A Study to Investigate Safety and Tolerability of Higher Infusion Rate to shORten the duraTion of FabrazymE Infusion
Phase: PHASE4
Conditions: Fabry's Disease
Sponsor: Sanofi

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Protocol LPS17726 – Version 3.0
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TITLE PAGE 
Protocol Title: A Study to investigate safety and tolerability of Higher infusion rate to 
shORten the duraTion of FabrazymE infusioN 
Protocol Number: LPS17726 
Amendment Number: Amendment 2.0 – Protocol Version 3.0 
Compound: Agalsidase beta/Fabrazyme® 
Brief Title: SHORTEN 
Study Phase: 4 
Sponsor Name:  Sanofi US. Services Inc. 
Legal Registered Address: 
55 Corporate Drive 
Bridgewater, NJ 08807 
USA  
Regulatory Agency Identifier Numbers: 
Registry 
ID 
IND 
007616 
Approval Date: 09 Jul 2024 
Medical Monitor name and contact information will be provided separately. 
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NCT Number: NCT06019728

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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
TABLE  
DOCUMENT HISTORY 
Document 
Date 
Substantial 
Region 
Amendment 2.0 
09-Jul-2024 
No 
Global 
Amendment 1.0 
20-May-2024 
Yes 
Global 
Original Protocol 
22-Jun-2023 
- 
- 
 
Amendment 2.0 (09 Jul 2024) 
Overall Rationale for the Amendment: 
This Amendment 2.0 (Protocol version 3.0) was developed for administrative change. 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
The name and address of 
Sponsor was updated as,  
“Sanofi US. Services Inc. 
55 Corporate Drive 
Bridgewater, NJ 08807 
USA” 
To correct the administrative 
error. 
 
