dose and patient group. Corresponding listings 
will also be presented. 
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General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 

The baseline value is defined as the last value prior to the first dose of GZ402666 in the
TDR12857 study

The re-baseline values is defined as the last non-missing assessment before patients switch to
20 mg/kg dose for LTS-switch patients.

The potentially clinically significant abnormality (PCSA) values are defined as abnormal
values considered medically important by the Sponsor according to predefined
criteria/thresholds based on literature review and defined by the Sponsor for clinical
laboratory tests, vital signs, and ECG (PCSA version dated May 2014 [Appendix A])

PCSA criteria will determine which patients had at least 1 PCSA during the treatment-
emergent adverse event period, taking into account all evaluations performed during the
treatment-emergent adverse event period, including nonscheduled or repeated evaluations.
The number of all such patients will be the numerator for the on-treatment PCSA percentage

The treatment-emergent PCSA denominator by group for a given parameter will be based on
the number of patients assessed for that given parameter in the treatment-emergent adverse
event period by dose and patient group on the safety population.

For quantitative safety parameters based on central laboratory/reading measurements,
descriptive statistics will be used to summarize results and change from baseline values by
visit and treatment group.

The analysis of the safety variables will be essentially descriptive and no systematic testing is
planned. Relative risks between groups and their 95% confidence intervals may be provided,
if relevant.
2.4.5.1 Analyses of adverse events 
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events.  
Pretreatment and posttreatment adverse events will be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the adverse event as pretreatment, treatment-emergent, 
or posttreatment.  The algorithm for imputing date/time of onset will be conservative and will 
classify an adverse event as treatment-emergent unless there is definitive information to determine it 
is pretreatment or posttreatment.  Details on classification of adverse events with missing or partial 
onset dates are provided in Section 2.5.3. 
Adverse event incidence tables will present adverse events grouped by SOC and PT, including the 
number and percentage of patients experiencing AEs in each SOC/PT category and the associated 
event counts (see the paragraph below for sorting order).  Multiple occurrences of the same event in 
the same patient will be counted only once in the tables within observation period presented 
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(pretreatment, treatment-emergent, and posttreatment). The denominator for computation of 
percentages is the safety population within each patient and dose group.  
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pretreatment, treatment-emergent, and posttreatment).  For that purpose, the 
table of all treatment-emergent adverse events presented by SOC and PT sorted by the internationally 
agreed SOC order and decreasing frequency of PTs within SOCs will define the presentation order 
for all other tables unless otherwise specified. Sorting according to frequency of PTs will be based 
on the sum of patient counts for the patients in the 20mg/kg dose groups. In the case of the AE by 
maximal severity tables, the sum of patient counts for the severe AEs from patients in the 20 mg/kg 
dose groups will be used for the sorting of PTs. 
For patients previously assigned to the 5 or 10 mg/kg dose groups in the TDR12857, entered the 
LTS13769 study, and switched to the 20 mg/kg dose group (LTS-switch group), additional AE 
summaries, as indicated in respective subsections below, will be generated for comparison of before- 
and after-rebaseline adverse events in these patients. 
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 

Overview of treatment-emergent adverse events, summarizing number and percentage of
patients and number of events with any
-
Treatment-emergent adverse event(s)
-
Severe treatment-emergent adverse event(s)
-
Serious treatment-emergent adverse event(s)
-
Treatment-emergent AESI(s)
-
IARs (protocol- and algorithm-defined)
-
Treatment-emergent adverse event(s) leading to permanent treatment discontinuation
-
Treatment-emergent adverse event leading to death

All treatment-emergent adverse events by primary SOC, HLGT, HLT, and PT, showing
number (%) of patients with at least 1 treatment-emergent adverse event and number of
events sorted by the SOC internationally agreed order.  The other levels (HLGT, HLT, and
PT) will be presented in alphabetical order.

All treatment-emergent adverse events by primary SOC and PT, showing the number (%) of
patients with at least 1 treatment-emergent adverse event and number of events, sorted by the
internationally agreed SOC order and by decreasing incidence of PTs within each SOC. This
sorting order will be applied to all other tables, unless otherwise specified.
-
Additional summaries of before- and after-rebaseline periods will be presented for the
LTS-switch group

All treatment-emergent adverse events by PT, showing the number (%) of patients with at
least 1 treatment-emergent adverse event and number of events, sorted by decreasing
incidence of PTs.
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
All treatment-emergent adverse events regardless of relationship and related by primary SOC
and PT, showing the number (%) of patients with at least 1 treatment-emergent adverse event
and number of events, sorted by the internationally agreed SOC order.  The PT levels will be
presented in alphabetical order.
-
Additional summaries of before- and after-rebaseline periods will be presented for the
LTS-switch group

All treatment-emergent adverse events by maximal severity, presented by primary SOC and
PT, showing the number (%) of patients with at least 1 treatment-emergent adverse event and
number of events by severity (ie, mild, moderate, or severe), sorted by the internationally
agreed SOC order and by decreasing incidence of PTs within each SOC.
-
Additional summaries of before- and after-rebaseline periods will be presented for the
LTS-switch group

A by-patient listing of AEs, ADA, and IgE, sorted chronologically, will be presented.
Analysis of all treatment-emergent serious adverse event(s) 

All treatment-emergent serious adverse events by primary SOC and PT, showing the number
(%) of patients with at least 1 serious treatment-emergent adverse event and number of
events, sorted by the internationally agreed SOC order and by decreasing incidence of PTs
within each SOC.
-
Additional summaries of before- and after-rebaseline periods will be presented for the
LTS-switch group

All treatment-emergent serious adverse events regardless of relationship and related to IMP,
by primary SOC  and PT, showing the number (%) of patients with at least 1 treatment-
emergent serious adverse event and number of events, sorted by the internationally agreed
SOC order. The PT levels will be presented in alphabetical order.
-
Additional summaries of before- and after-rebaseline periods will be presented for the
LTS-switch group

All treatment-emergent serious adverse events by maximal severity, presented by primary
SOC and PT, showing the number (%) of patients with at least 1 treatment-emergent adverse
event and number of events by severity (ie, mild, moderate, or severe), sorted by the
internationally agreed SOC order and by decreasing incidence of PTs within each SOC.
-
Additional summaries of before- and after-rebaseline periods will be presented for the
LTS-switch group
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 

All treatment-emergent adverse events leading to treatment discontinuation, by primary SOC
and PT, showing the number (%) of patients and number of events sorted by the
internationally agreed SOC order.  The PT level will be presented in alphabetical order
Analysis of standardized MedDRA query 
A comprehensive programming search of AEs which meet the Standardized MedDRA Query 
(SMQ) criteria for hypersensitivity and anaphylactic reaction will be used to identify adverse 
events that potentially are associated with symptoms of anaphylactic and hypersensitivity reaction. 
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Results of this search will be provided in a by patient listing by group. The most recent version of 
MedDRA SMQ will be used at the time of analysis. A medical review of these cases will be 
performed. 
A listing of potential immune mediated reactions will be provided. All treatment-emergent adverse 
events, by standardized MedDRA query (SMQ) and PT, showing the number (%) of patients and 
number of events with at least 1 PT, sorted by decreasing incidence of PTs within each SMQ. 
Analysis of adverse events with AESIs 

Treatment-emergent AESIs by Primary SOC and PT, showing the number (%) of patients and
number of events, sorted by the internationally agreed SOC order and by decreasing
incidence of PTs within each SOC.

