An Open-label Ascending Dose Cohort Study to Assess the Safety, Pharmacokinetics, and Preliminary Efficacy of Avalglucosidase Alfa (NeoGAA, GZ402666) in Patients With Infantile-onset Pompe Disease Treated With Alglucosidase Alfa Who Demonstrate Clinical Decline or Sub-optimal Clinical Response
Phase: PHASE2
Conditions: Glycogen Storage Disease Type II-Pompe's Disease
Sponsor: Genzyme, a Sanofi Company

Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002579 VERSION N°14.0 (04-FEB-2016) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL NO. 03 
COMPOUND: AVALGLUCOSIDASE ALFA/GZ402666 
An open-label ascending dose cohort study to assess the safety, 
pharmacokinetics, and preliminary efficacy of avalglucosidase alfa (neoGAA, 
GZ402666) in patients with infantile-onset Pompe disease treated with 
alglucosidase alfa who demonstrate clinical decline or sub-optimal clinical 
response 
STUDY NUMBER: ACT14132 
STUDY NAME: Pediatric open-label, ascending dose cohort study (Mini-COMET) 
VERSION DATE / STATUS: 05-Jan-2021 / Approved 
Version Number: 
1 
EudraCT  
2016-003475-21 
IND Number(s) 
109569 
WHO universal trial number: 
U1111-1179-4616 
Date: 
05-Jan-2021
Total number of pages: 
141 
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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: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
 
Document 
Country/ 
countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 03 (Global) 
All 
05-Jan-2021, version 01 (electronic 1.0) 
Amended Clinical Trial Protocol 02 (Global) 
All 
24-Mar-2020, version 01 (electronic 4.0) 
Protocol Amendment 03 
All 
27-Jul-2018, version 01 (electronic 2.0) 
Amended Clinical Trial Protocol 01 (DE) 
Germany only 
04-Oct-2017, version 01 (electronic 1.0) 
Protocol Amendment 02 (DE) 
Germany only 
04-Oct-2017, version 01 (electronic 1.0) 
Protocol Amendment 01 (GB) 
UK only 
02-Feb-2017, version 01 (electronic 1.0) 
Clinical Trial Protocol 
 
19-Oct-2016, version 01 (electronic 1.0) 
Amended protocol 03 (05 January 2021) 
This amended protocol 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. 
OVERALL RATIONALE FOR THE AMENDMENT 
Global changes 
• 
To include in this amendment, the recommendations that were developed for the Covid-19 
pandemic period and shared with the sites/Investigators. These recommendations will 
remain applicable after the end of the pandemic, especially 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 most updated wordings that are compliant with general guidance, including 
monitoring techniques. 
• 
To update the Sections 8.1 and 8.9 (home infusion), to harmonize across the different 
studies included in the avalglucosidase alfa development program. 
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Protocol amendment summary of changes table 
Section # and Name 
Description and Change 
Brief Rationale 
PROTOCOL AMENDMENT SUMMARY 
OF CHANGES TABLE 
Document formatting revision 
To update document history and provide 
overall rationale for the amendment 
Section 1.2 Flow chart;. 1.2.1 Treatment 
period; 1.2.2 Extension period (Week 27 
to Week 35) including details for Stage 2 
- Cohort 3 for patients switching to 
avalglucosidase alfa; 1.2.3 Extension 
period (Week 37 to Week 145); 1.2.4 
Extended long-term treatment period 
The footnote related to the 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 with the 
following text: “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 or their legally 
authorized representative (for pediatric 
patients) to ensure that no adverse event 
occurred during the observational 
period.” 
Due to Covid-19 pandemic restrictions, 
the observation period after the infusions 
performed at study site or infusion center 
was shortened or skipped for patient’s 
safety reasons. Also to lighten this period 
after the end of pandemic and in order to 
get 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(s) 
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 or their legally authorized 
representative (for pediatric patients) to 
ensure that no adverse event occurred 
during the observational period.” 
Due to Covid-19 pandemic restrictions, 
the observation period after the infusions 
performed at 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 get information in case this 
observation period is not performed, the 
observation time after the end of infusion 
is reduced to 1 hour. 
Section 8.9.1 Home infusion for patients 
receiving alglucosidase alfa 
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 (ie, after 6 months free of 
IARs instead of 12 months) or to resume 
home infusion quicker after interruption 
for IAR during home infusion. Some text 
is also updated to harmonize across the 
different studies included in the 
avalglucosidase alfa development 
program. 
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Section # and Name 
Description and Change 
Brief Rationale 
Section 8.9.2 Home infusion for patients 
receiving avalglucosidase alfa 
The text was updated to harmonize with 
other studies included in the 
avalglucosidase alfa development 
program. 
 
One of the bullet points was updated 
from: “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 no such 
IARs are present for at least 3 months.” 
To 
“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.” 
The home infusion text is amended to 
allow patients to benefit from home 
infusion sooner (ie, after 6 months free of 
IARs instead of 12 months) or to resume 
home infusion quicker after interruption 
for IAR during home infusion. Some text 
is also updated to harmonize across the 
different studies included in the 
avalglucosidase alfa development 
program. 
Section 10.3.1 Temporary treatment 
discontinuation with investigational 
medicinal product(s) 
Text was updated to clarify that 
temporary treatment discontinuation may 
be considered if patient becomes 
pregnant. 
To clarify that pregnancy is a reason for 
temporary treatment discontinuation and 
not permanent discontinuation. 
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 the recent Sanofi procedures, the 
direct sending of source documents to 
the Sponsor (except to 
Pharmacovigilance department) is no 
more recommended. 
Section 11.4.2 Analyses of safety data 
Definition of baseline value was updated. 
Clarification 
Sections 12 Regulatory, ethical, and 
study oversight considerations, 
Section 13 Study monitoring, and 
Section 14 Additional requirements 
Subsections and corresponding text in 
Sections 12, 13, and 14 were revised 
and updated to reflect practices, 
including monitoring techniques, as 
outlined in the current protocol template,. 
To align with the current protocol 
template 
Section 17.4: Appendix D (Protocol 
amendment history) 
Added new Section 17.4.2. 
To incorporate the changes from 
amended protocol 02 to amended 
protocol 03 
Throughout 
“2-hour post-infusion observation period” 
changed to “post-infusion observation 
period” 
To reflect the amendment specific 
changes 
Throughout 
Typos have been corrected where 
necessary. 
Minor editorial and document formatting 
revisions 
Clarifications 
 
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CLINICAL TRIAL SUMMARY 
COMPOUND: GZ402666 
STUDY No.: ACT14132  
STUDY NAME: Pediatric open-label, ascending dose cohort 
study (Mini-COMET) 
TITLE 
An open-label ascending dose cohort study to assess the safety, 
pharmacokinetics, and preliminary efficacy of avalglucosidase alfa (neoGAA, 
GZ402666) in patients with infantile-onset Pompe disease treated with 
alglucosidase alfa who demonstrate clinical decline or sub-optimal clinical 
response 
INVESTIGATOR/TRIAL LOCATION 
Worldwide 
PHASE OF DEVELOPMENT 
2 
STUDY OBJECTIVE(S) 
Primary objective: 
To evaluate the safety profile of avalglucosidase alfa in patients with 
infantile-onset Pompe disease (IOPD) previously treated with alglucosidase 
alfa. 
Secondary objectives: 
To characterize the pharmacokinetic (PK) profile of avalglucosidase alfa and 
to evaluate the preliminary efficacy of avalglucosidase alfa in comparison to 
alglucosidase alfa. 
Other objectives: 
To determine 
, and 
effect of avalglucosidase alfa treatment on functional endurance, respiratory 
function, health-related quality of life (HRQOL), pain, developmental disability, 
and hearing in patients with IOPD. 
STUDY DESIGN 
Multi-stage, phase 2, open-label, multicenter, multinational, ascending dose 
cohort, repeated intravenous (IV) infusion study of avalglucosidase alfa in 
pediatric patients with IOPD who have been previously treated with 
alglucosidase alfa and demonstrated clinical decline (Stage 1) or sub-optimal 
clinical response (Stage 2) in specified respiratory function, motor skills, 
cardiac parameters, and/or new onset of ptosis. 
Stage 1 
• 
Cohort 1 – at least 5 IOPD patients will receive avalglucosidase alfa 
at 20 mg/kg once every other week (qow) for 6 months. 
• 
Cohort 2 – at least 5 IOPD patients will receive avalglucosidase alfa 
at 40 mg/kg qow for 6 months. 
Stage 2 
• 
Cohort 3 – at least 10 IOPD patients will be randomized 1:1 to 
receive avalglucosidase alfa at the highest tolerated avalglucosidase 
alfa dose in Stage 1 (20 mg/kg qow or 40 mg/kg qow) or 
alglucosidase alfa treatment at current stable dose (defined by dose 
of alglucosidase alfa administered regularly for a minimum of 
6 months immediately prior to study entry) for 6 months. The 
randomization will be stratified on gender. 
If determined safe by an independent data monitoring committee (DMC) after 
the 3rd patient in the 20 mg/kg qow group (Cohort 1) has received the 3rd 
infusion of avalglucosidase alfa, and after 5 patients have started treatment in 
Cohort 1, the next cohort of avalglucosidase alfa at higher dose (40 mg/kg 
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qow) will be initiated (Cohort 2). Cohort 3 will be initiated after determination of 
the highest tolerated avalglucosidase alfa dose in Cohort 1 and Cohort 2 after 
at least 5 patients in Cohort 1 and at least 5 patients in Cohort 2 have received 
the 7th dose of avalglucosidase alfa (or completed Week 13 with a minimum 
of 6 infusions). 
After completion of treatment for 6 months (Week 25) and data collection for 
the primary analysis, the patients will continue on long-term avalglucosidase 
alfa treatment and follow-up in the Extension Period for up to a total of 7 years 
in the study. Cohort 3 patients receiving alglucosidase alfa will have the option 
to switch to treatment with avalglucosidase alfa in the extension period or 
discontinue the study. The data cut-off for the primary analysis will be after the 
last patient in Cohort 3 has completed 6 months of treatment (Week 25). 
Safety, efficacy, PK and 
 will be performed at 
scheduled visits throughout the study treatment period. Ventilator use, adverse 
events (AEs) and concomitant and pre-infusion medications/therapies will be 
monitored continuously throughout the study. 
If a patient in Cohort 1, receiving 20 mg/kg qow avalglucosidase alfa, 
experiences further clinical decline at or after Week 25 when compared to 
prior to enrollment in ACT14132, and as defined by more rapid worsening of 
criteria of clinical decline, which is sustained on repeated study assessments, 
the patient may be managed per the discretion of the Investigator, which may 
include return to treatment with commercially available alglucosidase alfa (and 
termination of trial participation) or increasing the avalglucosidase alfa dose to 
40 mg/kg qow (once this dose is considered acceptable after the end-of-cohort 
2 DMC meeting) or maximum tolerated dose (MTD) (once established) while 
being enrolled in the extension period of the study. 
If a patient in Cohort 2 or 3 experiences further clinical decline at or after 
Week 25 as defined by more rapid worsening of criteria of clinical decline than 
prior to study start, which is sustained on repeated study assessments, the 
patient may be managed per the discretion of the Investigator. This may 
include return to treatment with commercially available alglucosidase alfa (and 
termination of trial participation). 
Patients must have completed the 25-week treatment period of the study 
before dose increase of avalglucosidase alfa (or start of avalglucosidase alfa 
for patients receiving alglucosidase alfa in Cohort 3) will be considered. 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
The patient must have a documented acid α-glucosidase (GAA) deficiency 
from blood, skin or muscle tissue. The patient is aged <18 years old, has 
cardiac involvement at the time of Pompe disease diagnosis, has been 
receiving a stable dose of alglucosidase alfa regularly for a minimum of 
6 months immediately prior to study entry, and has documented (at least 
2 recent and consecutive assessments prior to study entry, not less than 
2 weeks apart) evidence of clinical decline or sub-optimal clinical response in 
at least 1 of the following parameters related to Pompe disease and NOT 
related to intercurrent illness as assessed by the Investigator, in addition to at 
least 1 previous assessment prior to onset of decline: 
For patients entering Stage 1 - clinical decline in at least 1 of the following 
parameters: respiratory function, motor skills, and/or cardiac parameters. 
For patients entering Stage 2 - sub-optimal clinical response in at least 1 of the 
following parameters: respiratory function, motor skills, and/or new onset of 
ptosis. 
 
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Exclusion criteria: 
The patient has persistent high antibody titers, has a high risk for a severe 
allergic reaction to avalglucosidase alfa, is concurrently participating in another 
clinical study using investigational treatment for Pompe disease, previous 
treatment in any cohort of the ACT14132 study, has known clinically significant 
organ disease, or requires any prohibited concomitant medications. 
Total expected number of patients 
Approximately 20 patients 
STUDY TREATMENT(s) 
 
Investigational medicinal product(s) 
• 
avalglucosidase alfa (recombinant human α-glucosidase conjugated 
with synthetic bis-mannose-6-phosphate-Man6 glycan) 
• 
alglucosidase alfa 
Formulation: 
Sterile lyophilized powder administered following reconstitution and dilution. 
Route(s) of administration: 
Intravenous (IV) infusion 
Dose regimen: 
Stage 1 
Cohort 1: avalglucosidase alfa 20 mg/kg qow 
Cohort 2: avalglucosidase alfa 40 mg/kg qow 
Stage 2 
Cohort 3: highest tolerated avalglucosidase alfa dose in Stage 1 or current 
stable dose of alglucosidase alfa. 
In the extension period, all patients will receive avalglucosidase alfa (20 mg/kg 
qow or 40 mg/kg qow or MTD once established). 
ENDPOINT(S) 
Primary endpoint: 
Data pertaining to the safety and tolerability of avalglucosidase alfa: 
• 
Assessment of AEs/treatment-emergent adverse events (TEAEs), 
including infusion-associated reactions (IARs) 
• 
Physical examinations including weight, height, and head 
circumference 
• 
Clinical laboratory evaluations including biochemistry, hematology, 
and urinalysis 
• 
Vital sign measurements 
• 
12-lead electrocardiogram (ECG) 
• 
Immunogenicity assessments 
Secondary endpoint(s): 
Pharmacokinetics: 
• 
Plasma parameters include maximum plasma concentration 
observed (Cmax), time to achieve maximum plasma concentration 
(tmax), area under the curve from time 0 to time of the last 
quantifiable concentration (AUC0-last), terminal half-life (t1/2z), 
clearance (CL), and volume of distribution (Vd) 
Change in the following parameters at 6 months: 
Efficacy: 
• 
Gross Motor Function Measure-88 (GMFM-88) and Gross Motor 
Function Classification System – Expanded and Revised 
(GMFCS-E&R) 
• 
Pompe Pediatric Evaluation of Disability Inventory (Pompe-PEDI) 
Functional Skills Scale: Mobility Domain 
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• 
Quick Motor Function Test [QMFT] 
• 
Echocardiography (ECHO) endpoints: left ventricular mass index 
(LVMI) and left ventricular mass (LVM) Z-score 
• 
Eyelid position measurements: Interpalpebral fissure distance 
(IPFD), margin reflex distance (MRD-1), margin pupil distance 
(MPD) 
• 
Creatine kinase (CK) 
Other endpoint(s): 
Pharmacogenetics: 
• 
 
 
 
• 
Optional stored DNA 
Pharmacodynamics: 
• 
Urinary Hex4 and 
 
 
• 
Muscle biopsy (optional) 
Tertiary endpoints: 
• 
6-minute walk test (6MWT) distance walked in patients who are able 
to ambulate at least 40 meters (approximately 130 feet) without 
stopping and without an assistive device 
• 
Pulmonary function testing (PFT) endpoints: percent predicted 
forced vital capacity (FVC), maximal inspiratory pressure (MIP) and 
maximal expiratory pressure (MEP) in patients who can reliably 
undergo testing and/or who are not invasively ventilated 
• 
Hours of ventilator use/day (Ventilator use diary) 
• 
PedsQL Generic Core Scale (≥24 months of age) 
• 
PedsQL Pediatric Pain Questionnaire (>5 years of age) 
• 
Pain visual analog scale (VAS) 
• 
Bayley-III (1-42 months of age or in case the developmental level of 
an individual patient is below the level required for the Leiter-3 Scale 
assessment) 
• 
Leiter-3 (≥42 months of age) 
• 
Hearing Testing 
• 
Motor Skills Checklist 
ASSESSMENT SCHEDULE 
The treatment period will comprise 15 visits including the screening visit 
(V1: Day -14 to Day -1, may be extended to up to 4 weeks in pre-specified 
situations [refer to Section 10.1.1]) and V2 (Day 1) through V15 (Week 25) 
occurring every 1 to 2 weeks for study drug infusion, safety assessment, PK, 
PD, and efficacy evaluations. The extension period will include study drug 
infusion, safety assessment, efficacy, and PD evaluations at selected visits 
from V16 (Week 27) through V76 (Week 145). An additional extended 
long-term treatment period of up to 226 weeks or until avalglucosidase alfa is 
approved in the patient’s country, whichever comes first; (refer to Appendix C 
[Section 17.3.1] for definition applicable for UK patients) will include biweekly 
visits (study drug infusion, AEs check, and vital signs) as well as less frequent 
visits for other assessments (every 4 weeks, 12 weeks, 24 weeks, and 
48 weeks). At the end of this period, an up to 4-week post-treatment 
observation period will close the patient’s participation. 
For all patients, all visits following V2 (Day 1) are calculated from the day of 
first infusion of investigational medicinal product (IMP) in 14-day increments 
with a window of ±7 days (in Cohort 3 participants, 7-day increments with a 
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window of ± 3 days for weekly (qw) alglucosidase alfa treatment) for infusions 
and safety assessments and ±14 days for all other assessments. 
(If one visit date is changed, the next visit should take place according to the 
original schedule). 
Note: Patients who prematurely discontinue treatment should be followed as 
scheduled. 
STATISTICAL CONSIDERATIONS 
Sample size determination: 
No formal sample size calculations have been performed. Sample size for this 
study was based upon empirical considerations. 
Analysis population: 
The primary analysis population for Stage 1 and the overall study is the safety 
population, which is defined as all patients who received at least 1 infusion 
(partial or total) in the study. 
The primary analysis population for Stage 2 (Cohort 3) is the modified 
intent-to-treat (mITT) population, defined as all randomized patients in 
Cohort 3 who received at least 1 infusion and with evaluable baseline efficacy 
assessment. 
Analysis of safety: 
Safety analyses will be performed using the safety population. 
All AEs will be coded using the most recent version of the Medical Dictionary 
for Regulatory Activities (MedDRA). Adverse event incidence tables will be 
presented by system organ class (SOC) sorted by internationally agreed 
order, preferred term (PT), and the number and percentage of patients 
experiencing an AE. Multiple occurrences of the same event in the same 
patient will be counted only once in the tables within a considered period. The 
denominator for computation of percentages is the safety population. 
All TEAEs, all TEAEs potentially related to study drug, all TEAEs leading to 
treatment discontinuation, all TEAEs that are IARs, all treatment-emergent 
serious adverse events (SAEs), including treatment-related SAEs, and all AEs 
with fatal outcome will be summarized descriptively. 
Additional safety data including clinical laboratory tests, vital signs, ECG, and 
immunogenicity will be summarized descriptively. 
Safety data will be summarized by cohort/treatment arm within each stage, as 
well as by avalglucosidase alfa dose levels (20 mg/kg, 40 mg/kg). 
Analysis of pharmacokinetics and preliminary efficacy: 
PK parameters will be summarized for each visit and dose level using 
descriptive statistics.  
For each of the preliminary efficacy parameters, observed measurements and 
changes over time from pretreatment to post-baseline visit will be summarized 
by dose cohort/treatment arm within each stage and study visit using 
descriptive statistics. 
For those efficacy parameters that are used to identify patients who have sub-
optimal response or clinical decline as part of inclusion criteria, patient profile 
(in terms of change over time) will be generated for those parameters where 
each patient will serve as his/her own control. Within Cohort 3, the effect of 
switching from alglucosidase alfa to avalglucosidase alfa will be assessed 
descriptively within each cohort/treatment arm using a composite score based 
on changes from pre-study to post 6 months avalglucosidase alfa treatment 
collected during the study. The control arm (alglucosidase alfa treatment) in 
Stage 2 will serve as a reference. 
The preliminary efficacy analysis will be performed within Cohort 3, based on 
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the modified ITT population. Additional efficacy data will be summarized 
descriptively in the safety population. 
DURATION OF STUDY PERIOD (per 
patient)  
The duration of the study for each patient will be at least 7 years. After the 
initial period of 145 weeks, an additional period of up to 226 weeks or until 
avalglucosidase alfa is approved in the patient’s country, whichever comes 
first (refer to Appendix C [Section 17.3.1] for definition applicable for UK 
patients), including: 
• 
An up to 14-day screening period (may be extended to up to 
4 weeks in pre-specified situations [refer to Section 10.1.1]); 
• 
A 25-week treatment period (primary analysis period [PAP]); 
• 
A 120-week extension period; 
• 
An up to 226 week extended long-term treatment period or until 
avalglucosidase alfa is approved in the patient’s country, whichever 
comes first (refer to Appendix C [Section 17.3.1] for definition 
applicable for UK patients), and; 
• 
An up to 4-week post-treatment observation period will close the 
patient’s participation. 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
Stage 1: Clinical Decliners
IOPD patients 
previously treated with 
alglucosidase alfa
Cohort 2: n = at least 5, 40 mg/kg avalglucosidase alfa, IV infusion qow for a total of 13 doses
Cohort 1: n = at least 5, 20 mg/kg avalglucosidase alfa, IV infusion qow for a total of 13 doses
D
D
D
D
D
D
D
D
D
D
D
D
D
SR
D8
W3
W5
W7
W9
W11 W13 W15 W17 W19 W21 W23 W25
D1
D
D
D
D
D
D
D
D
D
D
D
D
D
SR
D8
W3
W5
W7
W9
W11 W13 W15 W17 W19 W21 W23 W25
D1
Cohort 3: n = at least 10, randomized 1:1, highest tolerated avalglucosidase alfa dose in Stage 1
(IV infusion qow for a total of 13 doses ) versus continued alglucosidase alfa treatment
at current stable dose for 6 months (IV infusion qw/qow for a total of 25 or 13 doses)
D
D
D
D
D
D
D
D
D
D
D
D
D8
W3
W5
W7
W9
W11 W13 W15 W17 W19 W21 W23 W25
D1
Safety review after at least 5 patients each in Cohorts 1 & 2 have received the 7th dose
of avalglucosidse alfa (or completed W13 with a minimum of 6 infusions)
Stage 2: Suboptimal Response
IOPD patients 
previously treated with 
alglucosidase alfa
W = Week
D = avalglucosidase alfa or alglucosidase alfa infusion
SR = Safety review by an independent Data Monitoring Committee (DMC)
IOPD=infantile onset Pompe disease; IC=intravenous; qow=every other week; qw=weekly
Cohort 2 will be initiated if avalglucosidase alfa is determined safe by the DMC 
after the 3rd patient in Cohort 1 has received the 3rd infusion of avalglucosidase alfa.
Stage 2 will be initiated after the highest tolerated dose in Stage 1 is determined.
Cohort 3 continue current stable dose of alglucosidase alfa (qw/qow) or switch to avalglucosidase alfa 
qow
 
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W = Week
D = avalglucosidase alfa infusion
EOT = Eon of treatment visit
EOS = End of study visit
MTD = Maximum tolerated dose
* = Refer to Appendix C Section 17.3,1 
for definition applicable for UK patients
Extension period (Cohort 1 + 2 + 3)
avalglucosidase alfa (n = at least 20) 20 or 40 mg/kg or MTD IV infusion qow for a total of 60 infusions
W27
D
W29
D
W31
D
W33
D
W35
D
W37
D
W139
D
W141
D
W143
D
W145
D
//
Extended long-term Treatment Period (Cohort 1 + 2 + 3)
avalglucosidase alfa (n = at least 20) 20 or 40 mg/kg or MTD IV infusion qow for a total of up to 114 
doses or until avalglucosidase alfa is approved, whichever comes first*
W365
W367 W369 W371
W374
D
D
D
EOT
EOS
//
W157
D
D
D
D
D
W149
W151
W153 W155
D
W147
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Page 14 
1.2 
STUDY FLOW CHART 
Please refer to Section 10 for details. 
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1.2.1 Treatment period 
 
Period 
Screening/Baseline 
Treatment Period 
Day(D) or Week (W) 
Day -14 to Day -1 
D1 
D8 
W3 
W5 
W7 
W9 
W11 
W13 
W15 
W17 
W19 
W21 
W23 
W25 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit at clinical sitea 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history/Pompe history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GAA activityb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GAA mutation analysisc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRIM statusd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications/therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Retrospective chart reviewe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT contact (Screening, 
Enrollment/Randomization/Dispensing) 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study treatment administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
avalglucosidase alfa/alglucosidase alfa 
infusiong 
 
X 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
β-hCG pregnancy testh 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Physical examinationi 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
Height/body length/head 
circumferencej 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Body weight 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Vital signsk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECGl 
 
Xm 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
Hematology, biochemistryn, urinalysis 
X 
 
Xo 
 
Xo 
 
Xo 
 
X 
 
Xo 
 
Xo 
 
X 
Anti-avalglucosidase alfa antibodies 
(with testing for neutralizing antibodies 
in anti-avalglucosidase alfa antibody 
positive patients)p 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Anti-alglucosidase alfa antibodies (with 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
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Period 
Screening/Baseline 
Treatment Period 
Day(D) or Week (W) 
Day -14 to Day -1 
D1 
D8 
W3 
W5 
W7 
W9 
W11 
W13 
W15 
W17 
W19 
W21 
W23 
W25 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
testing for neutralizing antibodies in 
anti-alglucosidase alfa antibody 
positive patients)p 
Adverse event collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokineticsq 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
avalglucosidase alfa plasma samples  
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Pharmacodynamics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Hex4 samplesr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Muscle biopsy (optional)t 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ventilator use diaryu 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GMFM-88, GMFCS-E&Rv 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Motor Skills Checklistv 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
QMFT 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Pompe-PEDI, Functional Skills Scale: 
Mobility Domainv 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Bayley-III/Leiter-3 scalesw 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Echocardiographyl 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Hearing testingx 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Eyelid position measurementsy 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PedsQL Generic Core Scale 
questionnairez 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
PedsQL Pediatric Pain 
Questionnaireaa 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Pain VASaa 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
PFTbb 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
6MWTcc 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Pharmacogenetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored DNA sample (optional)s 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Period 
Screening/Baseline 
Treatment Period 
Day(D) or Week (W) 
Day -14 to Day -1 
D1 
D8 
W3 
W5 
W7 
W9 
W11 
W13 
W15 
W17 
W19 
W21 
W23 
W25 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
6MWT = 6-minute walk test; 
; BNP = brain natriuretic peptide; ADAs = anti-drug antibodies; β-hCG = beta-human chorionic gonadotropin; CK = creatine kinase; CRF = case 
report form; CRIM = cross-reactive immunologic material; D = Day; 
; DNA = deoxyribonucleic acid; ECG = electrocardiogram; EDTA = Ethylenediaminetetraacetic acid; EOS = end of study; 
GAA = acid α-glucosidase; GMFCS-E&R = Gross Motor Function Classification System – Expanded and Revised; GMFM-88 = Gross Motor Function Measure-88; IMP = investigational medicinal product; IRT = 
interactive response technology; PE = physical examination; PFT = pulmonary function testing; PedsQL = pediatric quality of life inventory; Pompe-PEDI = Pompe Pediatric Evaluation of Disability Inventory; PPT = 
plasma preparation tube; QMFT = Quick Motor Function Test; 
; VAS = visual analog scale; W=week 
a Clinic visit and/or visit by home infusion nurse for patients receiving alglucosidase alfa home infusion. In case of temporary treatment discontinuation, visit and assessment schedules will be adapted to the absence 
of infusion of avalglucosidase alfa as outlined in Section 10.1.7. Procedures and assessments are not presented in chronological order in the flow chart. Refer to Section 10.1 for the recommended order of 
procedures and assessments. Visits that are longer due to multiple assessments or procedures (eg, motor assessments, echocardiography, questionnaires) may be carried out over several days (refer to 
Section 10.1). Patients will be required to remain in the hospital or the infusion center for observation of AEs for 1 hour after each 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 or their legally authorized representative (for pediatric patients) to ensure that no adverse event occurred during the observational period. 
b If performed previously with historical results available, then the GAA activity does not need to be repeated, but result needs to be entered into the database. 
c Gene mutation analysis is mandatory for all patients. If gene mutation analysis was conducted prior to signing the informed consent, these results may be utilized provided that the analysis was conducted by a 
certified laboratory, written results are provided to the site, and parents give consent to utilize the results. Sample may be obtained at any other visit if not possible during screening due to blood volume limitation. 
d Blood testing for CRIM status to be analyzed by central laboratory. If CRIM status was determined prior to enrollment and a report of the results is on file with the site, then the assessment does not need to be 
repeated, but result needs to be entered into the database. Results of CRIM status determined by the central laboratory from blood samples obtained for this study will not be provided to the site but will be 
uploaded to the Sanofi central repository through external data transfer. 
e Retrospective chart review at screening/baseline to collect available data on clinical decline or sub-optimal clinical response as outlined in I 06 and I 07. 
f 
Enrollment of patients in Cohorts 1 and 2 and randomization of patients in Cohort 3: IRT contact will be performed anytime during screening period for screening, prior to IMP administration for all other concerned 
visits and on or before Day 1 for enrollment/randomization. 
g Biweekly administration or, for alglucosidase alfa in Cohort 3 only, weekly administration (current stable dose). For all patients, all visits following V2 (Day 1) are calculated from the day of first infusion of 
investigational medicinal product (IMP) in 14-day increments with a window of ±7 days (in Cohort 3 participants, 7 day increments with a window of ± 3 days for weekly (qw) alglucosidase alfa treatment) for 
infusions and safety assessments and ±14 days for all other assessments. 
h Female patients of childbearing potential only will have serum test for pregnancy at Screening, a urine β-hCG test up to 24 hours before D1 infusion and every 4 weeks thereafter. 
i 
Physical examination CRF will ask physician to record current muscle pain and cramps specifically at each PE assessment. Tanner stage will be assessed as part of the PE assessment at screening/baseline. 
j 
To be measured at screening/baseline, every 3 months up to Week 73 and then every 6 months until Week 145/EOS in all patients. 
k At every infusion. Vital signs include heart rate, systolic and diastolic blood pressure, respiratory rate, temperature, and oxygen saturation and 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. 
l 
12-lead ECG after at least 15 minutes in supine position (if supine is feasible for the patient). Review should be done at the site in a timely manner to determine if there are any safety concerns and for clinical 
management of the patient. In addition, reading will be done by central reader for analyses purposes only. 
m 12-lead ECG after at least 15 minutes in supine position (in triplicate predose at Day 1 only) and prior to receiving IMP: 3 ECGs within 5 minutes will be performed with at least 1 minute between 2 replicates. 
n Biochemistry panel will include BNP and CK.  
o Biochemistry assessments only for participants treated with avalglucosidase alfa. Sampling is not required for Stage 2 - Cohort 3 participants randomized to treatment with alglucosidase alfa. 
p Serum samples are collected pre-infusion at each time point. Additional samples may be taken if clinically indicated in the event of IARs. Stage 2 Cohort 3 patients receiving alglucosidase alfa treatment do not 
require sampling of anti- avalglucosidase alfa antibodies and neutralizing antibodies in anti-avalglucosidase alfa antibody positive patients at Day 8, Week 5, Week 9, Week 13, Week 17, Week 21. 
q Pharmacokinetic sampling schedule: prior to infusion; at the end of infusion; and 2, 4, 6, and 8 hours after the end of infusion at Day 1 and Week 25 and prior to infusion and 2 hours after the end of infusion at 
Week 13; additionally in the 40 mg/kg dose cohort 12 to 16 hours after the end of infusion at Day 1 and Week 25. For Stage 2 - Cohort 3 participants randomized to treatment with alglucosidase alfa, sampling of 
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avalglucosidase alfa pharmacokinetics is not required at Day 1, Week 13 and Week 25. Pharmacokinetic blood samples are to be collected within 15 minutes of scheduled time: predose and all samples 
immediately following the end of the infusion through 8 hours post infusion. 
r 
 