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TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................... 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ................................ 2 
TABLE OF CONTENTS ........................................................................................................ 3 
LIST OF TABLES ................................................................................................................... 6 
LIST OF FIGURES ................................................................................................................. 6 
1.0 
PROTOCOL SUMMARY .......................................................................................... 7 
1.1 
Synopsis ............................................................................................................ 7 
1.2 
Schema ............................................................................................................ 13 
1.3 
Schedule of Activities .................................................................................... 14 
2.0 
INTRODUCTION ..................................................................................................... 17 
2.1 
Study Rationale .............................................................................................. 17 
2.2 
Background .................................................................................................... 17 
2.3 
Benefit/Risk Assessment................................................................................ 18 
2.3.1 
Risk Assessment................................................................................ 19 
2.3.2 
Benefit Assessment ........................................................................... 20 
2.3.3 
Overall Benefit Risk Conclusion ...................................................... 21 
3.0 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ............................................... 22 
4.0 
STUDY DESIGN ....................................................................................................... 27 
4.1 
Overall Design ................................................................................................ 27 
4.2 
Scientific Rationale for Study Design .......................................................... 28 
4.3 
Justification for Dose ..................................................................................... 28 
4.4 
End of Study Definition ................................................................................. 28 
4.5 
End of Treatment Definition ........................................................................ 28 
4.6 
Study Stopping Criteria ................................................................................ 29 
4.6.1 
Stopping Criteria for Individual Participants .................................... 29 
4.6.2 
Criteria for Stopping the Study ......................................................... 29 
5.0 
STUDY POPULATION ............................................................................................ 30 
5.1 
Inclusion Criteria ........................................................................................... 30 
5.2 
Exclusion Criteria .......................................................................................... 30 
5.3 
Lifestyle Considerations ................................................................................ 31 
5.4 
Screen Failures ............................................................................................... 31 
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6.0 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY ...................... 32 
6.1 
Study Interventions Administered ............................................................... 32 
6.2 
Infusion Duration Guideline ......................................................................... 36 
6.3 
Preparation, Handling, Storage, and Accountability ................................. 38 
6.4 
Measures to Minimize Bias: Randomization and Blinding ....................... 39 
6.5 
Study Intervention Compliance ................................................................... 39 
6.6 
Dose Modification .......................................................................................... 40 
6.7 
Continued Access to Study Intervention After the End of the 
Study ............................................................................................................... 40 
6.8 
Treatment of Overdose ................................................................................. 40 
6.9 
Concomitant Therapy ................................................................................... 40 
6.9.1 
Rescue Medicine ............................................................................... 41 
7.0 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ................................... 42 
7.1 
Discontinuation of Study Intervention ........................................................ 42 
7.2 
Participant Discontinuation/Withdrawal from the Study ......................... 43 
7.3 
Lost to Follow-up ........................................................................................... 43 
8.0 
STUDY ASSESSMENTS AND PROCEDURES .................................................... 45 
8.1 
Collection of Demographic Characteristics ................................................ 45 
8.2 
Body Weight Measurements ......................................................................... 45 
8.3 
Efficacy Assessments ..................................................................................... 46 
8.3.1 
Plasma Lyso-GL3 Marker ................................................................. 46 
8.4 
Safety Assessments ........................................................................................ 46 
8.4.1 
Vital Signs ......................................................................................... 46 
8.4.2 
Clinical Safety Laboratory Tests ....................................................... 46 
8.5 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting ........................................................................................................ 47 
8.5.1 
Time Period and Frequency for Collecting AE and SAE 
Information ........................................................................................ 47 
8.5.2 
Method of Detecting AEs and SAEs ................................................. 47 
8.5.3 
Follow-up of AEs and SAEs ............................................................. 48 
8.5.4 
Regulatory Reporting Requirements for SAEs ................................. 48 
8.5.5 
Pregnancy .......................................................................................... 48 
8.5.6 
Adverse Events of Special Interest ................................................... 49 
8.6 
Pharmacokinetics .......................................................................................... 51 
8.7 
Pharmacodynamics ....................................................................................... 51 
8.8 
Genetics .......................................................................................................... 51 
8.9 
Biomarkers ..................................................................................................... 51 
8.10 
Immunogenicity Assessments ....................................................................... 51 
8.11 
Health Economics .......................................................................................... 52 
9.0 
STATISTICAL CONSIDERATIONS ..................................................................... 53 
9.1 
Statistical Hypotheses .................................................................................... 53 
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9.1.1 
Multiplicity Adjustment .................................................................... 53 
9.2 
Analysis Sets ................................................................................................... 53 
9.3 
Statistical Analyses ........................................................................................ 53 
9.3.1 
General Considerations ..................................................................... 53 
9.3.2 
Primary Endpoint Analysis ............................................................... 54 
9.3.3 
Secondary Endpoints Analysis .......................................................... 55 
9.3.4 
Exploratory Endpoints Analysis ....................................................... 55 
9.3.5 
Safety Analysis.................................................................................. 55 
9.4 
Interim Analysis ............................................................................................. 56 
9.5 
Sample Size Determination ........................................................................... 56 
10.0 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ................................................................................................. 57 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................... 57 
10.1.1 
Regulatory and Ethical Considerations ............................................. 57 
10.1.2 
Adequate Resources .......................................................................... 57 
10.1.3 
Financial Disclosure .......................................................................... 58 
10.1.4 
Insurance ........................................................................................... 58 
10.1.5 
Informed Consent Process................................................................. 58 
10.1.6 
Data Protection .................................................................................. 58 
10.1.7 
Committees Structure ........................................................................ 59 
10.1.8 
Dissemination of Clinical Study Data ............................................... 59 
10.1.9 
Data Quality Assurance ..................................................................... 59 
10.1.10 Source Documents ............................................................................ 60 
10.1.11 Study and Site Start and Closure ....................................................... 60 
10.1.12 Publication Policy ............................................................................. 61 
10.2 
Appendix 2: Reconstitution, Dose Preparation and Storage of 
Reconstituted Solution of Fabrazyme .......................................................... 63 
10.2.1 
Reconstitution and Dilution (Using Aseptic Technique) .................. 63 
10.2.2 
Storage of Reconstituted Solution ..................................................... 64 
10.3 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting for Study 
Intervention .................................................................................................... 65 
10.3.1 
Definition of AE ................................................................................ 65 
10.3.2 
Definition of SAE ............................................................................. 66 
10.3.3 
Recording and Follow-Up of AE and/or SAE .................................. 67 
10.3.4 
Reporting of SAEs ............................................................................ 69 
10.4 
Appendix 4: Contraceptive and Barrier Guidance and 
Collection of Pregnancy Information .......................................................... 70 
10.4.1 
Definitions ......................................................................................... 70 
10.4.2 
Collection of Pregnancy Information ................................................ 70 
10.5 
Appendix 5: Abbreviations and Definitions ................................................ 72 
10.6 
Appendix 6: Protocol Amendment History ................................................. 74 
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11.0 
REFERENCES .......................................................................................................... 84 
 