All treatment-emergent AESIs by maximal severity, presented by primary SOC and PT,
showing the number (%) of patients with at least 1 treatment-emergent adverse event and
number of events by severity (ie, mild, moderate, or severe), sorted by the internationally
agreed SOC order and by decreasing incidence of PTs within each SOC.

Summary tables of infusion associated reactions (IARs) as defined by the 2 definitions will
be presented by Primary SOC and PT for each patient group and dose level.

All IARs by maximal severity, presented by primary SOC and PT, showing the number (%)
of patients with at least 1 treatment-emergent adverse event and number of events by severity
(ie, mild, moderate, or severe), sorted by the internationally agreed SOC order and by
decreasing incidence of PTs within each SOC.

A detailed listing of patients who experience IARs including information on severity,
seriousness, relationship to IMP, timing from first infusion to the onset of the IAR, IAR
definition(s) met, action taken regarding study treatment, other action taken, and patient
outcome, will be provided.
Severe cutaneous and immune-mediated reactions 

Treatment-emergent severe cutaneous and immune-mediated reactions by Primary SOC and
PT, showing the number (%) of patients and number of events, sorted by the internationally
agreed SOC order and by decreasing incidence of PTs within each SOC.
Analysis of pretreatment and posttreatment adverse events 

All pretreatment adverse events will be presented in a patient listing.

All posttreatment adverse events will be presented in a patient listing.
Kaplan-Meier estimates 

A summary table of Kaplan-Meier estimates of TEAEs by 6-month time intervals will be
provided.
2.4.5.2 Deaths 
The following summaries of deaths will be generated for the safety population. 

Number (%) of patients who died by study period (on-study, on-treatment, posttreatment, and
poststudy) and, if captured, reasons for death Treatment-emergent adverse events leading to
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death (death as an outcome on the adverse event CRF page as reported by the Investigator) by 
primary SOC and PT showing number (%) of patients and number of events sorted by 
internationally agreed SOC order, with PT presented in alphabetical order within each SOC.  
2.4.5.3 Analyses of laboratory variables 
The summary statistics (including number, mean, median, standard deviation, minimum, and 
maximum) of all laboratory variables (central laboratory values, changes from baseline, and 
changes from rebaseline [LTS-switch group only]) will be calculated for each applicable visit or 
study assessment (baseline, each postbaseline time point) by patient and dose group. For select 
laboratory assessments (alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
creatinine, creatine kinase (CK), and creatine kinase MB band (CK-MB)), mean changes from 
baseline with the corresponding standard error will be plotted over time in each patient group and 
dose level. This section will be organized by biological function as specified in Section 2.1.4.3. 
The incidence of PCSAs (list provided in Appendix A) at any time during the treatment-emergent 
adverse event period will be summarized by biological function and treatment group according to 
the following baseline status categories: 

Normal/missing

Abnormal according to PCSA criteria
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
Drug-induced liver injury 
The liver function tests, namely AST, ALT, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity.  
The following analyses will be performed: 

Time to onset of the initial ALT or AST elevation (>3 × ULN) and total bilirubin elevation
(>2 × ULN), whichever comes first will be analyzed using Kaplan Meier estimates by study
cohort and treatment arm, if necessary.

A graph of distribution of peak values of ALT versus peak values of total bilirubin (in
logarithmic scale or in the scale of x ULN if appropriate) will also be presented. The graph
will be divided into 4 quadrants with a vertical line corresponding to 3 x ULN for ALT and a
horizontal line corresponding to 2 x ULN for total bilirubin if necessary. A similar graph will
be provided for peak values of AST versus peak values of total bilirubin.

Listing of possible Hy’s law cases identified by treatment group (eg, patients with any
elevated ALT or AST >3 x ULN, and associated with an increase in bilirubin >2 x ULN)
with ALT, AST, alkaline phosphatase and total bilirubin values if necessary.

Summary of the incidence of liver-related adverse events by treatment group if necessary.
The selection of preferred terms will be based on the hepatic disorder SMQ.
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2.4.5.4 Analyses of vital sign variables 
The summary statistics (including number, mean, median, standard deviation, minimum, and 
maximum) of all vital signs variables (observed values and changes from baseline) will be 
provided for pre-infusion measurements and the change from pre-infusion to the completion of the 
infusion by visit and by patient and dose group. The vital signs measurements at each infusion rate 
change will not be summarized, but will be included in the patient listing. 
The incidence of PCSAs at any time during the treatment-emergent adverse event period will be 
summarized by patient and dose group according to the following baseline status categories: 

Normal/missing

Abnormal according to PCSA criteria
2.4.5.5 Analyses of electrocardiogram variables 
The summary statistics (including number, mean, median, SD, minimum, and maximum) of all ECG 
variables (laboratory values, changes from baseline, and changes from rebaseline [LTS-switch group 
only]) will be calculated for each applicable visit or study assessment (baseline, each postbaseline 
time point) by patient and dose group. A listing of abnormal findings will be provided. 
The incidence of PCSAs at any time during the treatment-emergent adverse event period will be 
summarized by patient and dose group or according to the following baseline status categories:  

Normal/missing

Abnormal according to PCSA criterion or criteria
2.4.5.6 Analyses of Immunogenicity 
ADA incidence and characterization 
ADA status: ADA seroconversion is classified as always negative and ever positive. Baseline ADA 
status will be reported as negative or pre-existing ADA at initiation of treatment. 
The following incidence rates will be summarized descriptively for each treatment group: 

ADA prevalence rate, defined as
100 x (number of patients with treatment-induced ADA + pre-existing ADA)/ (number of
evaluable patients)

Treatment emergent ADA incidence, defined as
100 x (treatment boosted + treatment induced ADA positive patients)/(number of evaluable
patients),

Treatment induced ADA incidence, defined as,
100 x (treatment induced ADA positive patients)/(number of evaluable patients with ADA
negative at baseline),

Treatment boosted ADA incidence, defined as
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100 x (treatment boosted ADA positive patients)/(number of evaluable patients with ADA 
positive at baseline). 
Duration of ADA 
The kinetics and duration of the immune responses will be analyzed as follow: 

Onset time of ADA will be analyzed descriptively using summary statistics minimum, Q1,
median, Q3 and maximum.

Duration of ADA will be analyzed descriptively using summary statistics minimum, Q1,
median, Q3 and maximum. It will only be calculated for the patients with at least two ADA
positive samples. The median duration and the quartiles will be reported.
ADA titers 

ADA peak titer, last titer, and geometric mean titer will be summarized.

Graphs of ADA titer over time and boxplots of the highest post-baseline ADA titer will be
provided.
ADA Response Classification 
Response type classification will be provided. 

The number and percent of transient ADA response will be summarized descriptively. This
will be performed for the patients with at least two post baseline samples where the last
sampling timepoint is negative.

The number and percent of persistent ADA response and its subclassifications will be
summarized descriptively. This will be performed for the patients with treatment-induced
ADA detected at two or more sampling time points post-baseline.