 
 
s Blood samples will be obtained as blood volume permits and will not exceed the blood volume collection limit of < 7 mL/kg over an 8-week period. Sampling is prioritized for safety labs (hematology, biochemistry, 
ADA) and PK 
 
 
 
t 
Time points are suggested time points. 
u In the event patient requires ventilator support (invasive or non-invasive) at any time during study treatment the patient will be asked to complete a daily ventilator use diary. On a biweekly basis, the periods of 
ventilator use/day (daytime, nighttime, both) will be reported by the Investigator based on the ventilator use diary. 
v Patients included in Cohort 3 on the basis of sub-optimal clinical response documented by motor scale and/or clinical development evaluation tools other than GMFM-88 or Pompe-PEDI will undergo assessment 
with those tools in combination with the prescribed/planned testing at screening/baseline and Week 25.  
w The Bayley-III will be administered to patients from 1 month of age until the maximum score on each of the 3 administered scales has been obtained. Once the maximum score for a scale has been achieved, only 
the remaining scales will be administered. Bayley-III is to be discontinued when the patient reaches 42 months of age. Leiter-3 Scale assessment is to be performed at the last assessment of the Bayley-III Scales 
prior to the patient reaching 42 months of age. In case the developmental level of an individual patient is below the level required for the Leiter-3 Scale assessment, the patients should be assessed by the 
Bayley-III regardless of the patient’s age. 
x Hearing testing includes audiogram and brainstem auditory evoked potentials. 
y Separate informed consent will be sought to permit for the acquisition and use of photographs of the patient’s eyes in order to allow for independent review of eyelid position measurements by central reader. 
z PedsQL Generic Core Scales will be used in pediatric patients 2 years and older, using age appropriate reports 
aa Pain will be assessed by PedsQL Pediatric Pain Questionnaire for patients >5 years of age. Observer reported Pain VAS will be recorded in patients of all ages. 
bb Pulmonary function tests are not required for patients unable to reliably undergo testing or for patients who are invasively ventilated; reading will be done by central reader. 
cc 6MWT in patients who are able to ambulate at least 40 meters (approximately 130 feet) without stopping and without an assistive device. 
 
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1.2.2 Extension period (Week 27 to Week 35) including details for Stage 2 - Cohort 3 for 
patients switching to avalglucosidase alfa 
 
Period 
Extension Period 
Day(D) or Week (W) 
W27 
W28 
W29 
W31 
W33 
W35 
Visit 
V16 
V17a 
V18 
V19 
V20 
V21 
Visit at clinical siteb 
X 
X 
X 
X 
X 
X 
Concomitant medications/therapies 
X 
X 
X 
X 
X 
X 
IRT contact (Dispensing) 
X 
 
X 
X 
X 
X 
Study treatment administration 
 
 
 
 
 
 
avalglucosidase alfa 
X 
 
X 
X 
X 
X 
Safety 
 
 
 
 
 
 
Urine pregnancy testc 
 
 
X 
 
X 
 
Physical examinationd 
 
 
Xa 
 
Xa 
 
Body weight 
Xa 
 
X 
 
X 
 
Vital signse 
X 
 
X 
X 
X 
X 
ECGf 
 
 
Xa 
 
 
 
Biochemistryg 
 
X 
X 
 
X 
 
Anti-avalglucosidase alfa antibodies(with testing for 
neutralizing antibodies in anti-avalglucosidase alfa 
antibody positive patients)h 
 
X 
Xa 
 
Xa 
 
Adverse event collection 
X 
X 
X 
X 
X 
X 
Pharmacokineticsi 
 
 
 
 
 
 
avalglucosidase alfa plasma samples 
Xa 
 
 
 
 
 
Efficacy 
 
 
 
 
 
 
Ventilator use diaryj 
X 
 
X 
X 
X 
X 
AE = adverse event; BNP = brain natriuretic peptide; β-hCG = beta-human chorionic gonadotropin; CK = creatine kinase; CRF = case report 
form; D = Day; DNA = deoxyribonucleic acid; ECG = electrocardiogram; IRT = interactive response technology 
a Visit/assessment is only required for the avalglucosidase alfa switch patients. 
b In case of temporary treatment discontinuation, visit and assessment schedules will be adapted to the absence of infusion of avalglucosidase 
alfa as outlined in Section 10.1.7. Procedures and assessments are not presented in the chronological order in the flow chart. Refer to 
Section 10.1 for the recommended order of procedures and assessments. Visits that are longer due to multiple assessments or procedures 
(eg, motor assessments, echocardiography, questionnaires) may be carried out over several days (refer to Section 10.1). Patients will be 
required to remain in the hospital or the infusion center for observation of AEs for 1 hour after each 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 or their legally authorized representative (for pediatric patients) to ensure that no adverse event occurred 
during the observational period. 
c Female patients of childbearing potential only will have a urine β-hCG test. 
d Physical examination CRF will ask physician to record current muscle pain and cramps specifically at each PE assessment. 
e At every infusion. Vital signs include heart rate, systolic and diastolic blood pressure, respiratory rate, temperature, and oxygen saturation 
and 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. 
f 
12-lead ECG after at least 15 minutes in supine position (if supine is feasible for the patient). Review should be done at the site in a timely 
manner to determine if there are any safety concerns and for clinical management of the patient. In addition, reading will be done by central 
reader for analyses purposes only. 
g Biochemistry panel will include BNP and CK. 
h Serum samples are collected pre-infusion at each time point. Additional samples may be taken if clinically indicated in the event of IARs. 
i 
For patients participating in Cohort 3 and switching to avalglucosidase alfa at Week 27, pharmacokinetic sampling will be performed prior to 
infusion; at the end of infusion; and 2, 4, 6, and 8 hours after the end of infusion at Week 27 and prior to infusion and 2 hours after the end of 
infusion at Week 37; additionally in the 40 mg/kg dose cohort 12 to 16 hours after the end of infusion at Week 27. 
j 
In the event patient requires ventilator support (invasive or non-invasive) at any time during study treatment the patient will be asked to 
complete a daily ventilator use diary. On a biweekly basis, the periods of ventilator use/day (daytime, nighttime, both) will be reported by the 
Investigator based on the ventilator use diary. 
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Amended Clinical Trial Protocol No. 03  
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Page 20 
1.2.3 Extension period (Week 37 to Week 145) 
 
Period 
Extension Period 
Timing 
9 
Month 
(Week 
37) 
12 
Month 
(Week 
49) 
15 
Month 
(Week 
61) 
18 
Month 
(Week 
73) 
21 
Month 
(Week 
85) 
24 
Month 
(Week 
97) 
27 
Month 
(Week 
109) 
30 
Month 
(Week 
121) 
33 
Month 
(Week 
133) 
36 
Month 
(Week 
145) 
Visita 
V22 
V28 
V34 
V40 
V46 
V52 
V58 
V64 
V70 
V76 
Visit at clinical site 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications/therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study treatment administration 
 
IRT contact (Dispensing) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
avalglucosidase alfa infusionb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testd,e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationf 
X 
X 
Xg 
Xg 
 
X 
 
X 
 
X 
Height/body length/head 
circumferenceh 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Body weighte 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECGi 
Xg 
X 
 
X 
 
X 
 
X 
 
X 
Hematology, urinalysis 
 
X 
 
X 
 
X 
 
X 
 
X 
Biochemistryj 
Xk 
Xk 
Xk 
Xk 
X 
X 
X 
X 
X 
X 
Anti-avalglucosidase alfa 
antibodies (with testing for 
neutralizing antibodies in anti-
avalglucosidase alfa antibody 
positive patients)l 
Xm 
Xm 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokineticsn 
 
avalglucosidase alfa plasma 
samples 
X 
X 
 
 
 
 
 
 
 
 
Pharmacodynamics 
 
Urine Hex4 sampleso 
 
X 
 
X 
 
X 
 
X 
 
X 
Muscle biopsy (optional)q 
 
Xg 
 
 
 
 
 
 
 
X 
Efficacy 
 
Ventilator use diaryr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GMFM-88, GMFCS-E&R 
 
X 
 
X 
 
X 
 
X 
 
X 
Motor Skills Checklist 
 
X 
 
X 
 
X 
 
X 
 
X 
QMFT 
 
X 
 
X 
 
X 
 
X 
 
X 
Pompe-PEDI, Functional Skills 
Scale: Mobility Domain 
 
X 
 
X 
 
X 
 
X 
 
X 
Bayley-III / Leiter-3 scaless  
 
X 
 
X 
 
X 
 
X 
 
X 
Echocardiographyi 
 
X 
 
X 
 
X 
 
X 
 
X 
Hearing testingt 
 
X 
 
X 
 
X 
 
X 
 
X 
Eyelid position measurementsu 
 
X 
 
X 
 
X 
 
X 
 
X 
PedsQL Generic Core Scale 
 
X 
 
X 
 
X 
 
X 
 
X 
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Page 21 
Period 
Extension Period 
Timing 
9 
Month 
(Week 
37) 
12 
Month 
(Week 
49) 
15 
Month 
(Week 
61) 
18 
Month 
(Week 
73) 
21 
Month 
(Week 
85) 
24 
Month 
(Week 
97) 
27 
Month 
(Week 
109) 
30 
Month 
(Week 
121) 
33 
Month 
(Week 
133) 
36 
Month 
(Week 
145) 
Visita 
V22 
V28 
V34 
V40 
V46 
V52 
V58 
V64 
V70 
V76 
questionnairev 
Pediatric Pain Questionnairew 
 
X 
 
X 
 
X 
 
X 
 
X 
Pain VASw 
 
X 
 
X 
 
X 
 
X 
 
X 
PFTx 
 
X 
 
X 
 
X 
 
X 
 
X 
6MWTy 
 
X 
 
X 
 
X 
 
X 
 
X 
Pharmacogenetics 
 
6MWT = 6-minute walk test; ADA = anti-drug antibodies; β-hCG = beta-human chorionic gonadotropin; BNP = brain natriuretic peptide; CK = 
creatine kinase; CRF = case report form; 
; ECG = electrocardiogram; EDTA = Ethylenediaminetetraacetic acid; EOS = 
end of study; ERT = enzyme replacement therapy; GMFCS-E&R = Gross Motor Function Classification System – Expanded and Revised; 
GMFM-88 = Gross Motor Function Measure-88; IRT = interactive response technology; PedsQL = pediatric quality of life inventory; Pompe-PEDI 
= Pompe Pediatric Evaluation of Disability Inventory; PE = physical examination; PFT = pulmonary function testing; QMFT = Quick Motor 
Function Test; 
; VAS = visual analog scale 
a In case of temporary treatment discontinuation, visit and assessment schedules will be adapted to the absence of infusion of avalglucosidase 
alfa as outlined in Section 10.1.7. Procedures and assessments are not presented in the chronological order in the flow chart. Refer to 
Section 10.1 for the recommended order of procedures and assessments. Visits that are longer due to multiple assessments or procedures 
(eg, motor assessments, echocardiography, questionnaires) may be carried out over several days (refer to Section 10.1). Patients will be 
required to remain in the hospital or the infusion center for observation of AEs for 1 hour after each 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 or their legally authorized representative (for pediatric patients) to ensure that no adverse event occurred 
during the observational period. For patients undergoing home infusion (as per conditions and instructions provided in Section 8.9.2) visit at 
clinical site is not required for infusion only visits. Refer to Section 10.1.3 for the concerned weeks details. If avalglucosidase alfa is approved 
in the patient’s country before the patient reaches Week 145, the Week 145 visit will be performed as the end of treatment visit. 
b Avalglucosidase alfa to be administered at study site every other week. As per conditions and instructions provided in Section 8.1.2, 
avalglucosidase alfa infusion may occur at home. 
c At every infusion. Vital signs include heart rate, systolic and diastolic blood pressure, respiratory rate, temperature, and oxygen saturation 
and 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. 
d Female patients of childbearing potential only will have a urine β-hCG test. 
e Monthly. 
f 
Physical examination CRF will ask physician to record current muscle pain and cramps specifically at each PE assessment. Tanner stage will 
be assessed as part of the PE assessment at Week 49, Week 97 and Week 145.  
g For Stage 2 - Cohort 3 for patients switching to avalglucosidase alfa only. 
h To be measured at screening/baseline, every 3 months up to Week 73 and then every 6 months until Week 145/EOS in all patients. 
i 
12-lead ECG after at least 15 minutes in supine position (if supine is feasible for the patient). Review should be done at the site in a timely 
manner to determine if there are any safety concerns and for clinical management of the patient. In addition, reading will be done by central 
reader for analyses purposes only. 
j 
Biochemistry panel will include BNP and CK. 
k Biochemistry in all patients will additionally be collected monthly for the first 6 months of the extension period (Week 29, Week 33, Week 37, 
Week 41, Week 45, and Week 49) and for patients who switch to avalglucosidase alfa in Stage 2 – Cohort 3 for 6 more months (Week 53, 
Week 57, Week 61, Week 65, Week 69, Week 73). 
l 
Serum samples are collected pre-infusion at each time point. Additional samples may be taken if clinically indicated in the event of IARs. 
m Anti-avalglucosidase alfa antibodies (with testing for neutralizing antibodies for avalglucosidase alfa antibody positive patients) in 
Stage 2 - Cohort 3 avalglucosidase alfa switch patients will be collected monthly for the first 6 months of the extension period (Week 29, 
Week 33, Week 37, Week 41, Week 45, Week 49). 
n For patients participating in Cohort 3 and switching to avalglucosidase alfa at Week 27, pharmacokinetic sampling will be performed prior to 
infusion; at the end of infusion; and 2, 4, 6, and 8 hours after the end of infusion at Week 49 and prior to infusion and 2 hours after the end of 
infusion at Week 37; additionally in the 40 mg/kg dose cohort 12 to 16 hours after the end of infusion at Week 49. 
o 
 
 
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p Blood samples will be obtained as blood volume permits and will not exceed the blood volume collection limit of < 7 mL/kg over an 8-week 
period. Sampling is prioritized for safety labs (hematology, biochemistry, ADA) and PK and 
 
 
. 
q Time points are suggested time points. 
r 
In the event patient requires ventilator support (invasive or non-invasive) at any time during study treatment the patient will be asked to 
complete a daily ventilator use diary. On a biweekly basis (including for patients receiving home infusions, see Section 8.9.2), the periods of 
ventilator use/day (daytime, nighttime, both) will be reported by the Investigator based on the ventilator use diary. 
s The Bayley-III will be administered to patients from 1 month of age until the maximum score on each of the 3 administered scales has been 
obtained. Once the maximum score for a scale has been achieved, only the remaining scales will be administered. Bayley-III is to be 
discontinued when the patient reaches 42 months of age. Leiter-3 Scale assessment is to be performed at the last assessment of the 
Bayley-III Scales prior to the patient reaching 42 months of age. In case the developmental level of an individual patient is below the level 
required for the Leiter-3 Scale assessment, the patients should be assessed by the Bayley-III regardless of the patient’s age. 
t 
Hearing testing includes audiogram and brainstem auditory evoked potentials. 
u Separate informed consent will be sought to permit for the acquisition and use of photographs of the patient’s eyes in order to allow for 
independent review of eyelid position measurements by a central reader. 
v PedsQL Generic Core Scales will be used in pediatric patients 2 years and older, using age appropriate reports 
w Pain will be assessed by PedsQL Pediatric Pain Questionnaire for patients >5 years of age. Observer reported Pain VAS will be recorded in 
patients of all ages. 
x Pulmonary function tests are not required for patients unable to reliably undergo testing or for patients who are invasively ventilated. 
y 6MWT in patients who are able to ambulate at least 40 meters (approximately 130 feet) without stopping and without an assistive device. 
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1.2.4 Extended long-term treatment period 
 
Period 
Extended long-term treatment period 
Timinga 
Biweeklyb 
Every 4 
weeks 
(Monthly) 
Every 12 
weeks 
(Quarterly) 
Every 24 
weeks 
(Every 
6 Months) 
Every 48 
weeks 
(Yearly) 
End of 
treatment 
Visitc, a 
Visit at clinical sitec 
X 
X 
X 
X 
X 
X 
Concomitant medications/therapies 
X 
X 
X 
X 
X 
X 
Study treatment administration 
 
 
 
 
 
 
IRT contact (Dispensing) 
X 
X 
X 
X 
X 
X 
avalglucosidase alfa infusiond 
X 
X 
X 
X 
X 
X 
Vital signse 
X 
X 
X 
X 
X 
X 
Safety 
 
 
 
 
 
 
Urine pregnancy testf  
 
X 
X 
X 
X 
X 
Physical examinationg 
 
 
 
X 
X 
X 
Height/body length/head circumference 
 
 
 
X 
X 
X 
Body weight 
 
X 
X 
X 
X 
X 
ECGh 
 
 
 
 
X 
X 
Hematologyi, urinalysis 
 
 
 
X 
X 
X 
Biochemistryi,l, k 
 
 
 
X 
X 
X 
Anti-avalglucosidase alfa antibodies (with testing 
for neutralizing antibodies in anti-avalglucosidase 
alfa antibody positive patients) j,i 
 
 
X 
X 
X 
X 
Adverse event collection 
X 
X 
X 
X 
X 
X 
Efficacy 
 
 
 
 
 
 
Ventilator use diarym 
X 
X 
X 
X 
X 
X 
GMFM-88, GMFCS-E&R 
 
 
 
 
X 
X 
Motor Skills Checklist 
 
 
 
 
X 
X 
QMFT 
 
 
 
 
X 
X 
Pompe-PEDI, Functional Skills Scale: Mobility 
Domain 
 
 
 
 
X 
X 
Leiter-3 scales (Bayley-III scale)n  
 
 
 
 
X 
X 
Echocardiographyh 
 
 
 
 
X 
X 
Hearing testingo 
 
 
 
 
X 
X 
Eyelid position measurementsp 
 
 
 
X 
X 
X 
PedsQL Generic Core Scale questionnaireq 
 
 
 
 
X 
X 
PFTs 
 
 
 
 
X 
X 
6MWTt 
 
 
 
 
X 
X 
6MWT = 6-minute walk test; β-hCG = beta-human chorionic gonadotropin; BNP = brain natriuretic peptide; CK = creatine kinase; CRF = case 
report form; ECG = electrocardiogram; GMFCS-E&R = Gross Motor Function Classification System – Expanded and Revised; GMFM-88 = 
Gross Motor Function Measure-88; IRT = interactive response technology; PE = physical examination; PFT = pulmonary function testing; 
PedsQL = pediatric quality of life inventory; Pompe-PEDI = Pompe Pediatric Evaluation of Disability Inventory; QMFT = Quick Motor Function 
Test; VAS = visual analog scale 
a Refer to Section 10.1.4 for the concerned weeks details. Patients who permanently discontinue the study treatment prior to the scheduled 
end of treatment during the extended long-term treatment period will have assessments corresponding to the end of treatment visit. If the end 
of treatment visit occurs at the same time as a yearly visit, the yearly visit will not be performed. 
b In case of temporary treatment discontinuation, visit and assessment schedules will be adapted to the absence of infusion of avalglucosidase 
alfa as outlined in Section 10.1.7. Procedures and assessments are not presented in the chronological order in the flow chart. Refer to 
Section 10.1 for the recommended order of procedures and assessments. Visits that are longer due to multiple assessments or procedures 
(eg, motor assessments, echocardiography, questionnaires) may be carried out over several days (refer to Section 10.1). 
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c For patients undergoing home infusion (as per conditions and instructions provided in Section 8.9) visit at clinical site is not required for 
infusion only visits.  
d Avalglucosidase alfa to be administered at study site every other week. Patients will be required to remain in the hospital or the infusion 
center for observation of AEs for 1 hour after each 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 or their 
legally authorized representative (for pediatric patients) to ensure that no adverse event occurred during the observational period. As per 
conditions and instructions provided in Section 8.1.2, avalglucosidase alfa infusion may occur at home. 
e At every infusion. Vital signs include heart rate, systolic and diastolic blood pressure, respiratory rate, temperature, and oxygen saturation 
and are to be assessed prior to infusion, with each infusion rate change (including the start of infusion which is considered as first infusion 
rate change), at the end of the infusion and at the end of the post-infusion observation period. Collection windows are ±15 minutes. 
f 
Female patients of childbearing potential only will have a urine β-hCG test. 
g Physical examination CRF will ask physician to record current muscle pain and cramps specifically at each PE assessment. Tanner stage will 
be assessed as part of the PE assessment.  
h 12-lead ECG after at least 15 minutes in supine position (if supine is feasible for the patient). Review should be done at the site in a timely 
manner to determine if there are any safety concerns and for clinical management of the patient. In addition, reading will be done by central 
reader for analyses purposes only. Echocardiography can be performed on a more frequent basis upon need of abnormality follow-up. 
i 
Blood samples will be obtained as blood volume permits and will not exceed the blood volume collection limit of < 7 mL/kg over an 8-week 
period. 
j 
Serum samples are collected pre-infusion at each time point. Additional samples may be taken if clinically indicated in the event of IARs. 
k Fasted sample, prior to IMP infusion. 
l 
Biochemistry panel will include BNP and CK.  
m In the event patient requires ventilator support (invasive or non-invasive) at any time during study treatment the patient will be asked to 
complete a daily ventilator use diary. On a biweekly basis (including for patients receiving home infusions, see Section 8.9.2), the periods of 
ventilator use/day (daytime, nighttime, both) will be reported by the Investigator based on the ventilator use diary. 
n Leiter-3 Scale assessment is to be performed at the last assessment of the Bayley-III Scales prior to the patient reaching 42 months of age. 
In case the developmental level of an individual patient is below the level required for the Leiter-3 Scale assessment, the patients should be 
assessed by the Bayley-III regardless of the patient’s age. 
o Hearing testing includes audiogram and brainstem auditory evoked potentials. 
p Separate informed consent will be sought to permit for the acquisition and use of photographs of the patient’s eyes in order to allow for 
independent review of eyelid position measurements by a central reader. 
q PedsQL Generic Core Scales will be used in pediatric patients 2 years and older, using age appropriate reports. 
r 
Pain will be assessed by PedsQL Pediatric Pain Questionnaire for patients >5 years of age. Observer reported Pain VAS will be recorded in 
patients of all ages. 
s Pulmonary function tests are not required for patients unable to reliably undergo testing or for patients who are invasively ventilated. 
t 
6MWT in patients who are able to ambulate at least 40 meters (approximately 130 feet) without stopping and without an assistive device. 
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1.2.5 End of study 
Period 
End of Study Visit/Contacta 
Day (D) or Week (W) 
4 weeks after the last IMP infusion 
Visit 
EOS 
Concomitant medications/therapies 
X 
AE collection 
X 
AE = adverse event; EOS = end of study; ERT = enzyme replacement therapy; IMP = investigational medicinal product. 
a If the patient enrolls in another study or receives commercially available ERT, the follow-up period may be reduced from 4 to 2 weeks. 
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2 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL NO. 03 ....................................................................................... 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 3 
DOCUMENT HISTORY ................................................................................................................................... 3 
OVERALL RATIONALE FOR THE AMENDMENT ........................................................................................ 3 
CLINICAL TRIAL SUMMARY ........................................................................................................................ 6 
1 
FLOW CHARTS ............................................................................................................................. 12 
1.1 
GRAPHICAL STUDY DESIGN ...................................................................................................... 12 
1.2 
STUDY FLOW CHART .................................................................................................................. 14 
1.2.1 
Treatment period ............................................................................................................................ 15 
1.2.2 
Extension period (Week 27 to Week 35) including details for Stage 2 - Cohort 3 for patients 
switching to avalglucosidase alfa ................................................................................................... 19 
1.2.3 
Extension period (Week 37 to Week 145) ..................................................................................... 20 
1.2.4 
Extended long-term treatment period ............................................................................................ 23 
1.2.5 
End of study ................................................................................................................................... 25 
2 
TABLE OF CONTENTS ................................................................................................................ 26 
2.1 
LIST OF TABLES ........................................................................................................................... 32 
2.2 
LIST OF FIGURES ......................................................................................................................... 32 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 33 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 36 
5 
STUDY OBJECTIVES ................................................................................................................... 39 
5.1 
PRIMARY ....................................................................................................................................... 39 
5.2 
SECONDARY ................................................................................................................................ 39 
5.3 
OTHER ........................................................................................................................................... 39 
6 
STUDY DESIGN ............................................................................................................................ 40 
6.1 
DESCRIPTION OF THE STUDY ................................................................................................... 40 
6.2 
DURATION OF STUDY PARTICIPATION .................................................................................... 41 
6.2.1 
Duration of study participation for each patient ............................................................................. 41 
6.2.2 
Determination of end of clinical trial (all patients) .......................................................................... 41 
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6.3 
INTERIM ANALYSIS ...................................................................................................................... 41 
6.4 
STUDY COMMITTEES .................................................................................................................. 42 
6.4.1 
Data monitoring committee ............................................................................................................ 42 
7 
SELECTION OF PATIENTS .......................................................................................................... 43 
7.1 
INCLUSION CRITERIA .................................................................................................................. 43 
7.2 
EXCLUSION CRITERIA ................................................................................................................ 45 
7.2.1 
Exclusion criteria related to study methodology ............................................................................ 45 
7.2.2 
Exclusion criteria related to the active comparator and/or mandatory background therapies ....... 46 
7.2.3 
Exclusion criteria related to the current knowledge of Sanofi compound ...................................... 46 
7.2.4 
Additional exclusion criteria during or at the end of screening or run-in phase before 
randomization ................................................................................................................................. 46 
7.2.5 
Additional exclusion criteria related to country specific requirements ........................................... 46 
8 
STUDY TREATMENTS ................................................................................................................. 47 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) .......................................................................... 47 
8.1.1 
Treatment period: Day 1 to Week 25 (Month 6) ............................................................................ 48 
8.1.2 
Extension period: Week 27 to Week 145 (Month 36) and additional extension period from 
Week 147 onwards ........................................................................................................................ 49 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................. 50 
8.3 
BLINDING PROCEDURES ............................................................................................................ 50 
8.3.1 
Methods of blinding ........................................................................................................................ 50 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 50 
8.5 
PACKAGING AND LABELING ...................................................................................................... 50 
8.6 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 50 
8.7 
RESPONSIBILITIES ...................................................................................................................... 50 
8.7.1 
Treatment accountability and compliance...................................................................................... 51 
8.7.2 
Return and/or destruction of treatments ........................................................................................ 51 
8.8 
CONCOMITANT MEDICATION AND THERAPY .......................................................................... 52 
8.8.1 
Pretreatment for patients with infusion-associated reactions ........................................................ 52 
8.8.2 
Prohibited concomitant medications .............................................................................................. 52 
8.9 
HOME INFUSION .......................................................................................................................... 53 
8.9.1 
Home infusion for patients receiving alglucosidase alfa ................................................................ 53 
8.9.2 
Home infusion for patients receiving avalglucosidase alfa ............................................................ 54 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 56 
9.1 
PRIMARY ENDPOINT ................................................................................................................... 56 
9.1.1 
Safety endpoints ............................................................................................................................ 56 
9.1.1.1 
Adverse events .............................................................................................................................. 56 
9.1.1.2 
Laboratory safety variables ............................................................................................................ 56 
9.1.1.3 
Vital signs ....................................................................................................................................... 57 
9.1.1.4 
Electrocardiogram variables .......................................................................................................... 57 
9.1.1.5 
Physical examination ..................................................................................................................... 58 
9.1.1.6 
Body weight, height/length, and head circumference .................................................................... 58 
9.1.1.7 
Immunogenicity .............................................................................................................................. 58 
9.2 
SECONDARY ENDPOINTS .......................................................................................................... 59 
9.2.1 
Pharmacokinetics ........................................................................................................................... 59 
9.2.1.1 
Sampling time ................................................................................................................................ 59 
9.2.1.2 
Pharmacokinetics handling procedure ........................................................................................... 60 
9.2.1.3 
Bioanalytical method ...................................................................................................................... 60 
9.2.1.4 
Pharmacokinetics parameters ....................................................................................................... 61 
9.2.2 
Secondary efficacy endpoints ........................................................................................................ 61 
9.2.2.1 
Gross Motor Function Measure-88 (GMFM-88), Gross Motor Function Classification 
System - Expanded and Revised (GMFCS-E&R) ......................................................................... 61 
9.2.2.2 
Quick Motor Function Test ............................................................................................................. 62 
9.2.2.3 
Pompe Pediatric Evaluation of Disability Inventory (Pompe-PEDI) ............................................... 63 
9.2.2.4 
Echocardiography .......................................................................................................................... 63 
9.2.2.5 
Eyelid position measurements ....................................................................................................... 64 
9.3 
OTHER ENDPOINTS..................................................................................................................... 64 
9.3.1 
Pharmacogenetic assessment ....................................................................................................... 64 
9.3.1.1 
GAA activity testing ........................................................................................................................ 64 
9.3.1.2 
Cross-reactive Immunologic Material ............................................................................................. 64 
9.3.1.3 
Genotyping of human acid α-glucosidase gene............................................................................. 65 
 
