Conditions: Glycogen Storage Disease Type II;Pompe's Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 101
Healthy volunteers: no

Brief summary:
Primary Objective:

To determine the effect of avalglucosidase alfa treatment on respiratory muscle strength measured by percent (%) predicted forced vital capacity (FVC) in the upright position, as compared to alglucosidase alfa.

Secondary Objective:

To determine the safety and effect of avalglucosidase alfa treatment on functional endurance (6-minute walk test, inspiratory muscle strength (maximum inspiratory pressure), expiratory muscle strength (maximum expiratory pressure), lower extremity muscle strength (hand-held dynamometry), motor function (Quick Motor Function Test), and health-related quality of life (Short Form-12).

Detailed description:
The duration of the study per participant will be up to approximately 6 years that will consist of a 14-day screening period (may be extended up to 8 weeks in pre-specified situations), a 49-week blinded treatment period (except for the subgroup of pediatric patients aged 3 to less than (\<) 18 years enrolling directly in the open-label long-term follow-up phase), a 240-week open-label treatment period, and a 4-week post-treatment observation period.

Arms:
arm 1: Administered intravenously every 2 weeks arm 2: Administered intravenously every 2 weeks

Interventions: intervention 1: Avalglucosidase alfa (GZ402666) intervention 2: Alglucosidase alfa (GZ419829)
Intervention descriptions: intervention 1: Pharmaceutical form: powder for concentrate for solution for infusion Route of administration: intravenous intervention 2: Pharmaceutical form: powder for concentrate for solution for infusion Route of administration: intravenous

Protocol document:
Prot_002.pdf: 


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NAMES AND ADDRESSES OF
COORDINATING 
INVESTIGATOR
Name:
Address:
Tel:
Fax:
Email:
MONITORING TEAM’S 
REPRESENTATIVE
Name:
Address:
Tel:
Fax:
Email:
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 06 
UK only 
04-Feb-2022, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 05 
Canada only 
18-Nov-2021, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 04 (Global) 
All 
21-Dec-2020, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 03 (Global) 
All 
10-Apr-2019, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02 (Global) 
All 
18-Jul-2017, version 1 (electronic 2.0) 
Protocol Amendment 03 
All 
18-Jul-2017, version 1 (electronic 1.0) 
Protocol Amendment 02 (SE) 
Sweden only 
03-Aug-2016, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 01 (Global) 
All 
03-Aug-2016, version 1 (electronic 1.0) 
Protocol Amendment 01 
All 
03-Aug-2016, version 1 (electronic 1.0) 
Clinical Trial Protocol 
 
30-Mar-2016, version 1 (electronic 3.0) 
Amended protocol 06 (04 February 2022)
This amended protocol 06 is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
OVERALL RATIONALE FOR THE AMENDMENT
Under the current EFC14028 protocol applicable for patients in the UK (Amended protocol 04) 
the duration of the extended open-label avalglucosidase alfa long-term follow-up period is defined 
as ‘up to 144 weeks after the last patient has been enrolled in the study’. Last enrolled patient was 
a pediatric patient enrolled in the open-label period in August 2020. The 144-week period leads to 
May 2023. This date is inconsistent with the maximum period allowed per protocol, which is 
289 weeks of treatment, because all patients in the UK will reach Week 289 earlier than 
May 2023. In order to correct this discrepancy, the duration of the extended open-label 
avalglucosidase alfa long-term follow-up period will be defined as ‘up to the approval in the 
country or to the maximal duration planned in the study (ie, end of treatment at Week 289),
whichever occurs first’.
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Protocol amendment summary of changes table
Section # and Name
Description and Change
Brief Rationale
Protocol Amendment Summary of 
Changes 
Document formatting revision. 
To update document history and provide 
overall rationale for the amendment and 
summary of changes table. 
Section 17.3 Appendix C: Country-
specific requirements 
Revised text in Section 17.3.4 United 
Kingdom to state the following: 
In the UK, the duration of the extended 
open-label avalglucosidase alfa long-
term follow-up period will be defined as 
‘up to the approval in the country or to 
the maximal duration planned in the 
study (ie, end of treatment at 
Week 289), whichever occurs first’. 
To correct a discrepancy in the definition 
of duration of the extended open-label 
avalglucosidase alfa long-term follow-up 
period in the UK to not exceed the 
maximal planned 289-week duration of 
treatment in the study. 
Section 17.4 Appendix D: Protocol 
amendment history 
Added new section (Section 17.4.5). 
To incorporate the changes from 
amended protocol 05 to the amended 
protocol 06. 
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CLINICAL TRIAL SUMMARY
COMPOUND: GZ402666
STUDY No.: EFC14028
STUDY NAME: COMparative Enzyme replacement Trial with 
neoGAA versus rhGAA (COMET)
TITLE
A Phase 3 randomized, multicenter, multinational, double-blinded 
study comparing the efficacy and safety of repeated biweekly infusions 
of avalglucosidase alfa (neoGAA, GZ402666) and alglucosidase alfa in 
treatment-naïve patients with late-onset Pompe disease (LOPD) 
INVESTIGATOR/TRIAL LOCATION
Worldwide 
PHASE OF DEVELOPMENT
Phase 3 
STUDY OBJECTIVE(S)
Primary objective:
The primary objective of the study is to determine the effect of 
avalglucosidase alfa treatment on respiratory muscle strength as 
measured by Forced Vital Capacity (FVC) % predicted in the upright 
position, as compared to alglucosidase alfa. 
Secondary objectives:
Secondary objectives are to determine the safety and effect of 
avalglucosidase alfa treatment on functional endurance (6-minute walk 
test [6MWT]), inspiratory muscle strength (maximum inspiratory 
pressure [MIP]), expiratory muscle strength (maximum expiratory 
pressure [MEP]), lower extremity muscle strength (hand-held 
dynamometry [HHD]), motor function (Quick Motor Function Test 
[QMFT]), and health-related quality of life (Short Form-12 [SF-12]). 
Other Objectives:
Additional objectives are to determine the pharmacokinetics (PK), 
exploratory pharmacodynamics (PD), pharmacogenetics and effect of 
avalglucosidase alfa treatment on motor function (Gross Motor 
Function Measure-88 [GMFM-88] and Gait, Stair, Gower’s Maneuver, 
and Chair [GSGC]), upper extremity muscle strength (HHD), 
health-related quality of life (EuroQoL in 5 dimensions [EQ-5D-5L] and 
Pediatric Quality of Life Inventory [PedsQL] Generic Core Scale), and 
patient reported outcomes (Pompe Disease Symptom Scale [PDSS], 
Pompe Disease Impact Scale [PDIS], Rasch-built Pompe-specific 
Activity scale [R-PAct], and Patient Global Impression of Change 
[PGIC]).
STUDY DESIGN
A Phase 3 multicenter, multinational, randomized, double-blinded 
study comparing the efficacy and safety of avalglucosidase alfa and 
alglucosidase alfa (Myozyme®/Lumizyme®) in treatment-naïve patients 
with LOPD. 
The study includes 2 main periods: the blinded treatment period and 
the open-label avalglucosidase alfa long-term follow-up phase. 
Patients in the alglucosidase alfa arm will be switched to 
avalglucosidase alfa treatment after 12 months. 
Patients will remain blinded to the randomized treatment until after 
database is locked. 
Randomization will be in a 1:1 ratio with stratification factors based on 
baseline FVC, gender, age, and country (Japan or ex-Japan). 
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STUDY POPULATION
Main selection criteria
Inclusion criteria:
The patient has confirmed acid alpha-glucosidase (GAA) enzyme 
deficiency from any tissue source and/or 2 confirmed GAA gene 
mutations.
Exclusion criteria:
The patient is <3 years of age, has known Pompe specific cardiac 
hypertrophy, is wheelchair dependent, is not able to ambulate 
40 meters (approximately 130 feet) without stopping and without an 
assistive device, requires invasive-ventilation (non-invasive ventilation 
is allowed), is not able to successfully perform repeated FVC 
measurements in upright position of ≥30% predicted and 
≤85% predicted, or has had previous treatment with 
immunomodulation, alglucosidase alfa, or any investigational therapy 
for Pompe disease.
Total expected number of patients
Approximately 96 patients 
STUDY TREATMENT(s)
Investigational medicinal product(s)
Avalglucosidase alfa 
Alglucosidase alfa
Formulation:
Avalglucosidase alfa and alglucosidase alfa will be supplied as sterile 
lyophilized powder, administered following reconstitution and dilution
Route(s) of administration:
Avalglucosidase alfa and alglucosidase alfa will be administered by 
intravenous (IV) infusion
Dose regimen:
Avalglucosidase alfa and alglucosidase alfa, at a dose of 20 mg/kg of 
body weight every other week (qow)
ENDPOINT(S)
Primary endpoint: 
Change in FVC% predicted in the upright position from baseline to 
12 months (Week 49). 
Secondary endpoint(s):
Change in the following parameters from baseline to 12 months (Week 
49): 
Efficacy: 
x
6MWT distance walked; 
x
MIP and MEP (% predicted); 
x
Lower extremity muscle strength (HHD); 
x
Motor function (QMFT), and  
x
Health-related quality of life (SF-12). 
Safety: 
x
Assessment of adverse events (AEs)/treatment-emergent 
adverse events (TEAEs), including infusion-associated 
reactions (IARs); 
x
Clinical laboratory evaluations including hematology, 
biochemistry, urinalysis; 
x
Physical examination; 
x
Vital signs, height, body weight 
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x
12-lead electrocardiogram (ECG); 
x
Immunogenicity assessments. 
Other endpoints:
Tertiary endpoints: 
x
Motor function (GMFM-88 and GSGC); 
x
Upper extremity muscle strength (HHD), and 
x
Health-related quality of life (EQ-5D-5L and PedsQL). 
x
Pharmacokinetics, pharmacogenetics, and 
pharmacodynamics 
Exploratory endpoints for patient reported outcomes: 
x
PDSS/PDIS; 
x
R-PAct; 
x
PGIC. 
ASSESSMENT SCHEDULE
The study will comprise up to 76 visits including the Screening Visit 
(V1: Day -14 to Day -1); V2 (Day 1/Day 2) through V27 (Week 49) 
occurring every 1 to 2 weeks for study drug infusion, PK, safety 
assessment, and efficacy evaluations in the blinded treatment period; 
V28 (Week 51) through V76 (Week 145) for study drug infusion, safety 
assessment, and efficacy evaluations in the open-label 
avalglucosidase alfa long-term follow-up phase; an additional extended 
open-label avalglucosidase alfa long-term follow-up period of up to 
144 weeks (or until avalglucosidase alfa is approved in the patient’s 
country, whichever comes first; refer to Appendix C Section 17.3.3 for 
patients in Canada and Section 17.3.4 for definition applicable for UK 
patients) will include bi-weekly visits (study drug infusion, adverse 
events 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, the end of study visit/contact will be performed. 
If at the end of the recruitment, <4 pediatric patients aged 3 to 
<18 years are enrolled, up to 2 additional pediatric patients will be 
enrolled directly in the open-label avalglucosidase alfa long-term 
follow-up phase where they will receive avalglucosidase alfa. 
For this subgroup of pediatric patients, the study will comprise 52 visits 
including the Screening Visit (V1: Day -14 to Day -1) and the 
Enrollment Visit V2 (Day 1/Day 2); V3 (1 week after V2) through V52 
(Week 97) for study drug infusion, PK, safety assessment, and efficacy 
evaluations in the open-label avalglucosidase alfa long-term follow-up 
phase (refer to study flow chart Section 1.2.5.1 for V29 details); an 
additional extended open-label avalglucosidase alfa long-term follow-
up period of up to 144 weeks (or until avalglucosidase alfa is approved 
in the patient’s country, whichever comes first; refer to Appendix C 
Section 17.3.4 for definition applicable for UK patients) will include bi-
weekly visits (study drug infusion, AEs checks 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, the end 
of study visit/contact will be performed. 
For all patients, all visits following V2 are calculated from day of first 
infusion of investigational medicinal product (IMP) in 14-day 
increments with a window of ±7 days for infusions and safety 
assessments and ±14 days for all other assessments. 
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STATISTICAL CONSIDERATIONS
Sample size determination:
Sample size calculation is based on a comparison of FVC 
(% predicted) change from baseline at 12 months (Week 49). The 
study will be tested for non-inferiority (NI) first (with an NI margin of 
1.1%), followed by superiority testing if NI is achieved. A sample size 
of 96 (1:1 randomization ratio) will provide 80% power to demonstrate 
NI of avalglucosidase alfa versus alglucosidase alfa with 2-sided 5% 
significance level. The power calculation was based on 2-sample 
t-test. The following assumptions were made based on the 
alglucosidase alfa pivotal study for LOPD (LOTS) and the completed 
avalglucosidase alfa Phase 1/2 study (TDR12857): 
x
Common standard deviation of 5.1%; 
x
Mean treatment difference (avalglucosidase alfa – 
alglucosidase alfa) of 2.0%; 
x
Percent of patients with missing data to be 10%. 
Analysis population:
The modified intent-to-treat (mITT) population is defined as all 
randomized patients who received at least 1 infusion (partial or total). 
The mITT population is the primary analysis population for all efficacy 
endpoints. Patients will be analyzed in the treatment group to which 
they were randomized. 
The per protocol (PP) population is defined as a subset of the mITT 
population that excludes patients with major protocol deviations that 
potentially impact the primary efficacy endpoint. The criteria for 
exclusion of patients from the PP population will be determined and 
documented prior to database lock. The PP population will be used for 
sensitivity analysis purposes. 
The safety population is defined as all patients who received at least 
1 infusion (partial or total). All safety analyses will be performed on the 
safety population. Patients will be summarized based on the treatment 
they received. 
Analysis of efficacy:
The primary efficacy endpoint is the change from baseline to Week 49 
in FVC (% predicted) in upright position. 
The primary endpoint will be analyzed using a mixed model for 
repeated measures (MMRM) with change from baseline as outcome 
variable. The MMRM model will include the baseline FVC 
(% predicted) as a continuous variable, and gender, age, treatment 
group, visit, and treatment-by-visit interaction as fixed effects. An 
unstructured covariance matrix shared across treatment groups will be 
used to model the within-patient error, the Kenward-Roger 
approximation will be used to estimate the degrees of freedom, and 
the model will be fit using restricted maximum likelihood. This analysis 
will include all post-baseline assessments up to Week 49, regardless 
of treatment discontinuation status; missing data will not be imputed 
and will be assumed to be missing-at-random (MAR). Sensitivity 
analyses will be performed to assess the impact of missing data. 
The primary comparison of interest is the difference in least-square 
means between groups at the Week 49 visit. 
A US Food and Drug Administration (FDA)-specific primary analysis 
will be conducted using the method described above for those patients 
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in the mITT population 8 years of age or older in order to match the 
lower age range of patients in the LOTS trial of alglucosidase alfa. 
Analysis of safety:
Safety analyses will be performed using the safety population and the 
“as treated” 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 and preferred term (PT) sorted 
alphabetically for each treatment arm, by 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. The 
denominator for computation of percentages is the safety population 
within each treatment arm. 
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), all AEs with fatal outcome, and adverse 
event of special interest (AESI)s will be summarized descriptively by 
treatment groups. 
Additional safety data including clinical laboratory tests, vital signs, 
ECG, and immunogenicity will be summarized descriptively by 
treatment groups. 
DURATION OF STUDY PERIOD (per 
patient) 
After the initial period (blinded treatment period and open-label 
avalglucosidase alfa long-term follow-up period), an additional period 
of up to 144 weeks (or until avalglucosidase alfa is approved in 
patient’s country, whichever comes first; refer to Appendix C 
Section 17.3.3 for patients in Canada and Section 17.3.4 for definition 
applicable for UK patients), including: 
Blinded treatment period: 
x
An up to 14-day screening period (may be extended to up to 
8 weeks in pre-specified situations [refer to Section 10.1.2]); 
x
A 49-week blinded treatment period (Primary Analysis Period 
[PAP]), except for the subgroup of pediatric patients aged 
3 to <18 years enrolling directly in the open-label long-term 
follow-up phase. 
Open-label avalglucosidase alfa long-term follow-up period: 
x
An up to 96-week open-label treatment period (open-label 
avalglucosidase alfa long-term follow-up phase) for all 
patients regardless of prior randomization group;  
Extended open-label avalglucosidase alfa long-term follow-up period: 
x
An up to 144 week (or until avalglucosidase alfa is approved 
in the patient’s country, whichever comes first; refer to 
Appendix C Section 17.3.3 for patients in Canada and  
Section 17.3.4 for definition applicable for UK patients) 
extended open-label treatment period (extended open-label 
avalglucosidase alfa long-term follow-up phase) for all 
patients and 
x
An up to 4-week post-treatment observation period. 
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1
FLOW CHARTS
1.1
GRAPHICAL STUDY DESIGN
1.1.1
General Graphical Study Design
W = Week
D = Day
I = Infusion
IV = Intravenous
EOS = End of study visit
QOW = every other week
Screening
D -14 to D-1
Blinded Treatment Period 
Avalglucosidase alfa (n=48) or alglucosidase alfa (n=48)
20 mg/kg IV infusion qow for a total of 25 doses
D1
I
D8
W3
I
W5
I
W7
I
W9
I
W41
W43
W45
W47 W49
I
I
I
I
I
//
Open-label avalglucosidase alfa Long Term Follow-up
Avalglucosidase alfa (n|96) 20 mg/kg IV infusion qow for a total of 48 doses
W137 W139 W141 W143 W145
I
I
I
I
//
W61
I
I
I
I
I
W52 W53 W55 W57 W59
I
W51
Primary Analysis
after all patients
complete W49
Extended Open-label avalglucosidase alfa Long Term Follow-up
Avalglucosidase alfa (n|96) 20 mg/kg IV infusion qow for a total of up to 72 doses (or 
until avalglucosidase alfa is approved, whichever comes first)
W283 W285 W287 W289 W293
I
I
I
I
EOS
//
W157
I
I
I
I
I
W149
W151
W153 W155
I
W147
I
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1.1.2
Graphical study design for pediatric patients aged 3 to <18 years enrolling directly in the open-label long-term follow-up phase
W = Week
D = Day
I = Infusion
IV = Intravenous
EOS = End of study visit
QOW = every other week
Screening
D -14 to D-1
D1
I
D8
W3
I
W5
I
W7
I
W9
I
W89
W91
W93
W95 W97
I
I
I
I
I
//
Open-label avalglucosidase alfa Long Term Follow-up
Avalglucosidase alfa (n≤2) 20 mg/kg IV infusion qow for a total of 49 doses
Extended Open-label avalglucosidase alfa Long Term Follow-up
Avalglucosidase alfa (n≤2) 20 mg/kg IV infusion qow for a total of up to 72 doses (or 
until avalglucosidase alfa is approved, whichever comes first)
W235 W237 W239 W241 W245
I
I
I
I
EOS
//
W109
I
I
I
I
I
W101
W103 W105 W107
I
W99
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s
For pediatric patients, 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 laboratory 
tests (hematology, biochemistry, ADA) and PK and then exploratory tests. ACE genotyping and optional DNA storage samples may be obtained at any other visit if not possible during screening due to blood 
volume limitation. If no plasma sample or no DBS for exploratory biomarkers or microRNA can be taken at D1 for a given patient due to blood volume limitation, the corresponding samples (ie, DBS, plasma 
[EDTA] or plasma [PPT, microRNA]) will not be taken during the study for this patient. 
t
Biochemistry assessments only at Week 29, Week 33, Week 41, Week 45. 
u
Additional samples may be taken if clinically indicated in the event of IARs. During the blinded treatment period, patients in the avalglucosidase alfa treatment arm will be tested for anti-avalglucosidase alfa 
antibodies and patients in the alglucosidase alfa arm will be tested for anti-alglucosidase alfa antibodies; in addition, patients in the alglucosidase alfa treatment arm will also be tested for anti-avalglucosidase alfa 
antibodies at V27/W49 to get their baseline value. 
v
PK samples are to be collected prior to infusion; at the end of infusion; and 2, 4, 6, and 8 hours after the end of infusion at Day 1/Day 2 and Week 49 and prior to infusion and 2 hours after the end of infusion at 
Week 13, Week 25, and Week 37. PK parameters to include Cmax, AUC0-last, CL, and Vss where appropriate. 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. 
w Fasted urine or plasma sample. As blood volume permits (see footnote s), it is preferred to get DBS + plasma (EDTA) + plasma (PPT, microRNA), or DBS + plasma (EDTA), or DBS alone. 
x
GAA genotyping only if historical results not available. (Gene mutation analysis is mandatory for all patients. Blood sample results for patient gene mutation analysis must be obtained during screening/baseline in 
order to assess patient for study eligibility. If gene mutation analysis was conducted prior to signing the informed consent, these results may be collected provided that the analysis was conducted by a certified 
laboratory, written results are provided to the site, and patients/legally authorized guardians give consent to utilize the results. If interpretation of GAA genotyping is inconclusive for the diagnosis of Pompe disease, 
or if only 1 mutation has been reported, then GAA enzyme activity level, normal laboratory ranges and tissue source need to be provided in the interpretation field of the GAA genotyping e-CRF page for the 
purpose of confirming Pompe Disease. GAA enzyme activity level measured on a Dried Blood Spot sample is not considered as sufficient to confirm eligibility in this study; GAA enzyme activity level from another 
source (skin fibroblast, peripheral blood leukocyte or muscle biopsy sample) will be needed). 
y
This includes the use (if any) of mechanical ventilation (including both invasive and noninvasive) and assistive devices (eg, walker, cane, crutches). 
z
For visits where urine dipstick is required refer to Section 9.2.2.2 for conditions requiring sending a urine sample to central laboratory. 
Abbreviations: 6MWT = 6-minute walk test; ACE = angiotensin converting enzyme; ADA = anti-drug antibody; AE = adverse event; β-HCG = beta-human chorionic gonadotropin; DBS = dried blood spot; DNA = 
deoxyribonucleic acid; ECG = electrocardiogram; e-CRF = electronic case report form; EDTA = ethylene diamine tetraacetic acid; EQ-5D-5L = EuroQoL in 5 dimensions; GAA = acid α-glucosidase; GMFCS = Gross 
Motor Function Classification System; GMFM-88 = Gross Motor Function Measure-88; GSGC = Gait, Stair, Gower’s Maneuver, and Chair; Hex4 = glucose tetrasaccharide; HHD = hand-held dynamometer; IAR = 
infusion associated reaction; ; IMP = investigational medicinal product; IRT = interactive response technology; MEP = maximum expiratory pressure; MIP = maximum inspiratory pressure; PDSS/PDIS = Pompe 
Disease Symptom Scale and Pompe Disease Impact Scale; PedsQL = Pediatric Quality of Life Inventory; PFT = pulmonary function testing; PGIC = Patient Global Impression of Change; PK = pharmacokinetic; 
QMFT = Quick Motor Function Test, RNA = ribonucleic acid; R-PAct = Rasch-built Pompe-specific Activity scale; SF-12 = Short Form-12. 
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l
For pediatric patients, 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 laboratory 
tests (hematology, biochemistry, ADA) and then exploratory tests. If no plasma sample or no DBS for exploratory biomarkers or microRNA can be taken at D1 for a given patient due to blood volume limitation, the 
corresponding samples (ie, DBS, plasma [EDTA] or plasma [PPT, microRNA]) will not be taken during the study for this patient. 
m 12-lead ECG after at least 15 minutes in supine position and prior to receiving IMP. 
n
Biochemistry assessments only. 
o
Additional samples may be taken if clinically indicated in the event of IARs.  
p
Fasted urine or plasma sample. As blood volume permits (see footnote l), it is preferred to get DBS + plasma (EDTA) + plasma (PPT, microRNA), or DBS + plasma (EDTA), or DBS alone. 
q
Head circumference and Tanner stage are assessed as part of the physical examination in pediatric patients at baseline, Week 49, Week 97, and Week 145. 
r
End of treatment IRT contact after completion of last infusion. 
s
This includes the use (if any) of mechanical ventilation (including both invasive and noninvasive) and assistive devices (eg, walker, cane, crutches). 
t
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 and multiple questionnaires) may be carried out over 2 days. 
u
For visits where urine dipstick is required refer to Section 9.2.2.2 for conditions requiring sending a urine sample to central laboratory. 
Abbreviations: 6MWT = 6-minute walk test; ADA = anti-drug antibody; AE = adverse event; DBS = dried blood spot; ; e-CRF = electronic case report form; ECG = electrocardiogram; EDTA = ethylene diamine 
tetraacetic acid; EQ-5D-5L = EuroQoL in 5 dimensions; FVC = forced vital capacity; GMFCS = Gross Motor Function Classification System; GMFM-88 = Gross Motor Function Measure-88; GSGC = Gait, Stair, 
Gower’s Maneuver, and Chair; Hex4 = glucose tetrasaccharide; HHD = hand-held dynamometry; IAR = infusion associated reaction; IRT = interactive response technology; MEP = maximum expiratory pressure; MIP 
= maximum inspiratory pressure; PDSS/PDIS = Pompe Disease Symptom Scale and Pompe Disease Impact Scale; PedsQL = Pediatric Quality of Life Inventory; PFT = pulmonary function testing; PGIC = Patient 
Global Impression of Change; QMFT = Quick Motor Function Test; R-PAct = Rasch-built Pompe-specific Activity scale; SF-12 = Short Form-12. 
 
