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
Phase: PHASE2
Conditions: Glycogen Storage Disease Type II Pompe Disease
Sponsor: Genzyme, a Sanofi Company



Amended Clinical Trial Protocol 09 
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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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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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