 
 
 
9.3.1.6 
Optional stored DNA sample ......................................................................................................... 65 
9.3.2 
Pharmacodynamic variables .......................................................................................................... 66 
9.3.2.1 
Urine Hex4 levels ........................................................................................................................... 66 
 
 
9.3.2.3 
Optional muscle biopsy .................................................................................................................. 66 
9.3.3 
Tertiary endpoints .......................................................................................................................... 66 
9.3.3.1 
Pulmonary function testing (PFT) .................................................................................................. 66 
9.3.3.2 
Six-minute walk test ....................................................................................................................... 67 
9.3.3.3 
Ventilator use diary ........................................................................................................................ 67 
9.3.3.4 
PedsQL Generic Core Scale questionnaire ................................................................................... 68 
9.3.3.5 
Assessment of Pain (PedsQL Pediatric Pain Questionnaire and Observer reported pain 
visual analogue scale [VAS]) ......................................................................................................... 69 
9.3.3.6 
Bayley Scale of Infant and Toddler Development, Third Edition (Bayley-III) ................................. 69 
9.3.3.7 
Leiter International Performance Scale, Third Edition (Leiter-3) ................................................... 70 
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9.3.3.8 
Hearing testing ............................................................................................................................... 70 
9.3.3.9 
Motor Skills Checklist ..................................................................................................................... 71 
9.4 
FUTURE USE OF SAMPLES ........................................................................................................ 72 
9.5 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 72 
10 
STUDY PROCEDURES ................................................................................................................ 73 
10.1 
VISIT SCHEDULE .......................................................................................................................... 73 
10.1.1 
Screening/baseline visit ................................................................................................................. 73 
10.1.2 
Treatment period ............................................................................................................................ 76 
10.1.2.1 Day of first infusion (Day 1) ............................................................................................................ 76 
10.1.2.2 One week following first infusion (Week 2 [Day 8]) ....................................................................... 77 
10.1.2.3 Weekly (alglucosidase alfa only) .................................................................................................... 78 
10.1.2.4 Biweekly ......................................................................................................................................... 78 
10.1.2.5 Monthly ........................................................................................................................................... 78 
10.1.2.6 Every 3 months .............................................................................................................................. 79 
10.1.3 
Extension period (Week 27 to Week 145) ..................................................................................... 81 
10.1.3.1 Day of first infusion within the extension period (W27) .................................................................. 81 
10.1.3.2 One week following first infusion within the extension period ........................................................ 81 
10.1.3.3 Two weeks following first infusion within the extension period (Week 29) .................................... 81 
10.1.3.4 Every 2 weeks (Biweekly) .............................................................................................................. 82 
10.1.3.5 Every 4 weeks (Monthly) ................................................................................................................ 82 
10.1.3.6 Every 12 weeks (Quarterly) ........................................................................................................... 83 
10.1.3.7 Every 24 weeks (Every 6 months) ................................................................................................. 84 
10.1.4 
Extended long-term treatment period (From Week 147 onwards) ................................................ 86 
10.1.4.1 Biweekly ......................................................................................................................................... 86 
10.1.4.2 Every 4 weeks (Monthly) ................................................................................................................ 86 
10.1.4.3 Every 12 weeks (Quarterly) ........................................................................................................... 87 
10.1.4.4 Every 24 weeks (Every 6 months) ................................................................................................. 87 
10.1.4.5 Every 48 weeks (Yearly) and end of treatment visit ...................................................................... 88 
10.1.5 
End of study ................................................................................................................................... 89 
10.1.6 
Follow-up ........................................................................................................................................ 89 
10.1.7 
Follow-up for patients who temporarily or permanently discontinued the study treatment ............ 90 
10.2 
DEFINITION OF SOURCE DATA .................................................................................................. 91 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION ....................................... 92 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ........................... 92 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ........................... 93 
10.3.3 
List of criteria for permanent treatment discontinuation ................................................................. 93 
10.3.4 
Handling of patients after permanent treatment discontinuation ................................................... 94 
10.3.5 
Procedure and consequence for patient withdrawal from study .................................................... 94 
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10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING .......................... 95 
10.4.1 
Definitions of adverse events ......................................................................................................... 95 
10.4.1.1 Adverse event ................................................................................................................................ 95 
10.4.1.2 Serious adverse event ................................................................................................................... 95 
10.4.1.3 Adverse event of special interest ................................................................................................... 96 
10.4.2 
General guidelines for reporting adverse events ........................................................................... 97 
10.4.3 
Instructions for reporting serious adverse events .......................................................................... 98 
10.4.4 
Guidelines for reporting adverse events of special interest ........................................................... 98 
10.4.5 
Guidelines for management of specific laboratory abnormalities .................................................. 99 
10.5 
OBLIGATIONS OF THE SPONSOR ........................................................................................... 100 
10.6 
SAFETY INSTRUCTIONS ........................................................................................................... 101 
10.7 
ADVERSE EVENTS MONITORING ............................................................................................ 101 
11 
STATISTICAL CONSIDERATIONS ............................................................................................ 102 
11.1 
DETERMINATION OF SAMPLE SIZE ......................................................................................... 102 
11.2 
DISPOSITION OF PATIENTS ..................................................................................................... 102 
11.3 
ANALYSIS POPULATIONS ......................................................................................................... 102 
11.4 
STATISTICAL METHODS ........................................................................................................... 102 
11.4.1 
Extent of study treatment exposure and compliance ................................................................... 102 
11.4.1.1 Compliance .................................................................................................................................. 103 
11.4.2 
Analyses of safety data ................................................................................................................ 103 
11.4.2.1 Adverse events ............................................................................................................................ 104 
11.4.2.2 Clinical laboratory tests ................................................................................................................ 105 
11.4.2.3 Physical examination, vital signs, and electrocardiogram ........................................................... 105 
11.4.2.4 Anti-avalglucosidase alfa and anti-alglucosidase alfa antibodies, neutralizing antibodies, 
and other immunogenicity testing ................................................................................................ 105 
11.4.3 
Analyses of efficacy endpoints ..................................................................................................... 106 
11.4.3.1 Multiplicity considerations ............................................................................................................ 107 
11.4.4 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................. 107 
11.4.5 
Analyses of tertiary endpoints ...................................................................................................... 107 
11.5 
INTERIM ANALYSIS .................................................................................................................... 108 
12 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ........................... 109 
12.1 
REGULATORY AND ETHICAL CONSIDERATIONS .................................................................. 109 
12.2 
INFORMED CONSENT PROCESS ............................................................................................. 110 
13 
STUDY MONITORING................................................................................................................. 111 
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13.1 
DATA QUALITY ASSURANCE .................................................................................................... 111 
13.2 
SOURCE DOCUMENTS ............................................................................................................. 112 
14 
ADDITIONAL REQUIREMENTS ................................................................................................. 113 
14.1 
DATA PROTECTION ................................................................................................................... 113 
14.2 
STUDY AND SITE CLOSURE ..................................................................................................... 115 
14.3 
CLINICAL TRIAL RESULTS AND DISSEMINATION OF CLINICAL STUDY DATA................... 115 
14.4 
PUBLICATION POLICY ............................................................................................................... 116 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................ 118 
16 
BIBLIOGRAPHIC REFERENCES ............................................................................................... 119 
17 
APPENDICES .............................................................................................................................. 124 
17.1 
APPENDIX A: GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION .................................................................................................... 124 
17.2 
APPENDIX B: GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI .................................................................................................... 126 
17.3 
APPENDIX C: COUNTRY-SPECIFIC REQUIREMENTS ........................................................... 131 
17.3.1 
United Kingdom ............................................................................................................................ 131 
17.3.1.1 Requirement for local protocol amendment dated 02 Feb 2017 ................................................. 131 
17.3.1.2 Requirement for amended protocol dated 23 Mar 2020 .............................................................. 131 
17.3.2 
Germany ...................................................................................................................................... 131 
17.3.2.1 Requirement for local protocol amendment dated 04 Oct 2017 .................................................. 131 
17.3.3 
France .......................................................................................................................................... 132 
17.4 
APPENDIX D: PROTOCOL AMENDMENT HISTORY ................................................................ 133 
17.4.1 
Amended protocol 01: 27 Jul 2018 .............................................................................................. 133 
17.4.2 
Amended protocol 02: 24 Mar 2020 ............................................................................................. 134 
 
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2.1 
LIST OF TABLES 
Table 1 – PK sampling time .......................................................................................................................... 60 
Table 2 - List of pharmacokinetic parameters and definitions ....................................................................... 61 
Table 3 - Hearing assessments appropriate for age ..................................................................................... 71 
Table 4 - Summary of adverse event reporting instructions ........................................................................ 100 
 
2.2 
LIST OF FIGURES 
Not applicable. 
 
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3 
LIST OF ABBREVIATIONS 
 
4-MUG: 
4-methylumbelliferyl-α-D glucoside 
6MWT: 
6-minute walk test 
 
 
ADA: 
anti-drug antibody 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
ATS: 
American Thoracic Society 
AUC0-last: 
area under the curve from time 0 to time of the last quantifiable concentration  
BAEPs/BAERs: Brainstem auditory evoked potentials/responses 
BfArM: 
Federal Institute for Drugs and Medical Devices 
bis-M6P: 
bis-mannose-6-phosphate 
BNP: 
brain natriuretic peptide 
CDMS: 
clinical data management system 
CFR: 
Code of Federal Regulations 
CIOMS: 
Council for International Organizations of Medical Sciences 
CK: 
creatine kinase 
CL: 
total body clearance of a drug from plasma 
Cmax: 
maximum plasma concentration observed 
COVID-19: 
Coronavirus disease 2019 
CRF: 
case report form 
CRIM: 
cross-reactive immunologic material 
 
 
DMC: 
data monitoring committee 
ECG: 
electrocardiogram 
ECHO: 
echocardiography 
e-CRF: 
electronic case report form 
EDTA: 
ethylenediaminetetraacetic acid 
EOS: 
end of study 
ERT: 
enzyme replacement therapy 
FDA: 
US Food and Drug Administration 
FVC: 
forced vital capacity 
GAA: 
acid α-glucosidase 
GCP: 
Good Clinical Practice 
GDPR: 
General Data Protection Regulation 
GMFCS-E&R: Gross Motor Function Classification System - Expanded and Revised 
GMFM-88: 
Gross Motor Function Measure-88 
GSD: 
glycogen storage disorder 
HIPAA: 
Health Insurance Portability and Accountability Act 
HRQOL: 
health-related quality of life 
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IAR: 
infusion-associated reaction 
IB: 
Investigator’s Brochure 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation 
IEC: 
independent ethics committee 
Ig: 
immunoglobulin 
IgE: 
immunoglobulin E 
IMP: 
investigational medicinal product 
IOPD: 
infantile-onset Pompe disease 
IPFD: 
interpalpebral fissure distance 
IRB: 
institutional review board 
IRT: 
interactive response technology 
IUD: 
intrauterine device 
IUS: 
intrauterine hormone-releasing system 
IV: 
intravenous 
LLOQ: 
lower limit of quantitation 
LOPD: 
late-onset Pompe disease 
LVM: 
left ventricular mass 
LVMI: 
left ventricular mass index 
M6P: 
mannose-6-phosphate 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MEP: 
maximal expiratory pressure 
MHRA: 
Medicines and Healthcare products Regulatory Agency 
MIP: 
maximal inspiratory pressure 
mITT: 
modified intent to treat 
MPD: 
margin pupil distance 
MPS-I: 
mucopolysaccharidosis type-I 
MRD-1: 
margin reflex distance 
MTD: 
maximum tolerated dose 
PAP: 
primary analysis period 
PCR: 
polymerase chain reaction 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic(s) 
PE: 
physical examination 
PFT: 
pulmonary function test 
PK: 
pharmacokinetic(s) 
Pompe-PEDI: 
Pompe Pediatric Evaluation of Disability Inventory 
PPT: 
plasma preparation tube 
PR: 
interval from the beginning of the P wave until the beginning of the QRS 
complex 
PT: 
preferred term 
QMFT: 
Quick Motor Function Test 
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 
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qw: 
weekly 
rhGAA: 
recombinant human acid α-glucosidase 
RR: 
interval between the peaks of successive QRS complexes 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SOC: 
system organ class 
SUSAR: 
suspected unexpected serious adverse reaction 
t1/2z: 
terminal half-life 
TEAE: 
treatment-emergent adverse event 
tmax: 
time to achieve maximum plasma concentration 
ULN: 
upper limit of normal 
VAS: 
visual analog scale 
VAS-OBS: 
Observational Visual Analogue Score 
Vd: 
volume of distribution 
WOCBP: 
women of childbearing potential 
β-HCG: 
beta-human chorionic gonadotropin 
 
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4 
INTRODUCTION AND RATIONALE 
Pompe disease (also known as acid maltase deficiency or glycogen storage disorder (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. The resulting accumulation of glycogen 
in body tissues, especially cardiac and skeletal muscles, disrupts the architecture and function of 
affected cells leading to a variety of symptoms, clinical decline and ultimately death. In addition 
to being a lysosomal storage disorder, Pompe disease is also considered a neuromuscular disease, 
a metabolic myopathy, and a GSD. The estimated global incidence of Pompe disease is 1:40,000, 
with variations in incidence reported between different ethnic groups (1, 2, 3, 4). 
All presentations of Pompe disease are caused by the same underlying deficiency of lysosomal 
GAA. However, there is significant heterogeneity in the clinical presentation of Pompe disease, 
and the disease manifests as a broad clinical spectrum with a continuum of clinical signs and 
symptoms (4, 5, 6, 7). Pompe disease has been classified into different phenotypes based on age at 
onset of symptoms, extent of organ involvement, and rate of progression to death. These 
phenotypes range from a rapidly progressive infantile-onset form of the disease to a more slowly 
progressive late-onset form (with symptom onset any time after infancy through adulthood), 
although there is considerable variability and overlap between these 2 extremes. The majority of 
patients with Pompe disease are classified with the late-onset subtype. 
The most significant clinical manifestations of infantile-onset Pompe disease (IOPD) include 
cardiac abnormalities and muscle weakness leading to respiratory insufficiency (4). Infant patients 
present with cardiomegaly and cardiomyopathy leading to arrhythmias and cardiac failure (8). 
General muscle weakness causes a “floppy baby” appearance and impacts respiratory muscle 
function, commonly resulting in frequent infections and the requirement of assisted ventilation by 
six months of age (9). Further, infants with Pompe disease fail to meet early developmental 
milestones, like rolling and sitting, or experience regression if a skill is acquired (6). They also, 
experience difficulty in feeding, failure to thrive, hypotonia, and hepatomegaly (6, 10). In a 
natural history study of 168 infants, the ventilator-free survival rate was 16.9% at 12 months, 
8.5% at 18 months, and 4.9% at 24 months (9). Death typically occurs due to respiratory or 
cardiac failure before one year of age (6). 
Sanofi Genzyme 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 (11, 12) and its ability 
to stabilize respiratory function in children and adults with the disease (13). To achieve these 
benefits alglucosidase alfa is administered at a dose of 20 mg/kg every other week. 
Echocardiography 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. 
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Treatment of patients with IOPD with alglucosidase alfa has shown to be effective, especially if 
initiated shortly after birth. However, an unmet medical need exists in a proportion of IOPD 
patients treated with alglucosidase alfa at 20 mg/kg qow, who demonstrate sub-optimal treatment 
response, more precisely residual myopathy, and who may benefit from more potent treatment 
(14, 15, 16). Recent publications of clinical experience in IOPD patients receiving alglucosidase 
alfa doses greater or at higher frequency than the label dose of 20 mg/kg qow reflect generally 
good tolerance and safety experience of alternate dosing regimens (14, 17). 
Sanofi Genzyme is investigating a second generation ERT for Pompe disease called 
avalglucosidase alfa (rhGAA [alglucosidase alfa] conjugated with synthetic bis-mannose-6-
phosphate-Man6 glycan); alglucosidase alfa is produced in a mammalian cell line (Chinese 
hamster Ovary) using recombinant DNA technology. Avalglucosidase alfa is a modification of 
alglucosidase alfa that results in the conjugation of a number of hexamannose structures 
containing two terminal mannose-6-phosphate (M6P) moieties to oxidized sialic acid residues on 
alglucosidase alfa, thereby increasing bis-M6P levels on the compound. More detailed 
information on the compound is provided in the Investigator’s Brochure (IB). 
The benefits and risks assessment of avalglucosidase alfa for the Phase 2 ACT14132 study is 
based upon the nonclinical studies of avalglucosidase alfa in GAA knockout mice, CD 1 mice and 
cynomolgus monkey studies, as well as on the results from the clinical Phase 1/2 TDR12857 
study (in adult treatment-naïve late-onset Pompe disease [LOPD] patients and adult LOPD 
patients who had been treated with alglucosidase alfa prior to their study participation) and 
previous experience with alglucosidase alfa. In nonclinical studies, avalglucosidase alfa was more 
successful in reducing glycogen in muscle tissue compared to alglucosidase alfa. The safety 
profile of avalglucosidase alfa in both nonclinical and clinical studies has shown avalglucosidase 
alfa to be well tolerated; adverse events (AEs) and infusion-associated reactions (IARs) are 
mostly nonserious and usually manageable (see IB Section 7 for detailed discussion of risks). The 
potential benefits of avalglucosidase alfa, balanced against its known risks, support further 
investigation of the safety and efficacy of avalglucosidase alfa across the broad spectrum of 
Pompe disease, including both pediatric and adult patients. 
A risk of acute cardiorespiratory failure requiring intubation and inotropic support after infusion 
in IOPD patients with underlying cardiac hypertrophy is considered based on experience with 
alglucosidase alfa and due to fluid overload. Appropriate medical support and monitoring 
measures should be readily available during avalglucosidase alfa infusion, and infants with 
cardiac dysfunction may require prolonged observation times that should be individualized based 
on the needs of the patient. Caution should be taken with fluid volume infusion. 
The ACT14132 study will be the first exposure of avalglucosidase alfa in the IOPD population. 
The primary objective of this phase 2, open-label ascending dose cohort study is the assessment of 
safety and tolerability of administering avalglucosidase alfa in male and female pediatric patients 
with IOPD, who have been previously treated with alglucosidase alfa and demonstrated clinical 
decline or sub-optimal clinical response in specified respiratory function, motor skills, cardiac 
parameters, and/or new onset of ptosis. The proposed starting dose is aligned with the adult 
dosing in the completed open-label ascending dose study of repeated biweekly infusions of 
avalglucosidase alfa (TDR12857), in which safety and generally good tolerability was shown at 
all dose levels (5 mg/kg qow, 10 mg/kg qow and 20 mg/kg qow) in adult LOPD patients, who 
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were both treatment-naïve and previously treated with alglucosidase alfa, is also based on 
experience with alglucosidase alfa treatment, including similar alglucosidase alfa PK profile in 
pediatric and adult patients (Genzyme Study AGLU01602 and Genzyme Study AGLU02704). 
The 40 mg/kg qow dose is based on previous experience of overall good tolerance of 
alglucosidase alfa administration at 40 mg/kg in both clinical practice and clinical trial settings 
and is consistent with what is observed in clinical practice when IOPD patients do not respond to 
20 mg/kg qow dose of alglucosidase alfa and then receive 40 mg/kg of alglucosidase alfa (14, 17, 
18, Clinical Trials AGLU01602, AGLU01702, AGLU09411). In the present study 
avalglucosidase alfa doses are planned to be administered in an ascending manner between the 
first and second cohorts, supported by the monitoring of potential safety signals by an 
independent data monitoring committee (DMC). See Appendix C (Section 17.3.2) for an 
addendum to this section for Germany only. 
The first patients (at least 5) will be enrolled in the 20 mg/kg qow dose cohort. A decision to 
proceed from the 20 mg/kg qow dose to 40 mg/kg qow will be made by the Sponsor following a 
formal review by the DMC of Cohort 1 safety data after the third patient receives their third 
infusion of avalglucosidase alfa at 20 mg/kg qow. 
The relevant data for this decision should be, at a minimum, AEs including IARs, biochemistry 
results, electrocardiogram (ECG), blood pressure, and heart rate and any available immunology 
results as applicable. 
Depending on the tolerability profile observed in the dose level cohort of 20 mg/kg qow, one of 
the following decisions will be taken for the dose level cohort of 40 mg/kg qow: 
• 
Dose escalation may continue as scheduled. 
• 
The same dose may be administered in an additional cohort. 
• 
A higher intermediate dose between the current dose of 20 mg/kg qow and the next 
planned dose of 40 mg/kg qow may be administered to the next cohort. 
• 
A dose lower than current dose of 20 mg/kg qow may be administered to the next cohort, 
including the possibility of administering a lower dose than the starting dose. 
• 
ACT14132 may be stopped. 
For the purpose of this study, criteria as outlined in Section 10.3.1, Section 10.3.2, and 
Section 10.3.3, should be considered as guidance for the decision to stop avalglucosidase alfa 
administration to a patient or to stop the trial. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective of the study is to evaluate the safety profile of avalglucosidase alfa in 
patients with IOPD previously treated with alglucosidase alfa. 
5.2 
SECONDARY 
Secondary objectives are to characterize the pharmacokinetic (PK) profile of avalglucosidase alfa 
and to evaluate the preliminary efficacy of avalglucosidase alfa in comparison to alglucosidase 
alfa. 
5.3 
OTHER 
Additional objectives are to determine 
 