The number and percent of indeterminate ADA response will be summarized descriptively.
This will be performed for the patients with at least one post baseline sample.
Neutralizing ADA 
Incidence of neutralizing antibodies (inhibition of enzyme activity and inhibition of enzyme
uptake) will be reported for both treatment naïve and switch patients
Onset time of neutralizing ADA will be analyzed descriptively using summary statistics
minimum, Q1, median, Q3 and maximum.
Duration of neutralizing ADA will be analyzed descriptively using summary statistics
minimum, Q1, median, Q3 and maximum. It will only be calculated for the patients with at
least two ADA positive samples.
The following listings will be provided: 

Anti-avalglucosidase alfa alfa antibody titer values, neutralizing antibody, circulating
immune complex, anti-avalglucosidase alfa IgE antibody, serum tryptase activity,
complement activation, and skin testing performed

Listings of anti-avalglucosidae alfa ADA and inhibitory antibodies

Listings of anti-alglucosidae alfa ADA and inhibitory antibodies
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Association of ADA with PK 
The following analysis will be considered for switched patients: 1. Within Subject level AUC change 
from baseline to the last injection will be plotted by peak titer category. Gender will be separated by 
different color. 2. Between subject comparison of ADA-positive vs. ADA negative. Plot of AUC at 
baseline compared to timepoints where full PK assessment is available. Patients will be evaluated by 
titer categories based on titer category at the time of PK assessment.  Patients will be separated based 
on treatment groups.  3. Summary table to include AUC and % change from Day 1 at each scheduled 
visit by peak titer categories. 4. Data will be assessed for switch patients as appropriate.  
Association of ADA and PD marker 
Hex-4 is a clinically relevant PD marker that is related to the drug’s mechanism of action.  Summary 
table of number (%) of patients with elevated urinary hex-4 by titer value at the specified visit (eg, 
peak titer categories) over time will be provided.   
Evaluation of ADA on Relevant Safety Parameters 
To evaluate the effect of ADA and NAb on AEs, the number and percentage of patients experiencing 
any TEAEs, any treatment-emergent SAEs, or any IARs, hypersensitivity (narrow SMQ), and 
Anaphylactic reaction (narrow SMQ) will be presented by the following sub-categories: 1. ADA 
status (ever positive, always negative) 2. ADA peak titer category (always negative, peak titer 100-
800, 1600-6400, ≥12,800) 3. ADA response type (always negative, transient response (if occur), and 
persistent responses subcategories:  low response, intermediate response, high ADA response and 
tolerized at defined timepoints. 4.  Correlation of frequency of IAR and ADA peak titer.  5. 
Neutralizing antibody status (always negative, ever positive).   
Association of ADA with selected efficacy 
Correlation analysis will be performed between immunogenicity (ADA titers, response categories 
and neutralizing ADA) and FVC, 6MWT, (raw and percent predicted), MIP, MEP.   
2.4.5.7 Analyses of physical examination variables 
Percentage of patients in each category of physical examination findings will be summarized by visit, 
site/system, and patient/dose group. Shift from baseline to worst and last postbaseline findings will 
also be summarized by site/system and patient/dose group.  
2.4.6 Analyses of pharmacokinetic variables 
All the pharmacokinetic parameters described in Section 2.1.5 will be analyzed using the 
pharmacokinetic population. 
Individual assessments and descriptive statistics (mean, standard deviation [SD], median, 
minimum, maximum, geometric mean, and percent coefficient of variation [CV%]) will be 
presented for plasma concentration time data and PK parameters for each dose level and visit. 
Individual and mean (SD) plasma concentration time profile will be presented graphically for each 
visit. 
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To evaluate the effect of immunogenicity on the PK of avalglucosidase alfa, the following plots 
will be presented: 

Individual profiles of avalglucosidase alfa concentrations over time at 6-month visit and
yearly thereafter, grouped by patient/dose group and ADA status (ever positive, always
negative, baseline ADA positive [preexisting ADA], neutralizing antibody positive)