LIST OF TABLES  
Table 1 
Schedule of Activities ....................................................................................... 14 
Table 2 
Study Objectives and Estimands/Endpoints ..................................................... 22 
Table 3 
Study Interventions Administered .................................................................... 33 
Table 4 
Possible Antihistamines Administered as Premedication ................................ 34 
Table 5 
Primary Endpoint Analysis ............................................................................... 54 
Table 6 
Secondary Endpoint Analysis ........................................................................... 55 
Table 7 
Exploratory Endpoint Analysis ........................................................................ 55 
Table 8 
Total Infusion Volume Based on Participant Weight ....................................... 63 
 
LIST OF FIGURES  
Figure 1 
Study Schema .................................................................................................. 13 
Figure 2 
Guideline for Decreasing Infusion Duration for Participants ≥30 kg .............. 37 
Figure 3 
Guideline for Decreasing Infusion Duration for Participants <30 kg .............. 38 
 
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1.0 PROTOCOL SUMMARY  
1.1 
Synopsis  
Protocol Title: 
A Study to investigate safety and tolerability of Higher infusion rate to shORten the duraTion 
of FabrazymE infusioN 
Registry 
ID 
IND 
007616 
Rationale: 
This Phase 4 study will evaluate the safety and tolerability of Fabrazyme at current approved 
dose of 1 mg/kg with increases in the infusion rate and reduced infusion volume. This study 
aims to generate data to provide the guidance on how infusion rate can be safely increased 
(ie, infusion duration be reduced) and minimize the burden of the life-long treatment with 
Fabrazyme. 
Objectives, Endpoints, and Estimands: 
 
Objectives 
Estimand Description/Endpoints 
Primary 
 
• 
To investigate the safety and tolerability of the 
protocol to increase the rate of Fabrazyme 
infusion with reduced total time and volume of 
infusion 
Population: Participants with confirmed diagnosis of 
FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during the 
most recent 3 infusions. 
Treatment: Fabrazyme 1 mg/kg Q2W up to the rate 
tolerated (refer to Section 6.2), with oral 
premedications given 30 minutes prior to each 
infusion. 
Endpoint: % reduction of infusion duration from 
prestudy average of recent 3 infusions. 
Intercurrent events: A while-on-treatment approach 
will be applied, where the % reduction of infusion 
duration will be derived from the infusions actually 
received. Participants never observed to tolerate any 
infusion rate will be counted as having zero percent 
reduction. A treatment policy approach will be 
applied in case pre-medications are not given as 
described within the protocol. No action will be taken 
for this event for the analysis even when 
pre-medications are not given as described within the 
protocol. 
Summary measure: Median and quantiles of % 
reduction of infusion duration from prestudy average 
of recent 3 infusions. 
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Objectives 
Estimand Description/Endpoints 
 