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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 and multiple questionnaires) may be carried out over 2 days. 
b
For patients undergoing home infusion (as per conditions and instructions provided in Section 8.1) visit at clinical site is not required for infusion only visits. 
c
This includes the use (if any) of mechanical ventilation (including both invasive and noninvasive) and assistive devices (eg, walker, cane, crutches). 
d
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 no adverse event occurred during the observational period. As per conditions and instructions 
provided in Section 8.1, avalglucosidase alfa infusion may occur at home. 
e
Height will be measured every 6 months in pediatric patients only. 
f
Female patients of childbearing potential only. 
g
Vital signs (including heart rate, blood pressure, respiratory rate, temperature and oxygen saturation) 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, i.e., a total of 7 assessments. Collection windows are ±15 minutes. 
h
For pediatric patients, 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 laboratory 
tests and then exploratory tests. 
i
For visits where urine dipstick is required refer to Section 9.2.2.2 for conditions requiring sending a urine sample to central laboratory. 
j
Additional samples may be taken if clinically indicated in the event of IARs. ADA against avalglucosidase alfa only. 
k
FVC, MIP, and MEP (Additional parameters of respiratory function may be obtained and analyzed as appropriate). Ventilator use status and any change thereof will be recorded on the e-CRF by authorized site 
personnel.  
l
SF-12, EQ-5D-5L, R-PAct (during visit) and PDSS/PDIS (via an e diary daily for 2 weeks between visits) are to be conducted for patients who are ≥18 years of age at screening/baseline. 
m For selected countries (eg, UK, USA, Canada, Belgium and The Netherlands, to patients whose first language is English or Dutch). 
n
PGIC: Patients who are ≥18 years of age at the date of the concerned visit will complete this assessment annually. 
o
12-lead ECG after at least 15 minutes in supine position and prior to receiving IMP. 
p
Weight will be measured every 4 weeks in pediatric patients only 
Abbreviations: 6MWT = 6-minute walk test; ADA = anti-drug antibody; AE = adverse event; e-CRF = electronic case report form; ECG = electrocardiogram; EQ-5D-5L = EuroQoL in 5 dimensions; FVC = forced vital 
capacity; IAR = infusion associated reaction; IRT = interactive response technology; MEP = maximum expiratory pressure; MIP = maximum inspiratory pressure; PDSS/PDIS = Pompe Disease Symptom Scale and 
Pompe Disease Impact Scale; PedsQL = Pediatric Quality of Life Inventory; PFT = pulmonary function testing; PGIC = Patient Global Impression of Change; R-PAct = Rasch-built Pompe-specific Activity scale; 
SF-12 = Short Form-12. 
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1.2.4
End of study
Phase
End of Study Visit/Contacta
Day (D) or Week (W) 
4 weeks after the last IMP infusion 
Visit 
EOS 
Prior/concomitant medicationsb 
X 
AE collection 
X 
 
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. 
b
This includes the use (if any) of mechanical ventilation (including both invasive and noninvasive) and assistive devices (eg, walker, cane, crutches). 
Abbreviations: AE = adverse event; EOS = end of study; ERT = enzyme replacement therapy; IMP = investigational medicinal product. 
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d
All procedures are to be performed on the day of enrollment (Day 1), or day following enrollment (Day 2) to allow preparation of the IMP for infusion. 
e
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. 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 and multiple questionnaires) may be carried out over 2 days. For patients undergoing home infusion (as per conditions and instructions provided in Section 8.1) visit at clinical site is not required for 
infusion only visits. 
f
Demographic characteristics: age, gender, race, ethnicity 
g
This includes the use (if any) of mechanical ventilation (including both invasive and noninvasive) and assistive devices (eg, walker, cane, crutches). 
h
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 no adverse event occurred during the observational period. As per conditions and instructions 
provided in Section 8.1, avalglucosidase alfa infusion may occur at home. 
i
FVC, MIP, and MEP (Additional parameters of respiratory function may be obtained and analyzed as appropriate). Ventilator use status and any change thereof will be recorded on the e-CRF by authorized site 
personnel. 
j
Head circumference and Tanner stage are assessed as part of the physical examination in pediatric patients at baseline, Week 49 and Week 97. 
k
Female patients of childbearing potential only will have serum test for pregnancy at Screening, a urine beta hCG test up to 24 hours before first infusion (ie, D1/D2) and every 4 weeks thereafter. 
l
Vital signs (including heart rate, blood pressure, respiratory rate, temperature and oxygen saturation) 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, ie, a total of 7 assessments. Collection windows are ±15 minutes. 
m 12-lead ECG after at least 15 minutes in supine position (in triplicate 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
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 laboratory tests (hematology, 
biochemistry, ADA) and PK and then exploratory tests. ACE genotyping and optional DNA storage samples may be obtained at any other visit if not possible during screening due to blood volume limitation. If no 
plasma sample or no DBS for exploratory biomarkers or microRNA can be taken at D1 for a given patient due to blood volume limitation, the corresponding samples (ie, DBS, plasma [EDTA] or plasma [PPT, 
microRNA]) will not be taken during the study for this patient. 
o
Biochemistry assessments only. 
p
Additional samples may be taken if clinically indicated in the event of IARs. 
q
Pharmacokinetic samples are to be collected prior to infusion; at the end of infusion; and 2, 4, 6, and 8 hours after the end of infusion at Day 1/Day 2 and Week 49 and prior to infusion and 2 hours after the end of 
infusion at Week 13, Week 25, and Week 37. Pharmacokinetic parameters to include Cmax, AUC0-last, CL, and Vss where appropriate. 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
Fasted urine or plasma sample. As blood volume permits (see footnote n), it is preferred to get DBS + plasma (EDTA) + plasma (PPT, microRNA), or DBS + plasma (EDTA), or DBS alone. 
s
GAA genotyping only if historical results not available. (Gene mutation analysis is mandatory for all patients. Blood sample results for patient gene mutation analysis must be obtained during screening/baseline in 
order to assess patient for study eligibility. If gene mutation analysis was conducted prior to signing the informed consent, these results may be collected provided that the analysis was conducted by a certified 
laboratory, written results are provided to the site, and patients/legally authorized guardians give consent to utilize the results. If interpretation of GAA genotyping is inconclusive for the diagnosis of Pompe disease, 
or if only 1 mutation has been reported, then GAA enzyme activity level, normal laboratory ranges and tissue source need to be provided in the interpretation field of the GAA genotyping e-CRF page for the 
purpose of confirming Pompe Disease). GAA enzyme activity level measured on a Dried Blood Spot sample is not considered as sufficient to confirm eligibility in this study; GAA enzyme activity level from another 
source (skin fibroblast, peripheral blood leukocyte or muscle biopsy sample) will be needed). 
t
PGIC: Patients who are ≥18 years of age at the date of the concerned visit will complete this assessment at Week 49 & Week 97 
u
Visit not performed for these patients but indicated for consistency with the global population. 
v
For visits where urine dipstick is required, refer to Section 9.2.2.2 for conditions requiring sending a urine sample to central laboratory. 
Abbreviations: 6MWT = 6-minute walk test; ACE = angiotensin converting enzyme; ADA = anti-drug antibody; AE = adverse event; DBS = dried blood spot; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
e-CRF = electronic case report form; EDTA = ethylene diamine tetraacetic acid; EQ-5D-5L = EuroQoL in 5 dimensions; Hex4 = glucose tetrasaccharide; IAR = infusion associated reaction; IRT = interactive response 
technology; MEP = maximum expiratory pressure; MIP = maximum inspiratory pressure; PDSS/PDIS = Pompe Disease Symptom Scale and Pompe Disease Impact Scale; PedsQL = Pediatric Quality of Life 
Inventory; PFT = pulmonary function testing; PGIC = Patient Global Impression of Change; PK = pharmacokinetic; R-PAct = Rasch-built Pompe-specific Activity scale; SF-12 = Short Form-12. 
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d
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 no adverse event occurred during the observational period. As per conditions and instructions 
provided in Section 8.1, avalglucosidase alfa infusion may occur at home. 
e
Female patients of childbearing potential only. 
f
Vital signs (including heart rate, blood pressure, respiratory rate, temperature and oxygen saturation) 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, ie, a total of 7 assessments. Collection windows are ±15 minutes. 
g
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 laboratory tests and then 
exploratory tests. 
h
Additional samples may be taken if clinically indicated in the event of IARs. 
i
FVC, MIP, and MEP (Additional parameters of respiratory function may be obtained and analyzed as appropriate). Ventilator use status and any change thereof will be recorded on the e-CRF by authorized site 
personnel.  
j
PGIC: Patients who are ≥18 years of age at the date of the concerned visit will complete this assessment annually. 
k
12-lead ECG after at least 15 minutes in supine position and prior to receiving IMP. 
l
For visits where urine dipstick is required, refer to Section 9.2.2.2 for conditions requiring sending a urine sample to central laboratory. 
Abbreviations: 6MWT = 6-minute walk test; ADA = anti-drug antibody; AE = adverse event; ECG = electrocardiogram; e-CRF = electronic case report form; IAR = infusion associated reaction; IRT = interactive 
response technology; MEP = maximum expiratory pressure; MIP = maximum inspiratory pressure; PedsQL = Pediatric Quality of Life Inventory; PFT = pulmonary function testing; PGIC = Patient Global Impression of 
Change 
 
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1.2.5.3
End of study (pediatric patients enrolling directly in open-label follow-up phase)
Phase
End of Study Visit/Contacta 
Week (W) 
4 weeks after the last IMP infusion 
Visit 
EOS 
Prior/concomitant medicationsb 
X 
AE collection 
X 
 