Median (SD) trough avalglucosidase alfa concentrations over time at 6-month visit and yearly
thereafter, grouped by patient/dose group and ADA status (ever positive, always negative,
baseline ADA positive [preexisting ADA], neutralizing antibody positive)
If relationships are apparent, further quantitative/statistical analysis may be performed (eg, 
statistical significance, correlation coefficients). 
2.4.7 Analyses of pharmacodynamic variables 
Pharmacodynamic variables are described in Section 2.1.6. 
Descriptive statistics (including mean, SD, median, minimum, maximum, and 95% confidence 
intervals (CI) of changes) for both observed and change from baseline (and/or rebaseline, if 
specified) by study visit will be provided for quantitative parameters, by group and by each patient 
group/dose level, unless otherwise specified. Qualitative results that are categorical will be 
presented with number and percentage of patients in each category. If a linear trend in the change of 
a pharmacodynamic endpoint is observed, a longitudinal model may be employed to model change 
from baseline over time. 
Muscle MRI 
MRI data collected from the TDR12857 and LTS13769 studies will be summarized separately, due 
to the updated methods used for LTS13769. The Week 27 results from TDR12857 will be used as 
the LTS13769 baseline for LTS13769 study (see Section 2.5.1).  Descriptive statistics will be used 
for quantitative parameters to summarize changes over time from baseline/rebaseline for each study. 
The Mercuri grading will be presented both as a categorical variable (ie, number and percentage of 
patients in each grade over time will be presented) and as a continuous variable (ie, number, mean, 
SD, median, minimum, maximum, and 95% CI will be presented at each visit). Additional 
summaries will be presented for the patients previously allocated to the 5 or 10 mg/kg dose groups in 
the TDR13857 study and switched to 20 mg/kg in the LTS13769 study (see Section 2.5.1).The 
number of patients with abnormally high values for any specific muscle, as indicated by a T2 of >39 
ms, will be presented using descriptive statistics. 
Muscle biopsy 
Changes from the TDR12857 baseline over time will be used to summarize continuous variables. 
For qualitative measures, number and patients in each category over time will be presented.  
A correlative measure comparing the biopsied muscle and its MRI counterpart will also be 
performed. 
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Urine Hex4 
Urine Hex4 levels will be summarized using descriptive statistics at each scheduled study visit. 
Observed measurements, as well as change from baseline, will be summarized. If a linear trend in the 
change of urine Hex4 levels is observed, a longitudinal model may be employed to model change 
from baseline over time. In addition, 95% CIs of changes will be presented. Due to the small number 
of patients, nonlinear relationship will not be formally characterized. 
PK and urine Hex4 
To explore the relationship between PK endpoints and urine Hex4 levels, correlational statistics 
(Spearman or Pearson) at select visits where PK and urine Hex4 are assessed will be used. In 
addition, scatter plots and linear regression analysis may be used to describe the relationship between 
PK endpoints and urine Hex4 levels as appropriate. 
2.4.8 Pharmacogenetics 
Analyses of serum skeletal muscle RNA expression analysis and plasma circulating microRNA 
levels will be reported in a separate report. 
2.4.9 Analyses of quality of life/health economics variables 
Not applicable. 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
Baseline is defined as the last observation prior to the first treatment in the TDR12857 study, 
unless otherwise specified. In addition, a rebaseline value may be used for the summaries of 
select assessments for patients who previously enrolled in the 5 and 10 mg/kg dose groups and 
switched to the 20 mg/kg dose in the LTS13769 study, in order to compare changes before and 
after the switch. (In some cases, assessments were not repeated at the rebaseline visit, depending 
on the last available assessment dates [see protocol Section 10.1.2.7]. In such circumstances, the 
last available assessments prior to dose switch will be used for the rebaseline values of the 
parameters of interest.) 
Due to the centralized MRI reading procedures, there will be multiple Week 27 values, as the 
Week 27 image will be reread in accompany to each LTS13769 MRI read. The LTS13769 baseline 
will be the mean of the multiple Week 27 of the particular parameter. The previous Week 27 reads 
performed during the TDR12857 study will be presented in the presentation of data collected 
during the TDR12857 study period, but excluded in the calculation of the LTS13769 baseline, as 
the vendor [same vendor used for TDR12857] has upgraded their image processing capabilities. 
2.5.2 Data handling conventions for secondary efficacy variables 
None. 
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2.5.3 Missing data 
No imputation (single or multiple) is planned for this study. 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number and percentage of patients 
with missing data is presented. 
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing 
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date of 
last administration reported on the end-of-treatment CRF page. If this date is missing, the 
exposure duration should be left as missing. 
The last dose intake should be clearly identified in the CRF and should not be approximated by 
the last returned package date. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and posttreatment medication. 
Handling of adverse events with missing or partial date/time of onset 
Missing or partial adverse event onset dates and times will be imputed so that if the partial adverse 
event onset date/time information does not indicate that the adverse event started prior to treatment 
or after the treatment-emergent adverse event period, the adverse event will be classified as 
treatment-emergent. No imputation of adverse event end dates/times will be performed. These data 
imputations are for categorization purpose only and will not be used in listings. No imputation is 
planned for date/time of adverse event resolution. 
Handling of adverse events when date and time of first investigational medicinal product 
administration is missing 
When the date and time of the first IMP administration is missing, all adverse events that occurred 
on or after the day of randomization should be considered as treatment-emergent adverse events. 
The exposure duration should be kept as missing. 
The last dose intake should be clearly identified in the CRF and should not be approximated by 
the last returned package date. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product 
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
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Handling of missing severity of adverse events 
If the severity is missing for 1 of the treatment-emergent occurrences of an adverse event, the 
maximal severity on the remaining occurrences will be considered. If the severity is missing for 
all the occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities 
If a patient has a missing baseline he will be grouped in the category “normal/missing at baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and the 
other on a threshold value, with the first condition being missing, the PCSA will be based only on 
the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is > 0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L. When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
Handling of Repeat Laboratory measurements on the same day 
The average values will be used for the repeat laboratory measurements taken on the same day for 
each visit. 
Handling of ADA titer with missing or non-numerical values  
If the ADA titer is reported as “<value”, then the actual value is imputed as this value.  For example, 
“<100” will be imputed as 100.  A negative ADA status will be assumed as a value of 0 (will be 
excluded when geometric mean of the group needs to be calculated).  
2.5.4 Windows for time points 
For the purpose of changes over time analyses, select assessments will be assigned analysis visits 
by comparing actual visit dates with target visit dates and pre-defined visit windows. Specific 
algorithms in the assignments of the analysis visits such as the target study days and the 
corresponding visit windows are listed in Appendix B. 
2.5.5 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be included in the 
by-visit summaries if scheduled visit measurements are not available. If unscheduled visit 
happened on the same day of the scheduled visit in lab, the average value of those measurements 
will be used. The unscheduled visit measurements will be used for computation of baseline and 
PCSAs. 
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2.5.6 Pooling of centers for statistical analyses 
Investigation of the effects of geographic regions may be performed on an exploratory basis. 
2.5.7 Statistical technical issues 
Not applicable.  
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3 
INTERIM ANALYSIS 
A clinical study report will be produced at study completion. An interim report will also be produced 
if a sub-study analysis of data is performed to support regional regulatory requirements. 
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4 
DATABASE LOCK 
The database is planned to be locked at 30 days after last patient last visit. 
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS Version 9.4 or higher. 
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6 
REFERENCES 
1. Gibbons WJ, Fruchter N, Sloan S, Levy RD. Reference values for a multiple repetition 6 minute
walk test in healthy adults older than 20 years. J Cardiopulm Rehabil. 2001;21(2):87 93.
2. Enright PL, Sherrill DL. Reference equations for the six-minite walk in healthy adults. Am J
Respir Crit Care Med. 1998:158:1384-7.
3. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the
general U.S. population. Am J Respir Crit Care Med. 1999;159:179-87.
4. Evans JA, Whitelaw WA. The assessment of maximal respiratory mouth pressures in adult.
Respir Care. 2009;54:1348-59.
5. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference
values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur
Respir J. 2012;40(6):1324-43.
6. Biomedical Systems. Gneral Pulmonary Software Specifications and User Requirements.
Sponsor: Sanofi-Genzyme. Protocol: EFC14028.
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7 
LIST OF APPENDICES 
Appendix A: Potentially clinically significant abnormalities (PCSA) criteria 
Appendix B: Visit windows 
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Appendix A 
Potentially clinically significant abnormalities criteria 
Table 5 - Criteria for potentially clinically significant abnormality 
Measures 
Adult Criteria 
Pediatric Criteria 
Liver function tests 
ALT 
>3 x ULN 
>5 x ULN 
>10 x ULN 
>20 x ULN 
≥3 x ULN 
≥5 x ULN 
≥10 x ULN 
≥20 x ULN 
AST 
>3 x ULN 
>5 x ULN 
>10 x ULN 
>20 x ULN 
≥3 x ULN 
≥5 x ULN 
≥10 x ULN 
≥20 x ULN 
Alkaline Phosphatase 
>1.5 x ULN 
≥1.5 x ULN 
Total Bilirubin 
>1.5 x ULN 
>2 x ULN 
≥1.3 x ULN 
ALT and Total 
Bilirubin 
ALT >3 x ULN and Total Bilirubin >2 x ULN 
ALT ≥3 x ULN and Total Bilirubin ≥2 x ULN 
Hematology 
White Blood Cell 
(WBC) 
<3.0 GIGA/L (non-Black), <2.0 GIGA/L (Black), 
≥16.0 GIGA/L 
Birth/0 to 27 days old (Neonates)  
<4.0 GIGA/L 
>25.0 GIGA/L 
28 days/1 month to 23 months old (Infants)  
<4.0 GIGA/L 
>20.0 GIGA/L 
24 months/2 years to <6 years old (Children)  
>3.0 GIGA/L 
>16.0 GIA/L 
6 to <12 years old (Children)  
<5.0 GIGA/L 
>17.0 GIGA/L 
12 to 16/18 years old (Adolescents)  
<4.5 GIGA/L 
>13.5 GIGA/L 
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Measures 
Adult Criteria 
Pediatric Criteria 
Lymphocytes 
>4.0 GIGA/L
Birth/0 to 27 days old (Neonates)  
<1.2 GIGA/L 
>17.0 GIGA/L 
28 days/1 month to 23 months old (Infants)  
<2.0 GIGA/L 
>13.5 GIGA/L 
24 months/2 years to <6 years old (Children)  
<1.0 GIGA/L 
>9.5 GIGA/L 
6 to <12 years old (Children)  
<1.0 GIGA/L 
>8.0 GIGA/L 
12 to 16/18 years old (Adolescents)  
<0.6 GIGA/L 
>6.0 GIGA/L 
Neutrophils 
<1.5 GIGA/L (non-Black) 
<1.0 GIGA/L (Black) 
Birth/0 to 27 days old (Neonates)  
<4.0 GIGA/L (1 day old) 
<1.5 GIGA/L (2 – 7 days old) 
<1.25 GIGA/L (>7 day – 1 month old) 
>1 ULN 
28 days/1 month to 23 months old (Infants)  
<1.0 GIGA/L (1 – 3 months) 
<1.2 GIGA/L (3 – 24 months) 
>1 ULN 
24 months/2 years to <6 years old (Children)  
<1.2 GIGA/L 
>1 ULN 
6 to <12 years old (Children) 
<1.2 GIGA/L 
>1 ULN 
12 to 16/18 years old (Adolescents)  
<1.2 GIGA/L 
>1 ULN 
Monocytes 
>0.7 GIGA/L
Basophils 
>0.1 GIGA/L
Eosinophils 
>0.5 GIGA/L or 
>ULN if ULN ≥0.5 GIGA /L
>0.5 GIGA/L 
Or >ULN if ULN >0.5 GIGA/L 
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Measures 
Adult Criteria 
Pediatric Criteria 
Hemoglobin 
Males: ≤115 g/L (≤7.14 mmol/L), ≥185 g/L 
(≥11.48 mmol/L) 
Females: ≤95 g/L (5.9 mmol/L), ≥165 g/L 
(10.24 mmol/L) 
Decrease from Baseline:  ≥20 g/L (1.24 mmol/L) 
Birth/0 to 27 days old (Neonates)  
<86 mmol/L or 12.0 g/dL or any decrease > 0.31 mmol/L 
or 2 g/dL 
28 days/1 month to 23 months old (Infants)  
<1.40 mmol/L or 9.0 g/dL or any decrease > 0.31 mmol/L 
or 2 g/dL 
24 months/2 years to <16/18 years old (Children, 
Adolescents) 
<1.55 mmol/L or 10.0 g/dL or any decrease > 0.31 mmol/L 
or 2 g/dL 
Hematocrit 
Males : ≤0.37 v/v, ≥0.55 v/v 
Females : ≤0.32 v/v, ≥0.5 v/v 
Birth/0 to 27 days old (Neonates)  
<0.39 l/l or 40% 
>0.61 l/l or 47% 
28 days/1 month to 23 months old (Infants)  
<0.29 l/l or 29% 
>0.42 l/l or 42% 
24 months/2 years to <16/18 years old (Children, 
Adolescents) 
<0.32 l/l or 32% 
>0.47 l/l or 47% 
RBC 
≥6 TERA/L 
Platelets 
<100 GIGA/L  
≥ 700 GIGA/L 
<100 GIGA/L  
>700 GIGA/L 
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ECG – PCSA criteria 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
>90 bpm 
>90 bpm and increase from baseline ≥20bpm
>100 bpm 
>100 bpm and increase from baseline ≥20bpm
>120 bpm 
>120 bpm and increase from baseline ≥20 bpm
Birth/0 to 27 days old (Neonates)  
≤90 bpm and decrease from baseline≥20 bpm 
≥190 bpm and increase from baseline 
≥20 bpm 
28 days/1 month to 23 months old (Infants) 
≤80 bpm and decrease form baseline 
≥20 bpm 
≥175 bpm and increase from baseline 
≥20 bpm 
24 months/2 years to <6 years old (Children)  
≤75 bpm and decrease from baseline 
≥20 bpm 
≥140 bpm and increase from baseline 
≥20 bpm 
6 to <12 years old (Children)  
≤50 bpm and decrease from baseline 
≥20 bpm 
≥120 bpm and increase from baseline 
≥20 bpm 
12 to 16/18 years old (Adolescents)  
≤50 bpm and decrease from baseline 
≥20 bpm 
≥120 bpm and increase from baseline 
≥20 bpm 
PR 
>200 ms
>200 ms and increase from baseline ≥25% 
> 220 ms
>220 ms and increase from baseline ≥25% 
> 240 ms
> 240 ms and increase from baseline ≥25% 
Birth/0 to 27 days old (Neonates) ≥120 ms 
28 days/1 month to 23 months old (Infants) ≥140 ms 
24 months/2 years to <6 years old (Children) ≥160 ms 
6 to <12 years old (Children) ≥170 ms 
12 to 16/18 years old (Adolescents) ≥180 ms 
QRS 
>110 ms
>110 msec and increase from baseline ≥25% 
>120 ms
>120 ms and increase from baseline ≥25% 
Birth/0 to 27 days old (Neonates) ≥85 ms 
28 days/1 month to 23 months old (Infants) ≥85 ms 
24 months/2 years to <6 years old (Children) ≥95 ms 
6 to <12 years old (Children) ≥100 ms 
12 to 16/18 years old (Adolescents) ≥110 ms 
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QTc (either QTcF or 
QTcB) 
Absolute values (ms 
>450 ms
>480 ms
>500 ms
Increase from baseline 
30-60 ms
>60 ms
Birth/0 to <12 years old (Neonates, Infants, Children) 
Absolute values (ms) 
Borderline: 431 – 450 ms 
Prolonged*: >450 ms 
Additional: ≥500 ms 
AND 
Increase from baseline 
Borderline: Increase from baseline 30 – 60 ms 
Prolonged*: Increase from baseline >60 ms 
12 to 16/18 years old (Adolescents)  
Absolute values (ms) 
Borderline: 431 – 450 ms (Boys);451 – 470 ms (Girls) 
Prolonged*: >450 ms (Boys);>470 ms (Girls) 
Additional: ≥500 ms 
AND 
Increase from baseline 
Birth/0 to <12 years old (Neonates, Infants, Children) 
Absolute values (ms) 
Borderline: 431 – 450 ms 
Prolonged*: >450 ms 
Additional: ≥500 ms 
AND 
Increase from baseline 
Borderline: Increase from baseline 30 – 60 ms 
Prolonged*: Increase from baseline >60 ms 
12 to 16/18 years old (Adolescents)  
Absolute values (ms) 
Borderline: 431 – 450 ms (Boys);451 – 470 ms (Girls) 
Prolonged*: >450 ms (Boys);>470 ms (Girls) 
Additional: ≥500 ms 
AND 
Increase from baseline 
Borderline: Increase from baseline30 – 60 ms 
Prolonged*: Increase from baseline >60 ms 
*QTc prolonged and ΔQTc >60 ms are the PCSA to be identified in individual subjects/patients listings.
Clinical chemistry 
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Creatinine 
≥150 µmol/L (Adults) 
≥30%  increase from baseline 
≥100%  increase from baseline 
Birth/0 to <6 years old (Neonates, Infants, Children) 
>53 μmol/L or 0.6 mg/dL 
6 years to <12 years old (Children)  
≥90 μmol/L or 1.1 mg/dL 
12 years to 16/18 years old (Adolescents)  
≥132 μmol/L or 1.5 mg/dL 
Blood Urea Nitrogen 
≥17 mmol/L 
Birth/0 to 27 days old (Neonates)  
≥4.3 mmol/L or 12 mg/dl 
28 days/1 month to 16/18 years old (Infants, Children, 
Adolescents) 
≥6.4 mmol/L or 18 mg/dl 
Chloride 
<80 mmol/L 
>115 mmol/L
≤80 mmol/L 
≥115 mmol/L 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
≤129 mmol/L 
≥150 mmol/L 
Potassium 
<3  mmol/L 
≥5.5 mmol/L 
Birth/0 to 27 days old (Neonates)  
≤3.0 mmol/L 
≥7.0 mmol/L 
28 days/1 month to 23 months old (Infants)  
≤3.5 mmol/L 
≥6.0 mmol/L 
24 months/2 years to 16/18 years old (Children, 
Adolescents) 
≤3.5 mmol/L 
≥5.5 mmol/L 
Glucose 
  Hypoglycemia 
  Hyperglycemia 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); 
≥7 mmol/L (fasted) 
<2.7 mmol/L 
≥7 mmol/L (fasted after >12 hours of fast); 
≥10.0 mmol/L (unfasted) 
Albumin 
≤25 g/L 
Vital signs  
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Heart rate 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline ≥20 bpm 
Birth/0 to 27 days old (Neonates)  
≤90 bpm and decrease from baseline ≥20 bpm 
≥190 bpm and increase from baseline ≥20 bpm 
28 days/1 month to 23 months old (Infants) 
≤80 bpm and decrease form baseline ≥20 bpm 
≥175 bpm and increase from baseline ≥20 bpm 
24 months/2 years to <6 years old (Children) 
≤75 bpm and decrease from baseline ≥20 bpm 
≥140 bpm and increase from baseline ≥20 bpm 
6 to <12 years old (Children)  
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline ≥20 bpm 
12 to 16/18 years old (Adolescents) 
 ≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline ≥20 bpm 
Systolic BP 
≤95 mmHg and decrease from baseline ≥20 mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
Birth/0 to 27 days old (Neonates)  
≤60 mmHg and decrease from baseline ≥20 mmHg 
≥85 mmHg and increase from baseline ≥20 mmHg 
28 days/1 month to 23 months old (Infants) 
≤70 mmHg and decrease from baseline ≥20 mmHg 
≥98 mmHg and increase from baseline ≥20 mmHg 
24 months/2 years to <6 years old (Children) 
≤70 mmHg and decrease from baseline ≥20 mmHg 
≥101 mmHg and increase from baseline ≥20 mmHg 
6 to <12 years old (Children)  
≤80 mmHg and decrease from baseline ≥20 mmHg 
≥108 mmHg and increase from baseline ≥20 mmHg 
12 to 16/18 years old (Adolescents)  
≤90 mmHg and decrease from baseline ≥20 mmHg 
≥119 mmHg and increase from baseline ≥20 mmHg 
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Diastolic BP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
Birth/0 to 27 days old (Neonates)  
≤34 mmHg and decrease from baseline ≥10 mmHg 
≥50 mmHg and increase from baseline ≥10 mmHg 
28 days/1 month to 23 months old (Infants) 
≤34 mmHg and decrease from baseline ≥10 mmHg 
≥54 mmHg and increase from baseline ≥10 mmHg 
24 months/2 years to <6 years old (Children) 
≤34 mmHg and decrease from baseline ≥10 mmHg 
≥59 mmHg and increase from baseline ≥10 mmHg 
6 to <12 years old (Children)  
≤48 mmHg and decrease from baseline ≥10 mmHg 
≥72 mmHg and increase from baseline ≥10 mmHg 
12 to 16/18 years old (Adolescents)  
≤54 mmHg and decrease from baseline ≥10 mmHg 
≥78 mmHg and increase from baseline ≥10 mmHg 
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Appendix B 
Visit windows 
The analysis visits are assigned by comparing the distance between the calculated study day of 
each assessment (defined as time elapsed from the start of study drug in the TDR12857 study till 
the time of the assessment) with the listed target study days and the corresponding analysis 
windows of the applicable group of assessments, utilizing the general rules below:  
1. If more than one non-missing values are assigned to the same analysis visit, then the
assessment performed closest to the target study day will be used in the by-visit analysis.
2. Multiple values assessed on the same date will be averaged prior to being assigned an
analysis visit.
3. If two assessments are assessed on different dates but equidistant from the target date, the
values assessed on a later date will be used.
4. Use a combination of 2 & 3 in cases where there are multiple records equidistant from the
target study day. For example, for a post-baseline visit, if there are 2 records, 7 days before
the infusion and 3 records 7 days after the infusion, then take the 3 records after the
infusion and average them for analysis value.
All visits in the applicable datasets will be used, including scheduled and unscheduled visits. (For 
change from TDR12857 baseline analyses, rebaseline visit and assessments performed after 
rebaseline will be handled in the same manner.) Note that baseline is defined as the latest available 
observation before the first infusion in the TDR12857. 
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Table 1 — Analysis windows for 6MWT, PFTs, ECG, hematology, and urinalysis: 
VISIT (target study day*) 
Analysis Visit 
Analysis Visit Window (in 
study days*) 
Baseline 
Baseline 
Week 1@ in TDR  (1) 
Week 1 
      1  to     42 days 
Week 13 in TDR (85) 
Week 13 
    43  to   127 days 
Week 25 in TDR (169) 
Week 25 
  128  to   273 days/(1st day 
of LTS – 1)** 
Month 6 in LTS (365) 
Week 52 
  (1st day of LTS) to 456 
days 
Month 12 in LTS (547) 
Week 78 
  457  to   638 days 
Month 18 in LTS (730) 
Week 104 
  639  to   821 days 
Month 24 in LTS (912) 
Week 130 
  822  to 1003 days 
Month 30 in LTS (1095) 
Week 156 
1004  to 1186 days 
Month 36 in LTS  (1277) 
Week 182 
1187  to 1368 days 
Month 42 in LTS  (1460) 
Week 208 
1369  to 1551 days 
Month 48 in LTS  (1642) 
Week 234 
1552  to 1733 days 
Month 54 in LTS  (1825) 
Week 260 
1734  to 1916 days 
Month 60 in LTS  (2007) 
Week 286 
1917  to 2098 days 
Month 66 in LTS  (2190) 
Week 312 
2099  to 2281 days 
Month 72 in LTS  (2372) 
Week 338 
2282  to 2402 days 
@ Week 1 visit only applies to ECG, hematology, and urinalysis. 
*Study days are days since the first infusion in the TDR12857 study.
**For patients who enrolled in LTS13769, the upper boundary of the window is 273 days or (1st day of LTS
– 1), whichever is earlier; for patients who didn’t enroll in LTS13769, use study day 273 as cutoff.
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Table 2 – Immunogenicity (anti-alglucosidase alfa IgG antibody) – Group 2 patients only 
VISIT (target study day*) 
Analysis Visit 
Analysis Visit Window (in study days*) 
Baseline/Week 1 
Baseline 
Week 25 in TDR (169) 
Week 25 
  92  to   273 days/(1st day of LTS – 1)** 
Month 6 in LTS (365) 
Week 52 
  (1st day of LTS)  to  456 days 
Month 12 in LTS (547) 
Week 78 
  457  to   638 days 
Month 18 in LTS (730) 
Week 104 
  639  to   821 days 
Month 24 in LTS (912) 
Week 130 
  822  to 1003 days 
Month 30 in LTS (1095) 
Week 156 
1004  to 1186 days 
Month 36 in LTS  (1277) 
Week 182 
1187  to 1368 days 
Month 42 in LTS  (1460) 
Week 208 
1369  to 1551 days 
Month 48 in LTS  (1642) 
Week 234 
1552  to 1733 days 
Month 54 in LTS  (1825) 
Week 260 
1734  to 1916 days 
Month 60 in LTS  (2007) 
Week 286 
1917  to 2098 days 
Month 66 in LTS  (2190) 
Week 312 
2099  to 2281 days 
Month 72 in LTS  (2372) 
Week 338 
2282  to 2402 days 
*Study days are days since the first infusion in the TDR12857 study.
**For patients who enrolled in LTS13769, the upper boundary of the window is 273 days or (1st day of LTS – 1),
whichever is earlier; for patients who didn’t enroll in LTS13769, use study day 273 as cutoff.
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Table 3 – Immunogenicity (anti-avalglucosidase alfa [neoGAA] antibodies) 
VISIT (target study day*) 
Analysis Visit 
Analysis Visit Window (in study days*) 
Baseline/Week 1 
Baseline 
Week 5 in TDR (35) 
Week 5 
    23  to     50 days 
Week 9 in TDR (63) 
Week 9 
    51  to      78 days 
Week 13 in TDR (91) 
Week 13 
    79  to 
 106 days 
Week 17 in TDR (119) 
Week 17 
  107  to   134 days 
Week 21 in TDR (148) 
Week 21 
  135  to   163 days 
Week 25 in TDR (176) 
Week 25 
  164  to   183 days 
Week 27 in TDR (190) 
Week 27 
  184  to   198 days/(1st day of LTS - 1) 
Month 1 in LTS (213) 
Week 32 
(1st day of LTS) to 228 days 
Month 2 in LTS (244) 
Week 36 
  229  to    259 days 
Month 3 in LTS (274) 
Week 40 
  260  to   289 days 
Month 4 in LTS (304) 
Week 44 
  290  to   319 days 
Month 5 in LTS (335) 
Week 48 
  320  to   350 days 
Month 6 in LTS (365) 
Week 52 
  351  to   411 days 
Month 9 in LTS (456) 
Week 65 
  412  to   502 days 
Month 12 in LTS (547) 
Week 78 
  503  to   594 days 
Month 15 in LTS (639) 
Week 91 
  595  to   685 days 
Month 18 in LTS (730) 
Week 104 
  686  to  776 days 
Month 21 in LTS (821) 
Week 117 
  777  to  867 days 
Month 24 in LTS (912) 
Week 130 
  868  to  959 days 
Month 27 in LTS (1004) 
Week 143 
  960 to 1050 days 
Month 30 in LTS (1095) 
Week 156 
1051 to 1141 days 
Month 33 in LTS (1186) 
Week 169 
1142 to 1232 days 
Anonymized Page 53