Population: Participants with confirmed diagnosis of 
FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during the 
most recent 3 infusions. 
Treatment: Fabrazyme 1 mg/kg Q2W up to the rate 
tolerated (refer to Section 6.2), with oral 
premedications given 30 minutes prior to each 
infusion. 
Endpoint: Shortest infusion duration each participant 
tolerates. 
Intercurrent events: A while-on-treatment approach 
will be applied, where the % reduction of infusion 
duration will be derived from the infusions actually 
received. Participants never observed to tolerate any 
infusion rate will be counted as having duration 
greater than the maximum observed in their treatment 
group. A treatment policy approach will be applied in 
case pre-medications are not given as described 
within the protocol. No action will be taken for this 
event for the analysis even when pre-medications are 
not given as described within the protocol. 
Summary measure: Median and quantiles of the 
shortest infusion duration each participant tolerates. 
Secondary 
 
• 
To investigate the proportion of participants 
achieving the shortest planned duration of 
infusion time (20 minutes for participants ≥30 kg 
and 30 minutes for participants <30 kg) without 
experiencing any or the second IAR 
Population: Participants with confirmed diagnosis of 
FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during the 
most recent 3 infusions. 
Treatment: Fabrazyme 1 mg/kg Q2W up to the rate 
tolerated (refer to Section 6.2), with oral 
premedications given 30 minutes prior to each 
infusion. 
Endpoint: Binary: Participant achieved the shortest 
planned duration of infusion time (20 minutes for 
participants ≥30 kg and 30 minutes for participants 
<30 kg) without experiencing any IAR. 
Intercurrent events: A while-on-treatment approach 
will be applied. Participants never observed to 
tolerate any infusion rate will be counted as not 
achieving the shortest planned duration. A treatment 
policy approach will be applied in case 
pre-medications are not given as described within the 
protocol. No action will be taken for this event for the 
analysis even when pre-medications are not given as 
described within the protocol. 
Summary measure: Number and % of participants 
achieving the endpoint. 
 
Population: Participants with confirmed diagnosis of 
FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during the 
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Objectives 
Estimand Description/Endpoints 
most recent 3 infusions. 
Treatment: Fabrazyme 1 mg/kg Q2W up to the rate 
tolerated (refer to Section 6.2), with oral 
premedications given 30 minutes prior to each 
infusion. 
Endpoint: Binary: Participant achieved the shortest 
planned duration of infusion time (20 minutes for 
participants ≥30 kg and 30 minutes for participants 
<30 kg) without experiencing a second IAR. 
Intercurrent events: A while-on-treatment approach 
will be applied. Participants never observed to 
tolerate any infusion rate will be counted as not 
achieving the shortest planned duration. A treatment 
policy approach will be applied in case 
pre-medications are not given as described within the 
protocol. No action will be taken for this event for the 
analysis even when pre-medications are not given as 
described within the protocol. 
Summary measure: Number and % of participants 
achieving the endpoint. 
• 
To investigate the proportion of participants 
achieving infusion duration shorter than 
90 minutes without experiencing any or the 
second IAR 
Population: Participants with confirmed diagnosis of 
FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during the 
most recent 3 infusions. 
Treatment: Fabrazyme 1 mg/kg Q2W up to the rate 
tolerated (refer to Section 6.2), with oral 
premedications given 30 minutes prior to each 
infusion. 
Endpoint: Binary: Participant achieved infusion 
duration shorter than 90 minutes without 
experiencing any IAR. 
Intercurrent events: A while-on-treatment approach 
will be applied. Participants never observed to 
tolerate any infusion rate will be counted as not 
achieving the required duration. A treatment policy 
approach will be applied in case pre-medications are 
not given as described within the protocol. No action 
will be taken for this event for the analysis even when 
pre-medications are not given as described within the 
protocol. 
Summary measure: Number and % of participants 
achieving the endpoint. 
 