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. 
b
This includes the use (if any) of mechanical ventilation (including both invasive and noninvasive) and assistive devices (eg, walker, cane, crutches) 
AE = adverse event; EOS = end of study; ERT = enzyme replacement therapy; IMP = investigational medicinal product.
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2
TABLE OF CONTENTS
AMENDED CLINICAL TRIAL PROTOCOL 06 ..............................................................................................1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................................................3 
CLINICAL TRIAL SUMMARY ........................................................................................................................5 
1 
FLOW CHARTS.............................................................................................................................10 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................10 
1.1.1 
General Graphical Study Design ...................................................................................................10 
1.1.2 
Graphical study design for pediatric patients aged 3 to <18 years enrolling directly in the 
open-label long-term follow-up phase............................................................................................11 
1.2 
STUDY FLOW CHART ..................................................................................................................12 
1.2.1 
Blinded treatment period................................................................................................................12 
1.2.2 
Open-label avalglucosidase alfa long-term follow-up phasea........................................................17 
1.2.3 
Extended open-label avalglucosidase alfa long-term follow-up phase..........................................26 
1.2.4 
End of study ...................................................................................................................................28 
1.2.5 
Pediatric patients aged 3 to <18 years entering directly in the open-label avalglucosidase 
alfa long-term follow-up phase.......................................................................................................29 
1.2.5.1 
Screening and open-label avalglucosidase alfa long-term follow-up phase..................................29 
1.2.5.2 
Extended open-label avalglucosidase alfa long-term follow-up phase (pediatric patients 
enrolling directly in open-label follow-up phase)............................................................................35 
1.2.5.3 
End of study (pediatric patients enrolling directly in open-label follow-up phase) .........................37 
2 
TABLE OF CONTENTS ................................................................................................................38 
2.1 
LIST OF TABLES...........................................................................................................................45 
3 
LIST OF ABBREVIATIONS ..........................................................................................................46 
4 
INTRODUCTION AND RATIONALE.............................................................................................49 
5 
STUDY OBJECTIVES ...................................................................................................................51 
5.1 
PRIMARY.......................................................................................................................................51 
5.2 
SECONDARY ................................................................................................................................51 
5.3 
OTHER...........................................................................................................................................51 
6 
STUDY DESIGN ............................................................................................................................52 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................52 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................52 
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6.2.1 
Duration of study participation for each patient .............................................................................52 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................53 
6.3 
INTERIM ANALYSIS......................................................................................................................53 
6.4 
STUDY COMMITTEES..................................................................................................................53 
6.4.1 
Data monitoring committee ............................................................................................................53 
6.5 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUPS .............................53 
7 
SELECTION OF PATIENTS..........................................................................................................55 
7.1 
INCLUSION CRITERIA..................................................................................................................55 
7.2 
EXCLUSION CRITERIA ................................................................................................................55 
7.2.1 
Exclusion criteria related to study methodology ............................................................................55 
7.2.2 
Exclusion criteria related to the active comparator and/or mandatory background therapies.......56 
7.2.3 
Exclusion criteria related to the current knowledge of Sanofi Genzyme compound .....................56 
7.2.4 
Additional exclusion criteria during or at the end of screening or run-in phase before 
randomization.................................................................................................................................57 
7.2.5 
Additional exclusion criteria related to country-specific requirements ...........................................57 
8 
STUDY TREATMENTS .................................................................................................................58 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................58 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................61 
8.3 
BLINDING PROCEDURES............................................................................................................61 
8.3.1 
Methods of blinding........................................................................................................................61 
8.3.2 
Randomization code breaking during the study.............................................................................62 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................62 
8.5 
PACKAGING AND LABELING ......................................................................................................64 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................64 
8.7 
RESPONSIBILITIES ......................................................................................................................64 
8.7.1 
Treatment accountability and compliance......................................................................................64 
8.7.2 
Return and/or destruction of treatments ........................................................................................65 
8.8 
CONCOMITANT MEDICATION.....................................................................................................65 
8.8.1 
Pretreatment for patients with infusion-associated reactions ........................................................66 
8.8.2 
Prohibited concomitant medications ..............................................................................................66 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................67 
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9.1 
PRIMARY ENDPOINT ...................................................................................................................67 
9.1.1 
Primary efficacy endpoint...............................................................................................................67 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................67 
9.2.1 
Secondary efficacy endpoints ........................................................................................................67 
9.2.1.1 
Six-minute walk test .......................................................................................................................67 
9.2.1.2 
Pulmonary function testing.............................................................................................................68 
9.2.1.3 
Hand-held dynamometry (lower extremity muscle strength) .........................................................68 
9.2.1.4 
Quick Motor Function Test.............................................................................................................69 
9.2.1.5 
12-Item Short-Form Health Survey (SF-12)...................................................................................69 
9.2.2 
Safety endpoints ............................................................................................................................69 
9.2.2.1 
Adverse events ..............................................................................................................................69 
9.2.2.2 
Laboratory safety variables............................................................................................................70 
9.2.2.3 
Vital signs.......................................................................................................................................70 
9.2.2.4 
Electrocardiogram variables ..........................................................................................................70 
9.2.2.5 
Physical examination .....................................................................................................................71 
9.2.2.6 
Body weight and height..................................................................................................................72 
9.2.2.7 
Immunogenicity..............................................................................................................................72 
9.3 
OTHER ENDPOINTS.....................................................................................................................73 
9.3.1 
Tertiary efficacy endpoints .............................................................................................................73 
9.3.1.1 
Gait, Stair, Gower’s Maneuver, and Chair composite functional assessment...............................73 
9.3.1.2 
Gross Motor Function Measure .....................................................................................................73 
9.3.1.3 
Hand-held dynamometry (upper extremity muscle strength).........................................................74 
9.3.1.4 
5-Level EuroQoL in 5 dimensions..................................................................................................75 
9.3.1.5 
Pediatric Quality of Life Inventory ..................................................................................................75 
9.3.2 
Pharmacokinetics...........................................................................................................................75 
9.3.2.1 
Sampling time ................................................................................................................................75 
9.3.2.2 
Pharmacokinetics handling procedure...........................................................................................76 
9.3.2.3 
Bioanalytical method......................................................................................................................76 
9.3.2.4 
Pharmacokinetics parameters .......................................................................................................76 
9.3.3 
Pharmacogenetic assessment.......................................................................................................76 
9.3.3.1 
Genotyping of human acid α-glucosidase gene.............................................................................76 
9.3.3.2 
Angiotensin converting enzyme marker allele status.....................................................................77 
9.3.3.3 
Exploratory assessment of circulating microRNA in plasma .........................................................77 
9.3.3.4 
Optional stored DNA sample .........................................................................................................77 
9.3.4 
Pharmacodynamic variables..........................................................................................................78 
9.3.4.1 
Urine Hex4 levels...........................................................................................................................78 
9.3.4.2 
Exploratory urine, DBS, and plasma biomarkers...........................................................................78 
9.3.5 
Quality of life/health economic variables/other endpoints..............................................................78 
9.3.5.1 
Pompe Disease Symptom and Impact Scales...............................................................................78 
9.3.5.2 
Rasch-built Pompe-specific Activity scale .....................................................................................78 
9.3.5.3 
Patient Global Impression of Change ............................................................................................79 
9.4 
FUTURE USE OF SAMPLES ........................................................................................................79 
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9.5 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................79 
10 
STUDY PROCEDURES ................................................................................................................81 
10.1 
VISIT SCHEDULE..........................................................................................................................81 
10.1.1 
Prestudy IRT contact......................................................................................................................81 
10.1.2 
Screening period/baseline visit ......................................................................................................81 
10.1.3 
Blinded treatment period................................................................................................................83 
10.1.3.1 Day of first infusion (Day 1/Day 2) .................................................................................................83 
10.1.3.2 One week following first infusion (Week 2 [Day 8]) .......................................................................84 
10.1.3.3 Biweekly.........................................................................................................................................84 
10.1.3.4 Every 4 weeks................................................................................................................................85 
10.1.3.5 Every 12 weeks..............................................................................................................................85 
10.1.4 
Open-label avalglucosidase alfa long-term follow-up phase .........................................................86 
10.1.4.1 Every 2 weeks (Biweekly) ..............................................................................................................86 
10.1.4.2 One week following first infusion in open-label phase (Week 52) .................................................87 
10.1.4.3 Every 4 weeks................................................................................................................................87 
10.1.4.4 Every 12 weeks..............................................................................................................................87 
10.1.4.5 At 12 weeks, 24 weeks, and then every 24 weeks........................................................................88 
10.1.5 
Extended open-label avalglucosidase alfa long-term follow-up phase..........................................89 
10.1.5.1 Biweekly.........................................................................................................................................89 
10.1.5.2 Every 4 weeks (Monthly)................................................................................................................89 
10.1.5.3 Every 12 weeks (Quarterly) ...........................................................................................................90 
10.1.5.4 Every 24 weeks (every 6 months)..................................................................................................90 
10.1.5.5 Every 48 weeks (Yearly) and end of treatment visit ......................................................................91 
10.1.6 
End of study ...................................................................................................................................92 
10.1.7 
Visit schedule for pediatric patients aged 3 to <18 years enrolling directly in the open-label 
long-term follow-up phase (starting after screening period) ..........................................................92 
10.1.7.1 Day of first infusion (Day 1/Day 2) (pediatric patients enrolling directly in the open-label 
follow-up phase).............................................................................................................................92 
10.1.7.2 Open-label avalglucosidase alfa long-term follow-up phase (pediatric patients enrolling 
directly in the open-label follow-up phase) ....................................................................................93 
10.1.7.3 Extended open-label avalglucosidase alfa long -term follow-up phase (pediatric patients 
enrolling directly in open-label follow-up phase)............................................................................95 
10.1.7.4 End of study (pediatric patients enrolling directly in the open-label follow-up phase)...................97 
10.1.8 
Follow-up........................................................................................................................................97 
10.1.9 
Follow-up for patients who temporarily or permanently discontinued the study treatment............99 
10.2 
DEFINITION OF SOURCE DATA................................................................................................100 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.....................................101 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) .........................101 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) .........................102 
10.3.3 
List of criteria for permanent treatment discontinuation...............................................................102 
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10.3.4 
Handling of patients after permanent treatment discontinuation .................................................103 
10.3.5 
Procedure and consequence for patient withdrawal from study..................................................103 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ........................104 
10.4.1 
Definitions of adverse events.......................................................................................................104 
10.4.1.1 Adverse event ..............................................................................................................................104 
10.4.1.2 Serious adverse event .................................................................................................................104 
10.4.1.3 Adverse event of special interest.................................................................................................105 
10.4.2 
General guidelines for reporting adverse events .........................................................................106 
10.4.3 
Instructions for reporting serious adverse events ........................................................................107 
10.4.4 
Guidelines for reporting adverse events of special interest.........................................................108 
10.4.5 
Guidelines for management of specific laboratory abnormalities ................................................108 
10.5 
OBLIGATIONS OF THE SPONSOR ...........................................................................................110 
10.6 
SAFETY INSTRUCTIONS ...........................................................................................................110 
10.7 
ADVERSE EVENTS MONITORING............................................................................................111 
11 
STATISTICAL CONSIDERATIONS............................................................................................112 
11.1 
DETERMINATION OF SAMPLE SIZE.........................................................................................112 
11.2 
DISPOSITION OF PATIENTS .....................................................................................................112 
11.3 
ANALYSIS POPULATIONS.........................................................................................................113 
11.3.1 
Efficacy populations .....................................................................................................................113 
11.3.2 
Safety population .........................................................................................................................113 
11.3.3 
Extension treatment population ...................................................................................................113 
11.4 
STATISTICAL METHODS ...........................................................................................................113 
11.4.1 
Extent of study treatment exposure and compliance...................................................................114 
11.4.1.1 Extent of investigational medicinal product exposure..................................................................114 
11.4.1.2 Compliance ..................................................................................................................................114 
11.4.2 
Analyses of efficacy endpoints.....................................................................................................114 
11.4.2.1 Analysis of primary efficacy endpoints.........................................................................................114 
11.4.2.2 Analyses of secondary efficacy endpoints...................................................................................115 
11.4.2.3 Multiplicity considerations ............................................................................................................116 
11.4.3 
Open-label avalglucosidase alfa long-term follow-up phase .......................................................116 
11.4.4 
Analyses of safety data................................................................................................................117 
11.4.4.1 Adverse events ............................................................................................................................117 
11.4.4.2 Clinical laboratory tests................................................................................................................118 
11.4.4.3 Physical examination, vital signs, and electrocardiogram ...........................................................118 
11.4.4.4 Anti-avalglucosidase alfa antibodies, neutralizing antibodies, and other immunogenicity 
testing...........................................................................................................................................119 
11.4.5 
Analyses of pharmacokinetic and pharmacodynamic variables ..................................................119 
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11.4.6 
Analyses of patient reported outcomes (health-related quality of life/health economics 
variables and Patient Global Impression of Change [PGIC]) ......................................................120 
11.5 
INTERIM ANALYSIS....................................................................................................................120 
12 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS...........................121 
12.1 
REGULATORY AND ETHICAL CONSIDERATIONS..................................................................121 
12.2 
INFORMED CONSENT PROCESS.............................................................................................122 
13 
STUDY MONITORING.................................................................................................................124 
13.1 
DATA QUALITY ASSURANCE....................................................................................................124 
13.2 
SOURCE DOCUMENTS .............................................................................................................124 
14 
ADDITIONAL REQUIREMENTS.................................................................................................126 
14.1 
DATA PROTECTION...................................................................................................................126 
14.2 
STUDY AND SITE CLOSURE.....................................................................................................128 
14.3 
CLINICAL TRIAL RESULTS AND DISSEMINATION OF CLINICAL STUDY DATA...................128 
14.4 
PUBLICATION POLICY...............................................................................................................129 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................130 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................131 
17 
APPENDICES..............................................................................................................................133 
17.1 
APPENDIX A: GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION....................................................................................................133 
17.2 
APPENDIX B: GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................136 
17.3 
APPENDIX C: COUNTRY-SPECIFIC REQUIREMENTS ...........................................................140 
17.3.1 
Sweden ........................................................................................................................................140 
17.3.2 
France ..........................................................................................................................................141 
17.3.3 
Canada.........................................................................................................................................141 
17.3.4 
United Kingdom............................................................................................................................142 
17.4 
APPENDIX D: PROTOCOL AMENDMENT HISTORY................................................................143 
17.4.1 
Amended protocol 01: 03 Aug 2016 ............................................................................................143 
17.4.2 
Amended protocol 02: 18 Jul 2017 ..............................................................................................143 
17.4.3 
Amended protocol 03: 10 Apr 2019 .............................................................................................144 
17.4.4 
Amended protocol 04: 21 December 2020 ..................................................................................152 
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17.4.5 
Amended protocol 05: 18 November 2021 ..................................................................................154 
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2.1
LIST OF TABLES
Table 1 - List of pharmacokinetic parameters and definitions.......................................................................76 
Table 2 - Summary of adverse event reporting instructions........................................................................109 
Table 3 - Female Highly effective contraceptive methods ..........................................................................134 
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3
LIST OF ABBREVIATIONS
6MWT:
6-minute walk test
ACE:
angiotensin converting enzyme
ADA:
anti-drug antibody
AE:
adverse event
AESI:
adverse event of special interest
ALT:
alanine aminotransferase
AST:
aspartate aminotransferase
ATS/ERS:
American Thoracic Society/European Respiratory Society 
AUC:
area under the plasma concentration versus time curve from time 0 to time of 
last quantifiable concentration
CDMS:
clinical data management system
CL:
clearance
Cmax:
maximum plasma concentration
CRF:
case report form
DBS:
dried blood spot
DMC:
data monitoring committee
DNA:
deoxyribonucleic acid
ECG:
electrocardiogram
e-CRF:
electronic case report forms
EQ-5D-5L:
EuroQoL in 5 dimensions
ERT:
enzyme replacement therapy
FDA:
Food and Drug Administration
FEV1:
forced expiratory volume in the 1st second of the FVC maneuver
FVC:
forced vital capacity 
GAA:
acid alpha-glucosidase
GCP:
Good Clinical Practice
GDPR:
General Data Protection Regulation
GLI:
global lung initiative
GMFCS-E&R:
Gross Motor Function Classification System - Expanded and Revised
GMFM-88:
Gross Motor Function Measure-88
GSD:
glycogen storage disease
GSGC:
Gait, Stair, Gower’s maneuver, and Chair
Hex4:
glucose tetrasaccharide
HHD:
hand-held dynamometry
HLGT:
high level group term
HLT:
high level term
IAR:
infusion-associated reaction
IB:
Investigator’s Brochure
ICF:
informed consent form
ICH:
International Council for Harmonisation
IEC:
Independent Ethics Committee
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IgE:
immunoglobulin E
IMP:
investigational medicinal product
IRB:
institutional review board
IRT:
interactive response technology
IV:
intravenous
LLOQ:
lower limit of quantitation
LOPD:
late onset Pompe disease
M6P:
mannose-6-phosphate
MAR:
missing-at-random
MCS:
mental component summary
MedDRA:
Medical Dictionary for Regulatory Activity
MEP:
maximum expiratory pressure 
MIP:
maximum inspiratory pressure
mITT:
modified intent-to-treat
MMRM:
mixed model for repeated measure
NI:
non-inferiority
PAP:
primary analysis period
PCR:
polymerase chain reaction
PCS:
physical component summary
PCSA:
potentially clinically significant abnormality 
PD:
pharmacodynamics
PDIS:
Pompe Disease Impact Scale
PDSS:
Pompe Disease Symptom Scale
PedsQL:
Pediatric Quality of Life Inventory
PEF:
peak expiratory flow
PFT:
pulmonary function testing
PGIC:
Patient Global Impression of Change
PI:
Principal Investigator
PK:
pharmacokinetic(s)
PP:
per protocol
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
RNA:
ribonucleic acid
R-PAct:
Rasch-built Pompe-specific Activity scale
RR:
interval between the peaks of successive QRS complexes
SAE:
serious adverse event
SAP:
statistical analysis plan
SD:
standard deviation
SF-12:
Short Form-12
SOC:
system organ class
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SUSAR:
suspected unexpected serious adverse reaction
TEAE:
treatment-emergent adverse event
ULN:
upper limit of normal
Vss:
volume of distribution at steady state
β-HCG:
beta-human chorionic gonadotropin
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4
INTRODUCTION AND RATIONALE
Sanofi Genzyme is investigating an enzyme replacement therapy (ERT) for Pompe disease called 
avalglucosidase alfa (rhGAA conjugated with synthetic bis-mannose-6-phosphate-Man6 glycan);
rhGAA 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 2 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).
A proportion of patients with LOPD treated with alglucosidase alfa demonstrate suboptimal 
treatment response, in particular in respiratory function, and may benefit from a potentially more 
potent treatment (avalglucosidase alfa) (1). The efficacy and safety of avalglucosidase alfa in
treatment-naïve LOPD has not been evaluated in a controlled study. As there are no data on the 
safety and efficacy of avalglucosidase alfa in treatment-naïve pediatric LOPD patients 3 years and 
older, this study will be also conducted to evaluate treatment response in that population.
The benefits and risks assessment of avalglucosidase alfa for the Phase 3 EFC14028 study is 
based upon the nonclinical studies of avalglucosidase alfa in acid α-glucosidase (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 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; AEs and IARs are mostly non-serious 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.
The overall objective of this study is to evaluate the efficacy and safety of avalglucosidase alfa in
treatment-naïve patients with LOPD as compared to alglucosidase alfa. The primary objective of 
the study is to determine the effect of avalglucosidase alfa treatment on respiratory muscle 
strength as measured by FVC% predicted in the upright position. Additional secondary objectives 
are to evaluate the safety profile of avalglucosidase alfa in treatment-naïve patients with LOPD 
and to determine the effect of avalglucosidase alfa treatment on functional endurance (6MWT),
inspiratory muscle strength (MIP), expiratory muscle strength (MEP), lower extremity muscle 
strength (HHD), motor function (QMFT), and health-related quality of life (SF-12 in patients 
≥18 years of age). Other objectives are to determine the PK, exploratory PD, pharmacogenetics 
and effect of avalglucosidase alfa treatment on motor function (GMFM-88 and GSGC), upper 
extremity muscle strength (HHD), health-related quality of life (EQ-5D-5L and PedsQL Generic 
Core Scale), and patient reported outcomes (Pompe Disease Symptom Scale [PDSS], Pompe 
Disease Impact Scale [PDIS], Rasch-built Pompe-specific Activity scale [R-Pact], and Patient 
Global Impression of Change [PGIC]).
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The screening phase (time from signing of informed consent form to start of study treatment) 
should not exceed 14 days, but could be extended to a maximum of 8 weeks in pre-specified 
situations (refer to Section 10.1.2). Patients will be observed in a 12-month blinded treatment 
phase, in which patients will receive an IV infusion of 20 mg/kg avalglucosidase alfa or 
alglucosidase alfa biweekly (qow). This dose regimen is supported by data from a Phase 1/2 study 
showing a potential avalglucosidase alfa dose response after treatment for 6 months in previously 
untreated patients, with doses differentiated by improvement in FVC with avalglucosidase alfa
20 mg/kg qow versus stabilization with 5 mg/kg qow. Following the 12-month treatment period, 
patients will continue in the study in an open-label treatment period, in which all patients will 
receive an IV infusion of 20 mg/kg avalglucosidase alfa qow for long-term follow-up.
The primary and secondary endpoint assessments selected for this study have been used in 
previous studies in patients with LOPD.
Exclusion criteria limiting the study population to LOPD patients who are able to ambulate 
40 meters (approximately 130 feet) without stopping and without an assistive device, do not 
require invasive-ventilation, and have an FVC in upright position of ≥30% predicted and ≤85% 
predicted are intended to assure that patients can reliably and safely perform the required test 
procedures.
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5
STUDY OBJECTIVES
5.1
PRIMARY
The primary objective of the study is to determine the effect of avalglucosidase alfa treatment on 
respiratory muscle strength as measured by FVC% predicted in the upright position, as compared 
to alglucosidase alfa.
5.2
SECONDARY
Secondary objectives are to determine the safety and effect of avalglucosidase alfa treatment on 
functional endurance (6MWT), inspiratory muscle strength (MIP), expiratory muscle strength 
(MEP), lower extremity muscle strength (HHD), motor function (QMFT), and health-related 
quality of life (SF-12).
For the Canada-specific requirement regarding HHD, refer to Appendix C Section 17.3.3.
5.3
OTHER
Other objectives are to determine the PK, exploratory PD, pharmacogenetics and effect of 
avalglucosidase alfa treatment on motor function (GMFM-88 and GSGC), upper extremity muscle 
strength (HHD), health-related quality of life (EQ-5D-5L and PedsQL Generic Core Scale), and 
patient reported outcomes (PDSS/PDIS, R-PAct, and PGIC).
For the Canada-specific requirement regarding HHD, refer to Appendix C Section 17.3.3.
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6
STUDY DESIGN
6.1
DESCRIPTION OF THE STUDY
EFC14028 is a Phase 3, multicenter, multinational, randomized, double-blind, 12-month PAP
study comparing the efficacy and safety of avalglucosidase alfa and alglucosidase alfa (both at 
20 mg/kg qow) in treatment-naïve patients with LOPD ages 3 and above. The study includes an 
open-label avalglucosidase alfa long-term follow-up phase for all patients, in which patients in the 
alglucosidase alfa arm will be switched to avalglucosidase alfa treatment after 12 months. Patients 
will remain blinded to the randomized treatment until after database is locked. Randomization will 
be in a 1:1 ratio with stratification factors based on baseline FVC, gender, age, and country (Japan 
or ex-Japan).
At the end of the recruitment, if <4 pediatric patients aged 3 to <18 years are enrolled, in order to 
comply with Health Authority requirements to enroll a certain number of pediatric patients, up to 
2 additional pediatric patients will be screened and enrolled directly in the open-label 
avalglucosidase alfa long-term follow-up phase where they will receive avalglucosidase alfa.
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 up to approximately 3 years (151 weeks)
(or 2 years [99 weeks] for the subgroup of pediatric patients aged 3 to <18 years enrolling directly 
in the open-label long-term follow-up phase), including:
x
An up to 14-day screening period (refer to Section 10.1.2 for extended duration in 
pre-specified situations);
x
A 49-week blinded treatment period (PAP), except for the subgroup of pediatric patients 
aged 3 to <18 years enrolling directly in the open-label long-term follow-up phase;
x
An up to 96-week open-label treatment period (open-label avalglucosidase alfa long-term 
follow-up phase) for all patients regardless of prior randomization group; 
An extended open-label avalglucosidase alfa long-term follow-up period will last up to 
144 additional weeks (or until avalglucosidase alfa is approved in the patient’s country, whichever 
comes first; refer to Appendix C Section 17.3.3 for patients in Canada and Section 17.3.4 for 
definition applicable for UK patients) for all patients (extended open-label avalglucosidase alfa 
long-term follow-up phase). 
An up to 4-week post-treatment observation period will close the patient’s participation.
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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
No interim analysis is planned during the double-blinded PAP (refer to Section 6.2.1 for the 
details of the different periods). Note that the primary analysis for the study is performed at the 
end of PAP, when the database will be locked and a study report will be produced for regulatory 
submission. The study will continue for additional 2 years (open-label long-term extension) and 
with an additional extension period of up to 144 additional weeks or until avalglucosidase alfa is
approved in the patient’s country, whichever comes first (refer to Appendix C Section 17.3.3 for 
patients in Canada and Section 17.3.4 for definition applicable for UK patients). A final database 
lock will occur at the end of extension period, with a corresponding final study report generated.
After the primary analysis for PAP, interim analyses may be performed during the open-label 
extension period to provide additional information for regulatory purpose.
6.4
STUDY COMMITTEES
6.4.1
Data monitoring committee
An independent data monitoring committee (DMC), appointed by the Sponsor, will review 
unblinded 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, bi-annual reviews of safety data will be performed by the DMC. 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 the DMC member who is an allergist/immunologist. 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).
An independent statistical center will be used to provide unblinded data to the DMC through a 
completely confidential process, and act as liaison between the Sponsor biostatistician and the 
DMC.
6.5
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUPS
Study EFC14028 is being conducted as a Phase 3 multicenter, multinational, randomized, 
double-blinded study to minimize bias.
EFC14028 is a head-to-head study design to compare avalglucosidase alfa directly to 
alglucosidase alfa, which is the only available ERT for LOPD. The study will be conducted at a 
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dose of 20 mg/kg qow, which is the recommended labeled dose for alglucosidase alfa and is 
supported based on results from nonclinical studies and the safety and exploratory efficacy results 
from the Phase 1 TDR12857 clinical study as being likely to result in greater glycogen depletion 
in skeletal muscles and clinical efficacy than alglucosidase alfa without new safety concerns.
Because avalglucosidase alfa is expected to be at least as efficacious as alglucosidase alfa, it is 
considered appropriate to test first for NI and then for superiority.
The primary endpoint of the EFC14028 study is % predicted FVC in the upright position, which is 
one of the same primary endpoints used in the AGLU02704 (LOTS) trial, which was the basis for 
the approval of alglucosidase alfa in LOPD. FVC is an established measure of lung capacity, and 
respiratory insufficiency is a major source of morbidity and death in this patient population.
A 12-month duration for the PAP should be sufficient to see a treatment difference compared to 
alglucosidase alfa and to collect safety data, including the development of anti-drug antibody 
(ADA).
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7
SELECTION OF PATIENTS
7.1
INCLUSION CRITERIA
I 01.
The patient must provide signed, informed consent prior to performing any study-related 
procedures. Consent of a legally authorized guardian(s) is (are) required for legally minor 
patients as defined by local regulation. If the patient is legally minor, signed written 
consent shall be obtained from parent(s)/legal guardian and assent obtained from patients, 
if applicable.
I 02.
The patient has confirmed GAA enzyme deficiency from any tissue source and/or 
2 confirmed GAA gene mutations.
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 5 subsections:
7.2.1
Exclusion criteria related to study methodology
E 01. The patient is <3 years of age.
E 02. The patient has known Pompe specific cardiac hypertrophy.
E 03. The patient is wheelchair dependent.
E 04. The patient is not able to ambulate 40 meters (approximately 130 feet) without stopping 
and without an assistive device. Use of assistive device for community ambulation is 
appropriate.
E 05. The patient requires invasive-ventilation (non-invasive ventilation is allowed).
E 06. The patient is not able to successfully perform repeated FVC measurements in upright 
position of ≥30% predicted and ≤85% predicted.
E 07. The patient has had previous treatment with alglucosidase alfa or any investigational 
therapy for Pompe disease.
E 08. The patient (and patient’s legal guardian if patient is legally minor as defined by local 
regulation) is (are) not able to comply with the clinical protocol.
E 09. The patient is concurrently participating in another clinical study using investigational 
treatment or has taken other investigational drugs or prohibited concomitant medications
within 30 days or 5 half-lives from screening or randomization, whichever is longer.
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E 10. The patient has known history of drug or alcohol abuse within 6 months prior to the time 
of screening.
E 11. 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 that, in the opinion of the Investigator, precludes 
participation in the study or potentially decreases survival.
E 12. Patient with prior or current use of immune tolerance induction therapy.
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 Genzyme compound
E 13. Pregnant or breastfeeding female patient
E 14. 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 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. For patients in Sweden, 
refer to Appendix C (Section 17.3.1).
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). For patients in 
Sweden, refer to Appendix C (Section 17.3.1).
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 2 acceptable 
effective methods of contraception, a barrier method such as a condom or occlusive cap 
(diaphragm or cervical/vault cap) with spermicidal foam/gel/film/cream/suppository and an 
established non-barrier method such as oral, injected, or implanted hormonal methods, an 
intrauterine device, or intrauterine system for the entire duration of the treatment period and for at 
least 28 days after receiving the last study drug dose. Sterilized or infertile patients (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 or refer to Appendix C Section 17.3.1 for 
patients in Sweden).
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7.2.4
Additional exclusion criteria during or at the end of screening or run-in phase 
before randomization
E 15. Patient who has withdrawn consent before enrollment/randomization (starting from signed 
informed consent form)
E 16. 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 17. Any country-related specific regulation that would prevent the patient from entering the 
study
Note: FVC% predicted may be repeated up to 3 times during the screening period if American 
Thoracic Society/European Respiratory Society (ATS/ERS) quality criteria have not been met as 
assessed by the central laboratory. Repeat tests should not occur on the same day in order to allow 
the patient to rest.
Patients may be re-screened if their clinical condition changes. Patients who were screen failed 
because their FVC% predicted was >85% may be rescreened only if a clinically relevant 
worsening respiratory condition related to Pompe Disease and not related to intercurrent illness as 
assessed by the Investigator occurs.
In case of re-screening, the patient will be first screened failed in the interactive voice/web 
response system (IXRS), will sign a new written informed consent form and a new patient number 
will be provided. All screening assessments/procedures will have to be performed again, except 
GAA and angiotensin converting enzyme (ACE) genotyping.
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8
STUDY TREATMENTS
8.1
INVESTIGATIONAL MEDICINAL PRODUCT(S)
Avalglucosidase alfa, the IMP, will be supplied as a sterile, nonpyrogenic, lyophilized product in 
single-use vial containing approximately 100 mg of avalglucosidase alfa. Alglucosidase alfa
(IMP) 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.
Avalglucosidase alfa and alglucosidase alfa will be administered by IV infusion following 
reconstitution and dilution at a dose of 20 mg/kg body weight qow.
Quantity of vials required for each infusion will be calculated based on the patient`s weight. The 
total amount of IMP 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 for pediatric patients and 3 months in adult patients. 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. 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 
avalglucosidase alfa as outlined below under the subsection “Home infusion”) to determine if the 
patient is free of acute illness and is clinically stable to receive the infusion. Infusions will be 
postponed (see Section 8.7.1) if the patient is acutely ill on the scheduled day of infusion. Any 
modification to the dose and/or frequency of dosing is not permitted unless it is due to an AE, in 
which case it is not a protocol violation, but the Investigator must consult with the Sponsor in the 
event of a dose change. The Sponsor will consult the DMC for any dose change related to AE. No
dose increase above the maximum recommended dose of 20 mg/kg qow will be allowed for any 
patients.
Patients will be required to remain in the hospital or the infusion center for observation of AEs for 
1 hour after each infusion; see below for the patients receiving home infusion. Patients may be 
required to stay for a longer observation period at the Investigator’s discretion. In case the patient 
does not stay for this observation period (eg, as part of contingency measures for a regional or 
national emergency that is declared by a governmental agency), the Investigator (or appropriate 
designee) will contact the patient or their legally authorized representative (for pediatric patients) 
to ensure that no adverse event occurred during the observational period.
The study includes 2 main periods: the blinded treatment period and the open-label 
avalglucosidase alfa long-term follow-up phase.
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In the blinded treatment period avalglucosidase alfa or alglucosidase alfa will be administered by 
IV infusion every 2 weeks starting at Randomization Visit (Visit 2, Day 1/Day 2) continuing up to 
V27/W49 for a total of 25 doses.
Patients in the alglucosidase alfa arm will be switched to avalglucosidase alfa treatment after 
12 months.
In the open-label avalglucosidase alfa long-term follow-up phase, avalglucosidase alfa will be 
administered by IV infusion every 2 weeks starting at V28/W51 continuing up to V76/W145 for a 
total of 48 doses.
In the extended open-label avalglucosidase alfa extension period, avalglucosidase alfa will be 
administered by IV infusion every 2 weeks starting at V77/W147 and continuing up to 144 
additional weeks (or until avalglucosidase alfa is approved in the patient’s country, whichever 
comes first; refer to Appendix C Section 17.3.3 for patients in Canada and Section 17.3.4 for 
definition applicable for UK patients) for up to 72 additional doses.
For pediatric patients aged 3 to <18 years enrolling directly in the open-label long-term follow-up
phase, avalglucosidase alfa will be administered by IV infusion every 2 weeks starting at 
Randomization Visit (Visit 2, Day 1/Day 2) continuing up to V52/W97 for a total of 49 doses. For 
these patients, in the extended open-label avalglucosidase alfa extension period, avalglucosidase 
alfa will be administered by IV infusion every 2 weeks starting at V53/W99 and continuing up to 
144 additional weeks (or until avalglucosidase alfa is approved in the patient’s country, whichever 
comes first; refer to Appendix C Section 17.3.4 for definition applicable for UK patients) for up to 
72 additional doses.
For all patients, all visits following V2 are calculated from day of first infusion of IMP in 14 days 
increments with a window of ±7 days for infusions and safety assessments and ±14 days for all 
other assessments. There should not be less than 7 days between 2 IMP infusions. 
Patients who prematurely discontinue treatment should be followed as scheduled.
Home infusion
Home infusion may be possible in the open-label 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:
x
The Investigator must agree in writing that home infusion is appropriate for the patient. 
x
The patient must be willing and able to comply with home infusion procedures.
x
The patient has been trained on home infusion process.
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x
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, (eg, as part of 
contingency measures for a regional or national emergency that is declared by a 
governmental agency), with DMC agreement, the required period of 12 months with no 
history of moderate or severe IAR may be reduced to at least 6 months, to allow home 
infusion to be resumed sooner.
x
If this reduced period from 12 months to at least 6 months, is considered safe and after 
confirmation with the DMC (which will be documented in the Trial Master File), it will be 
considered as a permanent criterion after the unexpected event is resolved (eg.,
contingency measures for a regional or national emergency that is declared by a 
governmental agency are terminated).
x
No infusion rate increases will be allowed while a patient is receiving home infusions.
x
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.
x
Home infusion infrastructure, resources, and procedures must be established and available 
according to applicable regulations (see Appendix C Section 17.3.2 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.
x
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.
x
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.
x
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).
x
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.
x
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.
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x
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.
x
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.
x
Home Infusion Agency must keep source documentation of the infusion, including 
documentation of any AEs. Home Infusion Agency must be amenable to providing 
specific source documentation to the Sponsor, in agreed upon timeframe, and agree to be 
monitored.
The Principal Investigator (PI) is responsible for approving a patient’s initiation with home 
infusions and is still responsible for all study procedures and patient’s safety even when 
delegating infusion responsibilities to the home care company during this clinical study. 
It is the PI’s responsibility to guide staff on the clinical management of the patient in case of IARs 
or hypersensitivity or anaphylactic reactions. The PI will be the point of contact for home infusion 
agency staff in case of questions or emergency situations.
Infusions given in the home setting versus in the clinic will be captured through the case report 
form (CRF) forms for AEs and exposure.
8.2
NONINVESTIGATIONAL MEDICINAL PRODUCT(S)
Not applicable.
8.3
BLINDING PROCEDURES
8.3.1
Methods of blinding
Refer to Section 10.5 for suspected unexpected adverse drug reaction requiring unblinding by the
Sponsor.
In the double-blinded period of the study, avalglucosidase alfa and alglucosidase alfa will be 
provided as open-label supplies.
For blinding purposes, the on-site preparation of avalglucosidase alfa and/or alglucosidase alfa 
will therefore be performed by an independent unblinded pharmacist or an independent unblinded 
designee at the investigational site. The unblinded pharmacist or the unblinded designee should 
not be involved in activities that could be biased by the knowledge of the treatment assignment 
(eg, AE assessments, access to PD data) and will not disclose any information to anyone and 
ensure to maintain blinding condition of the study.
Each treatment kit will be labeled with a number generated by a computer program according to 
Sanofi procedure. The treatment numbers will be obtained by the unblinded pharmacist or the
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unblinded designee at the time of patient randomization and subsequent patients’ visits scheduled 
via centralized treatment allocation system (interactive response technology [IRT]).
In accordance with the double-blind design of the first blinded treatment period, study patients, 
Investigators and study site personnel, except for the unblinded pharmacist or the unblinded 
designee, will remain blinded to study treatment and will not have access to the randomization 
(treatment codes) except under circumstances described in Section 8.3.2. The unblinded 
pharmacist or the unblinded designee is not allowed to disclose any unblinded information to the 
blinded study site team and therefore should not take part to any discussion regarding AE 
assessments for the patients, except to give information in a blinded manner on the preparation of 
the IMP (eg, preparation steps order well followed, confirmation of the usual visual aspect of the 
IMP once diluted).
Additional measures will be taken to ensure blinding of the patients (see pharmacy manual for 
details).
8.3.2
Randomization code breaking during the study
In case of an AE, the code should only be broken in circumstances when knowledge of the IMP is 
required for treating the patient. 
Code breaking can be performed at any time by using the proper module of the IRT and/or by 
calling any other phone number provided by the Sponsor for that purpose. If the blind is broken, 
the Investigator should document the date, time of day, and reason for code breaking.
The code-breaking can also be performed by contacting the “24-hour alert system”. A patient 
card, including the relevant “24-hour alert system” telephone number will be provided to every 
patient who will participate in the study.
If the code is broken, the patient must withdraw from IMP administration. Please refer to 
Section 10.3 of the protocol for details on handling of patient treatment discontinuation.
At the facilities where the systemic drug concentration measurements, ADAs and selected 
biomarkers are determined, the samples will be analyzed prior to data base lock leading to 
unblinding of responsible bioanalysts. Bioanalysts are excluded from the clinical trial team. One 
programmer may be unblinded to prepare the dataset for population PK analysis. The procedure 
detailing the process to maintain blind beyond the programmer is described in a separate Sanofi 
quality document.
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, 
eligible patients will be randomized as described below.
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Treatment assignment and randomization will be performed using a centralized treatment 
allocation system/IRT. During the double-blind period, approximately 96 patients will be 
randomly assigned across sites to 1 of 2 treatment arms, avalglucosidase alfa or alglucosidase alfa 
at 20 mg/kg qow in a 1:1 ratio. Randomization will be performed within each of the following 
6 strata:
A) Age <18,
B) Age ≥18, all genders and FVC (% predicted), Japan,
C) Age ≥18, male and FVC (% predicted) <55%, ex-Japan,
D) Age ≥18, female and FVC (% predicted) <55%, ex-Japan,
E) Age ≥18, male and FVC (% predicted) ≥55%, ex-Japan,
F) Age ≥18, female and FVC (% predicted) ≥55%, ex-Japan.
To control the number of patients with high baseline FVC (% predicted), the percent of enrolled 
patients with baseline FVC (% predicted) of 80% to 85% will be capped at 15% of the total 
population.
The treatment kit number lists are generated centrally by the Sponsor. The IMPs (avalglucosidase 
alfa or alglucosidase alfa in blinded treatment period; avalglucosidase alfa in open-label long-term 
follow-up period and in additional extension open-label follow-up) are packaged in accordance 
with the lists.
The IRT (centralized treatment allocation system) generates the patient randomization list and 
allocates the treatment number and the corresponding treatment kits to the patients accordingly.
Investigator and assigned study site personnel will have access to blinded IRT menu/reports,
whereas the unblinded pharmacist or unblinded designee will have access to unblinded reports.
The treatment kits will be allocated using a centralized treatment allocation system (IRT) every 
2 weeks starting at Visit 2 (Day 1/Day 2). Multiple treatment kits will be required to be used for 
each IMP administration.
The number of vials of avalglucosidase alfa/alglucosidase alfa to be used for each infusion will be 
calculated using the latest available body weight data. Body weight will be measured at the time 
points specified in Section 1.2.
Before randomizing a patient, the Investigator or designee will have to contact the centralized 
treatment allocation system/IRT.
The pediatric patients aged 3 to <18 years enrolling directly in the in the open-label long-term 
follow-up phase, avalglucosidase alfa will not be randomized as they will be assigned to 
avalglucosidase alfa. 
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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.
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 designee. 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 unblinded pharmacist or the unblinded designee.
IMP accountability:
x
Unblinded pharmacist or unblinded designee will maintain records of the precise date, 
time of the drug administration and number of treatment units used for administration. 
This information can be available only to the unblinded pharmacist or unblinded designee 
at the site and unblinded monitor.
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x
The unblinded pharmacist or the unblinded designee will maintain records of the treatment 
numbers assigned by the central treatment allocation system/IRT at each visit.
x
The unblinded 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 from the scheduled infusion date
based on V2 (Day 1/Day 2). 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. Refer to Section 10.1.7 if the missed infusion is due to a missed visit.
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.
Used vials must be kept in their original secondary packaging (box) unless unique treatment 
number is printed on the vial which will allow reconciliation to be performed by site and Sponsor 
representative.
In some specific cases described in the monitoring plans (blinded and unblinded), reconciliation 
may be performed by blinded monitor, as long as the blinding is maintained as per conditions 
detailed in the monitoring plan.
Reconciliation of IMP kits allocated during patient’s double-blind period must be performed at 
the site by the unblinded pharmacist or the unblinded designee and unblinded monitor using 
treatment log forms and documented on-site IMP inventory countersigned by the unblinded 
pharmacist or the unblinded designee and unblinded monitor. A written authorization for 
destruction of used and unused IMP 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:
x
Site has appropriate facilities to destroy IMP;
x
Site has procedures to allow traceability of the batches and quantities destroyed, and 
delivers the corresponding destruction documentation/certificate; and
x
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
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 
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Screening/Baseline Evaluation Visit and during the course of the study will be recorded in the 
electronic Case Report Forms (e-CRF). 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 form.
Patients are restricted from participating in other concurrent investigational protocols that are not 
restricted to data and/or sample collection for patient demographic, disease and/or avalglucosidase 
alfa treatment purposes.
8.8.1
Pretreatment for patients with infusion-associated reactions
In clinical trials with alglucosidase alfa 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 immunoglobulin E 
(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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9
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT
9.1
PRIMARY ENDPOINT
9.1.1
Primary efficacy endpoint
Pulmonary function testing (PFT) will be performed locally at the time points specified in 
Section 1.2 and measured by a central laboratory. During the treatment period, the assessment will 
be completed before IMP infusion. Assessment should continue to be collected for at least up to 
Week 49, end of PAP, if the patient discontinues the treatment earlier.
The PFT administration protocol is standardized across sites in accordance with ATS/ERS 
guidelines (2). Per ATS/ERS 2005 quality standards, an adequate test requires a minimum of 
3 acceptable FVC maneuvers and acceptable repeatability needs to be met for the largest and 
next-largest FVC and forced expiratory volume in the 1st second of the FVC maneuver (FEV1) as 
outlined in the study manual. Patients may repeat the PFT assessment up to 3 times within the 
Screening Visit time window in case of failed quality as determined by the central laboratory
(refer to Section 7 for details on screening and re-screening conditions). For each PFT assessment, 
up to 8 efforts may be performed. Patients are not allowed to use noninvasive ventilation during 
this assessment. The primary efficacy endpoint is the change from baseline to Week 49 in FVC 
(% predicted) in upright position. FVC will be reported in liters and percent of predicted normal 
values based on age, gender, race, and height. Global Lung Initiative (GLI) 2012 reference 
equations will be used for this study (3).
Postbaseline PFT should meet the ATS/ERS 2005 quality standards. However, if no acceptable 
efforts can be recorded during the upright position PFT with up to 8 efforts, an additional PFT 
may be scheduled as soon as possible no later than 45 days after this failed planned test, if this is 
feasible for the patient. The highest acceptable effort will be kept in the database.