Statistical Analysis Plan  
25-Mar-2020
GZ402666-LTS13769 - avalglucosidase alfa 
Version number: 2
Property of the Sanofi Group - strictly confidential 
Page 54 
VISIT (target study day*) 
Analysis Visit 
Analysis Visit Window (in study days*) 
Month 36 in LTS (1277) 
Week 182 
1233 to 1324 days 
Month 39 in LTS (1369) 
Week 195 
1325 to 1415 days 
Month 42 in LTS (1460) 
Week 208 
1416 to 1506 days 
Month 45 in LTS (1551) 
Week 221 
1507 to 1597 days 
Month 48 in LTS (1642) 
Week 234 
1598 to 1689 days 
Month 51 in LTS (1734) 
Week 247 
1690 to 1780 days 
Month 54 in LTS (1825) 
Week 260 
1781 to 1871 days 
Month 57 in LTS (1916) 
Week 273 
1872 to 1962 days 
Month 60 in LTS (2007) 
Week 286 
1963 to 2054 days 
Month 63 in LTS (2099) 
Week 299 
2055 to 2145 days 
Month 66 in LTS (2190) 
Week 312 
2146 to 2236 days 
Month 69 in LTS (2281) 
Week 325 
2237 to 2327 days 
Month 72 in LTS (2372) 
Week 338 
2328 to 2402 days 
*Study days are days since the first infusion in the TDR12857 study.
**For patients who enrolled in LTS13769, the upper boundary of the window is 273 days or (1st day of LTS
– 1), whichever is earlier; for patients who didn’t enroll in LTS13769, use study day 273 as cutoff.
Anonymized Page 54