 effect of avalglucosidase alfa treatment on functional endurance, respiratory function, 
health-related quality of life (HRQOL), pain, developmental disability, and hearing in patients 
with IOPD. 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
ACT14132 is a multi-stage, phase 2, open-label, multicenter, multinational, ascending dose 
cohort, repeated intravenous (IV) infusion study of avalglucosidase alfa in pediatric patients with 
IOPD who have been previously treated with alglucosidase alfa and demonstrated clinical decline 
(Stage 1) or sub-optimal clinical response (Stage 2) in specified respiratory function, motor skills, 
cardiac parameters, and/or new onset of ptosis. 
Stage 1 
• 
Cohort 1 – at least 5 IOPD patients will receive avalglucosidase alfa at 20 mg/kg qow for 
6 months. 
• 
Cohort 2 – at least 5 IOPD patients will receive avalglucosidase alfa at 40 mg/kg qow for 
6 months. 
Stage 2 
• 
Cohort 3 – at least 10 IOPD patients will be randomized 1:1 to receive avalglucosidase 
alfa at the highest tolerated avalglucosidase alfa dose in Stage 1 (20 mg/kg qow or 
40 mg/kg qow) or alglucosidase alfa treatment at current stable dose (defined by dose of 
alglucosidase alfa administered regularly for a minimum of 6 months immediately prior to 
study entry) for 6 months. The randomization will be stratified on gender. 
The first 5 patients will be enrolled in the 20 mg/kg qow dose cohort. If determined safe by an 
independent DMC after the 3rd patient in the 20 mg/kg qow group (Cohort 1) has received the 3rd 
infusion of avalglucosidase alfa and after 5 patients have started treatment in Cohort 1, the next 
cohort of avalglucosidase alfa at higher dose (40 mg/kg qow) will be initiated (Cohort 2). 
Cohort 3 will be initiated after determination of the highest tolerated avalglucosidase alfa dose in 
Cohort 1 and Cohort 2 after at least 5 patients in Cohort 1 and at least 5 patients in Cohort 2 have 
received the 7th dose of avalglucosidase alfa (or completed Week 13 with a minimum of 
6 infusions). 
After completion of treatment for 6 months (Week 25) and data collection for the principal 
analysis, the patients will continue on long-term avalglucosidase alfa treatment and follow-up in 
the Extension Period for up to a total of 7 years in the study. Cohort 3 patients receiving 
alglucosidase alfa will have the option to switch to treatment with avalglucosidase alfa in the 
extension period or discontinue the study. The data cut-off for the primary analysis will be after 
the last patient in Cohort 3 has completed 6 months of treatment (Week 25). 
Safety, efficacy, PK and 
 will be performed at scheduled visits throughout 
the study treatment period. Ventilator use, AEs and concomitant and pre-infusion 
medications/therapies will be monitored continuously throughout the study. 
If a patient in Cohort 1, receiving 20 mg/kg qow avalglucosidase alfa, experiences further clinical 
decline at or after Week 25 when compared to prior to enrollment in ACT14132, and as defined 
by more rapid worsening of criteria of clinical decline, which is sustained on repeated study 
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assessments, the patient may be managed per the discretion of the Investigator, which may include 
return to treatment with commercially available alglucosidase alfa (and termination of trial 
participation) or increasing the avalglucosidase alfa dose to 40 mg/kg qow (once this dose is 
considered acceptable after the end-of-cohort 2 DMC meeting) or maximum tolerated dose 
(MTD) (once established) while being enrolled in the extension period of the study. 
If a patient in Cohort 2 or 3 experiences further clinical decline at or after Week 25 as defined by 
more rapid worsening of criteria of clinical decline than prior to study start, which is sustained on 
repeated study assessments, the patient may be managed per the discretion of the Investigator. 
This may include return to treatment with commercially available alglucosidase alfa (and 
termination of trial participation). 
Patients must have completed the 25-week treatment period of the study before dose increase of 
avalglucosidase alfa (or start of avalglucosidase alfa for patients receiving alglucosidase alfa in 
Cohort 3) will be considered. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The duration of the study for each patient will be at least 7 years, including: 
• 
An up to 14-day screening period (may be extended to up to 4 weeks in pre-specified 
situations [refer to Section 10.1.1]); 
• 
A 25-week treatment period (primary analysis period [PAP]); 
• 
A 120-week extension period.  
• 
An up to 226-week extended long-term treatment period or until avalglucosidase alfa is 
approved in the patient’s country, whichever comes first; (refer to Appendix C 
[Section 17.3.1] for definition applicable for UK patients)  
• 
An up to 4-week post-treatment observation period will close the patient’s participation. 
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/contact. 
6.3 
INTERIM ANALYSIS 
While all patients will be followed for up to 7 years during the study, the primary analysis for the 
study will be performed when all Cohort 3 patients have completed the 6-month primary analysis 
period (PAP). In addition, safety analyses will be performed in multiple time points by the DMC 
(see Section 6.4.1) to determine the dose for next cohort and the MTD. 
After the primary analysis for the PAP, interim analyses may be performed during the extension 
period to provide additional information for regulatory purpose. 
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6.4 
STUDY COMMITTEES 
6.4.1 Data monitoring committee 
An independent DMC, appointed by the Sponsor, will review data as outlined in the DMC charter, 
which is maintained separately from the study protocol. The DMC procedures will be detailed in 
the DMC charter and will have to be approved by the DMC members. 
During the course of the study, formal safety review will be performed by the DMC: 
• 
After the third avalglucosidase alfa infusion for the third patient in Cohort 1 at a dose level 
of 20 mg/kg qow; 
• 
After at least 5 patients in Cohort 1 and at least 5 patients in Cohort 2 have received their 
seventh avalglucosidase alfa infusion or completed Week 13 with a minimum of 
6 infusions at dose levels of 20 mg/kg qow and 40 mg/kg qow (if considered safe in 
Cohort 1), respectively; 
• 
Bi-annually, including at the time of the end of the PAP (all patients have been treated 
with avalglucosidase alfa or alglucosidase alfa for at least 6 months) and at the end of the 
study. 
In addition, the DMC will review safety data on an ad hoc basis as outlined in the DMC charter. 
IARs and other events which could require consultation of allergist/immunologist will be 
reviewed by an allergist/immunologist, who could be a member of the DMC. Should any major 
safety issues arise, final decisions regarding the study will be made by the Sponsor, taking into 
consideration the DMC opinion (as applicable). 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. The patient who has reached legal age of majority as defined by local regulation or the 
patient’s legal guardian(s) must provide signed informed consent prior to any study-related 
procedures being performed. If the patient is legally minor per local regulations, assent 
shall be obtained from the patient, if applicable. 
I 02. The patient must have a documented GAA deficiency from blood, skin or muscle tissue for 
confirmation of diagnosis of IOPD. 
I 03. The patient is aged <18 years old. 
I 04. The patient has cardiomyopathy at the time of diagnosis: ie, left ventricular mass index 
(LVMI) equivalent to mean age specific LVMI plus 2 standard deviations as published by 
Vogel (19). 
I 05. The patient has been receiving a stable dose of alglucosidase alfa regularly for a minimum 
of 6 months immediately prior to study entry. 
For patients participating in Stage 1: Clinical Decliners Dose Cohort 1 & 2 
I 06. The patient has evidence of clinical decline in at least 1 of the following parameters related 
to Pompe Disease and NOT related to intercurrent illness as assessed by the Investigator. 
To document decline, at least 2 recent and consecutive assessments prior to study entry, 
not less than 2 weeks apart, are required, in addition to at least 1 previous assessment prior 
to onset of decline: 
• 
Respiratory Function 
New development or worsening of respiratory failure requiring the use or increased use of 
ventilatory assistance (invasive or non-invasive). Ventilatory assistance must have been 
required for at least 4 weeks prior to study enrollment,  
OR 
• 
Motor Skills 
For patients ≤2 years of age at study entry, failure to acquire at least 2 new age appropriate 
gross motor milestones at least 6 months prior to study enrollment, eg: 
- 
Turning head side to side (supine) 
- 
Grasping small objects with hands 
- 
Transferring objects from hand to hand 
- 
Holding head upright with body supported 
- 
Rolling (supine to prone or prone to supine) 
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- 
Sitting (supported or unsupported) 
- 
Transition in and out of sitting (lying to sitting, sitting to quadruped) 
- 
Crawling 
- 
Pull to stand 
- 
Walking (with support, ie, cruising, or independently) 
- 
Squatting (stand to squat, squat to stand), 
- 
Walking up stairs (with assistance or independently) 
OR 
For patients >2 years of age at study entry, documented worsening of muscle weakness 
demonstrated by a loss of one of the following: 
- 
Independent ring 
- 
Independent ascending and descending stairs 
- 
Independent walking 
- 
Walking with an assistive device 
- 
Transitions from the floor to standing 
- 
Crawling 
- 
Independent sitting 
- 
Transitioning in and out of sitting 
- 
Holding head up in sitting 
- 
Functional use of upper extremities 
OR 
• 
Cardiac Parameters 
Left ventricular mass (LVM) Z-score ≥ 6 or LVMI ≥ 150 g/m2. 
For patients participating in Stage 2: Sub-optimal Responders Dose Cohort 3 
I 07. The patient has evidence of sub-optimal clinical response in at least 1 of the following 
parameters related to Pompe Disease and NOT related to intercurrent illness as assessed by 
the Investigator. To document sub-optimal response, at least 2 recent and consecutive 
assessments prior to study entry, not less than 2 weeks apart, are required in addition to at 
least 1 previous assessment prior to onset of decline: 
• 
Respiratory Function 
Documented sustained decline in relative % predicted forced vital capacity (FVC) change 
≥15% or new onset of non-invasive ventilator assistance. Ventilatory assistance must have 
been required for at least 4 weeks prior to study enrollment,  
OR 
• 
Motor Skills 
Documented worsening of muscle strength demonstrated by a developmental plateau or 
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decrease on the Gross Motor Function Measure-88 (GMFM-88) and/or in scaled score of 
the Pompe-Pediatric Evaluation of Disability Inventory (Pompe-PEDI), Functional Skills 
Scale: Mobility Domain, or in other motor scale and/or clinical developmental evaluation 
tools, 
OR 
• 
New onset of ptosis 
The occurrence of ptosis (drooping eyelids), confirmed by at least 2 sequential 
assessments. 
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 which are sorted and numbered in the following three subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. The patient has high antibody titer (anti-alglucosidase alfa antibody titer ≥1:25600) at 
2 consecutive time points not less than 1 month apart. 
E 02. The patient is concurrently participating in another clinical study using investigational 
treatment or has taken other investigational drugs within 30 days or 5 elimination half-lives 
of the investigational drugs from screening or randomization, whichever is longer. 
E 03. The patient has previously been treated in any cohort of the ACT14132 study. 
E 04. The patient has clinically significant organic disease (with the exception of symptoms 
relating to Pompe disease), including clinically significant cardiovascular, hepatobiliary, 
pulmonary, neurologic, or renal disease, or other medical condition, serious intercurrent 
illness, or extenuating circumstance, and which may be reflected in corresponding 
abnormal laboratory parameters, that, in the opinion of the Investigator, precludes 
participation in the study or potentially decreases survival. 
E 05. The patient has a high risk for a severe allergic reaction to avalglucosidase alfa (ie, 
previous moderate to severe anaphylactic reaction to alglucosidase alfa and/or patient has 
immunoglobulin E [IgE] antibodies to alglucosidase alfa, and/or a history of high sustained 
immunoglobulin G [IgG] antibody titers to alglucosidase alfa that in the opinion of the 
Investigator suggest a high risk for an allergic reaction to avalglucosidase alfa). 
E 06. The patient, in the opinion of the Investigator, requires any prohibited concomitant 
medications (eg, immune modulatory treatment) for the duration of the study. 
E 07. The patient and/or their parent/legal guardian, in the opinion of the Investigator, is unable 
to adhere to the requirements of the study. 
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7.2.2 Exclusion criteria related to the active comparator and/or mandatory background 
therapies  
None. 
7.2.3 Exclusion criteria related to the current knowledge of Sanofi compound  
E 08. Pregnant or breast-feeding female patient. 
E 09. Female patient of childbearing potential not protected by highly effective contraceptive 
method of birth control and/or who is unwilling or unable to be tested for pregnancy. The 
patient, if female and of childbearing potential, must have a negative serum pregnancy test 
(beta-human chorionic gonadotropin [β-HCG]) at screening/baseline. Pregnancy tests may 
be performed more frequently in some countries due to local legislations related to female 
patient of childbearing potential participating in clinical trials.  
E 10. Male participant with a female partner of childbearing potential not protected by 
highly-effective method(s) of birth control (see Appendix A [Section 17.1]). 
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 (IUD), or intrauterine system for the entire duration of the treatment period and 
for at least 28 days after receiving the last study drug dose. Sterilized or infertile subjects (defined 
as having undergone surgical sterilization, ie, vasectomy/bilateral tubectomy, hysterectomy and 
bilateral ovariectomy or as being postmenopausal, defined as at least 12 months of amenorrhea 
prior to enrollment) will be exempted from the requirements to use contraception in this study 
(see contraceptive guidance in Appendix A [Section 17.1]). 
7.2.4 Additional exclusion criteria during or at the end of screening or run-in phase 
before randomization 
E 11. Patient who has withdrawn consent before enrollment/randomization (starting from signed 
ICF). 
E 12. Despite screening of the patient, enrollment/randomization is stopped at the study level. 
7.2.5 Additional exclusion criteria related to country specific requirements 
E 13. Any country-related specific regulation that would prevent the subject from entering the 
study. 
If a patient does not meet all inclusion criteria or meets one or more exclusion criterion during the 
screening period, the patient may rescreen for the study once. The rescreening must be at least 
14 days after the initial screening failure. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
Avalglucosidase alfa will be supplied as a sterile, nonpyrogenic, lyophilized product in single-use 
vial containing approximately 100 mg of avalglucosidase alfa. Alglucosidase alfa is supplied as a 
sterile, nonpyrogenic, white to off-white, lyophilized cake or powder in a single-use vial 
containing 50 mg of alglucosidase alfa. 
Quantity of vials required for each infusion will be calculated by IRT based on the patient`s 
weight. 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; 
weight obtained at a previous infusion visit may be used for preparation of IMP, if obtained 
within a timeframe of 1 month. Each 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. For 
alglucosidase alfa only, the diluted solution should be filtered through a 0.2 – 0.22 micron, low 
protein-binding, in-line filter during administration to remove any visible particles. Specific 
details pertaining to the infusion volumes and rates as well as dose calculation, preparation, and 
administration of the investigational product 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 alglucosidase 
alfa as outlined in Section 8.9.1, conditions and instructions provided in Section 8.9.2 for patients 
who receive home infusion of avalglucosidase alfa) 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. The Sponsor will inform the DMC of any dose change related to AEs. For 
avalglucosidase alfa, no dose increase above the MTD of 20 mg/kg qow or 40 mg/kg qow (once 
determined) 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 Section 8.9.2 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 or their legally authorized representative (for 
pediatric patients) to ensure that no adverse event occurred during the observational period. 
Patients in the alglucosidase alfa arm in Stage 2 (Cohort 3) have the option to switch to 
avalglucosidase alfa treatment after the 6-month treatment period or discontinue the study. 
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For qow infusions, a time frame of ±7 days is acceptable using Day 1 as reference. For 
alglucosidase alfa weekly (qw) infusions, a time frame of ±3 days is acceptable using Day 1 as 
reference (If one visit date is changed, the next visit should take place according to the original 
schedule). 
The study includes 2 main periods, the 25-week treatment period and the up to 346-week 
extension period.  
8.1.1 Treatment period: Day 1 to Week 25 (Month 6) 
Stage 1 (Cohort 1 and Cohort 2) 
Cohort 1: At least 5 patients will receive avalglucosidase alfa by IV infusion following 
reconstitution and dilution at a dose of 20 mg/kg body weight every other week (qow) starting at 
V2/Day 1 continuing up to V15/W25 for a total of 13 doses (6 months). 
Cohort 2: If determined safe by an independent DMC after the 3rd patient in the 20 mg/kg qow 
group (Cohort 1) has received the 3rd infusion of avalglucosidase alfa, the next cohort of 
avalglucosidase alfa at higher dose (40 mg/kg qow) will be initiated (Cohort 2) after at least 
5 patients have started treatment in Cohort 1. 
At least five patients in Cohort 2 will receive avalglucosidase alfa by IV infusion following 
reconstitution and dilution at a dose of 40 mg/kg body weight every other week (qow) starting at 
V2/Day 1 continuing up to V15/W25 for a total of 13 doses (6 months). 
Stage 2 (Cohort 3) 
Cohort 3: This cohort will be initiated after determination of the highest tolerated avalglucosidase 
alfa dose in Cohort 1 and Cohort 2 after at least 5 patients in Cohort 1 and at least 5 patients in 
Cohort 2 have received the 7th dose of avalglucosidase alfa (or completed Week 13 with a 
minimum of 6 infusions). At least 10 patients will be randomized 1:1 in an open-label manner in 
Cohort 3 to receive avalglucosidase alfa at the highest tolerated dose determined in Stage 1 or 
alglucosidase alfa treatment at current stable dose (defined by dose of alglucosidase alfa 
administered regularly for a minimum of 6 months immediately prior to study entry) for the 
treatment duration of 6 months. 
• 
Patients randomized into avalglucosidase alfa arm will receive avalglucosidase alfa by IV 
infusion following reconstitution and dilution every other week (qow) at the highest 
tolerated dose determined in Stage 1, starting at V2/Day 1 continuing up to V15/W25 for a 
total of 13 doses (6 months). 
• 
Patients randomized into alglucosidase alfa arm will continue to receive alglucosidase alfa 
by IV infusion following reconstitution and dilution at their current stable dose (defined by 
the dose of alglucosidase alfa administered regularly for a minimum of 6 months 
immediately prior to study entry) for the duration of 6 months. 
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After completion of treatment for 6 months (Week 25) and data collection for the principal 
analysis, the patients will continue on long-term avalglucosidase alfa treatment and follow-up for 
up to a total of 7 years in the study.  
Cohort 3 patients receiving alglucosidase alfa during the treatment period (Day 1 to Week 25 
[Month 6]) will have the option to switch to treatment with avalglucosidase alfa in the extension 
period or discontinue the study. 
8.1.2 Extension period: Week 27 to Week 145 (Month 36) and additional extension period 
from Week 147 onwards 
All patients (from Cohorts 1, 2 and 3) will receive avalglucosidase alfa administered by IV 
infusion qow starting at V16/W27 continuing up to V76/W145 for a total of up to 60 doses. In 
order to allow study participants to continue to receive the investigational medicinal product 
(IMP) after Week 145, the study is extended to an additional period of up to 226 weeks or until 
avalglucosidase alfa is approved in the patient’s country, whichever comes first; (refer to 
Appendix C [Section 17.3.1] for definition applicable for UK patients) in which the patients will 
receive avalglucosidase alfa administered by IV infusion qow for up to an additional 72 doses. 
• 
Participants in Cohort 1 will receive avalglucosidase alfa at a dose of 20 mg/kg qow. If a 
patient in Cohort 1, receiving 20 mg/kg qow avalglucosidase alfa, experiences further 
clinical decline at or after Week 25 when compared to prior to enrollment in ACT14132, 
and as defined by more rapid worsening of criteria of clinical decline, which is sustained 
on repeated study assessments, the patient may be managed per the discretion of the 
Investigator, which may include return to treatment with commercially available 
alglucosidase alfa (and termination of trial participation) or increasing the avalglucosidase 
alfa dose to 40 mg/kg qow (once this dose is considered acceptable after the end-of-cohort 
2 DMC meeting) or MTD (once established) while being enrolled in the extension period 
of the study.  
• 
Participants in Cohort 2 will receive avalglucosidase alfa at 40 mg/kg qow or MTD (once 
established).  
• 
Participants in Cohort 3 will receive the MTD of avalglucosidase alfa as determined based 
on safety data from both dose levels in Cohort 1 and Cohort 2. 
If a patient in Cohort 2 or 3 experiences further clinical decline at or after Week 25 as defined by 
more rapid worsening of criteria of clinical decline than prior to study start, which is sustained on 
repeated study assessments, the patient may be managed per the discretion of the Investigator. 
This may include return to treatment with commercially available alglucosidase alfa (and 
termination of trial participation).  
Patients must have completed the 25-week treatment period of the study before dose increase of 
avalglucosidase alfa (or start of avalglucosidase alfa for patients receiving alglucosidase alfa in 
Cohort 3) will be considered. 
In case of temporary or permanent treatment discontinuation, patients will be asked to perform 
visit and assessment schedules as outlined in protocol Section 10.1.7. 
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8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
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 
Upon confirmation by the Investigator or Subinvestigator (if appropriately delegated) that the 
patient meets all eligibility criteria and completion of the screening and baseline assessments, in 
Stage 2 of the study (Cohort 3), at least 10 eligible IOPD patients will be randomized 1:1 to 
receive avalglucosidase alfa at the highest tolerated avalglucosidase alfa dose in Stage 1 or 
alglucosidase alfa treatment at current stable dose for 6 months (defined by dose of alglucosidase 
alfa administered regularly for a minimum of 6 months immediately prior to study entry). The 
randomization will be stratified on gender. 
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. 
8.7 
RESPONSIBILITIES 
The Investigator, the hospital 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. 
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Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) 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 the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
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 pharmacist or for Cohort 3 patients in the alglucosidase alfa arm already 
receiving home infusions, the Investigator or the Subinvestigator. 
IMP accountability: 
• 
Pharmacist or designee will record precisely the date, time of the drug administration and 
number of treatment units used for administration in the corresponding logs. 
• 
The pharmacist or designee records the lot number of the treatment assigned by the central 
treatment allocation system/IRT at each visit in the appropriate log. 
• 
The monitor assigned to the study will perform reconciliation. 
The patient’s compliance with the treatment regimen will be monitored in terms of the patient 
receiving the study drug infusion qow within a ±7-day window (or ±3-day window if the 
participant receives alglucosidase alfa qw in the treatment period as part of Cohort 3) from the 
scheduled infusion date based on V2 (Day 1). Missed, delayed, or incomplete infusions will be 
clearly documented. 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 
Destruction of IMP kits (ie, used, unused or expired) can be performed during the course of the 
study as well as at the end of the study once reconciliation has occurred by the monitor and 
written authorization has been provided by the Sponsor. 
IMP reconciliation must be performed at the site by the pharmacist or designee and monitor using 
Treatment Log forms. A written authorization for destruction of used and unused IMP vials must 
be provided by the Sponsor once the IMP reconciliation is achieved. 
Destruction at the site is strongly encouraged and can be performed provided that the following 
requirements are met: 
• 
Site has appropriate facilities to destroy IMP; 
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• 
Site has procedures to allow traceability of the batches and quantities destroyed, and 
delivers the corresponding destruction documentation/certificate; and; 
• 
Sponsor has provided written authorization to destroy IMP. 
In case the above requirements are not satisfied and the site cannot destroy IMP, the kits will be 
returned to Sponsor for destruction. 
8.8 
CONCOMITANT MEDICATION AND THERAPY 
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s). 
Medications and therapies taken by the patient during the 30-day period prior to the 
screening/baseline evaluation visit and during the course of the study will be recorded in the 
electronic case report forms (e-CRFs). Similarly, pre-infusion medications (if allowed; 
see Section 8.8.1) and assistive devices (eg, walker, cane, crutches) will be recorded in the e-CRF. 
The use (if any) of mechanical ventilation (including both invasive and noninvasive) will be 
recorded on the e-CRF ventilator use log. 
Patients are restricted from participating in other concurrent investigational protocols that are not 
restricted to data and/or sample collection for patient demographic and/or disease purposes. 
8.8.1 Pretreatment for patients with infusion-associated reactions 
In clinical trials with alglucosidase alfa and avalglucosidase alfa, some patients were pretreated 
with antihistamines, antipyretics, and/or corticosteroids. Infusion-associated reactions occurred in 
some patients even 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.  
Refer to Section 10.6 for IAR management recommendations including pretreatments. 
8.8.2 Prohibited concomitant medications 
Use of immunomodulation treatments (eg, methotrexate, rituximab, immunoglobulins, and other 
immunosuppressants), either alone or in combination, that would interfere with the evaluation of 
the immunogenic potential of avalglucosidase alfa is not allowed during participation in the study. 
In the case of administration of a prohibited treatment, the Sponsor must be notified, the treatment 
with IMP will be discontinued, and the patient will be asked to continue study assessments to the 
extent possible prior to study withdrawal. 
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8.9 
HOME INFUSION 
8.9.1 Home infusion for patients receiving alglucosidase alfa 
Patients who meet the specific criteria below may have the option for home infusion of 
alglucosidase alfa in countries where home infusion is available according to applicable regional 
regulations. 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 following criteria must be documented in the 
patient’s medical record: 
• 
For patients who are not receiving home infusions of alglucosidase alfa at study start: the 
patient must be clinically stable with no history of moderate or severe IARs or serious 
adverse events (SAEs) prior to study participation and have received at least 4 infusions 
during study participation with infusions monitored in a hospital or an infusion center 
prior to planned transition to home infusions. 
• 
For patients who are receiving home infusions of alglucosidase alfa prior to study entry: 
the patient must be clinically stable with no history of moderate or severe IARs or SAEs 
prior to study participation and have received at least 2 infusions during study 
participation with infusions monitored in a hospital or infusion center prior to resuming 
home infusions. 
• 
The patient must have no ongoing SAEs that, in the opinion of the Investigator, may 
impact the patient’s ability to tolerate infusion. 
• 
For patients receiving home infusions: the Home Infusion Agency staff must be trained by 
the Investigator prior to beginning home infusions. Any new staff member must be trained 
by the Investigator prior to resuming home infusions. The Investigator must confirm that 
the Home Infusion Agency staff has received training at least equivalent to that provided 
to new staff members. 
• 
The Home Infusion Agency staff must be trained in basic life support (cardiopulmonary 
resuscitation) and should have a process for requesting additional emergency services if 
needed. 
• 
If recurrent IARs or hypersensitivity/anaphylactic reactions occur, the Investigator should 
assess whether or not it is safe for the patient to continue to be treated via home infusion. 
The Sponsor should be notified about all IARs and consulted (as needed) if the patient 
experiences IARs suggestive of hypersensitivity reactions (refer to Section 10.6). 
• 
The Home Infusion Agency must keep source documentation of the infusion, including 
documentation of any AEs. The Home Infusion Agency must be amenable to providing 
specific source documentation to the Sponsor and agree to be monitored. The Investigator 
is still responsible for all study procedures and patient’s safety even when delegating 
infusion responsibilities to the home care company. 
The Investigator is responsible for approving a patient’s initiation with home infusions and is 
ultimately responsible for the safety of the patient during this clinical study. Refer to the home 
infusion guidance manual and pharmacy manual for further details regarding home infusions.  
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8.9.2 Home infusion for patients receiving avalglucosidase alfa 
Home infusion may be possible in the extension period, 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 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 and their legal guardian(s) must be willing and able to comply with home 
infusion procedures. 
• 
The patient or their legal guardian(s) has been informed and agreed on home infusion 
process by a dedicated home infusion staff. 
• 
The patient must, in the Investigator’s (or designee’s) opinion, have been clinically stable 
while receiving avalglucosidase alfa 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, such as 2020 
Coronavirus disease 2019 (COVID-19) outbreak, 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 started sooner. 
• 
If this reduced required period from at least 12 to at least 6 months is considered safe and 
after confirmation with the DMC as they did for COVID-19 outbreak, it will be considered 
as a permanent criterion after the unexpected event is resolved. 
• 
No infusion rate increases higher than the highest rate infused at the clinical site or dose 
increase will be allowed while a patient is receiving home infusions. In case of dose 
increase while being infused at home will return to the study site for their following 
infusion and will continue to receive infusions at the site for at least 6 months. If no IARs 
have occurred during this 6-month period, home infusion may be resumed. 
• 
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 regulations (see Appendix C [Section 17.3.3] 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. 
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• 
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 10.6). 
• 
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) and should have a process for requesting additional emergency services if 
needed. 
• 
The Home Infusion Agency must keep source documentation of the infusion, including 
documentation of any AEs and patient’s body weight measured as per study flow chart. 
The Home Infusion Agency must be amenable to providing specific source documentation 
to the Sponsor, in agreed upon timeframe, and agree to be monitored. The Investigator 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. 
• 
The periods of ventilator use/day (daytime, nighttime, both) will be reported to the 
Investigator by the Home infusion Agency based on the ventilator use diary. The 
Investigator will then report them in the case report form (CRF).  
• 
It is the Investigator’s responsibility to guide staff on the clinical management of the 
patient in case of IARs or hypersensitivity or anaphylactic reactions. The Investigator 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 e-CRF for 
AEs and exposure. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY ENDPOINT 
9.1.1 Safety endpoints 
9.1.1.1 Adverse events 
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 and therapies. 
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. 
Definitions of AEs, SAEs, and adverse events of special interest (AESIs), including reporting 
procedures, can be found in Section 10.4 to Section 10.7. 
Refer to the appropriate study documentation for guidelines on the evaluation of AEs, including 
relationship to study treatment, severity grading, outcome, and action taken regarding the IMP. 
9.1.1.2 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: aspartate aminotransferase (AST), alanine aminotransferase (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 (CK), CK with MB fraction, lactate 
dehydrogenase, 
- 
Brain natriuretic peptide (BNP). 
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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). 
9.1.1.3 Vital signs 
Vital signs include heart rate, systolic and diastolic blood pressure, respiratory rate, temperature, 
and oxygen saturation. Vital signs are to be assessed prior to infusion, with each infusion rate 
change (including the start of infusion that is considered as first infusion rate change), at the end 
of the infusion, and at the end of the post-infusion observation period. Collection windows are 
±15 minutes. 
9.1.1.4 Electrocardiogram variables 
Standard 12-lead ECGs are recorded at the time points specified in Section 1.2 after at least 
15 minutes in the supine position using an electrocardiographic device. The following will be 
assessed: heart rate, rhythm, interval from start of the Q wave to the end of the S wave (QRS), 
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 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, left ventricular hypertrophy criteria, right ventricular 
hypertrophy criteria, repolarization charges, and overall cardiac impression for each patient. For 
Day 1 only, and prior to receiving IMP, 3 ECGs within 5 minutes will be performed with at least 
1 minute between 2 replicates. 
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, and Subject 
ID, 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 collected. 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 with a date, 
time, and Subject ID. The digital recording, data storage, and transmission (whenever 
requested) need to comply with all applicable regulatory requirements (such as US Food 
and Drug Administration [FDA] Code of Federal Regulations [CFR], Title 21, Part 11). 
The Investigator who reads the ECG or appropriate designee (non-investigator physician who 
reads the ECG) 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 
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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 Investigator who reads the ECG or appropriate designee, 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 for 
analysis purposes and not for clinical management of the patient. 
9.1.1.5 Physical examination 
Physical examination (PE) 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. Physical examination CRF will ask 
physician to record current muscle pain and cramps specifically at each PE assessment. Tanner 
stage of sexual maturation will be assessed as part of the PE assessment at baseline and yearly 
thereafter. Details can be found in the study manual. 
9.1.1.6 Body weight, height/length, and head circumference 
Body weight will be measured in kilograms and collected monthly throughout the duration of the 
study. More frequent weight may be obtained at the discretion of the Investigator. 
Standing height or body length will be measured at baseline and every 3 months up to Week 73 
and then every 6 months and at the end of study (EOS). If possible, height will be measured in the 
morning of the study visit day, prior to the PFT, and by using the same stadiometer for all 
measurements. Standing height is preferred, but if not possible due to patient’s age or physical 
condition, body length is to be measured in the same position throughout the study. Head 
circumference will be measured at the same time points. 
9.1.1.7 Immunogenicity 
Immunogenicity assessments will include the following: 
• 
During the treatment period, pre-infusion samples from patients receiving avalglucosidase 
alfa will be collected at baseline and then every month for evaluation of 
anti-avalglucosidase alfa anti-drug antibody (ADA) and at baseline and every 3 months 
(V9 [Week 13], and V15 [Week 25]) for evaluation of anti-alglucosidase alfa ADA. In 
addition, samples will be collected at V3 (Day 8) to monitor for an early antibody response 
(for both anti-avalglucosidase alfa ADA and anti-alglucosidase alfa ADA). Pre-infusion 
samples from patients receiving alglucosidase alfa will be collected at baseline, V3 (Day 
8), V9 (Week 13), and V15 (Week 25) for evaluation of anti-alglucosidase alfa ADA and 
at baseline and V15 (Week 25) for evaluation of anti-avalglucosidase alfa ADA. 
• 
During the extension period, pre-infusion samples from patients receiving avalglucosidase 
alfa since the start of the study will be collected every 3 months for evaluation of 
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anti-avalglucosidase alfa ADA. Samples from patients in Cohort 3 switching to 
avalglucosidase alfa will be collected at V17 (Week 28), V18 (Week 29), and V20 
(Week 33) to monitor for an early antibody response (for avalglucosidase alfa), followed 
by collection every month for 6 months and then every 3 months for evaluation of anti-
avalglucosidase alfa ADA. 
• 
ADA seropositive patient serum will be assessed for neutralizing antibodies to 
avalglucosidase alfa and/or alglucosidase alfa, as appropriate, including inhibition of 
enzyme activity and uptake. 
Samples may be collected from patients and evaluated for IgE, complement activation, serum 
tryptase following moderate, severe, or recurrent mild IARs suggestive of hypersensitivity 
reactions (Section 10.6). 
In the event a patient exhibits signs or symptoms suggestive of systemic immune-mediated 
reactions involving skin and other organs, 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 manual for guidelines on the 
collection and shipment of the samples. 
9.2 
SECONDARY ENDPOINTS 
9.2.1 Pharmacokinetics 
9.2.1.1 Sampling time 
Blood samples for full evaluation of avalglucosidase alfa PK will be collected before and after 
infusions on V2 (Day 1) and V15 (Week 25) for participants who are treated with avalglucosidase 
alfa starting at Day 1. For participants in Stage 2 – Cohort 3 who are randomized to receive 
treatment with alglucosidase alfa at current stable dose during the Treatment Period and who 
switch to avalglucosidase alfa in the Extension Period, full PK profiles will be sampled on V16 
(Week 27) and V28 (Week 49). Sampling times are as follows: predose (prior to infusion); at the 
end of the infusion; and at 2, 4, 6, and 8 hours after the end of infusion. PK samples will also be 
taken prior to infusion and at 2 hours after the end of infusion at V9 (Week 13), or at V22 
(Week 37) for the avalglucosidase alfa switch patients. For patients in the 40 mg/kg dose cohorts, 
additional blood samples will be collected at 12 to 16 hours after infusions on V2 (Day 1) and 
V15 (Week 25), or on V16 (Week 27) and V28 (Week 49) for the avalglucosidase alfa switch 
patients (see Table 1). 
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Table 1 – PK sampling time 
Visit 
Cohort 1 patients 
Cohort 2 patients 
Cohort 3 patients 
randomized to 
avalglucosidase 
alfa 
Cohort 3 patients 
randomized to 
alglucosidase 
alfa and 
switching to 
avalglucosidase 
alfa in the 
extension period 
V2 (D1) 
Predose; end of 
infusion; 2, 4, 6 and 8 h 
after end of infusion 
Predose; end of 
infusion; 2, 4, 6, 8 and 
12-16 h after end of 
infusion 
Predose; end of 
infusion; 2, 4, 6, 8 and 
12-16 h after end of 
infusiona 
 
V9 (W13) 
Predose and 2 h after 
end of infusion 
Predose and 2 h after 
end of infusion 
Predose and 2 h after 
end of infusion 
 
V15 (W25) 
Predose; end of 
infusion; 2, 4, 6 and 8 h 
after end of infusion 
Predose; end of 
infusion; 2, 4, 6, 8 and 
12-16 h after end of 
infusion 
Predose; end of 
infusion; 2, 4, 6, 8 and 
12-16 h after end of 
infusiona 
 
V16 (W27) 
 
 
 
Predose; end of 
infusion; 2, 4, 6, 8 and 
12-16 h after end of 
infusiona 
V22 (W37) 
 
 
 
Predose and 2 h after 
end of infusion 
V28 (W49) 
 
 
 