Population: Participants with confirmed diagnosis of 
FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during the 
most recent 3 infusions. 
Treatment: Fabrazyme 1 mg/kg Q2W up to the rate 
tolerated (refer to Section 6.2), with oral 
premedications given 30 minutes prior to each 
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Objectives 
Estimand Description/Endpoints 
infusion. 
Endpoint: Binary: Participant achieved infusion 
duration shorter than 90 minutes without 
experiencing a second IAR. 
Intercurrent events: A while-on-treatment approach 
will be applied. Participants never observed to 
tolerate any infusion rate will be counted as not 
achieving the required duration. A treatment policy 
approach will be applied in case pre-medications are 
not given as described within the protocol. No action 
will be taken for this event for the analysis even when 
pre-medications are not given as described within the 
protocol. 
Summary measure: Number and % of participants 
achieving the endpoint. 
• 
To investigate the number and proportion of 
participants achieving each infusion duration 
planned in the study without experiencing any or 
the second IAR 
Population: Participants with confirmed diagnosis of 
FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during the 
most recent 3 infusions. 
Treatment: Fabrazyme 1 mg/kg Q2W up to the rate 
tolerated (refer to Section 6.2), with oral 
premedications given 30 minutes prior to each 
infusion. 
Endpoint: Binary, calculated separately for each 
infusion duration: Participant achieved infusion 
duration without experiencing any IAR. 
Intercurrent events: A while-on-treatment approach 
will be applied. Participants never observed to 
tolerate any infusion rate will be counted as not 
achieving the required duration for the infusion. A 
treatment policy approach will be applied in case 
pre-medications are not given as described within the 
protocol. No action will be taken for this event for the 
analysis even when pre-medications are not given as 
described within the protocol. 
Summary measure: For each infusion duration, 
number and % of participants achieving the endpoint. 
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Objectives 
Estimand Description/Endpoints 
 
Population: Participants with confirmed diagnosis of 
FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during the 
most recent 3 infusions. 
Treatment: Fabrazyme 1 mg/kg Q2W up to the rate 
tolerated (refer to Section 6.2), with oral 
premedications given 30 minutes prior to each 
infusion. 
Endpoint: Binary, calculated separately for each 
infusion duration: Participant achieved infusion 
duration without experiencing a second IAR. 
Intercurrent events: A while-on-treatment approach 
will be applied. Participants never observed to 
tolerate any infusion rate will be counted as not 
achieving the required duration for the infusion. A 
treatment policy approach will be applied in case 
pre-medications are not given as described within the 
protocol. No action will be taken for this event for the 
analysis even when pre-medications are not given as 
described within the protocol. 
Summary measure: For each infusion duration, 
number and % of participants achieving the endpoint. 
Safety 
 
• 
To investigate the influence of increased infusion 
rate on the safety of Fabrazyme treatment 
• 
Number, severity, and nature of AEs including 
IARs 
 