Statistical Analysis Plan  
25-Mar-2020
GZ402666-LTS13769 - avalglucosidase alfa 
Version number: 2
Property of the Sanofi Group - strictly confidential 
Page 55 
Table 4 – Biochemistry 
VISIT (target study day*) 
Analysis Visit 
Analysis Visit Window (in study days*) 
Baseline 
Baseline 
Week 1 in TDR (1) 
Week 1 
    1 to    8 days 
Week 3 in TDR (15) 
Week 3 
    9 to   21 days 
Week 5 in TDR (29) 
Week 5 
  22 to   35 days 
Week 7 in TDR (43) 
Week 7 
  36 to   49 days 
Week 9 in TDR (57) 
Week 9 
  50 to   63 days 
Week 11 in TDR (71) 
Week 11 
  64 to   77 days 
Week 13 in TDR (85) 
Week 13 
  78 to   91 days 
Week 15 in TDR (99) 
Week 15 
  92 to 105 days 
Week 17 in TDR (113) 
Week 17 
106 to 119 days 
Week 19 in TDR (127) 
Week 19 
120 to 133 days 
Week 21 in TDR (142) 
Week 21 
134 to 148 days 
Week 23 in TDR (156) 
Week 23 
149 to 162 days 
Week 25 in TDR (169) 
Week 25 
163 to 176 days/(1st day of LTS – 1)** 
Day 1/Week 0 in LTS (183) 
Week 28 
(1st day of LTS) to 198 days 
Month 1 in LTS (213) 
Week 32 
199 to 228 days 
Month 2 in LTS (244) 
Week 36 
229 to 259 days 
Month 3 in LTS (274) 
Week 40 
260 to 289 days 
Month 4 in LTS (304) 
Week 44 
290 to 319 days 
Month 5 in LTS (335) 
Week 48 
320 to 350 days 
Month 6 in LTS (365) 
Week 52 
351 to 380 days 
Month 7 in LTS (396) 
Week 56 
381 to 411 days 
Month 8 in LTS (426) 
Week 61 
412 to 441 days 
Anonymized Page 55