In addition, if the patient did not perform the PFT at a planned visit, the patient should be 
reminded to perform the PFT as soon as possible no later than 45 days after the missed test, if it is 
feasible for patient to perform the test within this period.
Refer to the study specific manual for instructions on test administration.
9.2
SECONDARY ENDPOINTS
9.2.1
Secondary efficacy endpoints
9.2.1.1
Six-minute walk test
The 6MWT (4) will be performed at the times specified in Section 1.2 to assess functional 
capacity in the late-onset Pompe population. During the treatment period, the assessment will be 
completed before IMP infusion. See the study specific functional outcome assessment manual for 
further details.
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The primary measurement is the distance walked in 6 minutes, measured in meters; the amount of 
time walked (to quantify endurance, as all patients may not complete the full 6-minute walk) will 
also be recorded. In addition, data will be collected for pre- versus post-test changes in heart rate. 
Testing equipment and administration techniques will be standardized among investigational sites. 
The distance (in meters) will be recorded and the corresponding percent predicted value will be 
calculated. Reference equations for the prediction of total distance walked applicable to the study 
population will be used (5, 6).
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, this must be recorded in the e-CRF. Also, if there is a change in device use 
during the trial, this must be recorded in the e-CRF.
9.2.1.2
Pulmonary function testing
Refer to Section 9.1.1 on the primary efficacy endpoint for information on PFT administration.
Secondary efficacy endpoints measured by PFT will include the assessment of MIP and MEP in 
the upright position. Additional parameters of respiratory function collected may be analyzed as
appropriate, including the assessment of FVC, MIP, and MEP in the supine position and (FEV1)
and peak expiratory flow (PEF) in the upright and supine positions.
9.2.1.3
Hand-held dynamometry (lower extremity muscle strength)
Hand-held dynamometry using the make technique will be performed at the time points specified 
in Section 1.2 (7). Equipment will be standardized across sites. During the treatment period, the 
assessment will be completed before IMP infusion. Stabilization procedures for all muscles 
groups will be followed to avoid use of compensatory muscles. To complete a make test the 
examiner holds the dynamometer stationary while the patient exerts a maximal force against the 
dynamometer. The patient makes a gradual increase in force and then completes an isometric hold 
for 4 to 5 seconds.
Lower extremity strength in the muscle groups detailed below will be tested by the same physical 
therapist or trained assessor.
x
Hip Flexion;
x
Hip Extension;
x
Hip Abduction;
x
Hip Adduction;
x
Knee Flexion;
x
Knee Extension;
x
Ankle Dorsiflexion;
x
Ankle Plantar Flexion.
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The limb tests will be completed bilaterally to account for differences in the generated force for 
the dominant and nondominant limb. Every muscle group will be measured 2 times and the
highest value will be reported in the e-CRF. Patients may use noninvasive ventilation during the 
dynamometry assessment. Refer to the study specific manual for instructions on test 
administration.
For the Canada-specific requirement regarding HHD refer to Appendix C Section 17.3.3.
9.2.1.4
Quick Motor Function Test
The 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 (8). 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 to 15 minutes. Refer to the study specific manual for 
instructions on test administration.
9.2.1.5
12-Item Short-Form Health Survey (SF-12)
The SF-12 Version 2.0 will be administered at the time points specified in Section 1.2. During the 
treatment period, the assessment will be completed before IMP infusion if possible. The SF-12 is 
comprised of a subset of 12 items from the SF-36 to reproduce the physical component summary 
(PCS) and mental component summary (MCS) scales (9). The SF-12 will be administered to 
assess health-related quality of life in patients ≥18 years of age at screening/baseline. The data 
from the questionnaire will be entered into the e-CRF by the site personnel.
9.2.2
Safety endpoints
9.2.2.1
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.
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 AESI, 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.
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9.2.2.2
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:
x
Hematology: red blood cell count, hematocrit, hemoglobin, white blood cell count with 
differential count (neutrophils, eosinophils, basophils, monocytes, and lymphocytes), 
platelets.
x
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, creatine kinase with MB fraction, lactate 
dehydrogenase.
Urinalysis will include urine color, appearance, specific gravity, proteins, glucose, erythrocytes, 
leucocytes, ketone bodies, and pH to be assessed:
x
Qualitatively: A dipstick is to be performed on a freshly voided specimen for qualitative 
detection using a reagent strip.
x
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). A urine sample will be sent to the central laboratory for that 
purpose.
9.2.2.3
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 which is considered as first infusion rate change), at the 
end of the infusion and at the end of the post-infusion observation period, ie, a total of 
7 assessments. Collection windows are ±15 minutes.
9.2.2.4
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),
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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:
x
A single 12-lead ECG (25 mm/s, 10 mm/mV) printout including date, time, and number of 
the patient, signature of the research physician, and at least 3 complexes for each lead. The 
study site cardiologist’s medical opinion and automatic values will be recorded in the 
e-CRF. This printout will be retained at the site.
x
A single digital file will be stored which enables manual reading when it is necessary 
(centralized reading of computerized ECGs); each digital file will be identified by 
theoretical time (day and time), real date and real time (recorder time), and patient number 
(eg, 3 digits). The digital recording, data storage, and transmission (whenever requested) 
need to comply with all applicable regulatory requirements (such as US FDA Code of 
Federal Regulations, Title 21, Part 11 or EU regulation Eudralex volume 4 annex 11).
The Investigator who reads the ECGs or appropriate designee (noninvestigator physician who
reads the ECGs) should review the ECGs in a timely manner to determine if there are any safety 
concerns and for clinical management of the patient. In the event of any clinically significant 
abnormal findings that meet the definition of an AE (see Section 10.4.1 for definitions and 
reporting), the Investigator will continue to monitor the patient with additional ECGs until the 
ECG returns to baseline or the Investigator determines that follow-up is no longer necessary.
In case of abnormal findings by the Investigator who reads the ECGs 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.
9.2.2.5
Physical examination
Physical examination will include, at a minimum, an assessment of the patient’s general 
appearance; skin; head, eyes, ears, nose, and throat; examinations of lymph nodes, abdomen, 
extremities/joints, neurological and mental status; heart and respiratory auscultation; peripheral 
arterial pulse; and pupil, knee, Achilles, and plantar reflexes. Head circumference and Tanner 
stage of sexual maturation will be assessed as part of the physical examination in pediatric 
patients at baseline and yearly thereafter. Details can be found in the study manual.
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9.2.2.6
Body weight and height
Body weight will be measured in kilograms and collected in the e-CRFs monthly for pediatric 
patients and every 3 months throughout the duration of the study for adults. More frequent weight 
may be obtained at the discretion of the Investigator.
Standing height will be measured in all patients at baseline and annually thereafter, and in 
pediatric patients additionally every 3 months up to Week 73 and then every 6 months. 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.
9.2.2.7
Immunogenicity
Immunogenicity assessments will include the following:
x
Samples will be collected from patients for evaluation of ADA every month up to 
Week 73 and then every 3 months throughout the duration of the study. In addition, 
samples will be collected from all patients at Week 2 (Day 8) and Week 52 (1 week after 
the first possible avalglucosidase alfa infusion in patients who received alglucosidase alfa 
during the blinded treatment period) to monitor for an early antibody response in 
avalglucosidase alfa-treated patients. 
-
Patients in the avalglucosidase alfa treatment arm will be tested for 
anti-avalglucosidase alfa antibodies and patients in the alglucosidase alfa treatment 
arm will be tested for anti-alglucosidase alfa antibodies; in addition, patients in the 
alglucosidase alfa treatment arm will also be tested for anti-avalglucosidase alfa 
antibodies at V27/W49 to get their baseline value. In the open-label follow-up phase, 
patients from the alglucosidase alfa treatment arm who have switched to 
avalglucosidase alfa will be tested for both anti-alglucosidase alfa antibodies and 
anti-avalglucosidase alfa antibodies. In these patients, ADA against alglucosidase alfa 
will no longer be tested in the extended open-label follow-up phase (ie, after 
Week 145). Patients who remain on avalglucosidase alfa treatment will continue to be 
tested for anti-avalglucosidase alfa antibodies. Patients who are positive for 
anti-avalglucosidase alfa antibodies will be tested to determine if the antibodies 
cross-react with alglucosidase alfa.
-
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).
x
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.
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x
See the study specific laboratory manual as well as the study manual for guidelines on the 
collection and shipment of antibody samples and for details on circulating immune 
complex testing.
9.3
OTHER ENDPOINTS
9.3.1
Tertiary efficacy endpoints
9.3.1.1
Gait, Stair, Gower’s Maneuver, and Chair composite functional assessment
Functional performance will be measured using the GSGC score at the time points specified in 
Section 1.2. During the treatment period, the assessment will be completed before IMP infusion. 
The GSGC total score can be obtained by adding the item scores of the 4 functional tests; item 
scores range from 1 to 7 for 3 items and 1 to 6 for 1 item (Arising from a chair). Total scores can 
vary from a minimum of 4 representing normal performance to a maximum of 27 representing the 
poorest functional score. The GSGC performance test has been validated for use with glycogen 
storage disease (GSD) type II patients and patients with Duchenne muscular dystrophy (10). Each 
of the functional items is also evaluated according to the time required to complete the task.
x
Time to walk 10 meters (Gait);
x
Time to climb 4 stairs (Stair);
x
Time to stand from sitting on the floor (Gower’s Maneuver);
x
Time to stand from sitting position in a chair (Chair).
See the study specific manual for further details.
9.3.1.2
Gross Motor Function Measure
The GMFM-88 (11) 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.
Of the 5 dimensions to the GMFM-88, 2 will be evaluated in this study:
x
Standing (13 items);
x
Walking, Running & 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.
This assessment will include the expanded and revised Gross Motor Function Classification 
System for the GMFM-88 (GMFCS-E&R) adapted for adults (12). The GMFCS emphasizes 
concepts in the World Health Organization’s International Classification of Functioning, 
Disability and Health. Emphasis is on performance in home, work and community settings 
without judgments about quality of movement or prognosis for improvement. The GMFCS is a 
5-level classification system 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 (12).
The general headings for the 5 levels are:
x
Level I
Walks without limitations
x
Level II 
Walks with limitations
x
Level III
Walks using a hand-held mobility device
x
Level IV
Self-mobility with limitations; may use powered mobility
x
Level V
Transported in a manual wheelchair
See the study specific manual for further details.
9.3.1.3
Hand-held dynamometry (upper extremity muscle strength)
Hand-held dynamometry using the make technique will be performed at the time points specified 
in Section 1.2 (7, 13). Equipment will be standardized across sites. During the treatment period, 
the assessment will be completed before IMP infusion. Stabilization procedures for all muscles 
groups will be followed to avoid use of compensatory muscles. To complete a make test, the
examiner holds the dynamometer stationary while the patient exerts a maximal force against the 
dynamometer. The patient makes a gradual increase in force and then completes an isometric hold 
for 4 to 5 seconds.
Upper extremity strength in the muscle groups detailed below will be tested by the same physical 
therapist or trained assessor.
x
Shoulder Flexion;
x
Shoulder Extension;
x
Shoulder Abduction;
x
Shoulder Adduction;
x
Elbow Flexion;
x
Elbow Extension;
x
Grip Strength.
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The limb tests will be completed bilaterally to account for differences in the generated force for 
the dominant and nondominant limb. Every muscle group will be measured 2 times and the 
highest value will be reported in the e-CRF. Patients may use noninvasive ventilation during the 
dynamometry assessment. See the study specific manual for further details.
For the Canada-specific requirement regarding HHD, refer to Appendix C Section 17.3.3.
9.3.1.4
5-Level EuroQoL in 5 dimensions
The EQ-5D-5L survey will be completed at the time points specified in Section 1.2. During the 
treatment period, the assessment will be completed before IMP infusion if possible. The EQ-5D-L
is a standardized instrument for use as a measure of health outcome (14). Applicable to a wide 
range of health conditions and treatments, it provides a simple descriptive profile and a single 
index value for health status. The EQ-5D-5L descriptive system comprises 5 dimensions of health 
(mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and is rated according to 
5 levels of health/ability (either no problem, slight problem, moderate problem, severe problem; 
or unable to perform activity or no, slight, moderate, severe, or extreme). The EQ VAS records 
the respondents’ self-rated health status on a vertical graduated (0-100) visual analogue scale. 
Patients who are ≥18 years of age at screening/baseline will complete this assessment. The data 
from the questionnaire will be entered into the e-CRF by the site personnel.
9.3.1.5
Pediatric Quality of Life Inventory
The PedsQL Generic Core Scales is a general health-related quality of life tool and will be 
completed at the time points specified in Section 1.2 by patients who are <18 years of age at 
screening/baseline. 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 encompasses 4 subscales including a patient’s health and activities, feelings, 
problems with school, and how the patient gets along with others (15). 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 entered into the e-CRF by the site personnel.
9.3.2
Pharmacokinetics
9.3.2.1
Sampling time
Blood samples for full evaluation of avalglucosidase alfa and alglucosidase alfa PK will be 
collected before and after infusions on Visit 2 (Day 1/Day 2) and Visit 27 (Week 49). Sampling 
times are as follows: pre-dose (prior to infusion), at the end of the infusion, and at 2, 4, 6, and 
8 hours after the end of infusion. In addition, sparse blood samples will be collected predose (prior 
to infusion) and at 2 hours after the end of infusion at Week 13, Week 25, and Week 37.
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.
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9.3.2.2
Pharmacokinetics handling procedure
Special procedures for collection, storage, and shipment will be provided in the study specific 
laboratory manual.
9.3.2.3
Bioanalytical method
Plasma samples will be analyzed using validated, sensitive and specific bioanalytical methods, 
namely, fluorometric assays using a 4-methylumbelliferyl-α-D-glucoside substrate to detect 
avalglucosidase alfa and alglucosidase alfa activity.
The lower limit of quantitation (LLOQ) is 12 ng/mL or 0.012 μg/mL for avalglucosidase alfa.
9.3.2.4
Pharmacokinetics parameters
The following pharmacokinetic parameters will be determined for avalglucosidase alfa and 
alglucosidase alfa based on non-compartmental analysis. The parameters will include Cmax and 
AUC0-last. If data permit, other parameters including clearance (CL) and volume of distribution at 
steady state (Vss) will be included. The definitions of the pharmacokinetic parameters are 
presented in Table 1.
Table 1 - List of pharmacokinetic parameters and definitions
Parameters
Drug/Analyte
Matrix
Definition/Calculation
Cmax 
avalglucosidase 
alfa/alglucosidase alfa 
Plasma 
Maximum plasma concentration observed 
AUC0-last 
avalglucosidase 
alfa/alglucosidase alfa 
Plasma 
Area under the plasma concentration versus time curve from time 0 to 
time of the last quantifiable concentration 
CL 
avalglucosidase 
alfa/alglucosidase alfa 
Plasma 
Total body CL of a drug from the plasma 
Vss 
avalglucosidase 
alfa/alglucosidase alfa 
Plasma 
Volume of distribution at steady state 
9.3.3
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.
9.3.3.1
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 
amplified by polymerase chain reaction (PCR) using gene specific primers and the resulting PCR 
products will be sequenced for the identification of mutations and genetic variation 
(polymorphisms and associated haplotypes) within the GAA gene.
Gene mutation analysis is mandatory for all patients but GAA genotyping is only to be performed 
if historical results are not available. Blood sample results for patient gene mutation analysis must 
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be obtained prior to screening/baseline in order to assess patient for study eligibility. However, 
results from the central laboratory may be used if performed during the screening period but 
should be obtained before the baseline visit to confirm eligibility. If gene mutation analysis was 
conducted prior to signing the informed consent, these results may be collected provided that the 
analysis was conducted by a certified laboratory, written results are provided to the site, and 
patient and/or legal guardian gives consent to utilize the results. If interpretation of GAA 
genotyping is inconclusive for the diagnosis of Pompe disease, or if only 1 mutation has been 
reported, then GAA enzyme activity level, normal laboratory ranges and tissue source needs to be 
provided in the interpretation field of the GAA genotyping e-CRF page for the purpose of 
confirming Pompe Disease.
9.3.3.2
Angiotensin converting enzyme marker allele status
DNA samples will also be collected as specified in Section 1.2 for an exploratory assessment of 
ACE (also known as DCP1) gene polymorphisms involving the absence (deletion, D allele) or 
presence (insertion, I allele) of a 287 base pair alu-repeat fragment located in intron 16 of the 
ACE gene. The ACE allele genotype status will be identified by PCR.
9.3.3.3
Exploratory assessment of circulating microRNA in plasma
Plasma samples will be collected as specified in Section 1.2 and assessed for circulating 
microRNA concentrations on both the whole-genome and individual gene levels.
9.3.3.4
Optional stored DNA sample
For those patients who signed the optional pharmacogenetic informed consent form, 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 Patient ID. This “double coding” is 
performed to separate a patient’s medical information and DNA data.
The clinical study data (coded by Patient 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 Patient 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.
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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.
Special procedures for storage and shipping of pharmacogenetic samples are described in detail in 
the study specific laboratory manual.
9.3.4
Pharmacodynamic variables
9.3.4.1
Urine Hex4 levels
Fasted urine samples for the assessment of urinary glucose tetrasaccharide (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.
9.3.4.2
Exploratory urine, DBS, and plasma biomarkers
Fasted DBS, plasma and urine will be collected prior to IMP infusion at the times specified in 
Section 1.2 for the assessment of exploratory biomarkers. Procedures for the collection, handling 
and shipment of all samples will be included in the study specific laboratory manual.
9.3.5
Quality of life/health economic variables/other endpoints
9.3.5.1
Pompe Disease Symptom and Impact Scales
The PDSS and PDIS will be completed as both a 24-hour recall PDSS (version 1.1) and PDIS 
(version 1.2), as well as a 7-day recall PDSS (version 1.7) and PDIS (version 1.27). After training 
by the site staff at screening/baseline, patients will complete the 24-hour version of the PDSS and 
PDIS daily throughout the entire screening period. The patients will also complete a one-time 
administered, 7-day recall version prior to first infusion (ie, at Day -1, Day 1, or Day 2). During 
the trial, patients will complete the 24-hour recall version of the scales daily via an e-diary for 
2 weeks between visits at the time points specified in Section 1.2. Patients ≥18 years of age at 
screening/baseline will complete this assessment. The PDSS and PDIS are both self-administered 
questionnaires specifically designed to capture the symptoms and impacts pertinent to patients 
with LOPD. The PDSS contains 12 questions on a scale from 0 (none) to 10 (as bad as I can 
imagine), while the PDIS contains 15 questions with varying scales implemented depending on 
question type. The data from these scales will be analyzed both separately and together as a 
composite. Since these are recall questionnaires, they can be completed by the patient anytime, 
but preferably at the same time of the day. In case of unavailability of the e-diary (eg, device 
dysfunction or deficiency), a paper version of the scale(s) will be used and the data will be 
transferred into the database.
9.3.5.2
Rasch-built Pompe-specific Activity scale
The R-PAct scale will be completed at the time points specified in Section 1.2 in selected 
countries (eg, UK, USA, Canada, Belgium and The Netherlands). Patients whose first language is 
English or Dutch and who are ≥18 years of age at screening/baseline will complete this 
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assessment. During the treatment period, the assessment will be completed before IMP infusion if
possible. The R-PAct is a self-administered questionnaire specifically suited to quantify the 
effects of Pompe disease on patient’s ability to carry out daily activities and their social 
participation. It consists of 18 items suited to quantify activity limitations, ranging from unable to 
perform daily life activities (0) to able to perform without difficulty (2) in patients with Pompe 
disease (16). The data from this questionnaire will be entered into the e-CRF by the site personnel.
9.3.5.3
Patient Global Impression of Change
The PGIC items will be completed at Week 49 (PAP patients and 2 additional pediatric patients in 
open-label period) and will be administered annually in follow-up during the extension period.
Patients who are ≥18 years of age at the concerned visit will complete this assessment at Week 49,
Week 97 and Week 145 (pediatric patients in open-label period will complete this assessment at 
Week 49 and Week 97). The PGIC items consist of 4 questions pertaining to overall 
disease-related symptoms, activities of daily living, as well as mobility and respiratory issues. The 
items range from -3 (a great deal worse) to 0 (no change) to 3 (a great deal better). The data from 
this scale will be used to support and validate additional endpoints in the trial.
9.4
FUTURE USE OF SAMPLES
Not all of the samples collected during this study may be required for the tests planned in this 
clinical trial. For patient s 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, Patient 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 
patient 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
The primary objective of the EFC14028 study is to determine the effect of avalglucosidase alfa
treatment on respiratory muscle strength as measured by FVC % predicted in the upright position,
as compared to alglucosidase alfa in approximately 96 patients with LOPD, male or female, aged 
from 3 years, and previously not treated with ERT. The PAP will be a 12-month phase from start 
of study treatment. The primary endpoint will be change in % predicted FVC from baseline to 
12 months (49 weeks).
The consensus of a survey of treaters conducted by Sanofi Genzyme highlighted respiratory 
function improvement as an ongoing unmet need in Pompe disease. In LOPD patients, 
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alglucosidase alfa leads to improvement in 6MWT and muscle function with stabilization of 
decline in respiratory function. The most common cause of death in Pompe disease is respiratory 
complications of long-term decline in respiratory function.
In previous alglucosidase alfa experience from the AGLU02704 double-blind placebo-controlled 
trial in late-onset patients, the patients from the alglucosidase alfa treated arm had a mean 
(±standard deviation [SD]) change from baseline in % predicted FVC of 1.56 ±4.3 at 6 months,
demonstrating stabilization. In a subsequent study of alglucosidase alfa in 18 late-onset patients 
(AGLU07310), there was an average improvement of 1.8 % in FVC. More recently, a Phase 1/2
trial (TDR12857) with avalglucosidase alfa in an LOPD population similar to AGLU07310 was 
completed, in which the mean (SD) change from baseline in % predicted FVC was 6.2 (3.15) in 
the 3 patients previously naïve to treatment dosed with 20 mg/kg avalglucosidase alfa or 5.2 when 
looking at the 6 patients from the 10 and 20 mg/kg treatment-naïve group. Replication of this 
preliminary clinical evidence of superiority of avalglucosidase alfa over the existing treatment of 
alglucosidase alfa with respect to pulmonary function should correlate to a clinically meaningful 
benefit in the context of the known long-term respiratory complications seen in Pompe disease.
The secondary objectives are to determine the effect of avalglucosidase alfa on change in 6MWT
distance walked, MIP and MEP % predicted, muscle strength (HHD), motor function (QMFT), 
and health-related quality of life (SF-12). In the context of availability of an existing treatment, 
assessment of these endpoints is important to assure that the new treatment is not less effective.
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10
STUDY PROCEDURES
10.1
VISIT SCHEDULE
It is recommended that assessments/procedures at a site visit are performed in the following order, 
if applicable:
1. Patient-reported outcomes and other questionnaires
2. Physical examination (including height, body weight, head circumference, Tanner stage)
and patient interview
3. Procedures:
-
ECG
-
PFT
4. Motor assessments
5. Safety and laboratory assessments
6. IMP administration
Visits that are longer due to multiple assessments or procedures (eg, motor assessments and 
multiple questionnaires) may be carried out over 2 days, consecutive or not. In any case, IMP 
administration will be the last procedure and the appropriate time needed for post-infusion
surveillance will be taken into account.
10.1.1 Prestudy IRT contact
x
IRT contact to inform identification of potential patient and initiation of IMP shipment for 
each patient
Information regarding the prestudy IRT contact can be found in the IRT manual.
10.1.2 Screening period/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 any 
action related to the study.
Patients who have signed their written informed consent will have the following procedures 
performed at screening/baseline.
x
Informed consent;
x
Inclusion/exclusion criteria;
x
Demographics and baseline characteristics:
-
Age (years);
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Gender;
-
Race;
-
Ethnicity;
x
Medical/Surgical history;
x
Pompe disease history, inclusive of GAA mutation and aspects of disability;
x
Physical examination (inclusive of head circumference and Tanner stage for pediatric 
patients only);
x
β-HCG pregnancy test (females of childbearing potential only);
x
Body weight;
x
Height;
x
Hematology, biochemistry, and urinalysis;
x
ADAs (with neutralizing antibodies in ADA-positive patients);
x
Urine Hex4 sample collection;
x
Exploratory biomarker urine sample collection;
x
GAA genotyping (if historical results are not available);
x
ACE genotyping;
x
Stored DNA sample (optional);
x
SF-12 (patients ≥18 years of age);
x
EQ-5D-5L (patients ≥18 years of age);
x
PedsQL (patients <18 years of age);
x
PDSS/PDIS (patients ≥18 years of age, 24-hour recall version daily [ie, during screening]
via an e-diary, as well as 7-day recall version prior to first infusion [ie, at Day -1, Day 1, 
or Day 2]);
x
R-PAct (patients ≥18 years of age);
x
PFT;
x
6MWT;
x
GSGC;
x
GMFM-88/GMFCS;
x
QMFT;
x
HHD (not applicable for Canadian sites, see Appendix C Section 17.3.3);
x
AE collection;
x
Prior/concomitant medications;
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x
IRT contact for notification of screening.
The recommended duration of the screening period is up to 14 days but may be extended to a 
maximum of 8 weeks in the following pre-specified situations:
x
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.
x
An intercurrent acute disease or event occurred during the screening period, which does 
not meet an exclusion criterion (see Section 7.2).
x
Up to 4 PFTs (original plus 3 repeat tests) may be required to meet ATS/ERS quality 
criteria.
x
The study or the IMP administration is temporarily put on hold due to a Sponsor decision 
(see Section 10.3.1).
FVC% predicted may be repeated up to 3 times during the screening period if ATS/ERS quality 
criteria have not been met as assessed by the central laboratory. Repeat tests should not occur on 
the same day in order to allow the patient to rest.
Re-screening may be allowed as described in Section 7.2.5.
Patients who meet all the inclusion criteria and none of the exclusion criteria will be eligible for 
inclusion in the study. Randomization should be performed just before the IMP administration at 
the first treatment visit.
For the subgroup of pediatric patients aged 3 to <18 years enrolling directly in the open-label 
long-term follow-up phase, an IRT call for enrollment will replace the randomization call and will 
be performed just before the IMP administration at the first treatment visit. Postscreening 
schedule for this subgroup of pediatric patients is detailed in Section 10.1.7.
10.1.3 Blinded treatment period
Patients enrolled in the study will have the following procedures performed starting at Day of first 
infusion. Day of first infusion should occur within 1 to 14 days after Screening/Baseline. All 
subsequent 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 and ±14 days for all other assessments.
A patient card will be provided to the patient once the patient is randomized (see study manual for 
details).
10.1.3.1 Day of first infusion (Day 1/Day 2)
The following will be performed on the day of randomization (Day 1), or day following 
randomization (Day 2) to allow preparation of the IMP for infusion:
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x
Inclusion/exclusion criteria;
x
Urine pregnancy test (females of childbearing potential only);
x
Body weight;
x
12-lead ECG (triplicate);
x
Vital signs (before, during, and following infusion);
x
Urine Hex4 sample collection;
x
Exploratory biomarker urine sample collection;
x
Exploratory biomarker DBS and plasma sample collection;
x
Plasma sample collection for microRNA analyses;
x
IRT contact to confirm patient randomization and treatment kits allocation;
x
PK plasma sample collection (before and following infusion);
x
Infusion of IMP;
x
AE collection;
x
Prior/concomitant medications;
x
PDSS and PDIS (patients ≥18 years of age at screening/baseline: 7-day recall version 
administered prior to first infusion (ie, at Day 1 or Day 2). 
Information regarding the infusion of the IMP can be found in the pharmacy manual.
This visit requires a stay at the site prior to and for at least 8 hours following IMP infusion as an 
in-patient or out-patient, as per hospital/center procedure. 
10.1.3.2 One week following first infusion (Week 2 [Day 8])
The following will be performed 1 week following the date of the first infusion:
x
Biochemistry;
x
ADAs (with neutralizing antibodies in ADA-positive patients);
x
AE collection;
x
Prior/concomitant medications.
10.1.3.3 Biweekly
The following will be performed every 2 weeks starting at the date of the first infusion (W3, W5, 
W7, W9, W11, W13, W15, W17, W19, W21, W23, W25, W27, W29, W31, W33, W35, W37, 
W39, W41, W43, W45, W47 and W49):
x
IRT contact for treatment kits allocation;
x
Vital signs (before, during, and following infusion);
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x
Infusion of IMP;
x
AE collection;
x
Prior/concomitant medications.
10.1.3.4 Every 4 weeks
The following assessments will be performed on a monthly basis (W5, W9, W13, W17, W21, 
W25, W29, W33, W37, W41, W45 and W49):
x
IRT contact for treatment kits allocation;
x
Vital signs (before, during, and following infusion);
x
Infusion of IMP;
x
Urine pregnancy test (females of childbearing potential only);
x
Biochemistry;
x
ADAs (with neutralizing antibodies in ADA-positive patients);
x
Body weight (for pediatric patients only);
x
AE collection;
x
Prior/concomitant medications.
10.1.3.5 Every 12 weeks
The following assessments will be performed at quarterly visits (Week 13, Week 25, Week 37,
and Week 49):
x
Physical examination (inclusive of head circumference and Tanner stage for pediatric 
patients only at Week 49);
x
Urine pregnancy test (females of childbearing potential only);
x
Body weight;
x
IRT contact for treatment kits allocation;
x
Height (for pediatric patients only and adult patients only at Week 49);
x
Hematology, biochemistry, and urinalysis;
x
ECG;
x
Vital signs (before, during, and following infusion);
x
PK plasma sample collection (before and following infusion);
x
ADAs (with neutralizing antibodies in ADA-positive patients);
x
Exploratory biomarker urine sample collection;
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x
Exploratory biomarker DBS and plasma sample collection;
x
Plasma sample collection for microRNA analyses;
x
Urine Hex4 sample collection;
x
SF-12 (patients ≥18 years of age at screening/baseline);
x
EQ-5D-5L (patients ≥18 years of age at screening/baseline);
x
PedsQL (patients <18 years of age at screening/baseline);
x
PDSS/PDIS (patients ≥18 years of age at screening/baseline, via an e-diary daily for
2 weeks between visits);
x
R-PAct (patients ≥18 years of age at screening/baseline);
x
PGIC (patients ≥18 years of age at screening/baseline, at Week 49 only);
x
PFT;
x
6MWT;
x
GSGC;
x
GMFM-88/GMFCS;
x
QMFT;
x
HHD (not applicable for Canadian sites, see Appendix C Section 17.3.3);
x
Infusion of IMP;
x
AE collection;
x
Prior/concomitant medications.
Week 49/Visit 27 requires a stay at the site prior to and for at least 8 hours following IMP 
infusion.
10.1.4 Open-label avalglucosidase alfa long-term follow-up phase
10.1.4.1 Every 2 weeks (Biweekly)
The following will be performed every 2 weeks starting at the date of the first infusion of the 
follow-up phase (Week 51 and then 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):
x
IRT contact for treatment kits allocation;
x
Vital signs (before, during, and following infusion);
x
Infusion of avalglucosidase alfa;
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AE collection;
x
Prior/concomitant medications.
10.1.4.2 One week following first infusion in open-label phase (Week 52)
The following will be performed 1 week following the date of the first infusion of the follow-up
phase:
x
Biochemistry;
x
ADAs (with neutralizing antibodies in ADA-positive patients);
x
AE collection;
x
Prior/concomitant medications.
10.1.4.3 Every 4 weeks
The following assessments will be performed every 4 weeks (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):
x
IRT contact for treatment kits allocation;
x
Vital signs (before, during, and following infusion);
x
Infusion of avalglucosidase alfa;
x
Body weight (for pediatric patients only);
x
Urine pregnancy test (females of childbearing potential only);
x
Biochemistry;
x
ADAs (with neutralizing antibodies in ADA-positive patients) (monthly through Week 73);
x
AE collection;
x
Prior/concomitant medications.
10.1.4.4 Every 12 weeks
The following assessments will be performed every 3 months (W61, W73, W85, W97, W109, 
W121, W133 and W145):
x
Urine pregnancy test (females of childbearing potential only);
x
Body weight;
x
IRT contact for treatment kits allocation;
x
Biochemistry;
x
ADAs (with neutralizing antibodies in ADA-positive patients);
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Vital signs (before, during, and following infusion);
x
Infusion of avalglucosidase alfa;
x
AE collection;
x
Prior/concomitant medications.
10.1.4.5 At 12 weeks, 24 weeks, and then every 24 weeks
The following assessments will be performed at Week 61, Week 73, Week 97, Week 121, and 
Week 145:
x
Physical examination (inclusive of head circumference and Tanner stage for pediatric 
patients only at Week 97, Week 145);
x
Urine pregnancy test (females of childbearing potential only);
x
Body weight;
x
IRT contact for treatment kits allocation;
x
Height (for pediatric patients only and for adult patients only at Week 97 and Week 145);
x
Hematology, biochemistry, and urinalysis;
x
ADAs (with neutralizing antibodies in ADA-positive patients);
x
ECG;
x
Vital signs (before, during, and following infusion);
x
Exploratory biomarker urine sample collection;
x
Exploratory biomarker DBS and plasma sample collection;
x
Plasma sample collection for microRNA analyses;
x
Urine Hex4 sample collection;
x
SF-12 (patients ≥18 years of age at screening/baseline);
x
EQ-5D-5L (patients ≥18 years of age at screening/baseline);
x
PedsQL (patients <18 years of age at screening/baseline);
x
PDSS/PDIS (patients ≥18 years of age at screening/baseline, via an e-diary daily for
2 weeks between visits);
x
R-PAct (patients ≥18 years of age at screening/baseline);
x
PGIC (patients ≥18 years of age at the concerned visit, annually);
x
PFT;
x
6MWT;
x
GSGC;
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GMFM-88/GMFCS;
x
QMFT;
x
HHD (not applicable for Canadian sites, see Appendix C Section 17.3.3);
x
Infusion of avalglucosidase alfa;
x
AE collection;
x
Prior/concomitant medications;
x
IRT call for end of treatment (Week 145 for patients not entering the extended open-label 
avalglucosidase alfa long-term follow-up phase only).
10.1.5 Extended open-label avalglucosidase alfa long-term follow-up phase
10.1.5.1 Biweekly
The following assessments will be performed every 2 weeks, starting at Week 147 and up to 
144 additional weeks (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) or until avalglucosidase 
alfa is approved in the patient’s country, whichever comes first (refer to Appendix C
Section 17.3.3 for patients in Canada and Section 17.3.4 for definition applicable for UK 
patients):
x
IRT contact for treatment kits allocation;
x
Vital signs (before, during, and following infusion);
x
Infusion of avalglucosidase alfa;
x
AE collection;
x
Prior/concomitant medications.
10.1.5.2 Every 4 weeks (Monthly)
The following assessments will be performed every 4 weeks, starting at Week 149 and up to 
144 additional weeks (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) or
until avalglucosidase alfa is approved in the patient’s country, whichever comes first (refer to 
Appendix C Section 17.3.3 for patients in Canada and Section 17.3.4 for definition applicable for 
UK patients):
x
IRT contact for treatment kits allocation;
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Vital signs (before, during, and following infusion);
x
Body weight (for pediatric patients only);
x
Infusion of avalglucosidase alfa;
x
Urine pregnancy test (females of childbearing potential only);
x
AE collection;
x
Prior/concomitant medications.
10.1.5.3 Every 12 weeks (Quarterly)
The following assessments will be performed every 12 weeks, starting at Week 157 and up to 
144 additional weeks (W157, W169, W181, W193, W205, W217, W229, W241, W253, W265, 
W277, W289) or until avalglucosidase alfa is approved in the patient’s country, whichever comes 
first (refer to Appendix C Section 17.3.3 for patients in Canada and Section 17.3.4 for definition 
applicable for UK patients):
x
IRT contact for treatment kits allocation;
x
Vital signs (before, during, and following infusion);
x
Infusion of avalglucosidase alfa;
x
Body weight;
x
Urine pregnancy test (females of childbearing potential only);
x
ADAs (with neutralizing antibodies in ADA-positive patients);
x
AE collection;
x
Prior/concomitant medications.
10.1.5.4 Every 24 weeks (every 6 months)
The following assessments will be performed every 24 weeks, starting at Week 169 and up to 
144 additional weeks (W169, W193, W217, W241, W265, W289) or until avalglucosidase alfa is
approved in the patient’s country, whichever comes first (refer to Appendix C Section 17.3.3 for 
patients in Canada and Section 17.3.4 for definition applicable for UK patients):
x
IRT contact for treatment kits allocation;
x
Vital signs (before, during, and following infusion);
x
Infusion of avalglucosidase alfa;
x
Body weight;
x
Urine pregnancy test (females of childbearing potential only);
x
ADAs (with neutralizing antibodies in ADA-positive patients);
x
AE collection;
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x
Prior/concomitant medications;
x
Height (in pediatric patients only);
x
Hematology, biochemistry, and urinalysis;
x
PFT;
x
6MWT;
x
SF-12 (patients ≥18 years of age at screening/baseline);
x
EQ-5D-5L (patients ≥18 years of age at screening/baseline);
x
PDSS/PDIS (patients ≥18 years of age at screening/baseline, via an e-diary daily for 
2 weeks between visits);
x
R-PAct (patients ≥18 years of age at screening/baseline).
10.1.5.5 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 
144 additional weeks after Week 145 (W193, W241, W289) or until avalglucosidase alfa is
approved in the patient’s country, whichever comes first (refer to Appendix C Section 17.3.3 for 
patients in Canada and Section 17.3.4 for definition applicable for UK patients):
x
IRT contact for treatment kits allocation;
x
Vital signs (before, during, and following infusion);
x
Infusion of avalglucosidase alfa;
x
Body weight;
x
Urine pregnancy test (females of childbearing potential only);
x
ADAs (with neutralizing antibodies in ADA-positive patients);
x
AE collection;
x
Prior/concomitant medications;
x
Height;
x
Hematology, biochemistry, and urinalysis;
x
ECG;
x
PFT;
x
6MWT;
x
SF-12 (patients ≥18 years of age at screening/baseline);
x
EQ-5D-5L (patients ≥18 years of age at screening/baseline);
x
PedsQL (patients <18 years of age at screening/baseline);
x
PDSS/PDIS (patients ≥18 years of age at screening/baseline, via an e-diary daily for
2 weeks between visits);
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R-PAct (patients ≥18 years of age at screening/baseline);
x
PGIC (patients ≥18 years of age at the concerned visit).
10.1.6 End of study
The following assessments will be performed at the end of study visit/contact (2 to 4 weeks after 
last infusion):
x
AE collection;
x
Prior/concomitant medications.
10.1.7 Visit schedule for pediatric patients aged 3 to <18 years enrolling directly in the 
open-label long-term follow-up phase (starting after screening period)
Pediatric patients aged 3 to <18 years enrolling directly in the open-label long-term follow-up
phase will have the following procedures performed starting at Day of first infusion. Day of first 
infusion should occur within 1 to 14-day after screening/baseline. All subsequent 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, and ±14 days for all other assessments.
x
IRT contact to inform identification of potential patient and initiation of IMP shipment for 
each patient
Information regarding the pre-study IRT contact can be found in the IRT manual.
10.1.7.1 Day of first infusion (Day 1/Day 2) (pediatric patients enrolling directly in the open-
label follow-up phase)
The following will be performed on the day of randomization (Day 1), or day following 
randomization (Day 2) to allow preparation of the IMP for infusion:
x
Inclusion/exclusion criteria;
x
Urine pregnancy test (females of childbearing potential only);
x
Body weight;
x
12-lead ECG (triplicate);
x
Vital signs (before, during, and following infusion);
x
Urine Hex4 sample collection;
x
Exploratory biomarker urine sample collection;
x
Exploratory biomarker DBS and plasma sample collection;
x
Plasma sample collection for microRNA analyses;
x
IRT contact to confirm patient enrollment and treatment kits allocation;
x
PK plasma sample collection (before and following infusion);
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x
Infusion of IMP;
x
AE collection;
x
Prior/concomitant medications. 
Information regarding the infusion of the IMP can be found in the pharmacy manual.
This visit requires a stay at the site prior to and for at least 8 hours following IMP infusion as an 
in-patient or out-patient, as per hospital/center procedure. A patient card will be provided to the 
patient once the patient is enrolled (see study manual for details).
10.1.7.2 Open-label avalglucosidase alfa long-term follow-up phase (pediatric patients 
enrolling directly in the open-label follow-up phase)
10.1.7.2.1One week following first infusion (Week 2)
The following will be performed 1 week following the date of the first infusion:
x
Biochemistry;
x
ADAs (with neutralizing antibodies in ADA-positive patients);
x
AE collection;
x
Prior/concomitant medications.
10.1.7.2.2Every 2 weeks (Biweekly)
The following will be performed every 2 weeks starting at Week 3 (W3, W5, W7, W9, W11, 
W13, W15, W17, W19, W21, W23, W25, W27, 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):
x
IRT contact for treatment kits allocation;
x
Vital signs (before, during, and following infusion);
x
Infusion of avalglucosidase alfa;
x
AE collection;
x
Prior/concomitant medications.
10.1.7.2.3Every 4 weeks
The following assessments will be performed every 4 weeks (W5, W9, W13, W17, W21, W25, 
W29, W33, W37, W41, W45, W49, W53, W57, W61, W65, W69, W73, W77, W81, W85, W89, 
W93 & W97): 
x
IRT contact for treatment kits allocation;
x
Vital signs (before, during, and following infusion);
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x
Infusion of avalglucosidase alfa;
x
AE collection;
x
Prior/concomitant medications;
x
Body weight;
x
Urine pregnancy test (females of childbearing potential only);
x
Biochemistry;
x
ADAs (with neutralizing antibodies in ADA-positive patients) (monthly through Week 73,
then at W97 only).
10.1.7.2.4Every 12 weeks until W73 and at W97
The following assessments will be performed every 12 weeks until W73 and at W97 (W13, W25, 
W37, W49, W61, W73 & W97): 
x
IRT contact for treatment kits allocation;
x
Vital signs (before, during, and following infusion);
x
Infusion of avalglucosidase alfa;
x
AE collection;
x
Prior/concomitant medications;
x
Body weight;
x
Urine pregnancy test (females of childbearing potential only);
x
Hematology, biochemistry, and urinalysis;
x
ADAs (with neutralizing antibodies in ADA-positive patients);
x
Physical examination (inclusive of head circumference and Tanner stage at W49 & W97);
x
Height;
x
ECG;
x
Exploratory biomarker urine sample collection;
x
Exploratory biomarker DBS and plasma sample collection;
x
Plasma sample collection for microRNA analyses;
x
Urine Hex4 sample collection;
x
PedsQL;
x
PGIC (patients ≥18 years of age at the concerned visit, at W49 and W97 only);
x
PFT;
x
6MWT;
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x
GSGC;
x
GMFM-88/GMFCS;
x
QMFT;
x
HHD;
x
IRT call for end of treatment (Week 97 for patients not entering the extended open-label 
avalglucosidase alfa long-term follow-up phase only).
10.1.7.3 Extended open-label avalglucosidase alfa long -term follow-up phase (pediatric 
patients enrolling directly in open-label follow-up phase)
10.1.7.3.1Biweekly
The following assessments will be performed every 2 weeks, starting at W99 and up to 144 
additional weeks (W99, W101, W103, W105, W107, W109, W111, W113, W115, W117, W119, 
W121, W123, W125, W127, W129, W131, W133, W135, W137, W139, W141, W143, W145, 
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) or until avalglucosidase alfa is
approved in the patient’s country, whichever comes first (refer to Appendix C Section 17.3.4 for 
definition applicable for UK patients):
x
IRT contact for treatment kits allocation;
x
Vital signs (before, during, and following infusion);
x
Infusion of avalglucosidase alfa;
x
AE collection;
x
Prior/concomitant medications.
10.1.7.3.2Every 4 weeks (Monthly)
The following assessments will be performed every 4 weeks, starting at W101 and up to 144 
additional weeks (W101, W105, W109, W113, W117, W121, W125, W129, W133, W137, 
W141, W145, W149, W153, W157, W161, W165, W169, W173, W177, W181, W185, W189, 
W193, W197, W201, W205, W209, W213, W217, W221, W225, W229, W233, W237, W241) or
until avalglucosidase alfa is approved in the patient’s country, whichever comes first (refer to 
Appendix C Section 17.3.4 for definition applicable for UK patients):
x
IRT contact for treatment kits allocation;
x
Vital signs (before, during, and following infusion);
x
Body weight (for pediatric patients only);
x
Infusion of avalglucosidase alfa;
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x
Urine pregnancy test (females of childbearing potential only);
x
AE collection;
x
Prior/concomitant medications.
10.1.7.3.3Every 12 weeks (Quarterly)
The following assessments will be performed every 12 weeks, starting at W109 and up to 144 
additional weeks (W109, W121, W133, W145, W157, W169, W181, W193, W205, W217, 
W229, W241) or until avalglucosidase alfa is approved in the patient’s country, whichever comes 
first (refer to Appendix C Section 17.3.4 for definition applicable for UK patients):
x
IRT contact for treatment kits allocation;
x
Vital signs (before, during, and following infusion);
x
Infusion of avalglucosidase alfa;
x
Body weight;
x
Urine pregnancy test (females of childbearing potential only);
x
ADAs (with neutralizing antibodies in ADA-positive patients);
x
AE collection;
x
Prior/concomitant medications.
10.1.7.3.4Every 24 weeks (every 6 months)
The following assessments will be performed every 24 weeks, starting at W123 and up to 144 
additional weeks (W123, W145, W169, W193, W217, W241) or until avalglucosidase alfa is
approved in the patient’s country, whichever comes first (refer to Appendix C Section 17.3.4 for 
definition applicable for UK patients):
x
IRT contact for treatment kits allocation;
x
Vital signs (before, during, and following infusion);
x
Infusion of avalglucosidase alfa;
x
Body weight;
x
Urine pregnancy test (females of childbearing potential only);
x
ADAs (with neutralizing antibodies in ADA-positive patients);
x
AE collection;
x
Prior/concomitant medications;
x
Height;
x
Hematology, biochemistry, and urinalysis;
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x
PFT;
x
6MWT.
10.1.7.3.5Every 48 weeks (Yearly) and end of treatment visit
The following assessments will be performed every 48 weeks, starting at W147 and up to 
144 additional weeks (W147, W193, W241) or until avalglucosidase alfa is approved in the 
patient’s country, whichever comes first (refer to Appendix C Section 17.3.4 for definition 
applicable for UK patients):
x
IRT contact for treatment kits allocation;
x
Vital signs (before, during, and following infusion);
x
Infusion of avalglucosidase alfa;
x
Body weight;
x
Urine pregnancy test (females of childbearing potential only);
x
ADAs (with neutralizing antibodies in ADA-positive patients);
x
AE collection;
x
Prior/concomitant medications;
x
Height;
x
Hematology, biochemistry, and urinalysis;
x
ECG;
x
PFT;
x
6MWT;
x
PGIC (patients ≥18 years of age at the concerned visit).
10.1.7.4 End of study (pediatric patients enrolling directly in the open-label follow-up
phase)
The following assessments will be performed at the end of study visit/contact (2 to 4 weeks after 
last infusion):
x
AE collection;
x
Prior/concomitant medications.
10.1.8 Follow-up
x
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.
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x
All AEs documented at a previous visit/contact that are designated as ongoing will be 
reviewed by the Investigator at subsequent visits/contacts.
x
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.
x
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.
x
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.
x
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.
x
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, V21/Week 37, V27/Week 49, V34/Week 61, 
V40/Week 73, V52/Week 97, V64/Week 121 [not applicable for pediatric patients 
aged 3 to <18 directly enrolled in the open-label long-term follow-up phase],
V76/Week 145 [not applicable for pediatric patients aged 3 to <18 directly enrolled in 
the open-label long-term follow-up phase], or any every 24 weeks visit of the extended
open-label long-term follow-up phase), 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 (see CRF completion guidelines for details regarding the CRF 
completion in this case). In these instances, this will not be considered a deviation but 
should be clearly documented in the patient’s file. Refer to Section 9.1.1 for details on 
PFT when missed.
x
Visits that are longer due to multiple assessments or procedures (eg, motor assessments 
and multiple questionnaires) may be carried out over 2 days. In any case, IMP 
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administration should be the last procedure and the appropriate time needed for 
post-infusion surveillance will be taken into account.
x
Postbaseline PFT should meet the ATS/ERS 2005 quality standards. However, if no 
acceptable efforts can be recorded during the upright position PFT with up to 8 efforts, an 
additional PFT may be scheduled as soon as possible no later than 45 days after this failed 
planned test, if this is feasible for the patient. The highest acceptable effort will be kept in 
the database.
x
In addition, if the patient did not perform the PFT at a planned visit, the patient should be 
reminded to perform the PFT test as soon as possible no later than 45 days after the missed 
test, if it is feasible for the patient to perform the test within this period.
10.1.9 Follow-up for patients who temporarily or permanently discontinued the study 
treatment
x
For those patients who discontinued treatment prior to the scheduled Week 49 visit, 
assessments related to the primary and secondary efficacy and safety endpoints will be 
performed every 3 months (ie, at Week 13, 25, 37, 49) if not done previously based on 
original protocol schedule (ie, PFT, 6MWT, SF-12, HHD, QMFT, AE, prior/concomitant 
medications, ECG, vital signs, laboratory tests [Urine pregnancy test (females of 
childbearing potential only), hematology, biochemistry, urinalysis, ADAs (with 
neutralizing antibodies in ADA-positive patients), exploratory biomarker urine sample 
collection, exploratory biomarker DBS and plasma sample collection, plasma sample 
collection for microRNA analyses, urine Hex4 sample collection], physical examination,
body weight and height) (refer to Section 10.1.3.5).
x
For those patients who discontinued treatment after the scheduled Week 49 visit but before 
Week 145 visit:
-
In case of permanent discontinuation: assessments corresponding to Week 145 as 
outlined in Section 10.1.4.5 will be performed if possible.
-
In case of temporary discontinuation: study visits can be adapted to visits when 
laboratory and/or clinical testing are scheduled, as much as possible, as long as the 
assessment time windows in the study protocol are respected.
x
For those patients who discontinued treatment during the extended open-label 
avalglucosidase alfa long-term follow-up phase:
-
In case of permanent discontinuation: assessments corresponding to the end of 
treatment visit as outlined in Section 10.1.5.5 and Section 10.1.7.3.5 will be performed 
if possible.
-
In case of temporary discontinuation, 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 and the patient come to visits when laboratory 
and/or clinical testing are scheduled, as much as possible, as long as the assessment 
time windows in the study protocol are respected.
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x
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 or permanently 
withdrawn from treatment.
x
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 10.1.5 and Section 10.1.7).
x
For patients permanently discontinued from study treatment, Investigator must perform 
end of treatment call to IRT.
x
For further guidance on handling of patient discontinuation, refer to Section 10.3.
10.2
DEFINITION OF SOURCE DATA
All evaluations that are reported in the e-CRF must be supported by appropriately identified 
source documentation. The results of certain examinations or evaluations recorded in the e-CRF 
may be considered to be source data.
The Investigator must provide the Sponsor or its designee direct access to each patient’s source 
documents. Source documents may include, but are not limited to, the following original 
documents, data, and records where information was first recorded:
x
Hospital records;
x
Medical histories and narrative statements relating to the patient’s progress;
x
Clinical and office charts;
x
Operative reports;
x
Laboratory notes/reports;
x
Memoranda and telephone notes/records;
x
Patients’ evaluation checklists;
x
Pharmacy or equivalent IMP room dispensing records;
x
Recorded data from automated instruments;
x
Copies of transcriptions certified after verification as being accurate copies;
x
Project-specific worksheets (eg, for study visits), including all worksheets developed 
specifically for this study;
x
X-ray images and corresponding reports;
x
ECG readings and corresponding reports;
x
MRI image sets and corresponding reports;
x
Video recordings of surgery.
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10.3
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the 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:
x
The patient was erroneously included in the study;
x
The patient experiences an intolerable or unacceptable AE;
x
The patient is unable to comply with the requirements of the protocol;
x
The patient participates in another investigational study without the prior written 
authorization of the Sponsor;
x
The patient becomes pregnant;
x
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 10.1.9).
Temporary treatment discontinuation decided by the Investigator corresponds to 1 or more doses
not administered to the patient.
All efforts should be made to continue to follow the patients for primary and key secondary 
endpoints, after the temporary treatment discontinuation.
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:
x
Any life-threatening AE not related to the patient’s underlying condition.
x
More than 1 AE rated severe, not related to the patient’s underlying condition, for which 
the relationship to treatment cannot be reasonably excluded.
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x
Any increase in ALT, AST, total bilirubin, or alkaline phosphatase >3x the baseline value,
except if the increased value is still in the normal range.
x
Any increase in ALT or AST >3x the upper limit of normal (ULN), in the presence of total 
bilirubin >2x ULN.
x
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:
x
Two patients develop the same life-threatening AE (eg, anaphylactic reaction), not related 
to their underlying condition.
x
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 may immediately decide to 
discontinue study drug dosing in all clinical trial patients and to not dose new patients prior to 
receipt of a DMC recommendation. 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 10.1.2).
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 and this should be documented in the 
e-CRF.
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.
Any code-breaking requested by the Investigator will lead to a permanent treatment 
discontinuation of the patient for whom the code was broken (see Section 8.3.2).
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10.3.4 Handling of patients after permanent treatment discontinuation
Patients will be followed-up according to the study procedures specified in this protocol (see 
Section 10.1.9), or up to recovery or stabilization of any AE to be followed-up as specified in this 
protocol, whichever comes last.
Since the primary study comparison is based on intent-to-treat principle using all randomized 
patients with any study treatment, missing data, especially the key study assessments during the 
PAP (Week 49) may potentially lead to biased results and challenges in assessing the treatment 
effect of the study drug. Therefore, all efforts should be made to continue to follow the patients 
for primary and key secondary endpoints, after a permanent discontinuation of treatment, in 
addition to the 4-weeks post-treatment safety follow-up. At the minimum, patients should be 
assessed at their regularly scheduled Week 49 visit (or as close as possible to Week 49 even if it 
may be outside of visit window) if treatment discontinuation occurred prior to that visit.
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 informed consent 
form) 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 
PAP (Week 49) including a PK sample, if appropriate, or if the patient withdraws from the study 
after the scheduled Week 49 visit, using the procedures normally planned for the last dosing day 
with the IMP (Week 145 in the open-label avalglucosidase alfa long-term follow-up phase or end 
of treatment visit in the extended open-label avalglucosidase alfa long-term follow-up phase).
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 10.1.6).
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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.
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
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 rerandomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.
10.4
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING
10.4.1 Definitions of adverse events
10.4.1.1 Adverse event
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.
10.4.1.2 Serious adverse event
An SAE is any untoward medical occurrence that at any dose:
x
Results in death, or
x
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.
x
Requires in-patient hospitalization or prolongation of existing hospitalization, or
x
Results in persistent or significant disability/incapacity, or
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x
Is a congenital anomaly/birth defect
x
Is a medically important event
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require 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 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x 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
10.4.1.3 Adverse event of special interest
An AE 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:
x
IARs:
IARs are defined as AESIs that occur during either the infusion or the observation period 
following the infusion which are deemed to be related or possibly related to the IMP. At the 
discretion of the Investigator, AEs occurring after completion of the post-infusion observation 
period that are assessed as related may also be considered IARs. Refer to Section 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.
x
Pregnancy:
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-
Pregnancy occurring in a female patient included in the clinical trial. Pregnancy will be 
recorded as an AESI with immediate notification in all cases. It will be qualified as an 
SAE only if it fulfills the SAE criteria.
-
Male patients will be instructed to notify the Investigator immediately if they discover 
that their sexual partner is pregnant.
-
In the event of pregnancy in a female participant, IMP should be discontinued.
-
Follow-up of the pregnancy is mandatory in a female participant or in a female partner 
of a male participant, until the outcome has been determined.
x
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 (see Section 8.1),