Abbreviations: AE = adverse event; FD = Fabry disease; IAR = infusion associated reaction; Q2W = every 2 weeks. 
Overall Design: 
This is a Phase 4, prospective, open label, single arm, interventional study, to be conducted in 
the US, to evaluate the safety and tolerability of Fabrazyme at approved dose of 1 mg/kg and 
increased infusion rate and reduced infusion volume. 
Screening will be performed up to 4 weeks prior to the first dose of study intervention. 
Eligible participants will receive treatment for up to 16 weeks and have an End-of-Study 
Visit 28 weeks after the start of the treatment.  
All 4 cohorts of this study will be enrolled simultaneously. 
Number of Participants: 
Up to 14 participants with Fabry disease will be enrolled to study intervention in 4 cohorts: 
• Cohort 1: 3 Fabrazyme experienced female participants (body weight ≥30 kg). 
• Cohort 2: 3 Fabrazyme experienced non-classic male participants (body weight ≥30 kg). 
• Cohort 3: 4 Fabrazyme experienced classic male participants (body weight ≥30 kg). 
• Cohort 4: 4 Fabrazyme experienced participants (body weight <30 kg). 
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Intervention Groups and Duration: 
This is a single arm study. All participants will receive Fabrazyme infusions at dose of 
1 mg/kg at the study site, for up to 16 weeks (9 infusions). The infusion duration will shorten, 
and the infusion rate will rise with each successfully tolerated infusion (ie, an infusion 
completed within a duration not exceeding 120% of planned duration, without IAR), until 
reaches the minimum infusion duration of 20 minutes for participants in cohorts 1 to 3 
(≥30 kg) and 30 minutes for participants in cohort 4 (<30 kg). When the participant 
successfully reaches the shortest infusion duration planned for the cohort which he/she 
belongs to, he/she will be considered a treatment completer and will not receive any further 
infusion as part of the study, regardless of whether the treatment period reaches 16 weeks or 
not. 
Non-investigational prophylactic premedication with acetaminophen (160 mg 
to 650 mg, depending on age) and one antihistamine (diphenhydramine 25 mg or 12.5 mg, or 
loratadine 10 mg or 5 mg, or cetirizine 5 mg or 2.5 mg, or fexofenadine 180 mg or 30 
mg - doses will depend on age) will be administered to all participants to avoid IARs, 
30 minutes prior to each infusion. Dexamethasone (5 mg to 7 mg, depending on age and 
weight) and montelukast (4 to 10 mg, depending on age) will also be administered as 
premedication for participants that presents an IAR during the study. 
Data Monitoring/Other Committee: No 
 
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1.2 
Schema  
Figure 1 
Study Schema  
 
Abbreviations: ADA = anti-drug antibody (ie, anti-agalsidase beta IgG antibody); AE = adverse event; AESI = adverse event of special interest; 
EOS = end-of-study; EOT = end-of-treatment; IAR = infusion associated reaction; lyso-GL3 = globotriaosylsphingosine; Q2W = every 2 weeks; 
SAE = serious adverse events; V = visit; W = week. 
a. 
V1 and V2 can take place on the same day. The number of visits during the Study Intervention Period (ie, Visits 2 to 10) may differ between 
participants, as those having a second IARs will discontinue the study intervention, and those who successfully reaches the shortest infusion duration 
planned for the cohort to which they belong will be considered as treatment completers. All participants will stay in the study for the follow-up visits at 
Week 12 and Week 28. 
b. IARs will be collected only during the Study Intervention Period which can be shorter than 16 weeks for some participants. 
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1.3 
Schedule of Activities  
Table 1 
Schedule of Activities 
Procedure 
Screening 
(Day -28 
to Day 1) 
a 
Study Intervention Period: up to 16 Weeksb 
EOS 
Notes 
Day 1 
Q2W (± 3 days) 
Except Week 12  
At Week 
12 
(± 3 days) 
Month 3 
At Week 
28 
(± 3 days) 
Month 6 
W0 
W2, W4, W6, W8, W10, W14, 
W16 
W12 
W28 
V1 
V2 
V3, V4, V5, V6, V7, V9, V10 c 
V8 
V11 
Written informed consent and 
participant’s assent (when 
applicable)/assignment of participant 
identification number 
X 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
Demography 
X 
 
 
 
 
Including but not limited 
to age, gender, 
race/ethnicity, and 
duration of Fabrazyme 
treatment before entering 
the study. 
Medical history 
X 
 
 
 
 
 
Current medical conditions  
X 
 
 
 
 
 
Urine pregnancy test (only for 
WOCBC) 
X 
 
 
 
 
If a urine test cannot be 
confirmed as negative, a 
serum pregnancy test is 
required. 
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Procedure 
Screening 
(Day -28 
to Day 1) 
a 
Study Intervention Period: up to 16 Weeksb 
EOS 
Notes 
Day 1 
Q2W (± 3 days) 
Except Week 12  
At Week 
12 
(± 3 days) 
Month 3 
At Week 
28 
(± 3 days) 
Month 6 
W0 
W2, W4, W6, W8, W10, W14, 
W16 
W12 
W28 
V1 
V2 
V3, V4, V5, V6, V7, V9, V10 c 
V8 
V11 
Vital signs and weight 
X 
X 
X 
Xd 
 