Statistical Analysis Plan  
25-Mar-2020
GZ402666-LTS13769 - avalglucosidase alfa 
Version number: 2
Property of the Sanofi Group - strictly confidential 
Page 56 
VISIT (target study day*) 
Analysis Visit 
Analysis Visit Window (in study days*) 
Month 9 in LTS (456) 
Week 65 
442 to 471 days 
Month 10 in LTS (487) 
Week 69 
  472 to   502 days 
Month 11 in LTS (517) 
Week 74 
  503 to   532 days 
Month 12 in LTS (547) 
Week 78 
  533 to   562 days 
Month 13 in LTS (578) 
Week 82 
  563 to   593 days 
Month 14 in LTS (609) 
Week 87 
  594 to   624 days 
Month 15 in LTS (639) 
Week 91 
  625 to   654 days 
Month 16 in LTS (670) 
Week 96 
  655 to   685 days 
Month 17 in LTS (700) 
Week 100 
  686 to   715 days 
Month 18 in LTS (730) 
Week 104 
  716 to   745 days 
Month 19 in LTS (761) 
Week 108 
  746 to   776 days 
Month 20 in LTS (791) 
Week 112 
  777 to   806 days 
Month 21 in LTS (821) 
Week 117 
  807 to   836 days 
Month 22 in LTS (852) 
Week 121 
  837 to   867 days 
Month 23 in LTS (883) 
Week 126 
  868 to   898 days 
Month 24 in LTS (912) 
Week 130 
  899 to   927 days 
Month 25 in LTS (944) 
Week 134 
  928 to   959 days 
Month 26 in LTS (974) 
Week 139 
  960 to   989 days 
Month 27 in LTS (1004) 
Week 143 
  990 to 1019 days 
Month 28 in LTS (1035) 
Week 147 
1020 to 1050 days 
Month 29 in LTS (1065) 
Week 152 
1051 to 1080 days 
Month 30 in LTS (1095) 
Week 156 
1081 to 1110 days 
Month 31 in LTS (1126) 
Week 160 
1111 to 1141 days 
Month 32 in LTS (1157) 
Week 165 
1142 to 1172 days 
Anonymized Page 56