Predose; end of 
infusion; 2, 4, 6, 8 and 
12-16 h after end of 
infusiona 
a If the cohort 3 dose of avalglucosidase alfa is 20 mg/kg qow, the 12-16 hours after the end of infusion sample will not be taken. 
Pharmacokinetic blood samples are to be collected within 15 minutes of scheduled time: predose 
and all samples immediately following the end of the infusion through 8 hours post infusion (12 to 
16 hours after infusions in the 40 mg/kg dose cohort). 
9.2.1.2 Pharmacokinetics handling procedure 
Special procedures for collection, storage, and shipment are provided in the study-specific 
laboratory manual. 
9.2.1.3 Bioanalytical method 
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. 
The lower limit of quantitation (LLOQ) is 12.0 ng/mL or 0.0120 μg/mL. 
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9.2.1.4 Pharmacokinetics parameters 
The following PK parameters will be determined for avalglucosidase alfa based on 
non-compartmental analysis. The parameters will include maximum plasma concentration 
observed (Cmax), time to achieve maximum plasma concentration (tmax), area under the curve from 
time 0 to time of the last quantifiable concentration (AUC0-last), and terminal half-life (t1/2z). If data 
permit, other parameters including total body clearance of a drug from plasma (CL) and volume 
of distribution (Vd) will be included. The definitions of the PK parameters are presented in Table 
2. 
Table 2 - List of pharmacokinetic parameters and definitions 
Parameters 
Drug/Analyte 
Matrix 
Definition/Calculation 
Cmax 
avalglucosidase alfa 
Plasma 
Maximum plasma concentration observed 
tmax 
avalglucosidase alfa 
Plasma 
Time to achieve maximum plasma concentration 
AUC0-last 
avalglucosidase alfa 
Plasma 
Area under the plasma concentration versus time curve from time 0 to 
time of the last quantifiable concentration 
t1/2z 
avalglucosidase alfa 
Plasma 
terminal half-life 
CL 
avalglucosidase alfa 
Plasma 
Total body clearance of a drug from the plasma 
Vd 
avalglucosidase alfa 
Plasma 
Volume of distribution 
 
9.2.2 Secondary efficacy endpoints 
9.2.2.1 Gross Motor Function Measure-88 (GMFM-88), Gross Motor Function 
Classification System - Expanded and Revised (GMFCS-E&R) 
The GMFM-88 (20) will be administered at the time points specified in Section 1.2 to evaluate 
changes in motor function. During the treatment period, the assessment will be completed before 
IMP infusion. The GMFM-88 was developed specifically to detect quantitative changes in gross 
motor function. There is no age cut-off for the GMFM-88. The GMFM-88 consists of 88 items 
organized into 5 dimensions: 
• 
Lying and rolling (17 items) 
• 
Sitting (20 items) 
• 
Crawling and kneeling (14 items) 
• 
Standing (13 items) 
• 
Walking, running and jumping (24 items). 
Items were selected to represent motor functions typically performed by children without motor 
impairments by 5 years of age. Each item is scored on a 4-point Likert scale (ie, 0 = cannot do; 
1 = initiates [<10% of the task]; 2 = partially completes [10% to <100% of the task]; 3 = task 
completion). The score for each dimension is expressed as a percentage of the maximum score for 
that dimension. Total score is obtained by adding the percentage scores for each dimension and 
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dividing the sum by the total number of dimensions. Therefore, each dimension contributes 
equally to the total score. 
While not originally validated for children with diagnoses other than cerebral palsy, the 
GMFM-88 has been used for other children with motor difficulties including children with 
osteogenesis imperfecta (21) and acute lymphoblastic leukemia (22). The GMFM-88 has been 
used to evaluate children and adults with Pompe disease (23) and was appropriate for use in this 
study because it measured change in motor performance over time secondary to an improvement 
or decline in muscle strength. 
This assessment will include the expanded and revised Gross Motor Function Classification 
System for the GMFM-88 (GMFCS-E&R) (24). The GMFCS-E&R emphasizes concepts in the 
World Health Organization’s International Classification of Functioning, Disability and Health. 
Emphasis is on usual performance in home, work and community settings without judgments 
about quality of movement or prognosis for improvement. The GMFCS-E&R is a 5 level 
classification system for specific age ranges consisting of Levels I to V based on self-initiated 
movement, with emphasis on sitting, transfers, and mobility. The distinctions between levels are 
based on functional limitations, the need for assistive mobility devices, and to a much lesser 
extent, quality of movement, and are designed to be meaningful in daily life (24). 
The general headings for the 5 levels are: 
• 
Level I  
Walks without limitations 
• 
Level II  
Walks with limitations 
• 
Level III 
Walks using a hand-held mobility device 
• 
Level IV 
Self-mobility with limitations; may use powered mobility 
• 
Level V 
Transported in a manual wheelchair 
See the study-specific functional outcome manual for further details. 
9.2.2.2 Quick Motor Function Test 
The Quick Motor Function Test (QMFT) will be administered at the time points specified in 
Section 1.2 to evaluate changes in motor function concurrently with the GMFM-88. During the 
treatment period, the assessment will be completed before IMP infusion. 
The QMFT is an observer administered test comprising 16 items specifically difficult for patients 
with Pompe disease (25). The items are scored separately on a 5-point ordinal scale (ranging from 
0 to 4) with a total score of all items ranging between 0 and 64 points. The test was validated in 
91 Pompe patients, aged 5 to 76 years, with different levels of disease severity. Test 
administration takes approximately 10-15 minutes. Refer to the study-specific functional outcome 
manual for instructions on test administration. 
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9.2.2.3 Pompe Pediatric Evaluation of Disability Inventory (Pompe-PEDI) 
A disease-specific version of the PEDI was developed to assess functional capabilities and 
performance in children with Pompe disease from 2 months through adolescence (26, 27, 28, 29). 
The Pompe-PEDI is comprised of a Functional Skills Scale and Caregiver Assistance Scale; both 
scales have three domains: Self Care, Mobility, and Social Function. The Pompe-PEDI includes 
all items from the original PEDI, as well as additional items in the Functional Skills Mobility and 
Self-Care domains to reflect clinically relevant functional skills for children with Pompe disease. 
Norm-based scoring was developed for these new items and scoring algorithms for the PEDI have 
been adjusted to reflect the additional normative data collected for the Pompe-PEDI. 
A trained assessor will administer the Pompe-PEDI, Functional Skills Scale: Mobility Domain to 
the patient or patient’s legal guardian. This domain was selected to measure change in mobility 
secondary to changes in muscle strength; the domain consists of 160 mobility items that a patient 
or legal guardian reports if the patient is capable or unable of performing. Test administration 
requires approximately 15 minutes. The Pompe-PEDI will be centrally scored. Results are 
reported as raw score, normative standard score (with standard error) and scaled score (with 
standard error). 
See the study-specific functional outcome manual for further details. 
9.2.2.4 Echocardiography 
Two-dimensional and M-mode echocardiography (ECHO) will be performed at the time points 
specified in Section 1.2 and a specified medium (eg, videotape or digital) will be sent to the core 
central cardiology laboratory for interpretation. A central cardiologist will review all ECHOs. 
This person will be blinded to the patient and study time point. The primary cardiac outcome 
assessments (measured and derived) to be recorded using off-line review include: left ventricle 
long axis, cross sectional area, end diastolic volume, end systolic volume, internal diameter, 
Septal wall diameter, Posterior wall diameter, Ejection Fraction, Left Ventricle sphericity, Left 
Ventricle thickness: dimension ratio, and LVM:volume ratio. M-mode parameters include: Left 
Ventricle Internal Dimension, Posterior Wall, Left Ventricle Internal Dimension, and Shortening 
Fraction. Systolic, Diastolic, and mean blood pressure will be determined. The following 
Tricuspid Valve/Mitral Valve parameters will also be assessed: Right Ventricular Pressure (by TR 
jet), TR gradient, Mitral Valve peak E, Mitral Valve peak A, E:A Ratio, and Mitral Valve 
deceleration time. 
The ECHOs will be performed according to the developed protocol as outlined in the core 
cardiology laboratory manual. The study site cardiologist will review the ECHO in a timely 
manner for clinical management of the patient as central laboratory results will not be given to 
sites. 
Any abnormal findings that meet the definition of an AE per Section 10.4.1.1 (eg, that result in an 
alteration in medical care, diagnostic or therapeutic) will be collected. All AEs will be recorded 
and followed as described in Section 10.4.2. 
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9.2.2.5 Eyelid position measurements 
Ptosis (drooping eyelids) has been shown to occur in Pompe disease amongst other 
ophthalmologic findings (30, 31). 
Separate informed consent will be sought to permit for the acquisition and use of photographs of 
the patient’s eyes in order to allow for independent review of eyelid position measurements by 
central reader. 
Study participants will have images taken of their eyes while wearing a pair of empty eyeglass 
frames with rulers attached as a standardized measurement tool at the time points specified in 
Section 1.2. The following eyelid position measurements will be performed by the central reader: 
• 
Interpalpebral fissure distance (IPFD) 
• 
Margin reflex distance-1 (MRD-1) 
• 
Margin pupil distance (MPD) 
Refer to the study manual for specific details on eyelid position measurements. 
9.3 
OTHER ENDPOINTS 
9.3.1 Pharmacogenetic assessment 
Pharmacogenetic samples will be collected at the time points specified in Section 1.2. Refer to the 
study-specific laboratory manual for guidelines on the collection and shipment of whole blood 
samples. Except for the genotyping of human GAA performed after 01-Jul-2018, the genetic 
results obtained from this study are not diagnostic and will be used for research purposes only. 
9.3.1.1 GAA activity testing 
If performed previously and historical results are available, then the GAA activity does not need 
to be repeated, but results and method will be collected. If results are not available, blood spot 
collection will be conducted at screening for standardized GAA activity testing. 
Collection techniques, processing instructions, and shipping instructions are included in the study 
manual. 
9.3.1.2 Cross-reactive Immunologic Material 
Cross-reactive immunologic material (CRIM) analysis (32) will be conducted at screening by 
obtaining blood sample only if previous written results are not available; if patients have prior 
results, the testing does not need to be repeated. Results will be collected. 
Results of CRIM status determined by the central laboratory from blood samples obtained for this 
study will not be provided to the site but will be uploaded to the Sanofi central repository through 
external data transfer. 
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Information for the collection and handling of these samples can be found in the study manual. 
9.3.1.3 Genotyping of human acid α-glucosidase gene 
If historical results are not available, a blood sample will be collected as specified in Section 1.2 
and sent to a centralized laboratory where it will be extracted to yield DNA. The DNA will be 
sent to another central laboratory where it will be amplified by polymerase chain reaction (PCR) 
using gene specific primers and the resulting PCR products will be sequenced for the 
identification of IOPD disease-associated variants within the GAA gene. 
 
 
 
 
 
 
 
 
 
 
9.3.1.6 Optional stored DNA sample 
For those patients who signed the optional pharmacogenetic ICF, a blood sample will be collected 
at the study visit as specified in Section 1.2 and this sample will be stored. 
This sample may be used to determine a possible relationship between genes and response to 
treatment with avalglucosidase alfa or alglucosidase alfa and possible side effects to the same. 
This blood sample will be transferred to a site that will, on behalf of Sanofi, extract DNA from the 
sample and that is managed by a contractor which can be located outside of your country, within 
or outside of the European Union. 
This blood sample, and the DNA that is extracted from it, will be assigned a second number, a 
Genetic ID (deidentification code) that is different from the Subject ID. This “double coding” is 
performed to separate a subject’s medical information and DNA data. 
The clinical study data (coded by Subject ID) will be stored in the clinical data management 
system (CDMS), which is a distinct database in a separate environment from the database 
containing the pharmacogenetic data (coded by Genetic ID). The key linking Subject ID and 
Genetic ID will be maintained by a third party, under appropriate access control. The matching of 
clinical data and pharmacogenetic data, for the purpose of data analysis, will be possible only by 
using this key, which will be under strict access control. All data will be reported only in coded 
form in order to maintain confidentiality. 
The DNA will be stored in the USA for up to 15 years from the completion of the clinical study 
report, after which the samples will be destroyed. 
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Special procedures for storage and shipping of pharmacogenetic samples are described in detail in 
the study-specific laboratory manual. 
9.3.2 Pharmacodynamic variables 
9.3.2.1 Urine Hex4 levels 
Fasting urine samples for the assessment of urinary Hex4 concentrations will be collected prior to 
IMP infusion as specified in Section 1.2. Procedures for the collection, handling and shipment of 
all urine samples will be included in the study-specific laboratory manual. 
 
 
 
 
 
 
9.3.2.3 Optional muscle biopsy 
Optional muscle biopsy (for patients having signed [or for whom legal guardian(s) has(have) 
signed] the specific informed consent) when applicable may be performed at the suggested time 
points described in Section 1.2. If a baseline biopsy is obtained at baseline/screening or Week 25 
(for Stage 2 – Cohort 3 patients switching to avalglucosidase alfa in the extension period), every 
effort should be made to obtain a follow-up biopsy as well. 
Needle or open biopsy of the lower extremity (quadriceps) muscle will be performed. Glycogen 
content will be measured by histomorphometric analysis or severity grading to determine how 
effectively IMP 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 manual. 
9.3.3 Tertiary endpoints 
9.3.3.1 Pulmonary function testing (PFT) 
Pulmonary function testing will be performed at the time points specified in Section 1.2. The PFT 
administration protocol is standardized across sites in accordance with the American Thoracic 
Society (ATS) guidelines (33). The PFT will include the assessment of FVC, forced expiratory 
volume in the first second of the FVC maneuver, maximal inspiratory pressure (MIP), maximal 
expiratory pressure (MEP), and peak expiratory flow in the upright and supine positions. 
Pulmonary function tests are not required for young patients unable to reliably undergo testing or 
for patients who are invasively ventilated, but missing assessments must be documented for 
analysis and potential impact on the study results. 
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9.3.3.2 Six-minute walk test 
The 6MWT (34) will be performed at the time points specified in Section 1.2 to assess functional 
capacity for patients that are ambulatory, defined as the ability to ambulate 40m (approximately 
130 feet) without stopping and without an assistive device. The 6MWT was originally developed 
as a global assessment of cardiac, respiratory, circulatory, and muscular capacity for adults (34). 
The 6MWT utilization has been expanded to neuromuscular disease research with adults and 
children, including studies of laronidase in mucopolysaccharidosis type-I (MPS-I) (35), 
idursulfase in mucopolysaccharidosis type II (36), and has proved safe, reliable and feasible in 
Duchenne muscular dystrophy (37). For administration to children, the guidelines proposed by the 
ATS have been modified to include accommodation to children’s instructional needs, strategies 
for ensuring motivation, and techniques for promoting safety (37). Testing equipment and 
administration techniques will be standardized among investigational sites.  
For the purpose of stabilization and if deemed necessary by the Investigator, the participant may 
use a walking device, such as cane or walker, during the assessment. If such a device is used 
during the assessment or there is a change in device use during the trial, this must be recorded in 
the e-CRF. 
During the treatment period, the assessment will be completed before IMP infusion. The distance 
(in meters) will be recorded and the corresponding percent predicted value will be calculated (38). 
In addition, data will be collected for pre- versus post-test changes in heart rate.  
See the study-specific functional outcome manual for further details. 
9.3.3.3 Ventilator use diary 
The Investigator will provide a respiratory diary to the patient (and/or the patient’s parent[s]/legal 
guardian[s]) to record the daily use (if any) of mechanical ventilation (including both invasive and 
non-invasive) at daytime and nighttime. The date the patient first became dependent on invasive 
ventilator, as well as the reasons for first ventilator use will be collected and results will be 
recorded in the e-CRF. If the patient requires mechanical invasive or non-invasive ventilator 
support during the study, the start date, stop date, and reasons for each episode of continuous 
mechanical ventilator support will be collected. Invasive ventilation is defined as mechanical 
ventilatory support applied with the use of an endotracheal tube or tracheostomy, and non-
invasive ventilation is defined as ventilatory support applied without the use of an endotracheal 
tube, ie, no invasion of the airway (39). On a biweekly basis, the periods of ventilator use/day 
(daytime, nighttime, both) will be reported by the Investigator based on the ventilator use diary 
and data recorded until (1) ventilator support is no longer needed; (2) patient death; or (3) end of 
study (whichever occurs first) . The date and reason that ventilator use is no longer needed will be 
recorded. The daily ventilator use diary is only required to be completed for patients using 
ventilator support. 
If the patient requires any invasive or non-invasive mechanical ventilation (excluding planned 
ventilatory support less than 3 days duration for a planned surgical procedure), the Investigator 
will describe the events leading up to the mechanical ventilation using the ventilator use form/log 
in the e-CRF. Refer to Section 10.4.1.2, Section 10.4.2 and Section 10.4.3 for details regarding 
recording and reporting events of new invasive ventilatory support (excluding planned ventilatory 
support less than 3 days duration for a planned surgical procedure). 
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9.3.3.4 PedsQL Generic Core Scale questionnaire 
The PedsQL Generic Core Scales is a general HRQOL tool and will be completed at the time 
points specified in Section 1.2. If patients are unable to complete this assessment, a parent-proxy 
form will be used. During the treatment period, the assessment will be completed before IMP 
infusion if possible, and the patients will continue on the age-specific assessment they first 
completed at screening/baseline, even if they exceed the age range for that specific tool over the 
trial duration. The 23-item PedsQL Generic Core Scale encompasses 4 subscales including a 
patient’s health and activities, feelings, problems with school, and how the patient gets along with 
others (40). Items are evaluated on a 5 point Likert scale with 0 = never, 1 = almost never, 
2 = sometimes, 3 = often, and 4 = almost always, and the data from the questionnaire will be 
collected. 
The 4 Multidimensional Scales and 3 Summary Scores are: 
• 
Scales 
- 
Physical Functioning (8 items) 
- 
Emotional Functioning (5 items) 
- 
Social Functioning (5 items) 
- 
School Functioning (5 items) 
• 
Summary Score 
- 
Total Scale Score (23 items) 
- 
Physical Health Summary Score (8 items) 
- 
Psychosocial Health Summary Score (15 items) 
Items are reverse scored and linearly transformed to a 0 –100 scale, so that higher scores indicate 
better HRQOL. To reverse score, transform the scale items to 0 – 100 as follows: 0 = 100, 1 = 75, 
2 = 50, 3 = 25, and 4 = 0. To create scale scores, the mean is computed by totaling the item scores 
and dividing by the number of items answered. This direct linear transformation does not affect 
the measurement properties of the scales, and is computed for ease of interpretation so that scores 
near 0 indicate poorer HRQOL and scores near 100 indicate better HRQOL. Scale scores are 
computed as the sum of the items divided by the number of items answered (this accounts for 
missing data). If more than 50% of the items in the scale are missing, the Scale score is not 
computed.  
When examining the total scale, scores of 4.4 and 4.5 are considered to be minimal clinically 
meaningful differences on the child self-report and parent-proxy report, respectively (41). 
Parents, children (ages 8 – 12 years), and adolescents (ages 13–18 years) may self-administer the 
PedsQL Generic Core Scale after instructions from the administrator. For younger children (ages 
5–7 years) or if the child or adolescent is unable to self-administer the PedsQL Generic Core 
Scale (eg, due to illness, fatigue, reading difficulties), the measure should be read aloud. 
The PedsQL Infant Scales version consists of the following 5 domains: (1) physical functioning, 
(2) physical symptoms, (3) emotional functioning, (4) social functioning, and (5) cognitive 
functioning. It includes formats for typically developing children 1 to 24 months old 
(parent-proxy report). The format, instructions, response scale, and scoring methods of the Infant 
Scales are identical to those of the Generic Core Scales. 
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9.3.3.5 Assessment of Pain (PedsQL Pediatric Pain Questionnaire and Observer reported 
pain visual analogue scale [VAS]) 
Pain will be assessed in patients at the time points specified in Section 1.2 using the following 
scales and questionnaire: 
9.3.3.5.1 PedsQL Pediatric Pain Questionnaire 
The 3-item PedsQL Pediatric Pain Questionnaire (42) comprises:  
• 
Present Pain 
• 
Worst Pain 
• 
The third item refers to the localization of pain and is not scored 
10 cm visual analog scales (VASs) from 0 (Not hurting / No discomfort / No pain) to 10 (Hurting 
a whole lot / Very uncomfortable / Severe pain) 
The format, instructions, Likert response scale, and scoring method are identical to the PedsQL 
4.0 Generic Core Scales, with higher scores indicating higher pain intensity. Present pain and 
worst pain are scored separately. The score is based on line length to the nearest 0.5 cm. There is 
no imputation process since these are single item VAS scales. The instructions for the standard 
version ask how much of a problem each item has been during the past one month. In this study, 
the PedsQL Pediatric pain Questionnaire will be applied to participants >5 years of age. 
9.3.3.5.2 Observer reported pain visual analogue scale (VAS) 
The Observational Visual Analogue Score (VAS-OBS, range 0-10) is a tool developed to measure 
subjective phenomena like pain. It consists of a 10-cm line in this study, either vertical or 
horizontal, anchored at the ends by labels such as “no pain” and “worst possible pain.” Observers 
estimate the level of perceived pain by putting a mark on the line. An observer uses the VAS to 
rate the intensity of the pain experienced by children (43). In this study, the VAS-OBS will be 
applied to all participants. 
9.3.3.6 Bayley Scale of Infant and Toddler Development, Third Edition (Bayley-III) 
The Bayley-III is an individually administered instrument that assesses the developmental 
functioning of infants and young children between 1 month and 42 months of age (44). For this 
study, the Cognitive Scale and Motor Scale will be utilized. The Cognitive Scale assesses how a 
child thinks, responds and learns about the world. The Motor Scale is comprised of two subtests: 
the Fine Motor subtest and the Gross Motor subtest. The Fine Motor subtest assesses how well a 
child can use his or her hands and fingers to perform activities. The Gross Motor subscale 
assesses how well a child can move his or her body. Normative data are available for the 
Bayley-III from 1 month to 42 months of age and were derived from a sample of US infants and 
children in 2004. Data were also collected from 668 children with specific clinical diagnoses, 
including Down syndrome, prematurity, cerebral palsy, language impairment, pervasive 
developmental disorder and fetal alcohol exposure. Raw scores and scaled scores will be reported 
for the Cognitive, Fine Motor, and Gross Motor subtests. Composite scores with percentile rank 
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and confidence intervals will be reported for the Cognitive Scale and the Motor Scale (a 
composite of the Fine Motor and Gross Motor subtests). 
The Bayley-III will be administered to patients from 1 month of age up to 42 months of age or 
until the maximum score on each of the 3 administered scales has been obtained according to the 
time points specified in Section 1.2. Once the maximum score for a scale has been achieved, only 
the remaining scales will be administered. Test administration takes approximately 90 minutes. 
Test results will be centrally scored by a trained assessor. 
See the study-specific functional outcome manual for further details. 
9.3.3.7 Leiter International Performance Scale, Third Edition (Leiter-3) 
The Leiter-3 (45) will be administered by a trained assessor to assess intellectual ability. The 
Leiter Scale was designed as a nonverbal measure of intellectual function, memory and attention 
for individuals who could not be validly assessed with standard intelligence tests. Special 
populations for whom the Leiter Scale was intended include those with communication disorders, 
hearing impairments, motor impairments, and certain types of learning disabilities.  
The Leiter-3, published in 2013, is an updated version of the Leiter-R. The Leiter-3 consists of 
two groups of subtests, the Cognitive Battery and the Attention/Memory Battery. Nonverbal 
Intelligence will be used in this study to estimate global intellectual ability. The first four subtests 
of the Cognitive Battery are compiled to assess Nonverbal Intelligence with a Nonverbal IQ 
Composite score. These subtests are: Figure Ground, Form Completion, Sequential Order, and 
Classification-Analogies. The fifth subtest (Visual Patterns) is an optional subtest, which may be 
administered if one of the four subtests is compromised. Raw and scaled scores will be reported 
for each administered subtest in addition to the Nonverbal IQ Composite score. 
The Leiter-3 will be administered to patients starting at the last assessment of the Bayley-III 
Cognitive Scale prior to the patient reaching 42 months of age and then, as specified in 
Section 1.2. Test administration takes approximately 60 minutes. Test results will be centrally 
scored by a trained assessor. 
In case the developmental level of an individual patient is below the level required for the Leiter-3 
Scale assessment, the patients should be assessed by the Bayley-III regardless of the patient’s age. 
See the study-specific functional outcome manual for further details. 
9.3.3.8 Hearing testing 
Hearing loss has been reported in patients with GSDs (46, 47). Furthermore, cochlear involvement 
has been demonstrated in a mouse model of Pompe disease, and hearing loss found in patients 
with IOPD (48). 
Hearing will be assessed at the time points specified in Section 1.2 using both Audiogram and 
Brainstem auditory evoked potentials/responses (BAEPs/BAERs). Refer to the study manual for 
specific details on hearing testing procedures. 
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9.3.3.8.1 Audiogram 
Refer to Table 3 for a list of commonly available hearing tests appropriate for infants and children 
of various ages. Abnormal hearing tests should be confirmed by more than one method, and 
should be correlated with the presence or absence of middle ear effusion. Results of the hearing 
testing will be collected. Refer to the study manual for specific details on hearing testing 
procedures. 
Table 3 - Hearing assessments appropriate for age 
Auditory test 
Developmental age of child 
Otoacoustic emission testing 
all ages 
Conditioned-oriented responses 
9 months to 2.5 years 
Visual reinforcement audiometry 
9 months to 2.5 years 
Play audiometry 
2.5 years to 4 years 
Conventional audiometry 
4 years and older 
Source: Cunningham, 2003 (49) 
9.3.3.8.2 Brainstem auditory evoked potentials/responses 
Brainstem auditory evoked potentials/responses will be recorded at the time points specified in 
Section 1.2 in order to measure the functioning of the auditory nerve and auditory pathways in the 
brainstem, thus aiding in the assessment of potential hearing loss in study participants. Since 
recording of BAEPs/BAERs may require sedation in young children which could pose 
unacceptable risks to patients who have significant cardiopulmonary compromise, BAEPs/BAERs 
should only be performed at the discretion of the Investigator. Missing assessments must be 
documented for analysis and potential impact on the study results. 
If clinically significant changes in hearing as compared to baseline results are noted, the changes 
will be documented as AEs. Clinical significance is defined as any variation in hearing tests that 
has medical relevance and may result in an alteration in medical care. The Investigator will 
continue to monitor the patient until the parameter returns to baseline or until the Investigator 
determines that follow-up is no longer medically necessary. 
9.3.3.9 Motor Skills Checklist 
The GMFCS-E&R is accompanied by the Motor Skills Checklist. The Motor Skills Checklist 
includes functional tasks included in GMFCS-E&R classifications. Trained assessors indicate 
skills that are descriptors of the child or youth’s current function in order to identify areas of 
change within each GMFCS-E&R level. The Motor Skills Checklist will be reviewed by a central 
scorer who assigns a classification of the Pompe Functional Classification Levels (Walker, 
Supported Walker, Supported Stander, Sitter, or Restricted Antigravity Movement) (50). See the 
study-specific functional outcome manual for further details. 
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9.4 
FUTURE USE OF SAMPLES 
Blood samples will be obtained as blood volume permits and will not exceed the blood volume 
collection limit of <7 mL/kg over an 8-week period. Sampling is prioritized for safety labs and PK 
and 
. 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.  
These samples will remain labelled with the same identifiers used during the study (ie, subject 
ID). They will 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). The samples may be stored, or used 
for as long as they last or are needed for research. 
9.5 
APPROPRIATENESS OF MEASUREMENTS  
Despite the significant impact of alglucosidase alfa on (ventilator-free) survival in patients who 
have been diagnosed at birth through neonatal screening programs and treated shortly thereafter, 
some patients exhibit slow declines in gross motor function and mobility starting at 18-24 months 
of age. This unmet need has only recently been revealed in these patients (14, 16, 51). 
The primary objective of the ACT14132 study is the assessment of safety and tolerability of 
administering avalglucosidase alfa in male and female patients with IOPD, who have been 
previously treated with alglucosidase alfa and demonstrated clinical decline or sub-optimal 
clinical response in specified respiratory function, motor skills, cardiac parameters, and/or new 
onset of ptosis. The PAP will be a 6-month period from start of study treatment. The primary 
endpoint will be data pertaining to the safety and tolerability of avalglucosidase alfa. 
The secondary objectives are to characterize the PK profile of avalglucosidase alfa and to evaluate 
the preliminary efficacy of avalglucosidase alfa in comparison to alglucosidase alfa. Efficacy 
endpoints in ACT14132 include motor function, respiratory function, quality of life, pain, cardiac 
function, eyelid measurements, and cognitive and auditory function. These endpoints represent 
systems affected by Pompe disease and where clinical decline or sub-optimal response to 
alglucosidase alfa has been observed (14, 16, 51). 
As a consequence of the evolution in the course of Pompe disease, demonstration of therapeutic 
activity that stabilizes or improves the long-term decline of specific clinical symptoms, such as 
gross motor function and mobility in alglucosidase alfa-treated IOPD patients will provide 
sufficient evidence of a treatment effect that is at least similar to alglucosidase alfa and could 
support an indication in all IOPD patients. In the context of availability of an existing treatment, 
assessment of these endpoints is important to assure that these patients can be safely switched 
from alglucosidase alfa to avalglucosidase alfa with potential stabilization of clinical symptoms. 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
Visits that are longer due to multiple assessments or procedures (eg, motor assessments, 
echocardiography, questionnaires) may be carried out over up to 5 days (not necessarily 
consecutively), starting at least 7 days after the last IMP infusion, in order to accommodate the 
patients and their care-takers. In case several assessments/procedures are performed during the 
same day, it is recommended that they are performed in the following order, if applicable. It is not 
necessary to complete all assessment/procedures of the same category (eg, motor assessments) on 
the same day. IRT contact for enrollment/randomization or dispensing can be performed at any 
time but before IMP administration. In any case, IMP administration, including vital signs and PK 
sampling when applicable, will be the last procedure of the last day and the appropriate time 
needed for post-infusion surveillance will be taken into account (refer to Section 8.1). 
1. Patient-reported outcomes and questionnaires (Ventilator use diary, PedsQL Generic Core 
Scale questionnaire, PedsQL pediatric pain questionnaire, Pain VAS, when applicable: no 
preferred order) 
2. Physical examination (including height/body length, body weight, head circumference, 
Tanner stage) and patient/legal guardian standard interview (global health status, AE, 
medication) 
3. Procedures: 
• 
Echocardiography, ECG, hearing testing, eyelid position measure (for patients 
having signed [or for whom legal guardian(s) has(have) signed] the specific 
informed consent): no preferred order 
• 
PFT 
4. Motor assessments (preferred order, not leading to protocol deviation if order is different 
based on patient needs and assessor availability): GMFM-88/QMFT, then 
Bayley-III/Leiter-3 scales, Pompe-PEDI (Functional Skills Scale, Mobility Domain), 
GMFCS-E&R, with Motor Skills Checklist and 6MWT. 
5. All laboratory assessments (blood, urine) and muscle biopsy (for patients having signed 
[or for whom legal guardian(s) has(have) signed] the specific informed consent) when 
applicable 
6. IMP administration including vital signs and PK sampling when applicable 
10.1.1 Screening/baseline visit 
The patient will receive information on the study objectives and procedures from the Investigator 
or an authorized assigned person. The patient will have to sign the informed consent prior to 
performing any study-related procedure. 
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Patients who meet all the inclusion criteria and none of the exclusion criteria will be eligible for 
inclusion in the study. For participants in Cohort 3, randomization will be performed prior to IMP 
administration. 
The recommended duration of the screening period is up to 14 days but may be extended to a 
maximum of 4 weeks in the following pre-specified situations: 
• 
One or more of the assessments/procedures were not properly conducted or results were 
flawed because of a proven and tracked device deficiency (eg, spirometer) or a proven and 
tracked vendor deficiency (eg, courier vendor responsible for transferring samples from 
investigating site to central laboratory). In this case, the test(s) will be repeated. 
• 
A concurrent acute disease or event occurred during the screening period, which does not 
meet an exclusion criterion (see Section 7.2). 
• 
The study or the IMP administration is temporarily put on hold due to a Sponsor decision 
(see Section 10.3.1). 
If a patient does not meet all inclusion criteria or meets one or more exclusion criterion during the 
screening period, the patient may rescreen for the study once. The rescreening must be at least 
14 days after the initial screening failure.  
In case of rescreening, the patient will be first screened failed in the IRT, will sign a new written 
ICF and a new patient number will be provided. All screening assessments/procedures will have 
to be performed again, except GAA and 
genotyping and CRIM status. 
For screening failures, the following data obtained during screening will be collected: patient’s 
demographic data, inclusion and exclusion criteria, relevant medical, surgical and Pompe disease 
history (if available), previous and concomitant medications (if available), AE data (if available) 
and reason for failure. 
Patients enrolled in the study will have the following procedures performed at screening/baseline. 
• 
Informed consent/assent; 
• 
Inclusion/exclusion criteria; 
• 
Demographics and baseline characteristics: 
- 
Age (years); 
- 
Gender; 
- 
Race; 
- 
Ethnicity; 
• 
Medical/Surgical history; 
• 
Pompe disease history, inclusive of GAA mutation, CRIM status, GAA activity, and 
aspects of disability; 
• 
Retrospective chart review to collect available assessments prior to study entry 
documenting clinical decline or sub-optimal clinical response as outlined in I 06 and I 07 
(refer to Section 7.1); 
• 
Physical examination (inclusive of Tanner stage); 
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• 
Body weight; 
• 
Height/body length; 
• 
Head circumference; 
• 
Lab: 
- 
Serum β-HCG pregnancy test (females of childbearing potential only); 
- 
Safety sampling: 
- 
Hematology, biochemistry (including BNP and CK), and urinalysis; 
- 
Anti-drug antibodies (with neutralizing antibodies in ADA-positive patients) for 
anti-avalglucosidase alfa and anti-alglucosidase alfa antibodies; 
- 
Biomarkers: 
- 
Urine Hex4 sample collection; 
- 
 