Vital signs include body 
temperature, heart rate, 
respiratory rate, and 
blood pressure., which 
will be assessed before 
and 1 hour after 
completion of each study 
intervention infusion. 
Refer to Sections 8.2 and 
8.4.1. 
Plasma Lyso-GL3 
 
X 
X 
X 
X 
Blood sampling should 
be done prior to study 
intervention infusion. To 
be done at a central lab. 
Serum for anti-agalsidase beta IgG 
antibody titers 
 
X 
X 
X 
X 
Blood sampling should 
be done prior to study 
intervention infusion. To 
be done at a central lab. 
Study interventionb 
 
X 
X 
X 
 
 
IAR monitoringe 
 
=============================→ 
 
 
AE monitoring  
=============================→ 
 
SAE monitoring 
=============================→ 
 
Concomitant medication review 
=============================→ 
 
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Abbreviations: AE = adverse event; EOS = end-of-study; IAR = infusion associated reaction; IgG = immunoglobulin G; lyso-GL3 = globotriaosylsphingosine; 
Q2W = every 2 weeks; SAE = serious adverse event; V = visit; W = week; WOCBP = women of childbearing potential. 
a. The Screening Visit (V1) and Day 1 Visit (V2) can take place on the same day. If that occurs, the procedures planned for both visits should be performed only 
once, and all the screening procedures must be completed prior to the infusion and other study-required procedures. 
b. The Study Intervention Period duration (up to 16 weeks) will depend on the participant’s tolerability of the continuous reduction of the infusion duration time. 
When the participant successfully reaches the shortest infusion duration planned for the cohort which he/she belongs to, he/she will be considered a 
treatment completer and will not receive any further infusion as part of the study. The study intervention will be permanently discontinued if the participant 
presents a second IAR. 
c. Participants may have a different number of visits during the Study Intervention Period. Visits 1, 2, 3, 8 and 11 should happen regardless of the number of 
infusions a participant receives. All other visits are planned but will occur only if the participant does not present any criteria to permanently discontinue the 
study intervention, such as having a second IAR, or only until the treatment is not considered completed. 
d. Applicable only if the study intervention is administered in this visit. Refer to footnote b. 
e. IAR monitoring will be performed only during the Study Intervention Period which can be shorter than 16 weeks for some participants. 
Note: If a participant is not able to visit the study site for any reason, they should contact the study site by telephone. Adverse event and concomitant medication 
details may be collected during a telephone call. It may not be possible to collect all clinical laboratory samples or conduct clinical assessments during this 
time, but any details should be recorded in the source document and electronic case report form (eCRF). If alternative arrangements can be agreed for the 
sample collection or clinical assessments, the details should be documented in the eCRF. 
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2.0 INTRODUCTION  
Recombinant human α-galactosidase A (αGAL) (Fabrazyme®, agalsidase beta) has been 
developed and manufactured by Sanofi. Fabrazyme was approved for the treatment of patients 
with Fabry disease (FD) by European Agency for the Evaluation of Medicinal Products in 
2001 and by Food and Drug Administration in 2003. 
2.1 
Study Rationale  
This Phase 4 study will evaluate the safety and tolerability of Fabrazyme at current approved 
dose with increased infusion rate and reduced infusion volume. This study aims to generate 
data to provide guidance on how infusion rate can be safely increased to minimize the burden 
of the life-long treatment with Fabrazyme. 
The infusion rate of Fabrazyme in the Company Core Data Sheet and the labels approved in 
most countries, including the US, is based on the pivotal Phase 3 study and its extension study 
data leading to recommended minimum infusion duration of 90 minutes, even when the 
patients tolerate the infusion very well. 
Data from real world 1,2 indicate that infusion durations less than 90 minutes are well tolerated 