adjusted according to the tested drug.
Of note, asymptomatic overdose has to be reported as a standard AE.
x
Clinical laboratory (change from baseline):
-
ALT or AST increase of ≥3 x ULN if baseline is <ULN, or ALT or AST increase ≥2 x
the baseline value if baseline is ≥ULN,
-
A maximum ALT value of ≥400 IU/L or AST value of ≥500 IU/L or an increase in 
direct, indirect, or total bilirubin of ≥2 x ULN,
-
Serum creatinine increase of >1.5 x the baseline value (and final serum creatinine 
value is >ULN).
In the event of an AESI, the Sponsor will be informed immediately 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
x
All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the informed consent form until the end of the study as defined by the 
protocol for that patient, are to be recorded on the corresponding page(s) or screen(s) of 
the e-CRF.
x
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).
x
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.
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x
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 1 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 postobservation period, 
each of the individual signs and/or symptoms comprising the reaction should be captured as 
individual AE terms.
x
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 PP, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor.
x
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.
x
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 2.
10.4.3 Instructions for reporting serious adverse events
In the case of occurrence of an SAE, the Investigator or any designees must immediately:
x
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.
x
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.
x
A back-up plan is available and should be used when the e-CRF system does not work.
Please refer to the Study Operations Manual for further guidance.
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team.
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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 screens in the e-CRF. Instructions for AE reporting are summarized in 
Table 2.
The needs for specific monitoring, documentation, and management of AESIs are described in 
this section.
For each defined AESI, consider carefully the need to collect additional specific information that 
would impact the study, such as:
x
Pre-existing related condition or lifestyle of interest for the AE (eg, habits, cardiovascular 
risk factor).
x
Expected list of associated signs and symptoms.
x
Corrective actions (eg, treatment discontinuation, concomitant treatment).
x
Diagnostic actions (eg, test[s] or procedure[s] results).
x
Additional descriptive factors.
x
Sequelae.
x
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.
x
Neutropenia,
x
Thrombocytopenia,
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x
ALT increase,
x
Acute renal insufficiency.
Refer to Section 10.4.1.3 for specific laboratory abnormalities that are identified as AESIs.
Table 2 - 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 or AST ≥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 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; AST = aspartate aminotransferase; ALT = alanine 
aminotransferase; IAR = infusion-associated reaction; IU/L = international units per liter; SAE = serious adverse event; ULN = upper limit of 
normal.
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10.5
OBLIGATIONS OF THE SPONSOR
During the course of the study, the Sponsor will report in an expedited manner:
x
All SAEs that are both unexpected and at least reasonably related to the IMP (suspected 
unexpected serious adverse reaction; SUSAR), to the regulatory authorities, independent 
ethics committee (IECs)/institutional review boards (IRBs) as appropriate and to the 
Investigators.
x
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.
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:
x
Assessments for circulating immune complex detection; and IgE, serum tryptase, and 
complement activation, following moderate, severe, or recurrent mild IARs suggestive of 
hypersensitivity reactions.
x
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, such a procedure may be initiated as per pharmacy 
manual guidelines. Depending on the phase of the study the patient will be in at the time of the
desensitization procedure, this one may be blinded (if the procedure is started when the patient is 
still in the double-blind phase) or unblinded (if the procedure is started when the patient is in one 
of the open-label phases).
If severe hypersensitivity or anaphylactic reactions occur, immediate discontinuation of the 
infusion should be considered, and appropriate medical treatment should be initiated. Severe 
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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
Sample size calculations are based on the primary efficacy endpoint of change from baseline to 
Week 49 in FVC (% predicted) upright position, with the following assumptions:
x
Normal distribution for the endpoint with a common SD of 5.1% predicted, which is 
estimated based on the data from previous trials (AGLU02704-LOTS),
x
Mean treatment difference (avalglucosidase alfa – alglucosidase alfa) of 2.0% predicted,
assumed based on a conservative estimate when comparing studies AGLU02704-LOTS 
and TDR12857,
x
A 2-sided 5% significance level,
x
Expected percent of missing data = 10%,
x
An NI margin of 1.1%, which is based on the estimated alglucosidase alfa effect from the 
placebo-controlled study (AGLU02704-LOTS). The proposed margin represents 
approximately 50% of the lower bound of the 80% confidence interval for the 
alglucosidase alfa versus placebo treatment effect.
A total sample size of 96 (1:1 randomization ratio) will provide approximately 80% power to 
demonstrate NI of avalglucosidase alfa versus alglucosidase alfa, when the true difference 
(avalglucosidase alfa – alglucosidase alfa) is 2.0% predicted. If the NI criterion is met, a test for 
superiority will be performed. If the true difference between avalglucosidase alfa and 
alglucosidase alfa is 3.5% predicted (as suggested based on cross-study comparisons between 
AGLU02704-LOTS and TDR12857), the study will have at least 85% power to demonstrate 
superiority of avalglucosidase alfa to alglucosidase alfa.
Calculations were made using East 6.3 software.
11.2
DISPOSITION OF PATIENTS
Screened patients will be defined as any patient who has signed the informed consent form. 
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.
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11.3
ANALYSIS POPULATIONS
The randomized population will include any patient who had been allocated to a randomized 
treatment arm regardless if study drug was administered.
11.3.1 Efficacy populations
The mITT population will include randomized patients who receive at least 1 infusion (partial or 
total). The mITT population will be used for all efficacy analyses unless otherwise specified. 
Analyses using the mITT population will be performed according to the treatment arm allocated 
by randomization and not actual treatment received.
The PP population will be a subset of the mITT population who have no major protocol 
deviations that are expected to interfere with assessments of the primary efficacy endpoint. This
population will be used for sensitivity analyses and described with more detail in the SAP.
11.3.2 Safety population
The safety population will include patients who receive at least 1 infusion (partial or total). The 
safety population will be analyzed according to which treatment was received, unless otherwise 
specified.
11.3.3 Extension treatment population
The extension treatment population will consist of patients who receive at least 
1 avalglucosidase alfa dose (partial or total) during the extension treatment period.
11.4
STATISTICAL METHODS
Unless otherwise specified, efficacy analyses will use the mITT population, where patients will be 
considered to be in the treatment group to which they were randomized. Safety analyses will use 
the safety population, where patients will be considered to be in the treatment group of the 
treatment they actually received.
For all analyses, the avalglucosidase alfa treatment group will be compared to the alglucosidase 
alfa group. While the primary comparison of interest is at 12 months (49 weeks), all summary 
statistics will be computed and displayed by treatment group and each scheduled assessment time
as well. Summary statistics for continuous variables will minimally include n, mean, SD,
minimum, median, and maximum. For categorical variables, frequencies and percentages will be 
presented. Graphical displays will be provided as appropriate.
Unless otherwise specified, all baseline values will be defined as the last non-missing value prior 
to randomization.
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11.4.1 Extent of study treatment exposure and compliance
11.4.1.1 Extent of investigational medicinal product exposure
The extent of study treatment exposure and compliance will be assessed and summarized within 
the first 12-month double-blind period for the safety population.
Duration of IMP exposure is defined as the last dose date – first dose date + 14 days, regardless of 
unplanned intermittent discontinuations.
11.4.1.2 Compliance
Treatment compliance, above-planned and under-planned dosing percentages will be summarized 
descriptively (N, mean, SD, median, min, and max). The percentage of patients with compliance
is <80% will be summarized. In addition, number and percentage of patients with at least 1 
above-planned dosing administration will be provided.
Treatment exposure beyond the 12-month double-blind period will be summarized separately.
11.4.2 Analyses of efficacy endpoints
Efficacy endpoints and assessments are provided in Section 9.
11.4.2.1 Analysis of primary efficacy endpoints
Refer to Section 9.1.1 for details on this endpoint.
The primary efficacy endpoint of change from baseline in FVC (% predicted) in upright position
to Week 49 will be analyzed in the mITT population using an MMRM with change from baseline 
as outcome variable. The MMRM model will include the baseline FVC (% predicted) and age 
(both as continuous variables), gender (male, female), treatment group, visit, and 
treatment-by-visit interaction as fixed effects. An unstructured covariance matrix shared across 
treatment groups will be used to model the within-patient error and the Kenward-Roger 
approximation will be used to estimate the degrees of freedom. The model will be fitted using 
restricted maximum likelihood. The difference between treatment groups will be estimated based 
on least-square means at the Week 49 visit within the MMRM model.
The primary analyses will be performed after all mITT patients have been followed for at least 
12 months after randomization. This analysis will include all post-baseline assessments up to 
Week 49, regardless of treatment discontinuation status; missing data will not be imputed and will 
be assumed to be missing-at-random (MAR).
The primary statistical objective is to test the NI of avalglucosidase alfa versus alglucosidase alfa 
at 5% level of significance. The null and alternative hypotheses based on an NI margin of 1.1 are 
described as H01 and Ha1 below:
x
H01: avalglucosidase alfa – alglucosidase alfa ≤-1.1 versus Ha1: avalglucosidase alfa –
alglucosidase alfa >-1.1
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The study will be considered to have met its primary statistical objective if the NI null hypothesis 
(H01) is rejected, or the lower bound of the 2-sided 95% confidence interval for the least square 
mean difference of avalglucosidase alfa – alglucosidase alfa is >-1.1.
After NI is demonstrated, a test for superiority of avalglucosidase alfa versus alglucosidase alfa 
will be performed with an overall 5% level of significance.
If the superiority null hypothesis of no difference between avalglucosidase alfa and alglucosidase 
alfa is rejected, and the point estimate for the difference favors avalglucosidase alfa, the statistical 
superiority of avalglucosidase alfa versus alglucosidase alfa can be claimed.
The same analysis as described above will be performed for the PP population to assess the 
robustness of the study outcome.
A US FDA-specific primary analysis will be conducted using the method described above for 
those patients in the mITT population 8 years of age or older in order to match the lower age 
range of patients in the LOTS trial of alglucosidase alfa.
Sensitivity analyses will be performed to assess the impact of missing data.
Additional supportive analyses for the primary efficacy endpoint will be performed, including 
subgroup analyses based on age, gender, and baseline FVC.
11.4.2.2 Analyses of secondary efficacy endpoints
Refer to Section 9.2.1 for details on these endpoints.
The secondary efficacy endpoints are change from baseline at week 49 for the following 
parameters:
x
6MWT distance walked (in meters);
x
MIP and MEP% predicted;
x
Lower extremity muscle strength (HHD);
x
Motor function as assessed by QMFT;
x
Health-related quality of life as assessed by SF-12.
Each of the secondary endpoints will be analyzed based on the MMRM model, similar to that 
described for the primary endpoint (the model will be further adjusted by baseline score of 
corresponding parameter), using the mITT population (with the exception of SF-12, which will be 
analyzed for a subset of mITT patients with age ≥18). The difference between treatment group 
will be assessed with least square mean difference at Week 49 estimated within the framework of 
MMRM model. P-value and corresponding 2-sided 95% CI will be provided.
For 6MWT endpoint, the statistical objective is to demonstrate the superiority of avalglucosidase 
alfa versus alglucosidase alfa.
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For MIP and MEP, the primary analysis will be based on % predicted value in upright position. 
For HHD, the primary analysis is based on the lower extremity summary score. For QMFT, the 
primary analysis is based on the total score, while each individual item score will be summarized 
descriptively. For SF-12, the PCS and MCS scales will be analyzed separately.
See Section 11.4.2.3 for consideration of multiplicity.
For the Canada-specific requirement regarding HHD refer to Appendix C Section 17.3.3.
11.4.2.3 Multiplicity considerations
The primary efficacy endpoint (FVC% predicted change from baseline) will be tested for NI of
avalglucosidase alfa versus alglucosidase alfa first. After the NI is demonstrated, the superiority 
of the avalglucosidase alfa versus alglucosidase alfa will be tested with the same overall 5% 
significance level.
After the superiority of avalglucosidase alfa versus alglucosidase alfa is demonstrated on the 
primary efficacy endpoint, the hypothesis testing for the secondary efficacy endpoints will 
proceed in a hierarchical fashion using the closed testing principle, and will stop if significance 
level of 5% is not achieved. Testing will proceed according to the following sequence:
1. 6MWT change from baseline to Week 49 (superiority test),
2. % predicted change from baseline to Week 49 for MIP (superiority test),
3. % predicted change from baseline to Week 49 for MEP (superiority test),
4. HHD (lower extremity summary score) change from baseline to Week 49 (superiority 
test).
Analysis of additional secondary endpoints will be considered for supportive purposes.
For the Canada-specific requirement regarding HHD, refer to Appendix C Section 17.3.1.
11.4.3 Open-label avalglucosidase alfa long-term follow-up phase
Efficacy data during the extension treatment phase will be summarized descriptively for each of 
the efficacy parameters through the last visit (up to the end of the extended open-label 
avalglucosidase alfa long-term follow-up phase). For the primary efficacy endpoint, the effect of 
switching treatment will be assessed for those patients who switched from alglucosidase alfa to 
avalglucosidase alfa during the extension period. For patients who receive avalglucosidase alfa
throughout the blinded treatment phase, as well as the long-term follow-up phase, long-term effect 
of avalglucosidase alfa will be assessed.
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11.4.4 Analyses of safety data
Refer to Section 9.2.2 for details on these endpoints.
The summary of safety results will be presented by treatment group.
All safety analyses will be performed on the safety population using the following common rules:
The baseline value is defined generally as the last available value before randomization.
The following definitions will be applied to laboratory parameters, vital signs and ECG.
x
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs, and ECG.
x
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.
Unless otherwise specified, primary safety analyses will be based on first 12 months of PAP for 
comparability of treatment effect. Data during the open-label period (beyond 12 months) will be 
summarized separately (by original treatment group as well as combined).
In addition, for patients who receive avalglucosidase alfa throughout the blinded treatment phase, 
as well as the long-term follow-up phase, long-term safety will be assessed using all data during 
the 2 periods.
11.4.4.1 Adverse events
All AEs will be coded using the most recent version of the MedDRA.
Adverse event observation period:
x
Pre-treatment AEs are defined as those AEs that developed or worsened prior to the 1st
study treatment.
x
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.
x
Post-treatment AEs are defined as those AEs that developed or worsened after the 
on-treatment period.
On-study period will include pre-treatment, on-treatment, and post-treatment period. Treatment-
emergent AEs for analysis purpose will include all on-treatment AEs.
Unless otherwise specified, the primary analysis of AEs will be based on TEAEs with onset date 
within the first 12 months PAP. Similar descriptive summaries will be performed for the 
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long-term follow-up period (after 12 months) separately based on those TEAEs with onset date 
beyond 12 months of double-blind period. A pooled AEs summary using all TEAEs during the 
avalglucosidase alfa exposure period will be provided as well.
Post-treatment AEs will be summarized separately.
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 
1 occurrence of the same AE with different reported severities. Relationships of the AE to 
treatment will be categorized as not related, unlikely related, possibly related, or related. The 
highest level of association will be reported in patients with differing relationships for the same 
AE.
Listings of AEs, SAEs, 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 treatment 
group, with details provided in the listing.
Death: The following deaths summaries will be generated:
x
Number (%) of patients who died by study period (TEAE, on-study) and reasons for death 
summarized on the safety population by treatment received.
x
Death in nonrandomized patients or randomized and not treated patients.
x
TEAE leading to death (death as an outcome on the AE e-CRF page as reported by the 
Investigator) by primary SOC, high level group term (HLGT), high level term (HLT) and 
PT showing number (%) of patients sorted by internationally agreed order of SOC and 
alphabetic order of HLGT, HLT, and PT.
11.4.4.2 Clinical laboratory tests
Observed measurements and changes from baseline to study time points in biochemistry, 
hematology, and urinalysis will be descriptively summarized. All laboratory values will be 
classified as normal, above normal, or below normal based on normal ranges provided by the 
laboratory. Individual listings of patients with potentially clinically significant abnormalities will 
be presented.
11.4.4.3 Physical examination, vital signs, and electrocardiogram
Potentially clinically significant findings observed during the TEAE observation 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 treatment group. Listings of abnormal findings/values 
from these data as well as from physical examination inclusive of body weight and height, as well 
as head circumference and Tanner stage in pediatric patients, will be presented.
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11.4.4.4 Anti-avalglucosidase 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 by treatment group using summary 
statistics. Anti-avalglucosidase 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.
11.4.5 Analyses of pharmacokinetic and pharmacodynamic variables
The list of PK parameters is listed in Section 9.3.2.4.
Pharmacokinetic exposures (Cmax and AUC0-last) for avalglucosidase alfa and alglucosidase alfa 
may be determined using non-compartmental analysis. If data allows, total body clearance of a 
drug (CL), and Vss 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 patient s and summarized using descriptive statistics by study week as 
appropriate.
To evaluate the effect of immunogenicity on the PK of avalglucosidase alfa, pre-dose 
immunoglobulin G (IgG) and neutralizing antibody titers for each patient will be analyzed 
graphically with respect to PK parameter for Week 1 (Day 1/Day 2), Week 13, Week 25,
Week 37, and Week 49. If relationships are apparent, further quantitative/statistical analysis may 
be performed (eg, statistical significance, correlation coefficients).
Pharmacodynamic endpoints as described in Section 9.3.4 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.
Similar analyses may be carried out to explore the relationship between other PD endpoints, 
biomarkers, efficacy assessments, and exploratory endpoints.
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11.4.6 Analyses of patient reported outcomes (health-related quality of life/health 
economics variables and Patient Global Impression of Change [PGIC])
Refer to Section 9.3.5 for details on these endpoints.
The 18 questions for the R-PAct will be scored according to the 0 (unable to perform) to 2 (able to 
perform without difficulty) Likert scale and will have a descriptive analysis by treatment group.
Scores for the PDSS and PDIS will be calculated separately for each questionnaire, as well as a 
composite score for both questionnaires together. The analysis will be descriptive and separated 
by treatment group.
Further details on the scoring algorithms will be provided in the SAP.
PGIC total score will be summarized descriptively by treatment group at each of the scheduled 
visits. Correlation of PGIC and primary and key secondary endpoints will be explored. 
11.5
INTERIM ANALYSIS
No interim analysis is planned during the double-blinded PAP (refer to Section 6.2.1 for the
details of the different periods). Note that the primary analysis for the study is performed at the 
end of PAP, when the database will be locked and a study report will be produced for regulatory 
submission. The study will continue for additional 2 years (open label long-term extension) and 
an additional extension period of up to 144 additional weeks (or until avalglucosidase alfa is
approved in the patient’s country, whichever comes first; refer to Appendix C Section 17.3.3 for 
patients in Canada and Section 17.3.4 for definition applicable for UK patients) and a final 
database lock will occur at the end of extension period, with a corresponding final study report 
generated.
After the primary analysis for PAP is completed, interim analyses may be performed during the 
open-label extension period to provide additional information for regulatory purpose. However, 
those additional analyses after PAP will be considered for supportive purpose and no significance 
level will be allocated to for analyses after the completion of PAP.
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12
REGULATORY, ETHICAL, AND STUDY OVERSIGHT
CONSIDERATIONS
12.1
REGULATORY AND ETHICAL CONSIDERATIONS
x
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]).
x
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.
x
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.
x
Protocols and any substantial amendments to the protocol will require Health Authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants.
x
The Investigator will be responsible for the following:
-
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC.
-
Determining whether an incidental finding (as per Sanofi policy) should be returned to 
a participant and, if it meets the appropriate criteria, to ensure the finding is returned 
(an incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding:
-
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and
-
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity. 
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-
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted 
out of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps.
-
In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings.
-
Notifying the IRB/IEC of SAEs or other significant safety findings as required by
IRB/IEC procedures.
-
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), European Medical Device Regulation 2017/745 for 
clinical device research (if applicable), and all other applicable local regulations.
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the 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
x
The Investigator or his/her representative will explain the nature of the study to the 
participants or their legally authorized representative, and answer all questions regarding 
the study, including what happens to the participant when his/her participation ends 
(post-trial access strategy for the study). 
x
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative [defined as parent(s) or guardian(s)] will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Privacy and Data Protection requirements including those of 
the GDPR and of the French law, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
x
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.
x
In case of ICF amendment while the participants are still included in the study, they must 
be re-consented to the most current version of the ICF(s). Where participants are not in the 
study anymore, teams in charge of the amendment must define if those participants must 
or not re-consent or be informed of the amendment (eg, if the processing of personal data 
is modified, if the Sponsor changes, etc.).
x
A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative. 
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Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses the use of remaining mandatory samples or 
new extra samples for optional exploratory research. The Investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Participants will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. A separate consent will be required to document a participant’s
agreement to allow any remaining specimens to be used for exploratory research. Participants who 
decline to participate in this optional research will not provide this separate consent.
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13
STUDY MONITORING
13.1
DATA QUALITY ASSURANCE
x
All participant data relating to the study will be recorded on printed or e-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.
x
Guidance on completion of CRFs will be provided in the CRF completion instructions.
x
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
x
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.
x
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
x
The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations).
x
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
13.2
SOURCE DOCUMENTS
x
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.
x
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.
x
Source documents include (but are not limited to): participant’s medical file, appointment 
books, original laboratory records, functional outcome assessment source document.
x
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
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x
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
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14
ADDITIONAL REQUIREMENTS
14.1
DATA PROTECTION
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy and Data Protection laws and regulations, including the 
GDPR. The study Sponsor is the Sanofi company responsible for ensuring compliance with this 
matter, when processing data from any individual who may be included in the Sanofi databases, 
including Investigators, nurses, experts, service providers, Ethics Committee members, etc. 
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party.
Protection of participant data
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective.
Patient race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Not Reported) or ethnicity (Hispanic or Latino, Not 
Hispanic or Latino, Not Reported, Unknown) will be collected in this study because these data are 
required by several regulatory authorities. In addition, it is unknown if race or ethnicity may have 
an impact on the Pompe disease ERT. It is now recognized that some drug metabolism are 
impacted by race (eg, warfarin [17]) and/or ethnicity (various drugs [18]).
x
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor. 
x
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent. 
x
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.
x
Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results.
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Protection of data related to professionals involved in the study 
x
Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or pre-
contractual relationship. They may be communicated to any company of the Sanofi group 
(“Sanofi”) or to Sanofi service providers, where needed.
x
Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com). 
x
In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list.
x
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.
x
Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably: 
-
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers,
-
Sanofi’s Binding Corporate Rules for intra-group transfers. 
x
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.
x
Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations.
x
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. 
x
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:
x
For study termination:
-
Information on the product leads to doubt as to the benefit/risk ratio.
-
Discontinuation of further study intervention development.
x
For site termination:
-
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor’s procedures, or GCP guidelines.
-
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator.
-
Total number of participants included earlier than expected.
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
14.3
CLINICAL TRIAL RESULTS AND DISSEMINATION OF CLINICAL STUDY DATA 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of
study results to the Investigator.
A Coordinating Investigator will be designated to review and sign the completed clinical study report. 
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Analysis of DBS, plasma and urine biomarkers, pharmacogenetic biomarkers, exploratory 
immunogenicity assessments, exploratory muscle biopsy and PK not included in the study report 
will be included in separate technical reports.
Study participants
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries.
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable 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 
x
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.
x
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.
x
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 before implementation.
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary.
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16
BIBLIOGRAPHIC REFERENCES
1. de Vries JM, van der Beek NA, Hop WC, Karstens FP, Wokke JH, de Visser M, et al. Effect 
of enzyme therapy and prognostic factors in 69 adults with Pompe disease: an open-label 
single-center study. Orphanet J Rare Dis. 2012;7:73.
2. 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.
3. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012;40(6):1324-43.
4. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS 
statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 
2002;166(1):111-7.
5. Gibbons WJ, Fruchter N, Sloan S, Levy RD. Reference values for a multiple repetition 6 
minute walk test in healthy adults older than 20 years. J Cardiopulm Rehabil. 2001;21(2):87-
93.
6. 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.
7. Andrews AW, Thomas MW, Bohannon RW. Normative values for isometric muscle force 
measurements obtained with hand-held dynamometers. Phys Ther. 1996;76(3):248-59.
8. 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.
9. Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of 
scales and preliminary tests of reliability and validity. Med Care. 1996;34(3):220-33.
10. Angelini C, Semplicini C, Tonin P, Filosto M, Pegoraro E, Sorarù G, et al. Progress in enzyme 
replacement therapy in glycogen storage disease type II. Ther Adv Neurol Disord. 
2009;2(3):143-53.
11. Russell DJ, Rosenbaum PL, Avery LM, Lane M. Gross motor function measure (GMFM-66 & 
GMFM-88) user’s manual. Cambridge University Press; 2002. 
12. 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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13. Hamilton GF, McDonald C, Chenier TC. Measurement of grip strength: validity and reliability 
of the sphygmomanometer and jamar grip dynamometer. J Orthop Sports Phys Ther. 
1992;16(5):215-9.
14. Herdman M, Gudex C, Lloyd A, Janssen MF, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 
2011;20(10):1727-36.
15. 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.
16. van der Beek NA, Hagemans ML, van der Ploeg AT, van Doorn PA, Merkies IS. The Rasch-
built Pompe-specific activity (R-PAct) scale. Neuromuscul Disord. 2013;23(3):256-64.
17. Schelleman H, Chen J, Chen Z, Christie J, Newcomb CW, Brensinger CM, et al. Dosing 
algorithms to predict warfarin maintenance dose in Caucasians and African Americans. Clin 
Pharmacol Ther. 2008;84(3):332-9.
18. Yasuda SU, Zhang L, Huang SM. The role of ethnicity in variability in response to drugs: 
focus on clinical pharmacology studies. Clin Pharmacol Ther. 2008;84(3):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 (WOCB)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy.
3. Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrolment.
CONTRACEPTIVE GUIDANCE
Male patients
x
Male participants with female partners of childbearing potential are eligible to participate 
if they agree to ONE of the following (during the protocol-defined time frame in 
Section 6.2):
-
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent
-
Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year as described in Table 3 when having penile-vaginal intercourse 
with a woman of childbearing potential who is not currently pregnant
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x
Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
(during the protocol-defined time frame)
x
Refrain from donating sperm for the duration of the study and for 1 month after the last 
dose of study treatment
x
Female participants of childbearing potential are eligible to participate if they agree to use 
a highly effective method of contraception consistently and correctly as described in 
Table 3.
Table 3 - Female Highly effective contraceptive methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation 
Oralb 
Intravaginal 
Transdermal 
Progestogen-only hormone contraception associated with inhibition of ovulation 
Oralb 
Injectable 
Highly Effective Methods That Are User Independenta
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS) 
Bilateral tubal occlusion 
Vasectomized partner
A vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be 
used.
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 treatment. 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 participant.
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 participants participating in clinical studies. 
b
Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy of the contraceptive 
method. In this case, TWO highly effective methods of contraception should be utilized during the treatment period and for at least 1 month, 
corresponding to time needed to eliminate study treatment after the last dose of study treatment. 
COLLECTION OF PREGNANCY INFORMATION
Male patients with partners of reproductive potential who become pregnant 
x
The Investigator will attempt to collect pregnancy information on any female partner of a 
male study patient who becomes pregnant while participating in this study. This applies 
only to patients who receive study treatment. After obtaining the necessary signed 
informed consent from the pregnant female partner directly, the Investigator will record 
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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 patients who become pregnant 
x
The Investigator will collect pregnancy information on any female patient, 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.
x
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 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 poststudy pregnancy which is considered reasonably related to the study 
treatment by the Investigator, will be reported to the Sponsor as described in 
Section 10.4.3. While the Investigator is not obligated to actively seek this information in 
former study patients, he or she may learn of an SAE through spontaneous reporting.
x
Any female participant who becomes pregnant while participating in the study will 
temporarily discontinue study treatment.
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17.3
APPENDIX C: COUNTRY-SPECIFIC REQUIREMENTS
17.3.1 Sweden
Provided an addendum to the protocol applicable only in Sweden with recommendations related 
to contraception and pregnancy testing in line with the Clinical Trial Facilitation Group (CTFG) 
guidance 2014.
www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf
The aim of this document was to supplement as part of the protocol the definitions of women of 
childbearing potential and fertile men and the list of birth control methods which may be 
considered as highly effective.
Definition of Women of Childbearing Potential and of Fertile Men
For the purpose of this document, a woman is considered of childbearing potential (WOCBP), 
ie, fertile, following menarche and until becoming postmenopausal unless permanently sterile. 
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy.
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.
For the purpose of this document, a man is considered fertile after puberty unless permanently 
sterile by bilateral orchidectomy.
Birth Control Methods Which May Be Considered As Highly Effective
For the purpose of this guidance, methods that can achieve a failure rate of less than 1% per year 
when used consistently and correctly are considered as highly effective birth control methods. 
Such methods include:
x
combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (1):
-
oral
-
intravaginal
-
transdermal
x
progestogen-only hormonal contraception associated with inhibition of ovulation (1):
-
oral
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-
injectable
-
implantable (2)
x
intrauterine device (IUD) (2)
x
intrauterine hormone-releasing system (IUS) (2)
x
bilateral tubal occlusion (2)
x
vasectomized partner (2,3)
x
sexual abstinence (4)
1. Hormonal contraception may be susceptible to interaction with the IMP, which may 
reduce the efficacy of the contraception method (see section 4.3 in the CTFG guidance).
2. Contraception methods that in the context of this guidance are considered to have low user 
dependency.
3. Vasectomized partner is a highly effective birth control method provided that partner is the 
sole sexual partner of the WOCBP trial participant and that the vasectomized partner has 
received medical assessment of the surgical success.
4. In the context of this guidance, 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 treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle 
of the patient.
17.3.2 France
Consistent with the French Health Authority position disallowing home infusion for all ERTs, the 
option for home infusion added in EFC14028 amended protocol 03 does not apply in France.
17.3.3 Canada
Due to operational challenges with the use of the HHD in Canada, several measures assessed with 
this device will be missing. Therefore, these assessments (HHD in lower extremity muscle 
strength [see Section 9.2.1.3] and HHD in upper extremity muscle strength [see Section 9.3.1.3])
will no longer be required in study participants in Canadian sites.
For enrolled patients wishing to start commercial treatment with avalglucosidase alfa in Canada 
after their participation in the EFC14028 study, and to avoid a treatment gap between the end of 
treatment visit of the EFC14028 study and the possibility to start commercial treatment with 
avalglucosidase alfa, the duration of study participation of patients in Canada is defined as 
follows:
An extended open-label avalglucosidase alfa long-term follow-up period will last up to 144 
additional weeks (or until avalglucosidase alfa is commercially available in Canada, whichever 
comes first) for all enrolled patients in Canada (extended open-label avalglucosidase alfa long-
term follow-up phase).
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17.3.4 United Kingdom
In the UK, the duration of the extended open-label avalglucosidase alfa long-term follow-up
period will be defined as ‘up to the approval in the country or to the maximal duration planned in 
the study (ie, end of treatment at Week 289), whichever occurs first’.
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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: 03 Aug 2016
Major changes specific to this global amendment include the following:
Protocol amendment summary of changes table
Section # and Name
Description of Change
Brief Rationale
Clinical Trial Summary, 
Sections 4, 7.1, and 7.2.1 
Change to the inclusion/exclusion criteria. 
Inclusion criteria I01 and exclusion criteria E08 
were reworded and E06 was modified. 
I01. and E08. were reworded in order to 
comply with local requirements regarding age 
of minors and adults. 
E06. was modified to allow more severely 
compromised patients into the study by 
reducing the lower cutoff for % predicted FVC 
from 40% to 30%. 
Clinical Trial Summary, 
Sections 1.1, 8.4, and 11.1 
Change to the sample size; sample size was 
increased from approximately 86 to 
approximately 96. 
Sample size was increased from 
approximately 86 to approximately 96 as a 
result of modification to the exclusion criteria 
for % predicted FVC (the primary efficacy 
endpoint) and using a more conservative 10% 
estimate for missing data. 
Throughout 
Minor editorial changes to spelling, punctuation, 
grammar, and syntax. 
Minor, therefore have not been summarized. 
17.4.2 Amended protocol 02: 18 Jul 2017
No substantial changes were made to the protocol. Throughout the protocol, following changes 
were included:
x
Minor editorial changes to spelling, punctuation, grammar, and syntax.
x
Table of contents was updated.
x
Flow charts were updated to reflect the study procedures in Section 10 and to clarify that 
AEs and concomitant medication use information are to be collected at each visit to assure 
that information is kept up to date.
x
Sections, table footnotes and citations, and references were renumbered.
x
Tables were reformatted.
x
Abbreviations were updated in text, Section 3 (Abbreviations), and table footnotes.
x
References were updated.
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x
Screening period was extended: The screening phase (time from signing of informed 
consent form to start of study treatment) should not exceed 14 days, but could be extended 
to a maximum of 8 weeks in pre-specified situations (refer to Section 10.1.2).
x
Added details of re-screening: Patients may be re-screened once if their clinical condition
changes. Patients who were screen failed because their FVC% predicted was >85% may 
be re-screened only if a clinically relevant worsening respiratory condition related to 
Pompe Disease and not related to intercurrent illness as assessed by the Investigator
occurs. In case of re-screening, the patient will be first screened failed in the IXRS, will 
sign a new written informed consent form and a new patient number will be provided. All 
screening assessments/procedures will have to be performed again, except GAA and ACE 
genotyping.
x
PFT details updated: Patients may repeat the assessment once up to three times within the 
Screening Visit time window in case of failed quality as determined by the central 
laboratory.
x
Clarification in the ADA tests was provided: Patients in the neoGAA treatment arm will 
be tested for anti-neoGAA antibodies and patients in the alglucosidase alfa treatment arm 
will be tested for anti-alglucosidase alfa antibodies. In the open label follow-up phase, 
patients from the alglucosidase alfa treatment arm who have switched to neoGAA will be 
tested for both anti-alglucosidase alfa antibodies and anti-neoGAA antibodies. Patients 
who remain on neoGAA treatment will continue to be tested for anti-neoGAA antibodies. 
Patients who are positive for anti-neoGAA antibodies will be tested to determine if the 
antibodies cross-react with alglucosidase alfa.
17.4.3 Amended protocol 03: 10 Apr 2019
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
x
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 
144 weeks (or until avalglucosidase alfa is approved in the patient’s country, whichever 
comes first; refer to Appendix C Section 17.3.4 for definition applicable for UK patients).
x
Enrollment of patients aged 3 to <18 years in the study has been challenging, mainly due 
to exclusion criterion related to respiratory function (requirements that FVC% predicted 
≤85%). At the end of the recruitment, if <4 patients aged 3 to <18 years are enrolled, in 
order to comply with Health Authority requirements to enroll a certain number of pediatric 
patients, up to 2 additional pediatric patients will be enrolled directly in the open-label 
avalglucosidase alfa long-term follow-up phase where they will receive avalglucosidase 
alfa. 
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x
In countries where it is permitted, home infusion of avalglucosidase alfa in the extension 
period may be allowed.
x
Language is added in the ‘randomization code-breaking during the study’ section, to 
document that an unblinded programmer will prepare the dataset for population PK 
analysis.
x
The statistical section is updated. Removed non-inferiority test of 6MWT from the testing 
order and used superiority instead for secondary endpoint of 6MWT in accordance with 
feedback from regulatory agency. Also, added superiority test of MEP to the hierarchical 
testing and updated definition of safety population. 
x
The mRNA test is removed since this test is not performed.
x
Clarifications are given regarding the conditions for temporary IMP discontinuation with 
DMC consultation (eg, in case of abnormal liver function test).
x
Collection of dry blood spot has been added for determination of exploratory biomarkers 
in addition to samples of urine and plasma to develop alternative assays and potentially 
reduce blood volume needed for testing in future.
Canadian-specific requirement
x
Due to operational challenges with the use of the hand-held dynamometers (HHD) in 
Canada, several measures assessed with these devices will be missing. Therefore, these 
assessments (HHD in lower extremity muscle strength, HHD in upper extremity muscle 
strength) will no longer be required in study participants in Canadian sites.
France-specific requirement
x
The option for home infusion added in this amended protocol 03 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
x
In the UK, the duration of the extended open-label avalglucosidase alfa long-term 
follow-up period will be defined as ‘up to 144 weeks after the last patient has been 
enrolled in the study’ to comply with the UK position regarding the protocol language to 
be used for study extensions.
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Protocol amendment summary of changes table
Section # and Name
Description and Change
Brief Rationale
Clinical Trial Summary 
Added the following description ‘an additional 
extension period of up to 144 weeks (or until 
avalglucosidase alfa is approved in the 
patient’s country, whichever comes first; refer to 
Appendix C Section 17.3.4 for definition 
applicable for UK patients) will include 
bi-weekly visits (study drug infusion, adverse 
events (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, the end of 
study visit/contact will be performed. 
If at the end of the recruitment, <4 pediatric 
patients aged 3 to <18 years are enrolled, up to 
2 additional pediatric patients will be enrolled 
directly in the open-label avalglucosidase alfa 
long-term follow-up phase where they will 
receive avalglucosidase alfa. 
For this subgroup of pediatric patients, the 
study will comprise 52 visits including the 
Screening Visit (V1: Day -14 to Day -1) and the 
Enrollment Visit V2 (Day 1/Day 2); V3 
(1 week after V2) through V52 for study drug 
infusion, PK, safety assessment, and efficacy 
evaluations in the open-label avalglucosidase 
alfa long-term follow-up phase; an additional 
extension period of up to 144 weeks (or until 
avalglucosidase alfa is approved in the 
patient’s country, whichever comes first; refer to 
Appendix C Section 17.3.4 for definition 
applicable for UK patients) will include 
bi-weekly visits (study drug infusion, AE checks 
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, the end of study visit/contact will 
be performed. 
For all patients, all visits following V2 are 
calculated from day of first infusion of IMP in 
14-day increments with a window of ±7 days for 
infusions and safety assessments and 
±14 days for all other assessments.’ 
To maintain internal consistency with other 
sections of the protocol corresponding to the 
potential enrollment of pediatric patients 
aged 3 to <18 years directly in the 
open-label avalglucosidase alfa long-term 
follow-up phase. 
Clinical Trial Summary 
Section 6.2.1 Duration of study 
participation for each patient 
Added following texts: 
For overall duration: ‘(or 2 years [99 weeks] for 
the subgroup of pediatric patients aged 3 to 
<18 years enrolling directly in the open-label 
long-term follow-up phase)’ 
For 49-week blinded treatment period: ‘except 
for the subgroup of pediatric patients aged 3 to 
In order to clarify the updated study periods 
and durations corresponding to the potential 
enrollment of pediatric patients aged 3 to 
<18 years directly in the open-label 
avalglucosidase alfa long-term follow-up 
phase. 
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Section # and Name
Description and Change
Brief Rationale
<18 years enrolling directly in the open-label 
long-term follow-up phase’ 
For extended open-label long-term follow-up 
period: ‘An extended open-label 
avalglucosidase alfa long-term follow-up period 
will last up to 144 additional weeks (or until 
avalglucosidase alfa is approved whichever 
comes first; refer to Appendix C Section 17.3.4 
for definition applicable for UK patients) for all 
patients (extended open-label avalglucosidase 
alfa long-term follow-up phase).’ 
Section 1.2.1 Blinded treatment 
period 
Section 1.2.2 Open-label 
avalglucosidase alfa long-term 
follow-up phase 
Section 1.2.5.1 Screening and 
open-label avalglucosidase alfa 
long-term follow-up phase 
Pharmacogenetics assessment of mRNA has 
been removed from schedule. 
This test is not performed. 
Section 1.2.1 Blinded treatment 
period 
Section 1.2.2 Open-label 
avalglucosidase alfa long-term 
follow-up phase 
Section 1.2.5.1 Screening and 
open-label avalglucosidase alfa 
Long-term Follow-up Phase 
Collection of dry blood spot has been added for 
determination of exploratory biomarkers in 
addition to samples of urine and plasma. 
Corresponding footnotes in study flow charts 
has been updated. 
To develop alternative assays and 
potentially reduce blood volume needed for 
testing in future. 
Section 1.2.2 Open-label 
avalglucosidase alfa long-term 
follow-up phase 
Section 8.1 Investigational 
medicinal product(s) 
Footnote “a” added and updated footnote “b” to 
add following details. ‘As per conditions and 
instructions provided in Section 8.1, 
avalglucosidase alfa infusion may occur at 
home.’ 
Added eligibility criteria for home infusion 
during the open-label extension period. The 
subgroup of pediatric patients aged 3 to 
<18 years enrolling directly in the open-label 
long-term follow-up phase will be eligible for 
home infusion after remaining stable on 
avalglucosidase alfa administration for at least 
12 months. 
In countries where it is permitted, home 
infusion of avalglucosidase alfa in the 
extension period may be allowed. 
Section 1.2.3 Extended open-
label avalglucosidase alfa long-
term follow-up phase 
Section 10.1.5 Extended 
open-label avalglucosidase alfa 
long-term follow-up phase 
Added the table and corresponding list of 
assessments for ‘Extended open-label 
avalglucosidase alfa long-term follow-up phase’ 
Added the assessments for this newly 
added phase. 
Section 1.2.5 Pediatric patients 
aged 3 to less than 18 years 
entering directly in the open-
label avalglucosidase alfa 
Added the table and corresponding list of 
assessments for ‘Screening and open-label 
avalglucosidase alfa long-term follow-up phase’ 
and ‘Extended open-label avalglucosidase alfa 
Added the assessments for the pediatric 
patients aged 3 to <18 years enrolling 
directly in the open-label avalglucosidase 
alfa long-term follow-up. 
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Section # and Name
Description and Change
Brief Rationale
long-term follow-up 
Section 10.1.7 Visit schedule 
for pediatric patients aged 3 to 
<18 years enrolling directly in 
the open-label long-term follow-
up phase (starting after 
screening period) 
long-term follow-up phase’ and ‘End of study’ 
Section 5 Study objectives 
Section 9.2.1.3 Hand-held 
dynamometry (lower extremity 
muscle strength) 
Section 9.3.1.3 Hand-held 
dynamometry (upper extremity 
muscle strength) 
Section 11.4.2.2 Analyses of 
secondary efficacy endpoints 
Section 11.4.2.3 Multiplicity 
considerations 
Added the following text under secondary and 
other objectives: ‘For the Canada-specific 
requirement regarding HHD, refer to 
Appendix C Section 17.3.3.’ 
For clarifying regarding the country-specific 
requirements. 
Section 6.1 Description of the 
study 
Added following description: ‘At the end of the 
recruitment, if <4 pediatric patients aged 3 to 
<18 years are enrolled, in order to comply with 
Health Authority requirements to enroll a certain 
number of pediatric patients, up to 2 additional 
pediatric patients will be screened and enrolled 
directly in the open-label avalglucosidase alfa 
long-term follow-up phase where they will 
receive avalglucosidase alfa.  
Added clarification regarding enrollment of 
the patients aged 3 to <18 years of age. 
Section 6.3 Interim analysis 
Section 11.5 Interim analysis 
Added the following text: ‘and an additional 
extension period of up to 144 additional weeks 
(or until avalglucosidase alfa is approved in the 
patient’s country, whichever comes first; refer to 
Appendix C Section 17.3.4 for definition 
applicable for UK patients)’ 
To cover the extended open-label long-term 
follow-up period. 
Section 7. Selection of patients 
Re-screening is no longer limited to only one 
re-screening possibility. 
Removal of this limitation in order to re-
screen pediatric patients who were screen 
failed twice because their FVC% predicted 
was >85% both times. 
Section 8.1 Investigational 
medicinal product(s) 
Added the following text: ‘In the extended open-
label avalglucosidase extension period, 
avalglucosidase alfa will be administered by 
IV infusion every 2 weeks starting at V77/W147 
and continuing up to 144 additional weeks (or 
until avalglucosidase alfa is approved in the 
patient’s country, whichever comes first; refer to 
Appendix C Section 17.3.4 for definition 
applicable for UK patients) for an additional up 
to 72 doses. 
For pediatric patients aged 3 to <18 years 
enrolling directly in the open-label long-term 
follow-up phase, avalglucosidase alfa will be 
Added the description regarding the visit 
schedule during the additional open-label 
extension period. 
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Section # and Name
Description and Change
Brief Rationale
administered by IV infusion every 2 weeks 
starting at Randomization Visit (Visit 2, Day 
1/Day 2) continuing up to V52/W97 for a total of 
49 doses. For these patients, in the extended 
open-label avalglucosidase alfa extension 
period, avalglucosidase alfa will be 
administered by IV infusion every 2 weeks 
starting at V53/W99 and continuing up to 
144 additional weeks (or until avalglucosidase 
alfa is approved in the patient’s country, 
whichever comes first; refer to Appendix C 
Section 17.3.4 for definition applicable for UK 
patients) for up to 72 additional doses. 
For all patients, all visits following V2 are 
calculated from day of first infusion of IMP in 
14-day increments with a window of ±7 days for 
infusions and safety assessments, and 
±14 days for all other assessments. There 
should not be less than 7 days between 2 IMP 
infusions.’
Section 8.3.2 Randomization 
code breaking during the study 
Added following text 'One programmer may be 
unblinded to prepare the dataset for population 
PK analysis. The procedure detailing the 
process to maintain blind beyond the 
programmer is described in a separate Sanofi 
quality document.' 
Language is added in the 'randomization 
code breaking during the study' section, to 
document that an unblinded programmer will 
prepare the dataset for population PK 
analysis. 
Section 8.7.2 Return and/or 
destruction of treatments 
Added following text: ‘In some specific cases 
described in the monitoring plans (blinded and 
unblinded), reconciliation may be performed by 
blinded monitor, as long as the blinding is 
maintained as per conditions detailed in the 
monitoring plan.’ 
Language added for reconciliation of IMP in 
specific cases. 
Section 9.1.1 Primary efficacy 
endpoint 
Added the following text ‘For each PFT 
assessment, up to 8 efforts may be performed.’ 
Clarification added for primary efficacy 
endpoint assessment. 
Section 9.2.2.2 Laboratory 
safety variables 
Added following text: ‘A urine sample will be 
sent to the central laboratory for that purpose’ 
Clarification provided that quantitative 
measurement of urine will be performed at 
central laboratory. 
Section 9.2.2.3 Vital signs 
Added the following clarification regarding 
infusion rate change ‘(including the start of 
infusion which is considered as first infusion 
rate change)’, and added following text 
regarding number of assessments ‘ie, a total of 
7 assessments’ 
Clarification added regarding infusion rate 
change and number vital signs 
assessments. 
Section 9.2.2.7 Immunogenicity 
Added following text: ‘In these patients, ADA 
against alglucosidase alfa will no longer be 
tested in the extended open-label follow-up 
phase (ie, after Week 145).’ 
Clarification provided for performing ADA 
test against alglucosidase alfa during 
extended open-label follow-up phase. 
Section 9.3.2.3 Bioanalytical 
method 
Updated the LLOQ from ‘12.5 ng/mL or 
0.013 μg/mL’ to ’12 ng/mL or 0.012 μg/mL’. 
Updated the LLOQ of the method for 
avalglucosidase alfa. 
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Section # and Name
Description and Change
Brief Rationale
Section 1.2.1 Blinded treatment 
period 
Section 1.2.5.1 Screening and 
Open-label avalglucosidase 
alfa Long-term Follow-up 
Phase 
Added following text in table footnote ‘x’ of 
Section 1.2.1 and table footnote ‘s’ of 
Section 1.2.5.1: ‘GAA enzyme activity level 
measured on a Dried Blood Spot sample is not 
considered as sufficient to confirm eligibility in 
this study; GAA enzyme activity level from 
another source (skin fibroblast, peripheral blood 
leukocyte or muscle biopsy sample) will be 
needed).’ 
Clarification added for genotyping and for 
biochemical diagnosis of Pompe disease if 
required. 
Section 9.3.3.1 Genotyping of 
human acid α-glucosidase 
gene 
Added the following texts: 
‘However, results from the central laboratory 
may be used if performed during the screening 
period but should be obtained before the 
Baseline Visit to confirm eligibility.’ 
Section 10.1.2 Screening 
period/baseline visit  
Added following text: ‘For the subgroup of 
pediatric patients aged 3 to <18 years enrolling 
directly in the open-label long-term follow-up 
phase, an interactive response technology 
(IRT) call for enrollment will replace the 
randomization call and will be performed just 
before the IMP administration at the first 
treatment visit. Post screening schedule for this 
subgroup of pediatric patients is detailed in 
Section 10.1.7.’ 
Clarification added for patients enrolling 
directly in the open-label long-term follow-up 
phase. 
Section 10.1.7 Visit schedule 
for pediatric patients 
Added section 10.1.7 and subsections of visit 
schedule for pediatric patients aged 3 to 
<18 years enrolling directly in the open-label 
long-term follow-up phase (starting after 
screening period).  
Clarification for visit schedule added for 
pediatric patients enrolling directly in the 
open-label long-term follow-up phase. 
Section 10.1.8 Follow-up 
Following clarification added for V64/Week 121: 
‘[not applicable for pediatric patients aged 3 to 
<18 directly enrolled in the open-label long-term 
follow-up phase]’ 
Following clarification added for V76/Week 145 
‘[not applicable for pediatric patients aged 3 to 
<18 directly enrolled in the open-label long-term 
follow-up phase], or any every 24 weeks visit of 
the extended open-label long-term follow-up 
phase’ 
Clarification added regarding assessments 
on V64/Week 121 and V76/Week 145. 
Section 10.1.9 Follow-up for 
patients who temporarily or 
permanently discontinued the 
study treatment 
Added the following text: ‘For those patients 
who discontinued treatment during the 
extended open-label avalglucosidase alfa long-
term follow-up phase, assessments 
corresponding to the End of Treatment Visit as 
outlined in Section 10.1.7.3.5 will be performed 
if possible’. 
Clarification added for patients who 
discontinued treatment during extended 
long-term follow-up phase. 
Section 10.3.1 Temporary 
treatment discontinuation with 
investigational medicinal 
Temporary IMP discontinuation criteria have 
been updated in case an AE occurs: 
x
Any life-threatening AE: deleted NCI and 
CTCAE reference is removed since it relates 
to oncology terminology. 
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EFC14028 - avalglucosidase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 151
Section # and Name
Description and Change
Brief Rationale
product(s) 
CTCAE ‘Grade 4’ 
More than 1 AE: deleted CTCAE ‘Grade 3 or 
Greater’  
Section 10.6 Safety instructions 
Added the following text: ‘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, such a procedure may be 
initiated as per pharmacy manual guidelines. 
Depending on the phase of the study the 
patient will be in at the time of the 
desensitization procedure, this one may be 
blinded (if the procedure is started when the 
patient is still in the double-blind phase) or 
unblinded (if the procedure is started when the 
patient is in one of the open-label phases)’. 
Text added for IAR evaluation at DMC and 
possibility of desensitization procedure. 
Section 11.3 Analysis 
populations 
Definition of safety population has been 
updated. 
Clarification added regarding the patients 
enrolled directly in open-label long-term 
follow-up period. 
Section 11.4 Statistical 
methods  
Deleted the following text ‘In the case that NI of 
FVC (% predicted) is demonstrated and the 
superiority of the primary efficacy endpoint is 
not achieved, additional supportive data on 
6MWT will be needed to demonstrate the 
clinical meaningfulness of the NI for the primary 
endpoint.’ 
The statistical section is updated: 
x
Primary endpoint FVC (% predicted): 
removed non-inferiority test of 6MWT 
from the testing order. 
x
Secondary endpoint (6MWT): the primary 
statistical objective changed from non-
inferiority to superiority of 
avalglucosidase alfa versus 
alglucosidase alfa. 
x
Added following superiority test to the 
hierarchical testing ‘% predicted change 
from baseline to Week 49 for MEP’. 
Updated in accordance with the feedback 
received from Regulatory Agency. 
Section 14.2 Record retention 
in study sites 
Section 14.5 Data protection 
Administrative changes made. 
Clarifications added in line with other 
sections. 
Section 17.3 Appendix C: 
Country-specific requirements 
 