- 
 
 
- 
GAA mutation analysis (if historical results are not available; may be obtained at any 
other visit if not possible during screening due to blood volume limitation) 
- 
Stored DNA sample (optional; may be obtained at any other visit if not possible during 
screening due to blood volume limitation); 
- 
Blood samples will be obtained as blood volume permits and will not exceed the blood 
volume collection limit of < 7 mL/kg over an 8-week period. Sampling is prioritized 
for safety labs (hematology, biochemistry, ADA) and PK and 
. 
• 
Muscle biopsy (optional); 
• 
Ventilator use diary; 
• 
PFT (in patients who can reliably undergo testing and/or who are not invasively 
ventilated); 
• 
6MWT (in patients who are able to ambulate at least 40 meters [approximately 130 feet] 
without stopping and without an assistive device); 
• 
GMFM-88/GMFCS-E&R 
• 
Motor Skills Checklist; 
• 
QMFT; 
• 
Pompe-PEDI, Functional Skills Scale: Mobility Domain; 
• 
Bayley-III/Leiter-3 scales; 
• 
Echocardiography; 
• 
Hearing testing; 
• 
Eyelid position measurements; 
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• 
PedsQL Generic Core Scale questionnaire (≥24 months of age); 
• 
PedsQL Pediatric Pain Questionnaire (>5 years of age); 
• 
Pain VAS; 
• 
AE collection; 
• 
Prior/concomitant medications/therapies; 
• 
IRT contact for notification of screening. 
10.1.2 Treatment period 
Patients enrolled in the study will have the following procedures performed starting at Day 1. Day 
of first infusion should occur within 1 to 14 days of consent. All subsequent numbered visits are 
calculated from day of first infusion of IMP in 14 day increments with a window of ±7 days for 
infusions and safety assessments (7 day increments with a window of ±3 days for qw 
alglucosidase alfa treatment in Stage 2 – Cohort 3 participants randomized to alglucosidase alfa 
treatment at current stable dose) and ±14 days for all other assessments. 
10.1.2.1 Day of first infusion (Day 1) 
The following will be performed on the day of first infusion (Day 1): 
• 
Inclusion/exclusion criteria; 
• 
IRT contact to confirm patient enrollment (Stage 1 patients, Cohorts 1 and 2) and 
randomization (Stage 2, Cohort 3 only); 
• 
Physical examination; 
• 
Body weight; 
• 
12-lead ECG (triplicate); 
• 
Vital signs (before, during, and following infusion: see Section 1.2); 
• 
Lab: 
- 
Urine β-HCG pregnancy test (females of childbearing potential only); 
- 
Biomarkers: 
• Urine Hex4 sample collection;  
• 
 
• 
 
• 
 
• Avalglucosidase alfa plasma PK sample collection (before and following infusion) 
in patients receiving avalglucosidase alfa: 
• For Cohort 1 and 2 patients and for Cohort 3 patients who are randomized in 
the avalglucosidase alfa group, this visit requires a stay at the site prior to and 
for at least 8 hours following the end of IMP infusion. 
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- 
For Cohort 2 patients and for Cohort 3 patients who are randomized in the 
avalglucosidase alfa group, another sample will be taken 12 to 16 hours after the end 
of IMP infusion. If the Cohort 3 dose of avalglucosidase alfa is 20 mg/kg qow, this 
additional sample will not be taken. Blood samples will be obtained as blood volume 
permits and will not exceed the blood volume collection limit of < 7 mL/kg over an 
8-week period. Sampling is prioritized for safety labs (hematology, biochemistry, 
ADA) and PK and 
 
 
 
 
 
• 
Ventilator use diary; 
• 
Eyelid position measurements; 
• 
Infusion of IMP; 
• 
AE collection; 
• 
Concomitant medications/therapies. 
Information regarding the infusion of the IMP can be found in the pharmacy manual. 
10.1.2.2 One week following first infusion (Week 2 [Day 8]) 
The following will be performed one week following the date of the first infusion: 
• 
Lab 
- 
Safety: 
- 
Biochemistry in patients receiving avalglucosidase alfa; 
- 
ADAs (with neutralizing antibodies in ADA positive patients) for 
anti-avalglucosidase alfa and anti-alglucosidase alfa antibodies for patients 
receiving avalglucosidase alfa; 
- 
ADAs (with neutralizing antibodies in ADA positive patients) for 
anti-alglucosidase alfa antibodies for patients receiving alglucosidase alfa; 
- 
Biomarkers: 
- 
Urine Hex4 sample collection; 
- 
Blood samples will be obtained as blood volume permits and will not exceed the blood 
volume collection limit of < 7 mL/kg over an 8-week period. Sampling is prioritized 
for safety labs (hematology, biochemistry, ADA) and PK and 
 
• 
AE collection; 
• 
Concomitant medications/therapies. 
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10.1.2.3 Weekly (alglucosidase alfa only) 
The following will be performed every week starting at the date of the first infusion for patients in 
Stage 2 – Cohort 3, who are randomized to receive alglucosidase alfa treatment at current stable 
dose and who have been receiving weekly infusions of alglucosidase alfa regularly for a minimum 
of 6 months immediately prior to study entry: 
• 
Vital signs (before, during, and following infusion: see Section 1.2); 
• 
Infusion of IMP; 
• 
AE collection; 
• 
Concomitant medications/therapies. 
10.1.2.4 Biweekly  
The following will be performed every 2 weeks (W3, W5, W7, W9, W11, W13, W15, W17, W19, 
W21, W23, and W25): 
• 
Lab: 
- 
Biomarkers: 
• 
Urine Hex4 sample collection; 
• 
Ventilator use diary; 
• 
Eyelid position measurements; 
• 
Vital signs (before, during, and following infusion: see Section 1.2); 
• 
IRT contact for IMP resupply; 
• 
Infusion of IMP; 
• 
AE collection; 
• 
Prior/concomitant medications/therapies. 
10.1.2.5 Monthly 
The following assessments will be performed on a monthly basis (W5, W9, W13, W17, W21, and 
W25): 
• 
Lab: 
- 
Biomarkers: 
• 
Urine Hex4 sample collection; 
- 
Urine β-HCG pregnancy test (females of childbearing potential only); 
- 
Safety: 
• 
Biochemistry in patients receiving avalglucosidase alfa; 
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• 
ADAs (with neutralizing antibodies in ADA-positive patients) for anti-
avalglucosidase alfa antibodies for patients receiving avalglucosidase alfa; 
• 
Ventilator use diary; 
• 
Eyelid position measurements; 
• 
Vital signs (before, during, and following infusion: see Section 1.2); 
• 
IRT contact for IMP resupply; 
• 
Infusion of IMP; 
• 
ECG (at Week 5); 
• 
Body weight; 
• 
Physical examination (at Week 5, Week 9, and Week 13); 
• 
AE collection; 
• 
Prior/concomitant medications/therapies. 
10.1.2.6 Every 3 months 
The following assessments will be performed at quarterly visits (W13 and W25): 
• 
Physical examination; 
• 
Body weight; 
• 
Height/body length/head circumference; 
• 
Lab: 
- 
Urine β-HCG pregnancy test (females of childbearing potential only); 
- 
Safety: 
• 
Hematology, biochemistry, and urinalysis; 
• 
ADAs (with neutralizing antibodies in ADA-positive patients) for 
anti-avalglucosidase alfa and anti-alglucosidase alfa antibodies for patients 
receiving avalglucosidase alfa, and anti-alglucosidase alfa antibodies only for 
patients in Stage 2-Cohort 3, who are randomized to receive alglucosidase alfa 
treatment at current stable dose (W13 only); 
• 
ADAs (with neutralizing antibodies in ADA positive patients) for 
anti-avalglucosidase alfa and anti-alglucosidase alfa antibodies (W25 only); 
- 
Biomarkers: 
• 
 
• 
 
• 
 
• 
Urine Hex4 sample collection; 
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- 
Avalglucosidase alfa plasma PK sample collection (before and following infusion) in 
patients receiving avalglucosidase alfa; 
• 
For Cohort 1 and 2 patients and for Cohort 3 patients who are randomized in the 
avalglucosidase alfa group, this visit requires a stay at the site prior to and for at 
least 8 hours following the end of IMP infusion (Week 25 only). 
• 
For Cohort 2 patients and for Cohort 3 patients who are randomized in the 
avalglucosidase alfa group, another sample will be taken 12 to 16 hours after the 
end of IMP infusion (Week 25 only). If the Cohort 3 dose of avalglucosidase alfa is 
20 mg/kg qow, this additional sample will not be taken. 
- 
Blood samples will be obtained as blood volume permits and will not exceed the blood 
volume collection limit of < 7 mL/kg over an 8-week period. Sampling is prioritized 
for safety labs (hematology, biochemistry, ADA) and PK and 
 
 
 
 
 
• 
ECG; 
• 
Vital signs (before, during, and following infusion: see Section 1.2); 
• 
Muscle biopsy (optional) at Week 25 only; 
• 
Ventilator use diary; 
• 
PFT (in patients who can reliably undergo testing and/or who are not invasively 
ventilated); 
• 
6MWT (in patients who are able to ambulate at least 40 meters [approximately 130 feet] 
without stopping and without an assistive device); 
• 
GMFM-88/GMFCS-E&R 
• 
Motor Skills Checklist; 
• 
QMFT; 
• 
Pompe-PEDI, Functional Skills Scale: Mobility Domain; 
• 
Bayley-III/Leiter-3 scales; 
• 
Echocardiography; 
• 
Hearing testing; 
• 
Eyelid position measurements; 
• 
PedsQL Generic Core Scale questionnaire (≥24 months of age); 
• 
PedsQL Pediatric Pain Questionnaire (>5 years of age); 
• 
Pain VAS; 
• 
IRT contact for IMP resupply; 
• 
Infusion of IMP; 
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• 
AE collection; 
• 
Concomitant medications/therapies. 
10.1.3 Extension period (Week 27 to Week 145) 
10.1.3.1 Day of first infusion within the extension period (W27) 
• 
Lab: 
- 
avalglucosidase alfa plasma PK sample collection (before and following infusion) for 
Stage 2 – Cohort 3 patients switching to avalglucosidase alfa in the extension period. 
For these patients this visit requires a stay at the site prior to and for at least 8 hours 
following the end of IMP infusion. Another sample will be taken 12 to 16 hours after 
the end of IMP infusion. If the Cohort 3 dose of avalglucosidase alfa is 20 mg/kg qow, 
this additional sample will not be taken; 
• 
Body weight for Stage 2 – Cohort 3 patients switching to avalglucosidase alfa in the 
extension period; 
• 
Ventilator use diary; 
• 
Vital signs (before, during, and following infusion: see Section 1.2); 
• 
IRT contact for IMP resupply; 
• 
Infusion of avalglucosidase alfa; 
• 
AE collection; 
• 
Concomitant medications/therapies. 
10.1.3.2 One week following first infusion within the extension period 
The following will be performed one week following the date of the first infusion of the extension 
period for patients in Stage 2 – Cohort 3 switching to avalglucosidase alfa (W28): 
• 
Biochemistry; 
• 
ADAs (with neutralizing antibodies in ADA-positive patients) for anti-avalglucosidase 
alfa; 
• 
AE collection; 
• 
Concomitant medications/therapies. 
10.1.3.3 Two weeks following first infusion within the extension period (Week 29) 
• 
Body weight; 
• 
Physical examination for patients in Stage 2 - Cohort 3 switching to avalglucosidase alfa 
in the extension period; 
• 
Ventilator use diary; 
• 
Lab: 
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- 
Urine β-HCG pregnancy test (females of childbearing potential only); 
- 
Safety: 
• 
Biochemistry; 
• 
ADAs (with neutralizing antibodies in ADA positive patients) for 
anti-avalglucosidase alfa antibodies in Stage 2 – Cohort 3 patients switching to 
avalglucosidase alfa in the extension period; 
• 
ECG in Stage 2 – Cohort 3 patients switching to avalglucosidase alfa in the extension 
period; 
• 
Vital signs (before, during, and following infusion (see Section 1.2); 
• 
IRT contact for IMP resupply; 
• 
Infusion of avalglucosidase alfa; 
• 
AE collection; 
• 
Concomitant medications/therapies. 
10.1.3.4 Every 2 weeks (Biweekly) 
The following will be performed every 2 weeks (W29, W31, W33, W35, W37, W39, W41, W43, 
W45, W47, W49, W51, W53, W55, W57, W59, W61, W63, W65, W67, W69, W71, W73, W75, 
W77, W79, W81, W83, W85, W87, W89, W91, W93, W95, W97, W99, W101, W103, W105, 
W107, W109, W111, W113, W115, W117, W119, W121, W123, W125, W127, W129, W131, 
W133, W135, W137, W139, W141, W143, and W145): 
• 
Ventilator use diary; 
• 
Vital signs (before, during, and following infusion (see Section 1.2); 
• 
IRT contact for IMP resupply; 
• 
Infusion of avalglucosidase alfa; 
• 
AE collection; 
• 
Concomitant medications/therapies. 
10.1.3.5 Every 4 weeks (Monthly) 
The following assessments will be performed on a monthly basis (W29, W33, W37, W41, W45, 
W49, W53, W57, W61, W65, W69, W73, W77, W81, W85, W89, W93, W97, W101, W105, 
W109, W113, W117, W121, W125, W129, W133, W137, W141, and W145): 
• 
Body weight; 
• 
Physical examination for patients in Stage 2 – Cohort 3 switching to avalglucosidase alfa 
in the extension period up to Week 37; 
• 
Lab: 
- 
Urine β-HCG pregnancy test (females of childbearing potential only); 
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- 
Safety: 
• 
Biochemistry (monthly for the first 6 months of the extension period in all subjects, 
up to Week 73 for patients in Stage 2 – Cohort 3 switching to avalglucosidase alfa 
in the extension period, and then every 3 months); 
• 
ADAs (with neutralizing antibodies in ADA-positive patients) for 
anti-avalglucosidase alfa antibodies through Week 49 in Stage 2 – Cohort 3 
patients switching to avalglucosidase alfa in the extension period and then every 
3 months; 
• 
Ventilator use diary; 
• 
Vital signs (before, during, and following infusion); 
• 
IRT contact for IMP resupply; 
• 
Infusion of avalglucosidase alfa; 
• 
AE collection; 
• 
Concomitant medications/therapies. 
10.1.3.6 Every 12 weeks (Quarterly) 
The following assessments will be performed every 3 months (W37, W49, W61, W73, W85, 
W97, W109, W121, W133, and W145): 
• 
Physical examination (up to Week 49 for all subjects, up to Week 73 for patients in 
Stage 2 – Cohort 3 switching to avalglucosidase alfa in the extension period, and then 
every 6 months); 
• 
Body weight; 
• 
Height/body length/head circumference (up to Week 73 and then every 6 months); 
• 
Lab: 
- 
Urine β-HCG pregnancy test (females of childbearing potential only); 
- 
Safety: 
• 
Biochemistry; 
• 
ADAs (with neutralizing antibodies in ADA-positive patients) for 
anti-avalglucosidase alfa antibodies; 
- 
Avalglucosidase alfa plasma PK sample collection (before and following infusion) for 
Stage 2 – Cohort 3 patients switching to avalglucosidase alfa in the extension period: 
at W37 and W49. For these patients the W49 visit (V28) requires a stay at the site prior 
to and for at least 8 hours following the end of IMP infusion. Another sample will be 
taken 12 to 16 hours after the end of IMP infusion. If the Cohort 3 dose of 
avalglucosidase alfa is 20 mg/kg qow, this additional sample will not be taken; 
- 
Blood samples will be obtained as blood volume permits and will not exceed the blood 
volume collection limit of < 7 mL/kg over an 8-week period. Sampling is prioritized 
for safety labs (hematology, biochemistry, ADA) and PK and 
 
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• 
ECG in Stage 2 - Cohort3 patients switching to avalglucosidase alfa in the extension 
period up to Week 37; 
• 
Ventilator use diary; 
• 
Vital signs (before, during, and following infusion (see Section 1.2); 
• 
IRT contact for IMP resupply; 
• 
Infusion of avalglucosidase alfa; 
• 
AE collection; 
• 
Concomitant medications/therapies. 
10.1.3.7 Every 24 weeks (Every 6 months) 
The following assessments will be performed every 6 months (W49, W73, W97, W121, and 
W145): 
• 
Physical examination (inclusive of Tanner stage at W49, W97, and W145); 
• 
Body weight; 
• 
Height/body length/head circumference; 
• 
Lab: 
- 
Urine β-HCG pregnancy test (females of childbearing potential only); 
- 
Safety: 
• 
Hematology, biochemistry, and urinalysis; 
• 
ADAs (with neutralizing antibodies in ADA-positive patients) for 
anti-avalglucosidase alfa; 
- 
Avalglucosidase alfa plasma PK sample collection (before and following infusion) for 
Stage 2 – Cohort 3 patients switching to avalglucosidase alfa in the extension period: 
at W37 and W49. For these patients the W49 visit (V28) requires a stay at the site prior 
to and for at least 8 hours following the end of IMP infusion. Another sample will be 
taken 12 to 16 hours after the end of IMP infusion. If the Cohort 3 dose of 
avalglucosidase alfa is 20 mg/kg qow, this additional sample will not be taken; 
- 
Biomarkers: 
• 
 
• 
 
• 
 
• 
Urine Hex4 sample collection; 
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- 
Blood samples will be obtained as blood volume permits and will not exceed the blood 
volume collection limit of < 7 mL/kg over an 8-week period. Sampling is prioritized 
for safety labs (hematology, biochemistry, ADA) and PK and 
 
 
 
 
 