Statistical Analysis Plan  
25-Mar-2020
GZ402666-LTS13769 - avalglucosidase alfa 
Version number: 2
Property of the Sanofi Group - strictly confidential 
Page 57 
VISIT (target study day*) 
Analysis Visit 
Analysis Visit Window (in study days*) 
Month 33 in LTS (1186) 
Week 169 
1173 to 1201 days 
Month 34 in LTS (1218) 
Week 173 
1202 to 1233 days 
Month 35 in LTS (1248) 
Week 178 
1234 to 1263 days 
Month 36 in LTS (1277) 
Week 182 
1264 to 1324 days 
Month 39 in LTS (1369) 
Week 195 
1325 to 1415 days 
Month 42 in LTS (1460) 
Week 208 
1416 to 1506 days 
Month 45 in LTS (1551) 
Week 221 
1507 to 1597 days 
Month 48 in LTS (1642) 
Week 234 
1598 to 1689 days 
Month 51 in LTS (1734) 
Week 247 
1690 to 1780 days 
Month 54 in LTS (1825) 
Week 260 
1781 to 1871 days 
Month 57 in LTS (1916) 
Week 273 
1872 to 1962 days 
Month 60 in LTS (2007) 
Week 286 
1963 to 2054 days 
Month 63 in LTS (2099) 
Week 299 
2055 to 2145 days 
Month 66 in LTS (2190) 
Week 312 
2146 to 2236 days 
Month 69 in LTS (2281) 
Week 325 
2237 to 2327 days 
Month 72 in LTS (2372) 
Week 338 
2328 to 2402 days 
*Study days are days since the first infusion in the TDR12857 study.
**For patients who enrolled in LTS13769, the upper boundary of the window is 176 days or (1st day of LTS – 1),
whichever is earlier; for patients who didn’t enroll in LTS13769, use study day 176 as cutoff.
Anonymized Page 57


Statistical Analysis Plan  
25-Mar-2020
GZ402666-LTS13769 - avalglucosidase alfa 
Version number: 2
Property of the Sanofi Group - strictly confidential 
Page 58 
Table 5 – Urine Hex4 
VISIT (target study day*) 
Analysis Visit 
Analysis Visit Window (in study days*) 
Baseline 
Baseline 
Week 1 in TDR (1) 
Week 1 
      1 to 
 8 days 
Week 3 in TDR (15) 
Week 2 
      9 to  21 days 
Week 5 in TDR (29) 
Week 5 
    22 to  35 days 
Week 7 in TDR (43) 
Week 7 
    36 to  49 days 
Week 9 in TDR (57) 
Week 9 
    50 to  63 days 
Week 11 in TDR (71) 
Week 11 
    64 to  77 days 
Week 13 in TDR (85) 
Week 13 
    78 to  91 days 
Week 15 in TDR (99) 
Week 15 
    92 to   105 days 
Week 17 in TDR (113) 
Week 17 
  106 to   119 days 
Week 19 in TDR (127) 
Week 19 
  120 to   133 days 
Week 21 in TDR (142) 
Week 21 
  134 to   148 days 
Week 23 in TDR (156) 
Week 23 
  149 to   162 days 
Week 25 in TDR (169) 
Week 25 
  163 to   176 days/(1st day of LTS – 1)** 
Month 6 in LTS (365) 
Week 52 
  (1st day of LTS) to 548 days 
Month 18 in LTS (730) 
Week 104 
  549 to   913 days 
Month 30 in LTS (1095) 
Week 156 
  914 to 1278 days 
Month 42 in LTS (1460) 
Week 208 
1279 to 1643 days 
Month 54 in LTS (1825) 
Week 260 
1644 to 2008 days 
Month 66 in LTS (2190) 
Week 312 
2009 to 2373 days 
Month 72 in LTS (2372) 
Week 338 
2374 to 2402 days 
*Study days are days since the first infusion in the TDR12857 study.
**For patients who enrolled in LTS13769, the upper boundary of the window is 176 days or (1st day of LTS
– 1), whichever is earlier; for patients who didn’t enroll in LTS13769, use study day 176 as cutoff.
Anonymized Page 58


Statistical Analysis Plan  
25-Mar-2020
GZ402666-LTS13769 - avalglucosidase alfa 
Version number: 2
Property of the Sanofi Group - strictly confidential 
Page 59 
Table 6 – Plasma concentration of avalglucosidase alfa 
VISIT (target study day*) 
Analysis Visit 
Analysis Visit Window (in study days*) 
Baseline 
Baseline 
Week 1 in TDR (1) 
Week 1 
      1 to     42 days 
Week 13 in TDR (85) 
Week 13 
    43 to   127 days 
Week 25 in TDR (169) 
Week 25 
  128 to   273 days/(1st day of LTS – 1)** 
Month 6 in LTS (365) 
Week 52 
  (1st day of LTS) to 548 days 
Month 18 in LTS (730) 
Week 104 
  549 to   913 days 
Month 30 in LTS (1095) 
Week 156 
  914 to 1278 days 
Month 42 in LTS (1460) 
Week 208 
1279 to 1643 days 
Month 54 in LTS (1825) 
Week 260 
1644 to 2008 days 
Month 66 in LTS (2190) 
Week 312 
2009 to 2373 days 
Month 72 in LTS (2372) 
Week 338 
2374 to 2402 days 
*Study days are days since the first infusion in the TDR12857 study.
**For patients who enrolled in LTS13769, the upper boundary of the window is 273 days or (1st day of LTS – 1),
whichever is earlier; for patients who didn’t enroll in LTS13769, use study day 273 as cutoff.
Anonymized Page 59


Statistical Analysis Plan  
25-Mar-2020
GZ402666-LTS13769 - avalglucosidase alfa 
Version number: 2
Property of the Sanofi Group - strictly confidential 
Page 60 
Table 7 –MRI, muscle biopsy 
VISIT (target study day*) 
Analysis Visit 
Analysis Visit Window (in study days*) 
Baseline 
Baseline 
Week 27 in TDR (184) 
Week 27 
  92 to   273 days/(1st day of LTS – 1)** 
Month 24 in LTS (365) 
Week 52 
(1st day of LTS) to 1278 days 
Month 48 in LTS (1095) 
Week 156 
1279 to 2008 days 
Month 72 in LTS (2372) 
Week 338 
2009 to 2402 days 
*Study days are days since the first infusion in the TDR12857 study.
**For patients who enrolled in LTS13769, the upper boundary of the window is 273 days or (1st day of LTS
– 1), whichever is earlier; for patients who didn’t enroll in LTS13769, use study day 273 as cutoff.
Other assessments not specified above, if presented in by-visit summary tables, will use the 
recorded visits, rather than defined analysis visits. 
By visit analyses of changes over time from rebaseline will use the rebased visits recorded. 
Anonymized Page 60


Approve & eSign 
[Name] 
Clinical 
26-Mar-2020 21:03:03 GMT+0000 
Approve & eSign 
[Name] 
Clinical 
27-Mar-2020 18:21:06 GMT+0000 
Anonymized Page 61
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