Added country-specific requirements for 
France. 
Clarified that home infusion is not allowed in 
France. 
Added country-specific requirements for 
Canada.  
Added due to operational challenges with 
the use of the HHD in Canada, several 
measures assessed with this device will be 
missing. Therefore, these assessments 
(HHD in lower extremity muscle strength, 
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Amended Clinical Trial Protocol 06
04-Feb-2022
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Section # and Name
Description and Change
Brief Rationale
HHD in upper extremity muscle strength) will 
no more be required in study participants in 
Canadian sites. 
Added country specific requirements for UK. 
The duration of the extended open-label 
avalglucosidase alfa long-term follow-up 
period will be defined as ‘up to 144 weeks 
after the last patient has been enrolled in the 
study’ in the UK. Hence, this wordings 
added to comply with the UK position 
regarding the protocol language to be used 
for study extensions. 
Throughout 
Added generic name of the investigational drug 
in addition to compound code. 
Minor editorial, typo error corrections, and 
document formatting revisions. 
Minor, therefore have not been summarized. 
17.4.4 Amended protocol 04: 21 December 2020
This amended protocol 04 is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
Overall Rationale for the Amendment
x
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 the 
information regarding the post-infusion surveillance period.
x
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.
x
To update Section 8.1 for details regarding home infusion, to harmonize this text across 
the different studies included in the avalglucosidase alfa development program.
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Amended Clinical Trial Protocol 06
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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. 
Clinical Trial Summary; 
Section 6.1 Description of the Study 
Requirement for a patient to remain 
blinded to the randomized treatment in 
the study is updated from ‘after 
database is locked and the primary 
analysis completed’ to just ‘after 
database is locked’. 
To update the text related to blinding. 
Section 1.2 - Flow chart: 1.2.1 Blinded 
treatment period; 1.2.2 Open-label 
avalglucosidase alfa long-term follow-up 
phase; 1.2.3 Extended open-label 
avalglucosidase alfa long-term follow-up 
phase. For pediatric patients enrolling 
directly in open-label period: 
1.2.5.1 Screening and open-label 
avalglucosidase alfa long-term follow-up 
phase: 1.2.5.2 Extended open-label 
avalglucosidase alfa long-term follow-up 
phase  
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 
were performed at the study site or 
infusion center was shortened or skipped 
for patient’s safety reasons. Also to 
lighten this period after the end of the 
pandemic and in order to obtain 
information in case this observation 
period is not performed, the observation 
time after the end of infusion is reduced to 
1 hour. 
Section 1.2.1 Blinded treatment period; 
Section 9.2.2.7 Immunogenicity 
Information related to the assessment 
related to ADA (with neutralizing 
antibodies in ADA-positive patients)s, u 
was revised to add the following 
information: “In addition, patients in the 
alglucosidase alfa treatment arm will 
also be tested for anti-avalglucosidase 
alfa antibodies at V27/W49 to get their 
baseline value”. 
To get the same level of information from 
patients receiving alglucosidase alfa 
treatment as compared with patients 
receiving avalglucosidase alfa treatment 
during the blinded treatment period. 
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 AE occurred during the 
observation period.” 
Due to COVID-19 pandemic restrictions, 
the observation period after the infusions 
were performed at the study site or 
infusion center was shortened or skipped 
for patient’s safety reasons. Also to 
lighten this period after the end of the 
pandemic and in order to obtain 
information in case this observation 
period is not performed, the observation 
time after the end of infusion is reduced to 
1 hour. 
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Section # and Name
Description and Change
Brief Rationale
Section 8.1 Investigational medicinal 
product(s) 
Under “Home infusion” subsection, the 
text was updated to harmonize with 
other studies included in the 
avalglucosidase alfa development 
program. 
The home infusion text is amended to 
allow patients to benefit from home 
infusion sooner in case of an unexpected 
event (i.e. after at least 6 months free of 
IARs instead of 12 months) or to resume 
home infusion sooner after interruption for 
IAR during home infusion. Some text is 
also updated to harmonize across the 
other studies included in the 
avalglucosidase alfa development 
program. 
Section 10.1.9 Follow-up for patients who 
temporarily or permanently discontinued 
the study treatment 
Text related to permanent and 
temporary discontinuation was updated. 
This change was made to avoid 
unnecessary clinic visits. 
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. 
Text was also updated to clarify that 
‘visit and assessment schedules will be 
adapted to the absence of infusion of 
IMP’. 
To clarify that pregnancy is a reason for 
temporary treatment discontinuation and 
not permanent discontinuation.  
Also, to clarify that ‘visit and assessment 
requirements will be changed in the 
absence of IMP. 
Section 10.4.3 Instructions for reporting 
serious adverse events 
Text was deleted regarding proactively 
sending the SAE-related reporting 
documents via fax or as photocopy. 
As per recent Sanofi procedures, the 
direct sending of source documents to the 
Sponsor (except to Pharmacovigilance 
department) is no more recommended. 
Section 12 Regulatory, ethical, and study 
oversight considerations; Section 13 
Study monitoring; Section 14 Additional 
requirements 
Headings, subsections, and 
corresponding text were fully updated in 
Sections 12, 13, and 14 to reflect current 
practices as outlined in the current 
protocol template, including monitoring 
techniques. 
To align with current protocol template. 
Section 17.4 Appendix D: Protocol 
amendment history 
Added new section (Section 17.4.3). 
To incorporate the changes from 
amended protocol 03 to the amended 
protocol 04. 
Throughout 
Minor editorial, document formatting, 
and typographical correction are made. 
Clarification. 
17.4.5 Amended protocol 05: 18 November 2021
This amended protocol 05 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
Under the current EFC14028 protocol (Amended protocol 04) patients will complete the study on 
Week 289 visit or upon approval of avalglucosidase alfa, whichever comes first. For enrolled 
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Amended Clinical Trial Protocol 06
04-Feb-2022
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Version number: 1
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Page 155
patients wishing to start commercial treatment with avalglucosidase alfa in Canada after their 
participation in the EFC14028 study, there might be a treatment gap between the end of treatment 
visit of the EFC14028 study (if based on approval of avalglucosidase alfa in Canada) and the time 
to being able to receive avalglucosidase alfa as a commercial treatment. In order to cover this gap, 
the patients’ participation in the open label phase of the study is extended until the Week 289 visit 
or availability of commercial avalglucosidase alfa, whichever comes first for enrolled patients in 
Canada.
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04-Feb-2022
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Protocol amendment summary of changes table
Section # and Name
Description and Change
Brief Rationale
Protocol Amendment Summary of 
Changes 
Document formatting revision. 
To update document history and provide 
overall rationale for the amendment and 
summary of changes table. 
Clinical trial summary: Assessment 
schedule, Duration of study period (per 
patient) 
Section 6.2.1 Duration of study 
participation for each patient 
Section 6.3 Interim analysis 
Section 8.1 Investigational medicinal 
product(s) 
Section 10.1.5.1 Biweekly to Section 
10.1.5.5 Every 48 weeks (Yearly) and 
end of treatment visit 
Section 11.5 Interim analysis 
Added reference to Section 17.3.3 
Canada. 
To allow the 2 enrolled adult patients in 
Canada to continue the study according 
to the planned schedule of assessments 
after approval of the product in Canada 
until the product is made commercially 
available in Canada. 
Section 17.3 Appendix C: Country-
specific requirements 
New text added to Section 17.3.3 
Canada to state the following: 
For enrolled patients wishing to start 
commercial treatment with 
avalglucosidase alfa in Canada after 
their participation in the EFC14028 
study, and to avoid a treatment gap 
between the end of treatment visit of the 
EFC14028 study and the possibility to 
start commercial treatment with 
avalglucosidase alfa, the duration of 
study participation of patients in Canada 
is defined as follows: 
An extended open-label avalglucosidase 
alfa long-term follow-up period will last 
up to 144 additional weeks (or until 
avalglucosidase alfa is commercially 
available in Canada, whichever comes 
first) for all enrolled patients in Canada 
(extended open-label avalglucosidase 
alfa long-term follow-up phase). 
To allow the 2 enrolled adult patients in 
Canada to continue the study according 
to the planned schedule of assessments 
after approval of the product in Canada 
until the product is made commercially 
available in Canada. 
Section 17.4 Appendix D: Protocol 
amendment history 
Added new section (Section 17.4.4). 
To incorporate the changes from 
amended protocol 04 to the amended 
protocol 05. 
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SAP_003.pdf: 
STATISTICAL ANALYSIS PLAN
A Phase 3 randomized, multicenter, multinational, double-blinded study 
comparing the efficacy and safety of repeated biweekly infusions of 
avalglucosidase alfa (neoGAA, GZ402666) to alglucosidase alfa in 
treatment-naïve patients with late onset Pompe disease 
GZ402666-EFC14028 
STATISTICIAN: [Name] 
DATE OF ISSUE: 14-Apr-2020 
Total number of pages:
85 
According to template: QSD-002643 VERSION 6.0 (06-JUL-2016)
Page 1 
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 
Anonymized Page 1
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Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 2
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1.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................8 
1.2 
OBJECTIVES...................................................................................................................................9 
1.2.1 
Primary objectives............................................................................................................................9 
1.2.2 
Secondary objectives.......................................................................................................................9 
1.2.3 
Other objectives ...............................................................................................................................9 
1.3 
DETERMINATION OF SAMPLE SIZE...........................................................................................10 
1.3.1 
Determination of the non-inferiority margin for the primary efficacy endpoint ...............................10 
1.3.2 
Estimated treatment differences between avalglucosidase alfa and alglucosidase alfa on 
change from baseline in FVC (% predicted upright) at Month 12 (Week 49) ................................12 
1.3.3 
Determination of the dropout rate ..................................................................................................13 
1.3.4 
Power calculations with different effect size assumptions.............................................................13 
1.4 
STUDY PLAN.................................................................................................................................14 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL................................16 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN .....................16 
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2.1 
ANALYSIS ENDPOINTS ...............................................................................................................18 
2.1.1 
Demographic and baseline characteristics ....................................................................................18 
2.1.2 
Prior or concomitant medications...................................................................................................19 
2.1.3 
Efficacy endpoints..........................................................................................................................20 
2.1.3.1 
Primary efficacy endpoint...............................................................................................................20 
2.1.3.2 
Secondary efficacy endpoint(s)......................................................................................................21 
2.1.3.3 
Additional efficacy endpoints .........................................................................................................26 
2.1.4 
Safety endpoints ............................................................................................................................31 
2.1.4.1 
Adverse events variables...............................................................................................................31 
2.1.4.2 
Deaths............................................................................................................................................34 
2.1.4.3 
Laboratory safety variables............................................................................................................34 
2.1.4.4 
Vital signs variables .......................................................................................................................35 
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2.1.4.5 
Electrocardiogram variables ..........................................................................................................35 
2.1.4.6 
Physical examination .....................................................................................................................35 
2.1.4.7 
Body weight and height..................................................................................................................35 
2.1.4.8 
Immunogenicity..............................................................................................................................36 
2.1.5 
Infusion associated reactions (IARs) .............................................................................................38 
2.1.6 
Pharmacokinetic endpoints............................................................................................................38 
2.1.7 
Pharmacogenetic endpoints ..........................................................................................................38 
2.1.8 
Pharmacodynamic endpoints.........................................................................................................38 
2.1.9 
Patient Global Impression of Change ............................................................................................38 
2.1.10 
Quality of life/health economic variables/other endpoints..............................................................39 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................39 
2.2.1 
Randomization and drug dispensing irregularities in PAP.............................................................41 
2.3 
ANALYSIS POPULATIONS...........................................................................................................41 
2.3.1 
Efficacy populations .......................................................................................................................42 
2.3.1.1 
Modified intent-to-treat population .................................................................................................42 
2.3.1.2 
Per-protocol population..................................................................................................................42 
2.3.2 
Safety population ...........................................................................................................................42 
2.3.3 
Additional analysis populations......................................................................................................43 
2.4 
STATISTICAL METHODS .............................................................................................................43 
2.4.1 
Demographics and baseline characteristics ..................................................................................43 
2.4.2 
Prior or concomitant medications...................................................................................................44 
2.4.3 
Extent of investigational medicinal product exposure and compliance .........................................44 
2.4.3.1 
Extent of investigational medicinal product exposure....................................................................44 
2.4.3.2 
Compliance ....................................................................................................................................45 
2.5 
ANALYSES OF EFFICACY ENDPOINTS .....................................................................................45 
2.5.1 
Analysis of primary efficacy endpoint in PAP ................................................................................46 
2.5.1.1 
Distance walked in 6MWT .............................................................................................................47 
2.5.1.2 
MIP and MEP from pulmonary function testing .............................................................................49 
2.5.1.3 
Hand-held dynamometry (lower extremity muscle strength) .........................................................49 
2.5.1.4 
Quick Motor Function Test.............................................................................................................50 
2.5.1.5 
12-item short form health survey ...................................................................................................50
2.5.2 
Multiplicity issues ...........................................................................................................................50 
2.5.3 
Sensitivity analyses for the primary efficacy endpoint in PAP .......................................................51 
2.5.3.1 
Sensitivity analyses to assess the impact of missing data ............................................................51 
2.5.3.2 
Sensitivity analyses with alternative model or different distribution assumption ...........................52 
2.5.3.3 
Sensitivity analyses with respect to the constancy assumption ....................................................53 
2.5.3.4 
Additional supportive analyses for the primary endpoint ...............................................................53 
2.5.4 
Subgroup analyses for the primary efficacy endpoint and key secondary efficacy endpoint 
in PAP ............................................................................................................................................54 
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2.5.5 
Additional efficacy analyses including PRO endpoints ..................................................................55 
2.5.5.1 
Analyses of efficacy data in ETP at PAP database lock................................................................55 
2.5.5.2 
Analysis of the effect of switching from alglucosidase alfa to avalglucosidase alfa ......................55 
2.6 
ANALYSES OF SAFETY DATA ....................................................................................................56 
2.6.1 
Analyses of adverse events ...........................................................................................................57 
2.6.2 
Evaluation of ADA on Relevant Safety Parameters.......................................................................60 
2.6.3 
Deaths............................................................................................................................................61 
2.6.4 
Analyses of laboratory variables....................................................................................................61 
2.6.5 
Analyses of vital sign variables ......................................................................................................62 
2.6.6 
Analyses of electrocardiogram variables .......................................................................................62 
2.6.7 
Analyses of physical examinations ................................................................................................62 
2.6.8 
Analyses of Immunogenicity parameters.......................................................................................63 
2.6.8.1 
ADA incidence and characterization..............................................................................................63 
2.6.8.2 
Duration of ADA .............................................................................................................................63 
2.6.8.3 
ADA titers .......................................................................................................................................63 
2.6.8.4 
ADA Response Classification ........................................................................................................63 
2.6.8.5 
Neutralizing ADA............................................................................................................................64 
2.6.8.6 
Cross-reactivity evaluation.............................................................................................................64 
2.6.9 
Association of ADA with PK ...........................................................................................................64 
2.6.10 
Association of ADA and PD marker...............................................................................................65 
2.6.11 
Association of ADA with selected efficacy .....................................................................................65 
2.7 
SUMMARY OF PHARMACOKINETIC DATA................................................................................65 
2.8 
ANALYSES OF PHARMACODYNAMICS ENDPOINT DATA.......................................................65 
2.9 
ANALYSES OF QUALITY OF LIFE/HEALTH ECONOMICS VARIABLES ...................................65 
2.10 
DATA HANDLING CONVENTIONS ..............................................................................................66 
2.10.1 
General conventions ......................................................................................................................66 
2.10.2 
Data handling conventions for primary and secondary efficacy variables.....................................66 
2.10.3 
Missing data handling in data presentation ...................................................................................66 
2.10.4 
Study day calculation .....................................................................................................................68 
2.10.5 
Windows for time points.................................................................................................................68 
2.10.6 
Unscheduled visits .........................................................................................................................69 
2.10.7 
Pooling of centers for statistical analyses......................................................................................69 
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APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ......................77 
APPENDIX B 
SCHEDULE OF THE EFFICACY ASSESSMENT ..............................................................85 
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Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
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Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 8
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Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
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Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
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Page 10
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Anonymized Page 10