• 
ECG; 
• 
Ventilator use diary; 
• 
Vital signs (before, during, and following infusion (see Section 1.2); 
• 
Muscle biopsy (optional) at Week 49 in Stage 2 – Cohort 3 switching to avalglucosidase 
alfa in the extension period, and Week145 in all patients; 
• 
PFT (in patients who can reliably undergo testing and/or who are not invasively 
ventilated); 
• 
6MWT (in patients who are able to ambulate at least 40 meters [approximately 130 feet] 
without stopping and without an assistive device); 
• 
GMFM-88/GMFCS-E&R 
• 
Motor Skills Checklist; 
• 
QMFT; 
• 
Pompe-PEDI, Functional Skills Scale: Mobility Domain; 
• 
Bayley-III/Leiter-3 scales; 
• 
Echocardiography; 
• 
Hearing testing; 
• 
Eyelid position measurements; 
• 
PedsQL Generic Core Scale questionnaire (≥24 months of age); 
• 
PedsQL Pediatric Pain Questionnaire (>5 years of age); 
• 
Pain VAS; 
• 
IRT contact for IMP resupply; 
• 
Infusion of avalglucosidase alfa; 
• 
AE collection; 
• 
Concomitant medications/therapies. 
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10.1.4 Extended long-term treatment period (From Week 147 onwards) 
10.1.4.1 Biweekly 
The following assessments will be performed every 2 weeks, starting at Week 147 and up to an 
additional 226 weeks after Week 145 (W147, W149, W151, W153, W155, W157, W159, W161, 
W163, W165, W167, W169, W171, W173, W175, W177, W179, W181, W183, W185, W187, 
W189, W191, W193, W195, W197, W199, W201, W203, W205, W207, W209, W211, W213, 
W215, W217, W219, W221, W223, W225, W227, W229, W231, W233, W235, W237, W239, 
W241, W243, W245, W247, W249, W251, W253, W255, W257, W259, W261, W263, W265, 
W267, W269, W271, W273, W275, W277, W279, W281, W283, W285, W287, W289, W291, 
W293, W295, W297, W299, W301, W303, W305, W307, W309, W311, W313, W315, W317, 
W319, W321, W323, W325, W327, W329, W331, W333, W335, W337, W339, W341, W343, 
W345, W347, W349, W351, W353, W357, W359, W361, W363, W365, W367, W369, and 
W371) or until avalglucosidase alfa is approved in the patient’s country, whichever comes first 
(refer to Appendix C [Section 17.3.1] for definition applicable for UK patients): 
• 
Ventilator use diary (for patients receiving home infusion: the ventilator use diary will be 
checked at site visits); 
• 
Vital signs (before, during, and following infusion: see Section 1.2); 
• 
IRT contact for IMP resupply; 
• 
Infusion of avalglucosidase alfa; 
• 
AE collection; 
• 
Concomitant medications/therapies. 
10.1.4.2 Every 4 weeks (Monthly)  
The following assessments will be performed every 4 weeks, starting at Week 149 and up to an 
additional 226 weeks after Week 145 (W149, W153, W157, W161,W165, W169, W173, W177, 
W181, W185, W189, W193, W197, W201, W205, W209, W213, W217, W221, W225, W229, 
W233, W237, W241, W245, W249, W253, W257, W261, W265, W269, W273, W277, W281, 
W285, W289, W293, W297, W301, W305, W309, W313, W317, W321, W325, W329, W333, 
W337, W341, W345, W349, W353, W357, W361, W365, and W369) or until avalglucosidase 
alfa is approved in the patient’s country, whichever comes first (refer to Appendix C 
[Section 17.3.1] for definition applicable for UK patients): 
• 
Body weight; 
• 
Lab: 
• 
Urine β-HCG pregnancy test (females of childbearing potential only); 
• 
Ventilator use diary (for patients receiving home infusion: the ventilator use diary will be 
checked at site visits); 
• 
Vital signs (before, during, and following infusion: see Section 1.2); 
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• 
IRT contact for IMP resupply; 
• 
Infusion of avalglucosidase alfa; 
• 
AE collection; 
• 
Concomitant medications/therapies. 
10.1.4.3 Every 12 weeks (Quarterly)  
The following assessments will be performed every 12 weeks, starting at Week 157 and up to an 
additional 226 weeks after Week 145 (W157, W169, W181, W193, W205, W217, W229, W241, 
W253, W265, W277, W289, W301, W313, W325, W337, W349, and W361) or until 
avalglucosidase alfa is approved in the patient’s country, whichever comes first (refer to 
Appendix C [Section 17.3.1] for definition applicable for UK patients): 
• 
Body weight; 
• 
Lab: 
• 
Urine β-HCG pregnancy test (females of childbearing potential only); 
• 
Safety: 
• 
ADAs (with neutralizing antibodies in ADA-positive patients) for 
anti-avalglucosidase alfa antibodies; 
• 
Ventilator use diary (for patients receiving home infusion: the ventilator use diary will be 
checked at site visits); 
• 
Vital signs (before, during, and following infusion: see Section 1.2); 
• 
IRT contact for IMP resupply; 
• 
Infusion of avalglucosidase alfa; 
• 
AE collection; 
• 
Concomitant medications/therapies. 
10.1.4.4 Every 24 weeks (Every 6 months)  
The following assessments will be performed every 24 weeks, starting at Week 169 and up to an 
additional 226 weeks after Week 145 (W169, W193, W217, W241, W265, W289, W313, W337, 
and W361) or until avalglucosidase alfa is approved in the patient’s country, whichever comes 
first (refer to Appendix C [Section 17.3.1] for definition applicable for UK patients): 
• 
Physical examination (inclusive of Tanner stage); 
• 
Height/body length/head circumference; 
• 
Body weight; 
• 
Lab: 
• 
Urine β-HCG pregnancy test (females of childbearing potential only); 
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• 
Safety: 
• 
ADAs (with neutralizing antibodies in ADA-positive patients) for 
anti-avalglucosidase alfa antibodies; 
• 
Hematology, biochemistry, and urinalysis; 
• 
Ventilator use diary (for patients receiving home infusion: the ventilator use diary will be 
checked at site visits); 
• 
Eyelid position measurements; 
• 
Vital signs (before, during, and following infusion: see Section 1.2); 
• 
IRT contact for IMP resupply; 
• 
Infusion of avalglucosidase alfa; 
• 
AE collection; 
• 
Concomitant medications/therapies. 
10.1.4.5 Every 48 weeks (Yearly) and end of treatment visit 
The following assessments will be performed every 48 weeks, starting at Week 193 and up to an 
additional 226 weeks after Week 145 (W193, W241, W289, W337 or end of treatment) or until 
avalglucosidase alfa is approved in the patient’s country, whichever comes first (refer to 
Appendix C [Section 17.3.1] for definition applicable for UK patients): 
• 
ECG; 
• 
Physical examination (inclusive of Tanner stage); 
• 
Height/body length/head circumference; 
• 
Body weight; 
• 
Lab: 
• 
Urine β-HCG pregnancy test (females of childbearing potential only); 
• 
Safety: 
• 
ADAs (with neutralizing antibodies in ADA-positive patients) for 
anti-avalglucosidase alfa antibodies; 
• 
Hematology, biochemistry, and urinalysis; 
• 
Ventilator use diary; 
• 
GMFM-88/GMFCS-E&R 
• 
Motor Skills Checklist; 
• 
QMFT; 
• 
Pompe-PEDI, Functional Skills Scale: Mobility Domain; 
• 
Leiter-3 scale (Bayley-III scale in case the developmental level of an individual patient is 
below the level required for the Leiter-3 Scale assessment); 
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• 
Echocardiography (can be performed on a more frequent basis upon need of abnormality 
follow-up); 
• 
Hearing testing; 
• 
Eyelid position measurements; 
• 
PedsQL Generic Core Scale questionnaire (≥24 months of age); 
• 
PFT (in patients who can reliably undergo testing and/or who are not invasively 
ventilated); 
• 
6MWT (in patients who are able to ambulate at least 40 meters [approximately 130 feet] 
without stopping and without an assistive device); 
• 
Vital signs (before, during, and following infusion: see Section 1.2); 
• 
IRT contact for IMP resupply (or end of treatment call for end of treatment visit); 
• 
Infusion of avalglucosidase alfa; 
• 
AE collection; 
• 
Concomitant medications/therapies. 
10.1.5 End of study 
The following assessments will be performed at follow-up visit/contact (two to four weeks after 
last infusion): 
• 
AE collection; 
• 
Concomitant medications/therapies. 
10.1.6 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 will be reported/collected in the clinical database. 
• 
In exceptional circumstances, if a visit is missed during the course of the study, the 
following should be followed: 
- 
If safety assessments/procedures should have been performed during that missed visit, 
they will be performed at the next visit, even if none was planned, using unscheduled 
lab kits for any lab samples. 
- 
If efficacy assessments/procedures should have been performed during that missed 
visit (ie, V9/Week 13, V15/Week 25, V22/Week 37, V28/Week 49, V40/Week 73, 
V52/Week 97, V64/Week 121, and V76/Week 145 or any every 24 or 48 weeks visit 
[depending on the assessment, see Section 1.2.4] of the extended long-term treatment 
period), they will be performed at the earliest possible date (which might exceed the 
authorized window) and will still be associated with the visit that was missed. In these 
instances, this will not be considered a deviation but should be clearly documented in 
the patient’s file. 
10.1.7 Follow-up for patients who temporarily or permanently discontinued the study 
treatment 
• 
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 the ACT14132 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. 
- 
A patient who will be enrolled but will not receive the first infusion due to a 
concurrent reason or event not related to the study, will be considered as being 
temporarily discontinued from the study drug and the rules described above will apply. 
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• 
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. 
Patients who permanently discontinue the study treatment prior to the scheduled Week 25 or after 
Week 25, but prior to the scheduled Week 145 visit, will have assessments corresponding 
respectively to Week 25 or Week 145 performed prior to or in combination with the safety 
assessment after last infusion (refer to Section 10.1.4). Patients who permanently discontinue the 
study treatment prior to the scheduled end of treatment during the extended long-term treatment 
period will have assessments corresponding to the end of treatment visit. 
10.2 
DEFINITION OF SOURCE DATA 
All evaluations that are reported in the e-CRF must be supported by appropriately identified 
source documentation.  
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 or equivalent IMP room 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. 
• 
Magnetic resonance imaging (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 treatment 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 e-CRF. 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. 
• 
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 (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(s) 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 pages of the e-CRF. Visit and assessment schedules will be adapted to the absence 
of infusion of IMP (refer to Section 1.2 and Section 10.1.7). 
Temporary treatment discontinuation decided by the Investigator corresponds to 1 or more doses 
not administered to the patient. 
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 AE not related to the patient’s underlying condition. 
• 
More than 1 AE rated severe, not related to the patient’s underlying condition, for which 
the relationship to treatment cannot be reasonably excluded. 
• 
Any increase in ALT, AST, total bilirubin, or alkaline phosphatase >3× the baseline value, 
except if the increased value is still within the normal range. 
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• 
Any increase in ALT or AST >3× the upper limit of normal (ULN), in the presence of total 
bilirubin >2× ULN. 
• 
Any AE that, in the opinion of the Investigator or Sponsor, raises significant concerns 
regarding the safety of the IMP administered dose. 
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 IMP-related death. 
After consideration of DMC recommendations, final decisions for discontinuation of study drug 
for all or selected clinical trial patients and for not dosing new patients will be made by the 
Sponsor. 
In the event a significant safety concern arises, the Sponsor will immediately decide to 
discontinue study drug dosing in all clinical trial patients and to not dose new patients, prior to 
receipt of DMC recommendation. This applies to a decision on dose escalation, as outlined in 
Section 4 as well. Investigational sites will be notified within 24 hours of the Sponsor’s 
notification of the event(s). 
If a temporary discontinuation of study drug occurs while one or more patient is currently in their 
screening period, this screening period might be extended (see Section 10.1.1). 
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. 
10.3.3 List of criteria for permanent treatment discontinuation 
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 reason(s) for treatment discontinuation in the source documents and in the e-CRF. 
If a patient experiences further clinical decline at or after Week 25 as defined by more rapid 
worsening of criteria of clinical decline than prior to study start, which is sustained on repeated 
study assessments, the patient may be managed per the discretion of the Investigator. This may 
include return to treatment with commercially available alglucosidase alfa (and termination of 
trial participation). 
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. 
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10.3.4 Handling of patients after permanent treatment discontinuation 
Patients will be followed according to the study procedures 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. 
Patients are encouraged to continue their regular scheduled study visits during the PAP (6 
months). At the minimum, a discontinuation visit should be scheduled after the premature 
permanent discontinuation of treatment, if occurred prior to week 25, where the patients will be 
assessed using the procedure normally planned for the final study visit (Week 25) including a PK 
sample, if appropriate. This full assessment visit can be combined with the 4-week safety follow-
up if necessary.  
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed by documenting the reason(s) for 
treatment discontinuation. 
Patients who permanently discontinue study treatment and who will be switched to commercial 
alglucosidase alfa will be withdrawn from the study. 
In the event that a patient dies, permission will be sought (through a separate ICF) for a research 
autopsy or post mortem research biopsy. Samples collected from these procedures will be used for 
research purposes only and data will not be included in any study analyses. 
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 without any effect on their care. Discontinuation of study 
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. Therefore, if 
patients no longer wish to take the IMP, they will be encouraged to remain in the study and attend 
the remaining visits (see Section 10.3.4). The value of critical study data collected during their 
continued involvement will be emphasized as important to the public health value of the study. 
If possible, the patients are assessed using the procedure normally planned for the last visit of the 
treatment phase (Week 25) including a PK sample, if appropriate; or if the patient withdraws from 
the study after the scheduled Week 25 visit, using the procedures normally planned for the 
Week 145 visit including a PK sample, if not performed previously in participants in Cohort 3 
switching to avalglucosidase alfa at Week 27 of the extension period. Patients need to be assessed 
4 weeks post last infusion. However, this 4 weeks post-infusion safety assessment may be 
combined with the regular scheduled visits indicated here (refer to Section 10.1.4). 
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 and, if the patient or the patient’s representative refuses or 
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is physically unavailable, the site should document and sign the reason for the patient’s failure to 
withdraw consent in writing. 
All study withdrawals should be recorded by the Investigator in the appropriate e-CRF and in the 
patient’s medical records when considered as confirmed. In the medical record, at least the date of 
the withdrawal and the reason should be documented. 
For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
Investigator should make the best effort to recontact the patient (eg, contact patient’s family or 
private physician, review 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 (SAP) will specify how these patients lost to follow-up for their 
primary endpoints will be considered. 
Patients who have withdrawn from the study cannot be re-randomized/reallocated (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 adverse event (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 
A serious adverse event (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, or 
• 
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 
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patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered a medically important event. The list is not 
intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm; 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc); 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
- 
Development of drug dependence or drug abuse; 
- 
ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT increase 
>10 × ULN; 
- 
Suicide attempt or any event suggestive of suicidality; 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling); 
- 
Bullous cutaneous eruptions; 
- 
Any new invasive ventilatory support (excluding planned ventilatory support less than 
3 days duration for a planned surgical procedure). 
10.4.1.3 Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified or removed during a study by protocol amendment. 
AESIs will include: 
• 
IARs 
- 
IARs are defined as AEs 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 10.6 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. 
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- 
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. 
• 
Symptomatic overdose (serious or nonserious) with IMP 
- 
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 protocol defined therapeutic interval, adjusted according to 
the tested drug. 
Of note, asymptomatic overdose has to be reported as a standard AE, and is not considered 
an AESI. 
• 
Clinical laboratory (change from baseline) 
- 
ALT or AST increase of ≥3 × ULN if baseline is <ULN, or ALT or AST increase ≥2 × 
the baseline value if baseline is ≥ULN; 
- 
A maximum ALT value of ≥400 IU/L (except if baseline value is ≥400 IU/L) or AST 
value of ≥500 IU/L (except if baseline value is ≥500 IU) or an increase in direct, 
indirect, or total bilirubin of ≥2 × ULN; 
- 
Serum creatinine increase of >1.5 × the baseline value (and final serum creatinine 
value is >ULN). 
In the event of an AESI, the Sponsor will be informed immediately (and within 24 hours), using 
the AE form together with the SAE complementary form to be entered in the e-CRF. 
10.4.2 General guidelines for reporting adverse events 
• 
All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the ICF until the end of the study as defined by the protocol for that patient, 
are to be recorded on the e-CRF. 
• 
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 
study treatment, 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 study treatment or by the study procedure(s). 
• 
If the Investigator assesses the AE related to study treatment and the Investigator cannot 
reasonably explain the AE by other factors (such as clinical state, concomitant therapy, 
and /or other interventions) or if the cause of the AE is unknown by the Investigator, the 
relationship to study treatment must be checked "Related" by the Investigator. 
• 
The Investigator should check "Not Related" when there is a clear alternative cause to the 
event other than the study treatment according to the Investigator. 
There is one exception to this rule. In instances where a patient experiences an IAR (refer to 
Section 10.6), 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.  
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• 
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. 
Instructions for AE reporting are summarized in Table 4. 
See Appendix C (Section 17.3.2) for an addendum to this section for Germany only. 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
• 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay. 
• 
All further data updates should be recorded in the e-CRF as appropriate, within 24 hours 
of knowledge of the SAE. 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. 
• 
A back-up plan is available and should be used when the e-CRF system does not work. 
Please refer to the study 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  
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the e-CRF. 
Instructions for AE reporting are summarized in Table 4. 
The needs for specific monitoring, documentation, and management of AESIs are described in 
this section. 
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For each defined AESI, consider carefully the need to collect additional specific information that 
would impact the study, 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). 
10.4.5 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix B (Section 17.2). 
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices, 
• 
Neutropenia; 
• 
Thrombocytopenia; 
• 
ALT increase; 
• 
Acute renal insufficiency. 
Refer to Section 10.4.1.3 for specific laboratory abnormalities that are identified as AESIs. 
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Table 4 - Summary of adverse event reporting instructions 
Event 
category 
Reporting 
timeframe 
Specific events in this category 
Case Report Form completion 
AE form 
Safety  
Complementary 
Form 
Other 
specific 
forms 
AE (non-SAE, 
non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
SAE (non-AESI 
or AESI) 
Expedited 
(within 24 hours) 
Any AE meeting seriousness criterion per 
Section 10.4.1.2 
Yes 
Yes 
No 
 
 
Death 
Yes 
Yes 
Yes 
AESI  
Expedited 
(within 24 hours) 
IAR 
Yes 
Yes 
No 
 
 
Pregnancy 
Yes 
Yes 
Yes 
 
 
Symptomatic overdose 
Yes 
Yes 
Yes 
 
 
ALT≥3 ULN (if baseline ALT<ULN) and 
ALT≥2 x baseline (if baseline ALT≥ULN) 
Yes 
Yes 
Yes 
 
 
AST≥3 ULN (if baseline AST<ULN) and 
AST≥2 x baseline (if baseline AST≥ULN) 
Yes 
Yes 
No 
 
 
ALT ≥400 IU/L (except if baseline value ≥ 
400 IU/L) or AST ≥500 IU/L (except if 
baseline value ≥ 500 IU/L), or increase in 
direct, indirect, or total bilirubin ≥2 x ULN 
Yes 
Yes 
Yes 
 
 
Serum creatinine >1.5 x baseline  
(if final creatinine >ULN) 
Yes 
Yes 
No 
AE = adverse event; SAE = serious adverse event; AESI = adverse event of special interest; IAR = infusion-associated reaction; ALT = alanine 
aminotransferase; ULN = upper limit of normal; AST = aspartate aminotransferase; IU/L = international units per liter 
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, ie, any 
suspected unexpected serious adverse reaction (SUSAR), to the regulatory authorities, 
independent ethics committee (IECs)/institutional review boards (IRBs) as appropriate and 
to the Investigators. 
• 
All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
Adverse events that are considered expected will be specified by the reference safety information 
(IB for avalglucosidase alfa and label for alglucosidase alfa).  
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
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10.6 
SAFETY INSTRUCTIONS 
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 IB 
(Sections 7.1.2 and 7.1.3) for further guidance on the management of IARs. 
Moderate, severe, and recurrent mild IARs will be discussed with the DMC. If the DMC 
recommends or suggests that a desensitization procedure to the IMP could be proposed to the 
patient, in agreement with the Investigator and the patient’s guardian(s), such a procedure may be 
initiated as per guidelines in the pharmacy manual. 
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 cardiopulmonary resuscitation 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. 
10.7 
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 
11.1 
DETERMINATION OF SAMPLE SIZE 
No formal sample size calculations have been performed. Sample size for this study was based 
upon empirical considerations. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who signed the ICF. 
For Cohort 3, randomized patients consist of all patients who have been allocated a treatment kit 
based on the randomization process for participants. Patients treated without being randomized 
will not be considered as randomized and will not be included in any efficacy population. For any 
patient randomized more than once, only the data associated with the first randomization will be 
used in any analysis population. The safety experience associated with any later randomization 
will be assessed separately. 
11.3 
ANALYSIS POPULATIONS 
Safety population: all patients who received at least 1 infusion (partial or total) in the study. 
Modified intent-to-treat (mITT) population: all randomized patients in Cohort 3 who received at 
least 1 infusion and with evaluable baseline efficacy assessment, analyzed according to the 
treatment group allocated by randomization. 
11.4 
STATISTICAL METHODS 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study drug exposure will be assessed by the duration of study drug exposure, 
number of infusions, and amount of dose received. The extent of study drug exposure will be 
summarized in the safety population. 
Duration of study drug exposure is defined below:  
For the PAP 
• 
Duration of IMP exposure is defined as the first dose date in the extension period (or 
14 days after the last dose date in PAP if the patient is not continuing in extension period) 
minus (–) first dose date in the treatment period, regardless of unplanned intermittent 
discontinuations. 
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For the extension period, 
• 
Duration of IMP exposure is defined as 14 days after the last dose in the extension period 
minus (–) the first dose date in the extension period, regardless of unplanned intermittent 
discontinuations. This is defined only for Cohort 3 alglucosidase alfa patients who are 
switched to avalglucosidase alfa and treated in the extension period. 
For the overall treatment duration, 
• 
Duration of avalglucosidase alfa total exposure is defined as 14 days after last 
avalglucosidase alfa dose in study minus (–) first avalglucosidase alfa dose date in the 
study. This is defined for all patients other than the Cohort 3 alglucosidase alfa patients. 
The duration of IMP exposure will be summarized descriptively as a quantitative variable 
(number, mean, SD, median, minimum, and maximum), as well as categorical variable 
(eg, <2 months, 2-4 months, 4-6 months for the PAP). 
The cumulative dose information for the considered period (PAP or overall treatment period) will 
be assessed by the total number of infusions received in the considered period, as well as total 
amount of IMP in mL (if this information is available from the database) received in the 
considered period. These data will be summarized descriptively. 
For Cohorts 1 and 2, and Cohort 3 avalglucosidase alfa patients, both duration of IMP exposure 
and cumulative dose will be summarized for the PAP, as well as the overall treatment period. For 
Cohort 3 alglucosidase alfa patients, both duration of IMP exposure and cumulative dose will be 
summarized for the PAP; in addition, duration of IMP exposure will be summarized for the 
extension period after switching to avalglucosidase alfa. 
11.4.1.1 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. Compliance to the treatment regimen will be 
monitored by site personnel during the study.  
Treatment compliance for the PAP and the extension period respectively will be summarized 
descriptively as quantitative variable using the safety population. The number and percentage of 
patients with noncompliance (missed 2 or more consecutive infusions not for safety cause, or 
missed ≥20% of total doses in the treatment or extension period) will be provided.  
11.4.2 Analyses of safety data 
In general, for the PAP, the summary of safety results will be presented by study cohort/treatment 
arm within each stage, as well as by dose levels among the avalglucosidase alfa-treated patients. 
For the overall avalglucosidase alfa treatment period, the summary of safety results will be 
presented by dose levels among avalglucosidase alfa patients. All safety results that have been 
collected at the time of the analysis will be included for the overall treatment period summaries. 
For Cohort 3 alglucosidase alfa patients, the summary of safety results for the extension period 
will be presented separately. Safety endpoints are presented in Section 9.1.1. 
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All safety analyses will be performed on the safety population using the following common rules: 
The baseline value is defined as the last non-missing value prior to first IMP intake. Further 
details will be provided in the SAP. 
The following definitions will be applied to laboratory parameters, vital signs and ECG. 
• 
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to pre-defined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs, and ECG. 
• 
PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, 
including unscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the on-treatment PCSA percentage. 
11.4.2.1 Adverse events 
All AEs will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA). Adverse event incidence tables will be presented by system organ class 
(SOC) sorted by internationally agreed order, preferred term (PT), and the number and percentage 
of patients experiencing an AE. Multiple occurrences of the same event in the same patient will be 
counted only once in the tables within a considered period. The denominator for computation of 
percentages is the safety population. 
AE observation period: 
• 
Pretreatment AEs are defined as those AEs that developed or worsened prior to the 
1st study treatment. 
• 
On-treatment AEs are defined as those AEs that developed or worsened between the 
1st study treatment date to the last study treatment date +4 weeks. 
• 
Post-treatment AEs are defined as those AEs that developed or worsened after the 
on-treatment period. 
On-study period will include pretreatment, on-treatment, and post-treatment period. 
Treatment-emergent adverse events (TEAEs) for analysis purpose will include all On-treatment 
AEs. 
Unless otherwise specified, the primary analysis of AE will be based on TEAEs with onset date 
within the first 25 weeks PAP. Similar descriptive summaries will be performed for the long-term 
extension period (after 25 weeks) separately based on those TEAEs with onset date beyond 25 
weeks of treatment phase. A pooled AE summary using all TEAEs during the avalglucosidase alfa 
exposure period will be provided as well. 
Post-treatment AEs will be summarized separately. 
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The incidence of TEAEs, AESI (including IARs), will also be tabulated (frequencies and 
percentages) 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. Relationship of the AE to treatment 
will be categorized as related/not related. The highest level of association will be reported in 
patients with differing relationships for the same AE. 
Listings of AEs, SAEs, IARs and AESIs for all patients will be provided, which will include 
severity and relationship to treatment, as well as actions taken regarding treatment, and patient 
outcome. 
The incidence of AEs leading to study discontinuations will also be summarized by study cohort 
and treatment group, as well as by dose levels among avalglucosidase alfa patients, with details 
provided in the listing. 
Death: The following deaths summaries will be generated: 
• 
Number (%) of patients who died by study period (TEAE, on-study) and reasons for death 
summarized on the safety population by treatment received; 
• 
Death in nonrandomized patients or randomized and not treated patients; 
• 
TEAE leading to death (death as an outcome on the AE e-CRF page as reported by the 
Investigator). 
11.4.2.2 Clinical laboratory tests 
Observed measurements and changes from baseline to study time points in biochemistry, 
hematology, and urinalysis will be descriptively summarized by study cohort and treatment group, 
as well as by dose levels among avalglucosidase alfa-treated patients. All laboratory values will 
be classified as normal, above normal, or below normal based on normal ranges provided by the 
laboratory. Individual listings of patients with potentially clinically significant abnormalities will 
be presented. 
11.4.2.3 Physical examination, vital signs, and electrocardiogram 
Potentially clinically significant findings observed during the on-treatment period for vital signs 
(including but not limited to blood pressure, heart rate, respiratory rate, etc) and ECG (QTc, PR 
interval, etc) will be summarized by study cohort and treatment group, as well as by dose levels 
among avalglucosidase alfa-treated patients. Listings of abnormal findings/values from these data 
as well as from PE assessment inclusive of body weight and height, as well as head circumference 
and Tanner stage, will be presented. 
11.4.2.4 Anti-avalglucosidase alfa and anti-alglucosidase alfa antibodies, neutralizing 
antibodies, and other immunogenicity testing 
Percentage of patients who seroconverted to avalglucosidase alfa, time to seroconversion and peak 
anti-avalglucosidase alfa antibody titer will be summarized using summary statistics.  
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Anti-avalglucosidase alfa and anti-alglucosidase alfa 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, 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. 
11.4.3 Analyses of efficacy endpoints 
Efficacy endpoints are presented in Section 9.2.2. 
To evaluate the effect of switching to avalglucosidase alfa after having received alglucosidase alfa 
at current stable dose, comparative assessment on a composite score and several other efficacy 
endpoints will be conducted using the mITT population in Cohort 3.  
The composite score will be constructed considering 3 domains: GMFM-88 and GMFCS-E&R, 
ptosis, and respiratory function (the use of respiratory device). Within each domain, the change 
from baseline to Week 25 will be classified into improvement, unchanged, and worsening with 
respect to pre-defined minimally important difference in each domain. The corresponding score 
will be determined based on both the baseline status and the change from baseline to Week 25. 
The difference in average composite scores between avalglucosidase alfa and alglucosidase alfa 
patients will be used as the test statistic. Due to the small sample size, statistical inference will be 
derived based on the re-randomization approach instead of the asymptotic approximation. 
Specifically, all possible randomization sequences that are consistent with the selected 
randomization design (matched pairs design with 5 pairs or stratified randomization stratifying on 
gender) will be generated, the test statistics will be calculated for all randomization sequences, 
and the statistical significance level will be calculated as the proportion of more or equally 
extreme scenarios than the observed one, among all possible scenarios. 
The composite score will also be summarized descriptively by treatment group in Cohort 3. 
For those efficacy parameters that are used to identify patients who have sub-optimal response or 
decline as part of inclusion criteria, patient profile (in terms of change over time) will be 
generated for those parameters where each patient will serve as his/her own control. Effect of 
switching from alglucosidase alfa to avalglucosidase alfa will be assessed descriptively within 
each cohort/treatment arm based on changes from pre-study (collected by retrospective chart 
review at screening/baseline) to 6 months post-avalglucosidase alfa treatment collected during the 
study. The control arm (alglucosidase alfa treatment) in Stage 2 will serve as a reference. 
Efficacy will also be summarized for all cohorts based on the safety population (all treated 
patients). For each of the efficacy parameters, observed measurements and changes over time 
from baseline to each post-baseline visit will be summarized by study cohort and treatment arm 
within each stage using descriptive statistics. Continuous data will be summarized using the 
number of available observations, mean, standard deviation (SD), median, minimum, and 
maximum in each study cohort/treatment group. Categorical and ordinal data will be summarized 
using the number and percentage of patients in each study cohort/treatment group. Denominators 
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for the percentages will be based on the safety population with evaluable data on the 
corresponding endpoint. 
11.4.3.1 Multiplicity considerations 
Multiplicity adjustment is not needed as there is only one hypothesis test for the composite score 
defined above between avalglucosidase alfa and alglucosidase alfa groups in Cohort 3. 
11.4.4 Analyses of pharmacokinetic and pharmacodynamic variables 
The list of PK parameters is listed in Section 9.2.1.4. 
PK exposures (Cmax, AUC0-last and t1/2z) for avalglucosidase alfa may be determined using non-
compartmental analysis. If data allow, total body clearance of a drug (CL) and Vd will be 
determined. If data do not lend to non-compartmental analysis, model-based approaches such as 
nonlinear mixed effects modeling may be used. Values will be reported for individual subjects 
and summarized using descriptive statistics by study week as appropriate. 
To evaluate the effect of immunogenicity on the PK of avalglucosidase alfa, predose IgG and 
neutralizing antibody titers for each patient will be analyzed graphically with respect to PK 
parameter. If relationships are apparent, further quantitative/statistical analysis may be performed 
(eg, statistical significance, correlation coefficients). 
Pharmacodynamic endpoints as described in Section 9.3.2 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 PD endpoint is observed, longitudinal 
model may be employed to model change from baseline over time. In addition, 95% confidence 
intervals of changes will be presented. 
Urine Hex4 levels normalized by creatinine 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% confidence intervals 
of changes will be presented.  
Correlation between PK endpoints and Hex4 levels may be explored as appropriate. 
 
 
11.4.5 Analyses of tertiary endpoints 
Tertiary endpoints are presented in Section 9.3.3. 
For each of the tertiary endpoints, observed measurements and changes over time from baseline to 
each post-baseline visit will be summarized by study cohort and treatment arm within each stage 
using descriptive statistics. Continuous data will be summarized using the number of available 
observations, mean, standard deviation (SD), median, minimum, and maximum in each dose 
cohort/treatment group. Categorical and ordinal data will be summarized using the number and 
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percentage of patients in each dose cohort/treatment group. Denominators for the percentages will 
be based on the safety population with evaluable data on the corresponding endpoint. 
11.5 
INTERIM ANALYSIS 
While all patients will be followed for up to 7 years during the study, the primary analysis for the 
study will be performed when all Cohort 3 patients have completed the 6-month PAP. In addition, 
safety analyses will be performed in multiple time points by DMC (see Section 6.4.1) to 
determine the dose for next cohort and the MTD. 
After the primary analysis for the PAP, interim analyses may be performed during the extension 
period to provide additional information for regulatory purpose. 
Since there is only one hypothesis test for the composite score to be performed at the end of the 
PAP, no adjustment is needed for the interim analyses. 
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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.  
• 
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 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.  
- 
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. 
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- 
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), 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 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 
participant or his/her legally authorized representative and answer all questions regarding 
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, 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). When participants are no longer 
in the study, teams in charge of the amendment must define if those participants must re-
consent or not 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 the participant’s legally 
authorized representative.  
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 electronic CRF 
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.  
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• 
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) 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF 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.  
• 
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.  
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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 e-CRF 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. 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF 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 & Data Protection laws and regulations, including the 
GDPR (General Data Protection Regulation). 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 [52]) and/or ethnicity (various drugs [53]). 
• 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; 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 local data protection law. 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. 
• 
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
• 
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 
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development of the investigational product, including to support negotiations with payers 
and publication of result. 
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 used by/communicated to any company of the 
Sanofi group (“Sanofi”) or to Sanofi service providers, where needed. 
• 
Personal data can be processed for other studies. 
• 
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 agency’s 
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 European Economic 
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 subject and should assure 
appropriate subject 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. The Coordinating Investigator will be designated based upon patient participation in the 
study. 
Analysis of 
 
 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 data sets 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. 
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• 
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 to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, 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 case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought where applicable before implementation. 
In some instances, an amendment may require a change to the ICF. The Investigator must receive 
an IRB/IEC approval/favorable opinion concerning the revised ICF prior to implementation of the 
change and patient signature should be re-collected if necessary. 
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16 
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outcome in classic infantile Pompe disease: an open-label single-center study. J Inherit Metab 
Dis. 2016;39(3):383-90. 
19. Vogel M, Staller W, Buhlmeyer K. Left ventricular myocardial mass determined by cross-
sectional echocardiography in normal newborns, infants, and children. Pediatr Cardiol. 
1991;12(3):143-9. 
20. Russell DJ, Rosenbaum PL, Avery LM, Lane M. Gross motor function measure (GMFM-66 & 
GMFM-88) user’s manual. Cambridge University Press; 2002.  
21. Ruck-Gibis JH, Plotkin H, Hanley J, Wood-Dauphinee S. Reliability of the gross motor 
function measure for children with osteogenesis imperfecta. Pediatr Phys Ther. 2001;13(1):10-
7. 
22. Wright MJ, Halton JM, Martin RF, Barr RD. Long-term gross motor performance following 
treatment for acute lymphoblastic leukemia. Med Pediatr Oncol. 1998;31(2):86-90. 
23. Winkel LP, Van den Hout JM, Kamphoven JH, Disseldorp JA, Remmerswaal M, Arts WF, et 
al. Enzyme replacement therapy in late-onset Pompe’s disease: a three-year follow-up. Ann 
Neurol. 2004;55(4):495-502. 
24. Palisano RJ, Rosenbaum P, Bartlett D, Livingston MH. Content validity of the expanded and 
revised Gross Motor Function Classification System. Dev Med Child Neurol. 
2008;50(10):744-50. 
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25. van Capelle CI, van der Beek NA, de Vries JM, van Doorn PA, Duivenvoorden HJ, Leshner 
RT, et al. The quick motor function test: a new tool to rate clinical severity and motor function 
in Pompe patients. J Inherit Metab Dis. 2012;35(2):317-23. 
26. Haley SM, Dumas HM, Rabin JP, Ni P. Early recovery of walking in children and youths after 
traumatic brain injury. Dev Med Child Neurol. 2003;45(10):671-5. 
27. Haley SM, Fragala MA, Aseltine R, Ni P, Skrinar AM. Development of a disease-specific 
disability instrument for Pompe disease. Pediatr Rehabil. 2003;6(2):77-84. 
28. Haley SM, Fragala-Pinkham MA, Ni PS, Skrinar AM, Kaye EM. Pediatric physical 
functioning reference curves. Pediatr Neurol. 2004;31(5):333-41. 
29. Haley SM, Ni P, Fragala-Pinkham MA, Skrinar AM, Corzo D. A computer adaptive testing 
approach for assessing physical functioning in children and adolescents. Dev Med Child 
Neurol. 2005;47(2):113-20. 
30. Prakalapakorn SG, Proia AD, Yanovitch TL, DeArmey S, Mendelsohn NJ, Aleck KA, et al. 
Ocular and histologic findings in a series of children with infantile Pompe disease treated with 
enzyme replacement therapy. J  Pediatr Ophthalmol Strabismus. 2014;51(6):355-9. 
31. Slingerland NW, Polling JR, van Gelder CM, van der Ploeg AT, Bleyen I. Ptosis, extraocular 
motility disorder, and myopia as features of pompe disease. Orbit. 2011;30(2):111-3. 
32. Bali DS, Goldstein JL, Rehder C, Kazi ZB, Berrier KL, Dai J, Kishnani PS. Clinical 
laboratory experience of blood CRIM testing in infantile Pompe disease. Mol Genet Metab 
Rep. 2015;5:76-9. 
33. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation 
of spirometry. Eur Respir J. 2005;26(2):319-38. 
34. American Thoracic Society. ATS Statement: Guidelines for the Six-Minute Walk Test. Am J 
Respir Crit Care Med. 2002;166(1):111-7. 
35. Wraith JE, Clarke LA, Beck M, Kolodny EH, Pastores GM, Muenzer J, et al. Enzyme 
replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-
controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). J 
Pediatr. 2004;144(5):581-8. 
36. Muenzer J, Wraith JE, Beck M, Giugliani R, Harmatz P, Eng CM, et al. A phase II/III clinical 
study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter 
syndrome). Genet Med. 2006;8(8):465-73. 
37. McDonald CM, Henricson EK, Han JJ, Abresch Rt, Nicorici A, Elfiring GL, et al. The 6-
Minute walk test as a new outcome measure in Duchenne Muscular Dystrophy. Muscle and 
Nerve. 2010;41(4):500-10. 
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38. Geiger R, Strasak A, Treml B, Gasser K, Kleinsasser A, Fischer V, et al. Six-minute walk test 
in children and adolescents. J Pediatr. 2007;150(4):395-9. 
39. American Thoracic Society. International consensus conferences in intensive care medicine: 
noninvasive positive pressure ventilation in acute respiratory failure. Am J Respir Crit Care 
Med. 2001;163(1):283-91. 
40. Varni JW, Seid M, Kurtin PS. PedsQL™ 4.0: Reliability and validity of the Pediatric Quality 
of Life Inventory™ Version 4.0 Generic Core Scales in healthy and patient populations. Med 
Care. 2001;39(8):800-12. 
41. Varni JW, Burwinkle TM, Seid M, Skarr D. The PedsQ 4.0 as a pediatric population health 
measure: feasibility, reliability, and validity. Ambul Pediatr. 2003;3(6):329-41. 
42. Varni JW, Waldron SA, Gragg RA, Rapoff MA, Bernstein BH, Lindsley CB, et al. 
Development of the Waldron/Varni pediatric pain coping inventory. Pain. 1996;67(1):141-50. 
43. van Dijk M, Koot HM, Saad HH, Tibboel D, Passchier J. Observational visual analog scale in 
pediatric pain assessment: useful tool or good riddance? Clin J Pain. 2002;18(5):310-6. 
44. Bayley N. Bayley Scales of Infant and Toddler Development. Third ed: Harcourt Assessment, 
Inc.; 2005. 
45. Roid GH, Miller LJ, Poplun M, Koch C. Leiter International Performance Scale- 3rd Edition 
(Leiter3). Wood Dale, IL: Stoelting; 2013. 
46. Galton DJ, Reckless JP & Taitz LS.  Triglyceride storage disease.  A report of two affected 
children associated with neurological abnormalities. Acta Paediatr Scand.1976;65(6):761-768. 
47. Jurecka W, Aberer E, Mainitz M, Jurgensen O. Keratitis, ichthyosis, and deafness syndrome 
with glycogen storage. Arch Dermatol. 1985;121(6):799-801. 
48. Kamphoven JH, de Ruiter MM, Winkel LP, Van den Hout HM, Bijman J, De Zeeuw CI, et al. 
Hearing loss in infantile Pompe's disease and determination of underlying pathology in the 
knockout mouse. Neurobiol Dis. 2004;16(1):14-20. 
49. Cunningham MD and Cox EO. Hearing Assessment in Infants and Children: 
Recommendations Beyond Neonatal Screening. Pediatrics. 2003;111(2):436-440. 
50. Hahn SH, Kronn D, Leslie ND, Pena LDM, Tanpaiboon P, Gambello MJ, et al. Efficacy, 
safety profile, and immunogenicity of alglucosidase alfa produced at the 4,000-liter scale in 
US children and adolsecents with Pompe disease: ADVANCE, a phase IV, open-label 
prospective study. Genet Med 2018;20(10):1284-94. 
51. Kishnani PS, Beckemeyer AA, Mendelsohn NJ. The new era of Pompe disease: advances in 
the detection, understanding of the phenotypic spectrum, pathophysiology, and management. 
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(Vol. 160, No. 1, pp. 1-7). Wiley Subscription Services, Inc., A Wiley Company. 
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52. Schelleman, H., Chen, J., Chen, Z., Christie, J., Newcomb, C., Brensinger, et al. Dosing 
Algorithms to Predict Warfarin Maintenance Dose in Caucasians and African Americans. Clin 
Pharmacol Ther. 2008;84: 332–9. 
53. Yasuda, S., Zhang, L. and Huang, S.-M. 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 
APPENDICES 
17.1 
APPENDIX A: GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION 
DEFINITIONS 
Woman of childbearing potential (WOCBP) 
A woman is considered of reproductive potential (WOCBPWOCBP), ie, fertile, following 
menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE  
Male and Female Subjects 
 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationb 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormone contraception associated with inhibition of ovulationb 
− oral 
− injectable 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationb  
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole 
sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If 
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not, an additional highly effective method(s) of contraception should be used. Spermatogenesis cycle is 
approximately 90 days.) 
• Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the subject.) 
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for subjects participating in 
clinical studies. 
b) Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the 
efficacy of the contraceptive method. In this case TWO highly effective methods of contraception 
should be used during the treatment period and for at least 28 days after the last dose of study treatment. 
 
COLLECTION OF PREGNANCY INFORMATION 
Male subjects with partners of reproductive potential who become pregnant  
• 
The Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study. After 
obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. 
• 
Partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor. 
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for procedure. 
Female subjects who become pregnant  
• 
The Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study;  
• 
Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant's pregnancy.  
• 
Participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on participant and neonate, which will be forwarded to 
the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond 
the estimated delivery date.  
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• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
For the purpose of this study 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 (please refer to 
Section 10.4.1.2). 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE. 
• 
A spontaneous abortion is always considered to be an SAE and will be reported as such. 
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably related 
to the study treatment by the Investigator, will be reported to the Sponsor as described in 
Section 10.1.6. While the Investigator is not obligated to actively seek this information in former 
study subjects, he or she may learn of an SAE through spontaneous reporting.  
17.2 
APPENDIX B: GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI 
Note: A final decision regarding permanent discontinuation of IMP will be made by the Sponsor 
after consideration of DMC recommendations. 
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Neutrophils < 1500/mm3 or according to ethnic 
group
NEUTROPENIA
Repeat immediately a full blood count if value 
close to 1500/mm3
Neutrophils < 1500/mm3 confirmed 
with signs of infection  
Neutrophils < 1500/mm3 confirmed 
with no signs of infection  
1.
DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.
PERFORM biological 
investigations for infection
1.
DISCONTINUE
Investigational 
Medicinal Product
2.
INVESTIGATE for 
infection
In both situations
3.
INFORM the local monitor
4.
INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X-rays, etc.
5.
PERFORM and collect the following investigations (results): 
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella
6.
DECISION for bone marrow aspiration: to be taken in specialized unit
7.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
8.
MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
Note: 
•The procedures described in the above flowchart are to be discussed with the patient only in case 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
•For individuals of African descent, the relevant value of concern is <1000/mm3
Neutropenia is to be recorded as AE only if at least one of the criteria listed in Section 10.4.3 is met
 
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AE in Section 10.4.2 is met. 
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Platelets < 100 000/mm3 (rule out EDTA – induced 
pseudo-thrombocytopenia)
THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample)
Platelets  < 100 000/mm3 confirmed 
with bleeding  
Platelets  < 100 000/mm3 confirmed 
with no bleeding
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE for 
bleeding
In both situations
3.
INFORM the local Monitor
4.
QUESTION about last intake of quinine (drinks), alcoholism, heparin administration
5.
PERFORM or collect the following investigations: 
•
Complete blood count, schizocytes, creatinine
•
Bleeding time and coagulation test (fibrinogen, INR or PT, aPTT), Fibrin 
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
7.
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 1 in the case of associated anemia and/or leukopenia
•
On Day 8 if platelets remain < 50 000/mm3
8.
MONITOR the platelet count every day for at least one week and then regularly 
until it returns to normal
Note: 
The procedures above flowchart are to be discussed with the patient only in case described in the 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
Thrombocytopenia is to be recorded as AE only if at least one of the criteria listed in Section 10.4.3 
is met
 
Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Section 10.4.2 is met. 
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INCREASE IN ALT
ALT > 3 ULN
Confirm ALT > 3 ULN
Retest within 72 hours of initial 
sample*
No
Yes
COMPLETE the specific CRF forms for 
„ALT Increase” and inform the 
Monitoring Team within 24 hours
Total Bilirubin > 2 ULN 
No
Yes
ALT > 5 ULN (if baseline ALT ≤ 2 ULN), or 
ALT >8 ULN (if baseline ALT > 2 ULN)
Continue IMP administration
No
Monitor LFTs every 72 hours
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
Yes
Permanent Discontinuation of IMP
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or hypotension and/or episode of 
arrhythmia in the previous 72 hours; rule out muscular injury
3.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV  IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
4.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
5.
CONSIDER consulting with hepatologist
6.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances suggesting hepatic 
encephalopathy
7.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to normal/baseline or clinical 
resolution.
8.
FREEZE serum sample (5ml x 2)
9.
In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done
 
 
*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation.  
Note: 
• “Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the 
baseline visit. The algorithm does not apply to the instances of increase in ALT during screening. 
• See Section 10.4 for guidance on safety reporting. 
• Normalization is defined as ≤ ULN or baseline value, if baseline value is >ULN. 
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Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below
50 mL/mn
ACUTE RENAL FAILURE
Can be rapidly reversed:
• By volume repletion
• Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: anemia, 
hyperkalemia, hyperuricemia, metabolic 
acidosis, cardiac insufficiency, 
pulmonary edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
Investigational Medicinal Product by 
renal route
1.
Investigational Medicinal 
Product may be continued
2.
MONITOR serum creatinine 
until return to baseline level
1.
INFORM the local monitor
2.
DISCONTINUE
Investigational Medicinal Product 
administration
3.
HOSPITALIZATION should be 
considered and seek for nephrologic  
advice
4.
PERFORM the following 
examinations: 
•
BP, HR, hydration status, ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
COLLECT/STORE one sample 
following handling procedures 
described in PK sections (for studies 
with PK sampling) and freeze one 
serum sample (5 mL) on Day 1 
(cessation of investigational 
medicinal product)
6.
MONITOR renal function until 
return to baseline level (every day at 
the beginning, then every week)
Acute renal failure is to be recorded as AE only if at least one of the criteria listed in 
Section 10.4.3 is met
 
Acute renal failure is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Section 10.4.2 is met. 
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17.3 
APPENDIX C: COUNTRY-SPECIFIC REQUIREMENTS 
17.3.1 United Kingdom 
17.3.1.1 Requirement for local protocol amendment dated 02 Feb 2017 
An amendment to the protocol applicable in the United Kingdom was written in response to a 
request by the Medicines and Healthcare products Regulatory Agency (MHRA) medical reviewer. 
In alignment with requirements from the MHRA, the last paragraph of Section 10.3.1 underlines 
that final decisions regarding 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, this decision may be 
made prior to receipt of the Data Monitoring Committee (DMC) recommendation. 
10.3 HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
The following text: 
In the event a significant safety concern arises, the Sponsor may immediately decide to 
discontinue study drug dosing in all clinical trial patients and to not dose new patients, prior to 
receipt of DMC recommendations  
Is replaced with: 
In the event a significant safety concern arises, the Sponsor may will immediately decide to 
discontinue study drug dosing in all clinical trial patients and to not dose new patients, prior to 
receipt of DMC recommendations. This applies to a decision on dose escalation, as outlined in 
Section 4 as well. 
17.3.1.2 Requirement for amended protocol dated 23 Mar 2020 
In order to comply with the UK position regarding the protocol language, the duration of the 
additional follow-up phase will be defined as ‘up to 144 weeks after the last patient has been 
enrolled in the study’. 
17.3.2 Germany 
17.3.2.1 Requirement for local protocol amendment dated 04 Oct 2017 
• 
Provide an amendment to the protocol applicable only in Germany in response to a request 
by the Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for Drugs 
and Medical Devices [BfArM]) 
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In section(s): 10.4.2 
Rationale: In principle, all changes in laboratory values, vital signs and electrocardiograms which 
occur within a clinical trial and which the study investigator assesses as clinically relevant must 
be documented as adverse events. 
In alignment with requirements from the BfArM the following update is added as a local protocol 
amendment for Germany. 
In section(s): 
10.4.2 General guidelines for reporting adverse events 
The following text: 
• 
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. 
Is replaced with: 
• 
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, and/or 
- 
Otherwise deemed by the Investigator to be clinically significant. 
17.3.3 France 
Consistent with the French Health Authority position disallowing home infusion for all ERTs, the 
option for home infusion added in ACT14132 amended protocol 02 does not apply in France. 
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17.4 
APPENDIX D: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes for the current amendment is located directly 
before the Clinical Trial Summary. 
17.4.1 Amended protocol 01: 27 Jul 2018 
Major changes (eg, substantial changes according to European Clinical Trial Applications 
guidance) for modifying the Final Version of the Protocol were made as part of this protocol 
amendment.  
• 
Change to the sample size 
In section(s): tabulated clinical trial summary, Sections 1.1, 4, 6.1, 6.4.1, 8.1.1 and 8.4 of 
the protocol 
Rationale: 
- 
Cap of 5 patients per cohort in Stage 1, Cohort 1 and Cohort 2, has been removed to 
alleviate constraints in conduct of the study and maximize the collection of data in 
pediatric patients. At least 10 patients will be included in Cohort 3. 
• 
Change to endpoints 
In section(s): tabulated clinical trial summary, Sections 1.2.1, 1.2.3, 9.3.3.5, 9.3.3.5.2, 
10.1.1, 10.1.2.6, 10.1.3.7, and 16 of the protocol 
Rationale: 
- 
FLACC assessment has been removed from the protocol to reduce patient and 
investigational staff burden due to the limited expected value of the assessment. 
• 
Change to sampling for pharmacodynamic variables 
In section(s): tabulated clinical trial summary, Sections 1.2.1, 1.2.3, 2, 3, 9.3.2.2, 10.1.2.1, 
10.1.2.6, 10.1.3.6, 10.1.3.7 and 14.9 of the protocol 
 
 
 
 
. 
• 
Change to inclusion/exclusion criteria 
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In section(s): Sections 7.2.1 and 8.8.2 of the protocol 
Rationale: 
- 
E 06. Beta-blockers are no longer a prohibited concomitant medication as they are 
considered standard of care in this IOPD patient population. 
Globally, reference to the investigational medicinal product (product code GZ402666) has been 
changed from neoGAA to its recently approved International Nonproprietary Name, 
avalglucosidase alfa. 
17.4.2 Amended protocol 02: 24 Mar 2020 
Overall Rationale for the Amendment 
Global changes 
• 
In order to allow study participants to continue to receive the investigational medicinal 
product (IMP) after Week 145, the study has been extended to an additional period of up 
to 226 weeks (Week 371) or until avalglucosidase alfa is approved in the patient’s country, 
whichever comes first (refer to Appendix C [Section 17.3.1] for definition applicable for 
UK patients). 
• 
In countries where it is permitted, home infusion of avalglucosidase alfa in the extension 
period may be allowed (refer to Appendix C [Section 17.3.3] for France]). 
• 
Clarifications were given regarding the conditions for temporary IMP discontinuation with 
DMC consultation. 
• 
Clarifications were given regarding AESI related to LFT values that can fluctuate as part 
of the underlying Pompe disease. 
• 
Clarification was given in the tertiary endpoints that the Motor Skills Checklist is 
completed in concert with the Gross Motor Function Classification System, Expanded and 
Revised. 
• 
Clarification was given in the description of some tertiary endpoints. 
• 
Clarification was given regarding the possibility of additional interim analysis for 
regulatory purpose during the extension period. 
• 
Clarification was given regarding the order of motor assessments. 
• 
As patients are no longer treated with alglucosidase alfa after Week 25 when entering the 
extension period, the collection of samples for analysis of anti-alglucosidase alfa 
antibodies was removed from the follow-up after primary analysis period (PAP). 
• 
Sections 12, 13, and 14 were updated to reflect practices as outlined in the current protocol 
template. 
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France-specific requirement 
• 
The option for home infusion added in this amended protocol 02 does not apply in France 
to be consistent with the French Health Authority position disallowing home infusion for 
all enzyme replacement therapies (ERT). 
United Kingdom-specific requirement 
• 
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 and Change 
Brief Rationale 
Clinical trial summary (Secondary 
endpoints) 
Section 9.2.1.4 (Pharmacokinetics 
parameters) 
Section 11.4.4 (Analyses of 
pharmacokinetic and pharmacodynamic 
variables) 
Terminal half-life (t1/2z) was added as an 
additional PK parameter 
Although tested, this parameter was not 
presented in the protocol. It is then 
added. 
Clinical trial summary (Tertiary 
endpoints)  
Section 9.3.3.9 (Motor Skills Checklist) 
Motor Skills Checklist was added under 
tertiary endpoints 
Although tested, this parameter was not 
included as an endpoint. Since this 
evaluation is complementary to other 
motor evaluations it is then added under 
tertiary endpoints.  
Clinical trial summary (Assessment 
schedule, Duration of study period), 
Section 6.2.1 (Duration of study 
participation for each patient),  
Section 8.1.2 (Extension period: Week 
27 to Week 145 (Month 36) and 
additional extension period from Week 
147 onwards) 
An additional extended follow-up period 
of up to 226 weeks and corresponding 
text was added including text to comply 
with the United Kingdom (UK) position 
regarding the protocol language with 
regards to the study follow-up period 
duration. 
To allow study participants to continue to 
receive the investigational medicinal 
product (IMP) after Week 145.  
Clinical trial summary (Assessment 
schedule) 
Section 10.1.2 (Treatment period) 
Language for time window for visits is 
updated 
Clarification and consistency with other 
studies of the program 
Section 1.2.1 (Treatment period)-Efficacy 
Motor Skills Checklist was added. 
To comply with the addition of this 
parameter in the tertiary endpoints. 
Section 1.2.1 (Treatment period)-
Footnote “a” 
Additional text was added in case of 
temporary discontinuation 
Clarification 
Section 1.2.1 (Treatment period)-
Footnote “g” 
The footnote was edited to adopt the 
amendment-specific change 
Clarification and consistency with other 
studies of the program 
Section 1.2.1 (Treatment period)-
Footnote “u” 
The footnote was edited regarding use 
and reporting of ventilator diary 
Clarification 
Section 1.2.2 (Extension period 
(Week 27 to Week 35)  including details 
for Stage 2 - Cohort 3 for patients 
switching to avalglucosidase alfa) Safety 
Deleted anti-alglucosidase alfa 
antibodies assessments post primary 
analysis period (PAP)  
As patients are no longer treated with 
alglucosidase alfa in ETP, the 
measurement of anti-alglucosidase alfa 
after PAP is no longer needed. 
Section 1.2.2 (Extension period 
(Week 27 to Week 35) including details 
for Stage 2 - Cohort 3 for patients 
switching to avalglucosidase alfa) 
Footnote “b” 
Additional text was added in case of 
temporary discontinuation  
Clarification 
Section 1.2.2 (Extension period (Week 
27 to Week 35) including details for 
Stage 2 - Cohort 3 for patients switching 
to avalglucosidase alfa) Footnote “j” 
The footnote was edited regarding use 
and reporting of ventilator diary  
Clarification 
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Section # and Name 
Description and Change 
Brief Rationale 
Section 1.2.3 (Extension period (Week 
37 to Week 145) 
• 
Section heading was updated from 
Week 149 to Week 145 
• 
The column for the 4-week follow-
up visit/contact and 37 Month 
(Week 149) was deleted 
• 
Deleted anti-alglucosidase alfa 
antibodies assessments post PAP 
• 
Efficacy: Motor Skills Checklist was 
added. 
• 
Footnote “a”: Additional text was 
added regarding temporary 
discontinuation and instruction was 
added regarding home infusion 
• 
Footnote “b”: Additional text added 
regarding possibility of home 
infusion of avalglucosidase alfa 
• 
Footnote “r”: The footnote was 
edited regarding use and reporting 
of ventilator diary 
To reflect the amendment specific 
changes and including additional 
extended follow-up period 
Section 1.2.4 (Extended long-term 
treatment period) 
New schedule of assessment regarding 
extended long-term treatment period was 
added. 
To reflect the amendment-specific 
changes 
Section 1.2.5 (End of study) 
New schedule of assessment regarding 
end of study was added. 
To reflect the amendment-specific 
changes 
Section 6.3 (Interim analysis) and 
Section 11.5 (Interim analysis) 
New text was added regarding possibility 
of additional interim analysis for 
regulatory purpose during the extension 
period 
Clarification 
Section 8.1 (Investigational medicinal 
product(s)) 
• 
Clarification that the use of an in-
line filter is for alglucosidase alfa 
infusions only 
• 
The following text was added: “The 
Sponsor will inform the DMC of any 
dose change related to AEs” 
• 
Extension period of “120-week” 
changed to “up to 346-week” 
Clarification 
Section 8.9 (Home infusion)  
Section 8.9.1 (Home infusion for patients 
receiving alglucosidase alfa) 
New section for home infusion details 
including the re-numbered section on 
home infusion for alglucosidase alfa and 
the new section on home infusion for 
avalglucosidase alfa 
Implementation of home infusion of 
avalglucosidase alfa as an option, where 
allowed. 
Section 8.9.2 (Home infusion for patients 
receiving avalglucosidase alfa) 
New section and corresponding text 
regarding home infusion for patients 
receiving avalglucosidase alfa was 
added. 
To reflect the amendment-specific 
changes 
Section 9.1.1.3 (Vital signs) 
Text updated to clarify what is included in 
the definition of infusion rate change  
Clarification 
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Section # and Name 
Description and Change 
Brief Rationale 
Section 9.1.1.7 (Immunogenicity) 
Updated anti-avalglucosidase alfa 
assessment period and deleted 
anti-alglucosidase alfa assessments. 
As patients are no longer treated with 
alglucosidase alfa in ETP, the 
measurement of anti-alglucosidase alfa 
after PAP is no longer needed. 
Section 9.2.1.3 (Bioanalytical method) 
Updated lower limit of quantification from 
12.50 ng/mL (or 0.0130 ng/mL) to 
12.0 ng/mL (or 0.0120 ng/mL)  
Clarification 
Section 9.2.2.4 (Echocardiography) 
Text is updated to clarify that M-mode is 
also performed 
Clarification 
Section 9.3.3.3 (Ventilator use diary) 
Text was updated regarding reporting of 
periods for ventilator use/day 
Clarification 
Section 9.3.3.9 (Motor Skills Checklist) 
New section for Motor Skills Checklist 
and corresponding text was added. 
To reflect the amendment-specific 
changes 
Section 10.1 (Visit schedule) 
The order for evaluating motor 
assessments was edited, the Motor Skills 
Checklist was added, and GSGC scale 
was deleted. 
Clarification 
Section 10.1.1 (Screening/baseline visit) 
Motor Skills Checklist was added for 
GMFCS-E&R 
To comply with the addition of this 
parameter in the tertiary endpoints. 
Section 10.1.2.2 (One week following 
first infusion (Week 2 [Day 8])) 
Added text for anti-alglucosidase alfa 
anti-drug antibodies (ADA) assessments. 
Clarification 
Section 10.1.2.5 (Monthly) 
The following bullet points were added: 
• 
Biomarkers: 
o 
Urine Hex4 sample collection 
• 
Ventilator use diary; 
• 
Eyelid position measurements; 
• 
Vital signs (before, during, and 
following infusion: see Section 1.2); 
• 
IRT contact for IMP resupply; 
• 
Infusion of IMP; 
Clarification for visit exhaustivity  
Section 10.1.2.6 (Every 3 months) 
• 
Motor Skills Checklist was added for 
GMFCS-E&R 
• 
New bullet list as “IRT contact for 
IMP resupply” was added 
To reflect the amendment-specific 
changes and clarification for visit 
exhaustivity 
Section 10.1.3 (Extension period) 
Section heading was adjusted to 
“Extension period (Week 27 to 
Week 145)” 
Clarification.  
Section 10.1.3.2 (One week following 
first infusion within the extension period) 
Deleted assessments for 
anti-alglucosidase alfa antibodies  
As patients are no longer treated with 
alglucosidase alfa in ETP, the 
measurement of anti-alglucosidase alfa 
after PAP is no longer needed. 
Section 10.1.3.3 (Two weeks following 
first infusion within the extension period 
(Week 29)) 
• 
New bullet list as “IRT contact for 
IMP resupply” was added 
Clarification for visit exhaustivity 
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Section # and Name 
Description and Change 
Brief Rationale 
Section 10.1.3.4 (Every 2 weeks 
(Biweekly)) 
• 
Section heading updated and added 
“Every 2 weeks” 
• 
"W147" removed from list of time 
points 
Clarification 
Section 10.1.3.5 (Every 4 weeks 
(Monthly)) 
• 
Section heading updated and added 
“Every 4 weeks” 
• 
New bullet list as “ventilator use 
diary” was added 
• 
New bullet list as “IRT contact for 
IMP resupply” was added 
Clarification for visit exhaustivity 
Section 10.1.3.6 (Every 12 weeks 
(Quarterly)) 
• 
Section heading changed from 
“Every 3 months” to “Every 
12 weeks (Quarterly)” 
• 
Deleted assessments for 
anti-alglucosidase alfa antibodies 
• 
New bullet list as “ventilator use 
diary” was added 
• 
New bullet list as “IRT contact for 
IMP resupply” was added 
Clarification for visit exhaustivity. 
As patients are no longer treated with 
alglucosidase alfa in ETP, the 
measurement of anti-alglucosidase alfa 
after PAP is no longer needed. 
Section 10.1.3.7 (Every 24 weeks (every 
6 months)) 
• 
Updated section heading and added 
“Every 24 weeks” 
• 
Deleted assessments for 
anti-alglucosidase alfa antibodies 
• 
The following text was added: 
“Avalglucosidase alfa plasma PK 
sample collection (before and 
following infusion) for Stage 2 – 
Cohort 3 patients switching to 
avalglucosidase alfa in the 
extension period: at W37 and W49. 
For these patients the W49 visit 
(V28) requires a stay at the site 
prior to and for at least 8 hours 
following the end of IMP infusion. 
Another sample will be taken 12 to 
16 hours after the end of IMP 
infusion. If the Cohort 3 dose of 
avalglucosidase alfa is 20 mg/kg 
qow, this additional sample will not 
be taken;” 
• 
Motor Skills Checklist was added 
The following bullet points were added: 
• 
IRT contact for IMP resupply; 
• 
Infusion of avalglucosidase alfa; 
• 
AE collection; 
• 
Concomitant medications/therapies. 
Clarification for visit exhaustivity. 
As patients are no longer treated with 
alglucosidase alfa in ETP, the 
measurement of anti-alglucosidase alfa 
after PAP is no longer needed. 
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Section # and Name 
Description and Change 
Brief Rationale 
Section 10.1.4 (Extended long-term 
treatment period (From Week 147 
onwards) 
New section and corresponding text was 
added for extended long-term treatment 
period 
To reflect the amendment-specific 
changes 
Section 10.1.6 (Follow-up) 
Text was updated in case of missed visit 
where efficacy assessments/procedures 
to be performed 
Clarification 
Section 10.1.7 (Follow-up for patients 
who temporarily or permanently 
discontinued the study treatment) 
The following text was added: “Patients 
who permanently discontinue the study 
treatment prior to the scheduled end of 
treatment during the extended long-term 
treatment period will have assessments 
corresponding to the end of treatment 
visit.” 
Clarification 
Section 10.3.1 (Temporary treatment 
discontinuation with investigational 
medicinal product(s)) 
The bulleted list was changed from: “Any 
increase in ALT, AST, total bilirubin, or 
alkaline phosphatase >3x the baseline 
value” to “Any increase in ALT, AST, total 
bilirubin, or alkaline phosphatase >3 × 
the baseline value, except if the 
increased value is still within the normal 
range.” 
Clarification 
Section 10.4.1.3 (Adverse event of 
special interest) and Table 4 (Summary 
of adverse event reporting instructions) 
The criteria was changed from: “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” to “A maximum ALT value of 
≥400 IU/L (except if baseline value is 
≥400 IU/L) or AST value of ≥500 IU/L 
(except if baseline value is ≥500 IU) or 
an increase in direct, indirect, or total 
bilirubin of ≥2 x ULN” 
Clarification 
Section 10.6 (Safety instructions) 
The following text was added: “Moderate, 
severe, and recurrent mild IARs will be 
discussed with the DMC. If the DMC 
recommends or suggests that a 
desensitization procedure to the IMP 
could be proposed to the patient, in 
agreement with the Investigator and the 
patient’s guardian(s), such a procedure 
may be initiated as per guidelines in the 
pharmacy manual.” 
Text added for IAR evaluation by DMC 
with the possibility of desensitization 
procedure 
Section 11.4.1.1 (Compliance) 
Updated the compliance text.  
Clarification 
Section 11.4.2.4 (Anti-avalglucosidase 
alfa and anti-alglucosidase alfa 
antibodies, neutralizing antibodies, and 
other immunogenicity testing) 
Updated the text pertaining to 
summarization of anti-avalglucosidase 
alfa and anti-alglucosidase alfa titer.  
Clarification 
Section 11.4.3 (Analyses of efficacy 
endpoints) 
Updated the text for composite score.  
Clarification 
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Section # and Name 
Description and Change 
Brief Rationale 
Section 12 (Regulatory, ethical, and 
study oversight considerations),  
Section 13 (Study monitoring) 
Section 14 (Additional requirements) 
The sections were updated to reflect the 
current protocol template-specific text. 
To align with current protocol template 
Section 16 (Bibliographic references) 
New reference #50 was added and 
subsequent references were 
renumbered.  
Reference to new text added.  
Section 17.3: Appendix C 
(Country-specific requirements) 
The section was updated to include 
UK- and France-specific amendment text 
Administrative update. 
Section 17.4: Appendix D (Protocol 
amendment history) 
New section and corresponding text was 
added 
Administrative update. 
Throughout 
Typos have been corrected where 
necessary. 
Clarifications 
Throughout 
Minor editorial and document formatting 
revisions 
Minor, therefore have not been 
summarized 
 
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