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 11
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LOTS (AGLU02704) (Study 
1)
Randomized, double-blind,
Myozyme (20 mg/kg qow) vs. 
placebo, N = 90
Mean chg from BL at Week
52 was 1.651 (Myozyme) and 
-1.865 for placebo, with a LS
mean difference of 3.5.
-Age 8 years
-6MWT 40 meters
-FVC (%) upright between
30%-80%
-GAA enzyme deficiency and
2 GAA gene mutations
EMBASSY (Study 2)
Single arm study at
Myozyme 20 mg/kg qow, N =
16
Mean chg from BL at 
Week 26 was 1.8
-Age 18
-6MWT 50 meters
-FVC (%) upright 50%
-GAA deficiency and.or
confirmed GAA gene
mutation and no known
cardiac hypertrophy
TDR12857 (Study 3)
Open label, multi-dose 
cohorts with avalglucosidase 
alfa at 5, 10, 20 mg/kg qow
Group 1 (naïve LOPD) 
10 + 20mg/kg cohorts 
combined: Mean chg from BL 
at Week 25 was 5.21  
Subgroup with baseline 
FVC <85% (N = 5): Mean 
chg from BL at Week 25 was 
4.39 (10 + 20mg/kg), or 6.15 
(20 mg/kg only)
-Age 18
-6MWT 50 meters
-FVC (%) upright 50%
-GAA deficiency and.or
confirmed GAA gene
mutation and no known
cardiac hypertrophy
Group 1: LOPD treatment 
naive
Group 2: LOPD switch from 
Myozyme
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Anonymized Page 11


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 12
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All patients
9 months (38 weeks)
3.77
4.74
(2.36, 5.18)
12 months (52 weeks)
3.64
4.98
(2.14, 5.15)
18 months (78 weeks)
3.73
5.35
(2.09, 5.37)
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Anonymized Page 12


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 13
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avalglucosidase alfa from Study 3 (10 mg/kg or 20 mg/kg dose level) vs. all Mz patients from Study 1 and 2
avalglucosidase alfa
6
5.2
3.6, CI: (2.03, 6.98)
alglucosidase alfa
72
1.6
avalglucosidase alfa from Study 3 20mg/kg patients  vs. all Mz patients from Study 1 and 2
avalglucosidase alfa
3
6.2
4.6, CI: (2.03, 8.33 )
alglucosidase alfa
72
1.6
*Confidence interval for the difference was based on Hodges-Lehmann exact confidence interval due to small sample size in the
avalglucosidase alfa arm.
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Anonymized Page 13


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 14
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5.0 (estimated from the MMRM model with all patients data)
1.5
66.4%
27.9%
2.0
81.1%
45.0%
2.5
91.0%
63.0%
3.0
96.4%
78.5%
3.5
98.8%
89.4%
5.1 (estimated from within arm SD from evaluable alglucosidase alfa patients only)
1.5
64.7%
27.0%
2.0
79.6%
43.5%
2.5
89.9%
61.3%
3.0
95.8%
76.9%
3.5
98.5%
88.2%
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Anonymized Page 14


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 15
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Anonymized Page 15


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 16
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3
10-Apr-2019
Updated definition of Safety 
Population to include up to 2 
pediatric patients who will be 
enrolled directly in the open-label 
avalglucosidase alfa long term 
follow-up phase
In order to comply with Health 
Authority requirements to enroll a 
certain number of pediatric 
patients, up to 2 additional
pediatric patients will be enrolled 
directly in the open-label 
avalglucosidase alfa long-term 
follow-up phase where they will 
receive avalglucosidase alfa
3
10-Apr-2019
Added following superiority test to 
the hierarchical testing ‘% predicted 
change from baseline to Week 49 
for MEP’.
We will have chance to make 
claim in the label for the 
secondary endpoint MEP
3
10-Apr-2019
Removed non-inferiority test of 
6MWT in the fixed sequence testing 
to control multiplicity.
Updated in accordance with the 
feedback received from 
Regulatory Agency.
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Anonymized Page 16


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 17
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Anonymized Page 17


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 18
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Anonymized Page 18


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 19
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Anonymized Page 19


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 20
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Anonymized Page 20


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 21
2.1.3.2
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Female
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Anonymized Page 21


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 22
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174 – 0.83 * age
131 – 0.86 * age
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35 + 5.5 * age
24 + 4.8 * age
MIP
18 years old (9)
120 – 0.41 * age
108 – 0.61 * age
7–17 years old (10)
44.5 + 0.75 * weight
40 + 0.57 * weight
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Anonymized Page 22


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 23
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Anonymized Page 23


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 24
7DEOH$GXOWDJH!PXVFOHVWUHQJWKUHIHUHQFHHTXDWLRQVWRGHWHUPLQHKHDOWK\SUHGLFWHG
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Hip Flexion (12)
R
9.8067 [-(age×.33) + (gender×19.19)+((weight/height2) × .66) + 34.44]
Hip Flexion (12)
L
9.8067 [-(age×.29) + (gender×18.75)+((weight/height2) × .47) + 36.05]
Hip Extension (12)
R
9.8067 [-(age×.21)+(gender×15.19)+((weight/height2) × .14) + 33.52]
Hip Extension (12)
L
9.8067 [-(age×.23)+(gender×15.02)+((weight/height2) × .17) + 33.88]
Hip Abduction (13)
R & L
195.24 – 62.4(1-gender) – 1.184(age) + .198 (weight x 9.8067)
Knee Flexion (12)
R
9.8067 [-(age×.16)+(gender×8.78)+((weight/height2) × .08) + 22.47]
Knee Flexion (12)
L
9.8067 [-(age×.17) + (gender×7.67) + ((weight/height2) × .14) + 21.10]
Knee Extension (12)
R
9.8067 [-(age×.38) + (gender×18.44) + ((weight/height2) × .62) + 34.41]
Knee Extension (12)
L
9.8067 [-(age×.38) + (gender×17.68) + ((weight/height2) × .62) + 33.61]
Ankle Dorsiflexion (12)
R
9.8067 [-(age×.12) + (gender×7.93) + ((weight/height2) × .11) + 22.87]
Ankle Dorsiflexion (12)
L
9.8067 [-(age×.13) + (gender×8.12) + ((weight/height2) × .15) + 21.91]
* Age in years; gender: male=1, female=0; weight in kgs; height in meters.
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Boy
182
182
225
232
261
245
198
289
337
301
395
Girl
162
184
175
195
177
264
232
308
281
288
301
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Boy
128
124
131
153
174
151
158
225
306
356
312
Girl
109
122
117
124
104
140
171
227
244
257
244
Knee extensors
Boy
156
157
185
194
267
239
225
296
370
362
396
Girl
148
177
166
173
198
265
250
346
280
325
373
Knee flexors
Boy
111
105
158
180
185
195
268
218
201
273
307
327
382
Girl
92
99
154
171
160
180
175
246
221
301
271
282
336
Foot dorsal flexors
Boy
71
76
104
130
137
141
154
149
170
218
257
267
291
Girl
75
76
95
114
121
137
130
178
177
214
207
220
232
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Hip extensors
Boy
80
131
170
210
226
277
Girl
76
124
157
174
226
267
Anonymized Page 24


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 25
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Anonymized Page 25


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 26
2.1.3.3
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Anonymized Page 26


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 27
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Anonymized Page 27


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 28
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Anonymized Page 28


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 29
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Anonymized Page 29


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 30
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Anonymized Page 30


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 31
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Anonymized Page 31


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 32
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Anonymized Page 32


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
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Anonymized Page 33


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 34
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Anonymized Page 34


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 35
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Physical examination
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Anonymized Page 35


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 36
2.1.4.8
Immunogenicity
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Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
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Anonymized Page 37


Statistical Analysis Plan
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Anonymized Page 38


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
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Anonymized Page 39


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
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Anonymized Page 40


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
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Anonymized Page 41


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 42
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Anonymized Page 42


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 43
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Anonymized Page 43


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
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Anonymized Page 44


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
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Anonymized Page 45


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 46
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Anonymized Page 46


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 47
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2.5.1.1
Distance walked in 6MWT
2.5.1.1.1 Primary analysis of 6MWT based on distance walked
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Anonymized Page 47


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 48
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Anonymized Page 48


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 49
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2.5.1.2
MIP and MEP from pulmonary function testing
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2.5.1.3
Hand-held dynamometry (lower extremity muscle strength)
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Anonymized Page 49


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 50
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Anonymized Page 50


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 51
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Anonymized Page 51


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 52
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Anonymized Page 52


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 53
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Additional supportive analyses for the primary endpoint
2.5.3.4.1 Responder analysis
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Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 54
2.5.3.4.2 Changes in respiratory support
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Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 55
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2.5.5.1
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Anonymized Page 55


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 56
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Anonymized Page 56


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 57
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Anonymized Page 57


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
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Anonymized Page 58


Statistical Analysis Plan
14-Apr-2020
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Version number: 3
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Anonymized Page 59


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
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Anonymized Page 60


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
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Anonymized Page 61


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 62
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Anonymized Page 62


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 63
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Anonymized Page 63


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
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Anonymized Page 64


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 65
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Anonymized Page 65


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 66
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Anonymized Page 66


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 67
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Anonymized Page 67


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 68
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Screening/Baseline
Day -14 to -1
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Day 85 ±14
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Week 25
Day 169 ±14
Day 169 (-42, +41)
Week 37
Day 253 ±14
Day 253 (-42, +41)
Week 49
Day 337 ±14
(Day 337 -42, the day prior to the 1st ETP treatment 
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Week 61
Day 421 ±14
(the day after the 1st ETP treatment, Day 421 +41)
Week 73
Day 505 ±14
Day 505 (- 42, +83)
Week 97
Day 673 ±14
Day 673 (-84, +83)
Week 121
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Anonymized Page 68


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 69
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Week 217
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Anonymized Page 69


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 70
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Anonymized Page 70


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 71
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Anonymized Page 71


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 72
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Anonymized Page 72


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 73
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Anonymized Page 73


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 74
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Anonymized Page 74


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 75

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Anonymized Page 75


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 76

/,672)$33(1',&(6
$SSHQGL[$
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Anonymized Page 76


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 77
$SSHQGL[$
3RWHQWLDOO\FOLQLFDOO\VLJQLILFDQWDEQRUPDOLWLHVFULWHULD
7DEOH3&6$DEQRUPDOLWLHV
0HDVXUHV
$GXOW&ULWHULD
3HGLDWULF&ULWHULD
Liver function tests
ALT
>3 x ULN
>5 x ULN
>10 x ULN
>20 x ULN
≥3 x ULN
≥5 x ULN
≥10 x ULN
≥20 x ULN
AST
>3 x ULN
>5 x ULN
>10 x ULN
>20 x ULN
≥3 x ULN
≥5 x ULN
≥10 x ULN
≥20 x ULN
Alkaline Phosphatase
>1.5 x ULN
≥1.5 x ULN
Total Bilirubin
>1.5 x ULN
>2 x ULN
≥1.3 x ULN
ALT and Total Bilirubin
ALT >3 x ULN and Total Bilirubin >2 x ULN
ALT ≥3 x ULN and Total Bilirubin ≥2 x ULN
Hematology
White Blood Cell (WBC)
<3.0 GIGA/L (non-Black), <2.0 GIGA/L (Black),
≥16.0 GIGA/L
Birth/0 to 27 days old (Neonates) 
<4.0 GIGA/L
>25.0 GIGA/L
28 days/1 month to 23 months old (Infants) 
<4.0 GIGA/L
>20.0 GIGA/L
24 months/2 years to <6 years old (Children) 
>3.0 GIGA/L
>16.0 GIA/L
Anonymized Page 77


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 78
0HDVXUHV
$GXOW&ULWHULD
3HGLDWULF&ULWHULD
6 to <12 years old (Children) 
<5.0 GIGA/L
>17.0 GIGA/L
12 to 16/18 years old (Adolescents) 
<4.5 GIGA/L
>13.5 GIGA/L
Lymphocytes
>4.0 GIGA/L
Birth/0 to 27 days old (Neonates) 
<1.2 GIGA/L
>17.0 GIGA/L
28 days/1 month to 23 months old (Infants) 
<2.0 GIGA/L
>13.5 GIGA/L
24 months/2 years to <6 years old (Children) 
<1.0 GIGA/L
>9.5 GIGA/L
6 to <12 years old (Children) 
<1.0 GIGA/L
>8.0 GIGA/L
12 to 16/18 years old (Adolescents) 
<0.6 GIGA/L
>6.0 GIGA/L
Anonymized Page 78


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 79
0HDVXUHV
$GXOW&ULWHULD
3HGLDWULF&ULWHULD
Neutrophils
<1.5 GIGA/L (non-Black)
<1.0 GIGA/L (Black)
Birth/0 to 27 days old (Neonates)
<4.0 GIGA/L (1 day old)
<1.5 GIGA/L (2 – 7 days old)
<1.25 GIGA/L (>7 day – 1 month old)
>1 ULN
28 days/1 month to 23 months old (Infants) 
<1.0 GIGA/L (1 – 3 months)
<1.2 GIGA/L (3 – 24 months)
>1 ULN
24 months/2 years to <6 years old (Children) 
<1.2 GIGA/L
>1 ULN
6 to <12 years old (Children)
<1.2 GIGA/L
>1 ULN
12 to 16/18 years old (Adolescents) 
<1.2 GIGA/L
>1 ULN
Monocytes
>0.7 GIGA/L
Basophils
>0.1 GIGA/L
Eosinophils
>0.5 GIGA/L or
>ULN if ULN ≥0.5 GIGA /L
>0.5 GIGA/L
Or >ULN if ULN >0.5 GIGA/L
Anonymized Page 79


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 80
0HDVXUHV
$GXOW&ULWHULD
3HGLDWULF&ULWHULD
Hemoglobin
Males: ≤115 g/L (≤7.14 mmol/L), ≥185 g/L (≥11.48 mmol/L)
Females: ≤95 g/L (5.9 mmol/L), ≥165 g/L (10.24 mmol/L)
Decrease from Baseline:  ≥20 g/L (1.24 mmol/L)
Birth/0 to 27 days old (Neonates) 
<86 mmol/L or 12.0 g/dL or any decrease > 0.31 mmol/L or 2 g/dL
28 days/1 month to 23 months old (Infants) 
<1.40 mmol/L or 9.0 g/dL or any decrease > 0.31 mmol/L or 2 g/dL
24 months/2 years to <16/18 years old (Children,
Adolescents)
<1.55 mmol/L or 10.0 g/dL or any decrease > 0.31 mmol/L or 2 g/dL
Hematocrit
Males : ≤0.37 v/v, ≥0.55 v/v
Females : ≤0.32 v/v, ≥0.5 v/v
Birth/0 to 27 days old (Neonates) 
<0.39 l/l or 40%
>0.61 l/l or 47%
28 days/1 month to 23 months old (Infants) 
<0.29 l/l or 29%
>0.42 l/l or 42%
24 months/2 years to <16/18 years old (Children,
Adolescents)
<0.32 l/l or 32%
>0.47 l/l or 47%
RBC
≥6 TERA/L
Platelets
<100 GIGA/L 
≥ 700 GIGA/L
<100 GIGA/L 
>700 GIGA/L
ECG – PCSA criteria
HR
<50 bpm
<50 bpm and decrease from baseline ≥20 bpm
<40 bpm
<40 bpm and decrease from baseline ≥20 bpm
<30 bpm
<30 bpm and decrease from baseline ≥20 bpm
Birth/0 to 27 days old (Neonates) 
≤90 bpm and decrease from baseline≥20 bpm
≥190 bpm and increase from baseline
≥20 bpm
28 days/1 month to 23 months old (Infants)
≤80 bpm and decrease form baseline
Anonymized Page 80


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 81
0HDVXUHV
$GXOW&ULWHULD
3HGLDWULF&ULWHULD
>90 bpm
>90 bpm and increase from baseline ≥20bpm
>100 bpm
>100 bpm and increase from baseline ≥20bpm
>120 bpm
>120 bpm and increase from baseline ≥20 bpm
≥20 bpm
≥175 bpm and increase from baseline
≥20 bpm
24 months/2 years to <6 years old (Children) 
≤75 bpm and decrease from baseline
≥20 bpm
≥140 bpm and increase from baseline
≥20 bpm
6 to <12 years old (Children)
≤50 bpm and decrease from baseline
≥20 bpm
≥120 bpm and increase from baseline
≥20 bpm
12 to 16/18 years old (Adolescents)
≤50 bpm and decrease from baseline
≥20 bpm
≥120 bpm and increase from baseline
≥20 bpm
PR
>200 ms
>200 ms and increase from baseline ≥25%
> 220 ms
>220 ms and increase from baseline ≥25%
> 240 ms
> 240 ms and increase from baseline ≥25%
Birth/0 to 27 days old (Neonates) ≥120 ms
28 days/1 month to 23 months old (Infants) ≥140 ms
24 months/2 years to <6 years old (Children) ≥160 ms
6 to <12 years old (Children) ≥170 ms
12 to 16/18 years old (Adolescents) ≥180 ms
QRS
>110 ms
>110 msec and increase from baseline ≥25%
>120 ms
>120 ms and increase from baseline ≥25%
Birth/0 to 27 days old (Neonates) ≥85 ms
28 days/1 month to 23 months old (Infants) ≥85 ms
24 months/2 years to <6 years old (Children) ≥95 ms
6 to <12 years old (Children) ≥100 ms
12 to 16/18 years old (Adolescents) ≥110 ms
QTc (either QTcF or QTcB)
Absolute values (ms
Birth/0 to <12 years old (Neonates, Infants, Children)
Absolute values (ms)
Anonymized Page 81


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 82
0HDVXUHV
$GXOW&ULWHULD
3HGLDWULF&ULWHULD
>450 ms
>480 ms
>500 ms
Increase from baseline 
30-60 ms
>60 ms
Borderline: 431 – 450 ms
Prolonged*: >450 ms
Additional: ≥500 ms
AND
Increase from baseline
Borderline: Increase from baseline 30 – 60 ms
Prolonged*: Increase from baseline >60 ms
12 to 16/18 years old (Adolescents) 
Absolute values (ms)
Borderline: 431 – 450 ms (Boys);451 – 470 ms (Girls)
Prolonged*: >450 ms (Boys);>470 ms (Girls)
Additional: ≥500 ms
AND
Increase from baseline
Borderline: Increase from baseline30 – 60 ms
Prolonged*: Increase from baseline >60 ms
*QTc prolonged and ΔQTc >60 ms are the PCSA to be identified in individual subjects/patients listings.
Clinical chemistry
Creatinine
≥150 μmol/L (Adults)
≥30% increase from baseline
≥100% increase from baseline
Birth/0 to <6 years old (Neonates, Infants, Children)
>53 μmol/L or 0.6 mg/dL
6 years to <12 years old (Children) 
≥90 μmol/L or 1.1 mg/dL
12 years to 16/18 years old (Adolescents) 
≥132 μmol/L or 1.5 mg/dL
Blood Urea Nitrogen
≥17 mmol/L
Birth/0 to 27 days old (Neonates) 
≥4.3 mmol/L or 12 mg/dl
28 days/1 month to 16/18 years old (Infants, Children, Adolescents)
≥6.4 mmol/L or 18 mg/dl
Chloride
<80 mmol/L
>115 mmol/L
≤80 mmol/L
≥115 mmol/L
Anonymized Page 82


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 83
0HDVXUHV
$GXOW&ULWHULD
3HGLDWULF&ULWHULD
Sodium
≤129 mmol/L
≥160 mmol/L
≤129 mmol/L
≥150 mmol/L
Potassium
<3 mmol/L
≥5.5 mmol/L
Birth/0 to 27 days old (Neonates) 
≤3.0 mmol/L
≥7.0 mmol/L
28 days/1 month to 23 months old (Infants) 
≤3.5 mmol/L
≥6.0 mmol/L
24 months/2 years to 16/18 years old (Children, Adolescents)
≤3.5 mmol/L
≥5.5 mmol/L
Glucose
Hypoglycemia
Hyperglycemia
≤3.9 mmol/L and <LLN
≥11.1 mmol/L (unfasted);
≥7 mmol/L (fasted)
<2.7 mmol/L
≥7 mmol/L (fasted after >12 hours of fast);
≥10.0 mmol/L (unfasted)
Albumin
≤25 g/L
Vital signs 
Heart rate
≤50 bpm and decrease from baseline ≥20 bpm
≥120 bpm and increase from baseline ≥20 bpm
Birth/0 to 27 days old (Neonates) 
≤90 bpm and decrease from baseline ≥20 bpm
≥190 bpm and increase from baseline ≥20 bpm
28 days/1 month to 23 months old (Infants)
≤80 bpm and decrease form baseline ≥20 bpm
≥175 bpm and increase from baseline ≥20 bpm
24 months/2 years to <6 years old (Children)
≤75 bpm and decrease from baseline ≥20 bpm
≥140 bpm and increase from baseline ≥20 bpm
6 to <12 years old (Children) 
≤50 bpm and decrease from baseline ≥20 bpm
≥120 bpm and increase from baseline ≥20 bpm
12 to 16/18 years old (Adolescents)
≤50 bpm and decrease from baseline ≥20 bpm
Anonymized Page 83


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 84
0HDVXUHV
$GXOW&ULWHULD
3HGLDWULF&ULWHULD
≥120 bpm and increase from baseline ≥20 bpm
Systolic BP
≤95 mmHg and decrease from baseline ≥20 mmHg
≥160 mmHg and increase from baseline ≥20 mmHg
Birth/0 to 27 days old (Neonates) 
≤60 mmHg and decrease from baseline ≥20 mmHg
≥85 mmHg and increase from baseline ≥20 mmHg
28 days/1 month to 23 months old (Infants)
≤70 mmHg and decrease from baseline ≥20 mmHg
≥98 mmHg and increase from baseline ≥20 mmHg
24 months/2 years to <6 years old (Children)
≤70 mmHg and decrease from baseline ≥20 mmHg
≥101 mmHg and increase from baseline ≥20 mmHg
6 to <12 years old (Children) 
≤80 mmHg and decrease from baseline ≥20 mmHg
≥108 mmHg and increase from baseline ≥20 mmHg
12 to 16/18 years old (Adolescents) 
≤90 mmHg and decrease from baseline ≥20 mmHg
≥119 mmHg and increase from baseline ≥20 mmHg
Diastolic BP
≤45 mmHg and decrease from baseline ≥10 mmHg
≥110 mmHg and increase from baseline ≥10 mmHg
Birth/0 to 27 days old (Neonates) 
≤34 mmHg and decrease from baseline ≥10 mmHg
≥50 mmHg and increase from baseline ≥10 mmHg
28 days/1 month to 23 months old (Infants)
≤34 mmHg and decrease from baseline ≥10 mmHg
≥54 mmHg and increase from baseline ≥10 mmHg
24 months/2 years to <6 years old (Children)
≤34 mmHg and decrease from baseline ≥10 mmHg
≥59 mmHg and increase from baseline ≥10 mmHg
6 to <12 years old (Children) 
≤48 mmHg and decrease from baseline ≥10 mmHg
≥72 mmHg and increase from baseline ≥10 mmHg
12 to 16/18 years old (Adolescents) 
≤54 mmHg and decrease from baseline ≥10 mmHg
≥78 mmHg and increase from baseline ≥10 mmHg
Anonymized Page 84


Statistical Analysis Plan
14-Apr-2020
GZ402666-EFC14028
Version number: 3
Property of the Sanofi Group - strictly confidential
Page 85
$SSHQGL[%
6FKHGXOHRIWKHHIILFDF\DVVHVVPHQW
7DEOH6FKHGXOHRIHIILFDF\DVVHVVPHQW
3$3
(73
6FUHQQLQJ%DVHOLQH
:
:
:
:
:
:
:
:
:
(YHU\
ZHHNV
(QGRI
WUHDWPHQW
PFT
X
X
X
X
X
X
X
X
X
X
X
X
6MWT
X
X
X
X
X
X
X
X
X
X
X
X
Hand-held 
dynamometry
X
X
X
X
X
X
X
X
X
X
GMFM-88/GMFCS
X
X
X
X
X
X
X
X
X
X
QMFT
X
X
X
X
X
X
X
X
X
X
GSGC
X
X
X
X
X
X
X
X
X
X
SF-12
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D-5L
X
X
X
X
X
X
X
X
X
X
X
X
PedsQL
X
X
X
X
X
X
X
X
X
X
X
X
PDSS/PDIS
X
X
X
X
X
X
X
X
X
X
X
X
R-PAct
X
X
X
X
X
X
X
X
X
X
X
X
Anonymized Page 85


Signature Page for
efc14028-16-1-9-sap 
$SSURYH	H6LJQ
$SSURYH	H6LJQ
Anonymized Page 86
[Name]
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