by adult male and female patients. Additionally, the data from Japanese post marketing 
surveillance study also indicate that young boys with classic FD with body weight <30 kg 
tolerated up to 1 mg/kg/hour of infusions with Fabrazyme that were completed in 60 
minutes 3. 
2.2 
Background  
Fabry disease is a rare, x-linked, genetic disorder caused by mutations in the gene encoding 
the lysosomal enzyme, αGAL. The resultant enzymatic deficiency leads to the progressive 
accumulation of glycosphingolipids, most notably globotriaosylceramide (GL3), in lysosomes 
of a variety of cell types and tissues. Fabry disease is a progressive disorder that takes years to 
advance to end stage organ failure. Over a period of decades, the progressive accumulation of 
glycosphingolipids impairs vital organ function, putting patients with FD at risk of developing 
renal failure, cardiovascular dysfunction, and stroke. Fabry disease management consists of 
disease-specific treatment with enzyme replacement therapy (ERT), chemical chaperone and 
symptomatic/adjuvant treatments targeted at preventing and treating disease related symptoms 
and complications. Fabrazyme (agalsidase beta) is a recombinant human α-galactosidase 
enzyme approved to be used in patients with FD in over 80 countries/regions. 
Fabrazyme showed significant reduction in plasma globotriaosylsphingosine (lyso-GL3) and 
GL3 levels in clinical trials, indicating that agalsidase beta has a good pharmacodynamic 
effect on these markers at the recommended dose of 1 mg/kg every 2 weeks (Q2W) 4. In 
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addition, when infused at the recommended dose for 6 months, Fabrazyme cleared or reduced 
GL3 in renal, cardiac, and dermal microvascular endothelia and other cells, with long-term 
sustained results in most patients evaluated. Specifically, for renal interstitial capillary 
endothelium, 100% GL3 clearance was achieved (baseline versus Week 26) at the 
recommended dose. Based on the Phase 3, the Phase 3 extension, and the Phase 4 study 
results, it was demonstrated that early treatment may alleviate symptoms and prevent further 
progression of this lethal disease before irreversible damage has occurred 5. 
2.3 
Benefit/Risk Assessment  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of Fabrazyme may be found in the US package insert 6. 
The Sponsor will immediately notify the Principal Investigator if any additional safety or 
toxicology information becomes available during the study. 
This study will be performed in compliance with the protocol, International Council for 
Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP), and applicable regulatory requirements. 
The Sponsor and Investigator may take appropriate urgent safety measures in order to protect 
the participants of a clinical study against any immediate hazard to their health or safety. If 
such measures are taken, the Sponsor shall immediately (no later than 3 days from the date the 
measures are taken) give written notice to the licensing authority and the relevant ethics 
committee of the measures taken and the circumstances giving rise to those measures. 
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2.3.1 
Risk Assessment  
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Study Intervention Fabrazyme 
Anaphylaxis and hypersensitivity 
reactions 
Life-threatening anaphylactic and 
severe hypersensitivity reactions 
have been observed in patients 
during Fabrazyme infusions. In 
clinical trials and post marketing 
safety experience with Fabrazyme, 
approximately 1% of patients 
developed anaphylactic or severe 
hypersensitivity reactions during 
Fabrazyme infusion 6. 
Participants with history of 
significant allergic disease or 
hypersensitivity to Fabrazyme or 
other medicinal products will be 
excluded from this study 
(Section 5.2). Only participants 
who had not experienced any IAR 
during 3 most recent infusions will 
be included 
IARs 
In clinical trials of Fabrazyme, 
59% of participants experienced 
IARs during Fabrazyme 
administration, some of which 
were severe 6. 
IARs are AESI in this study. The 
incidence and severity of IARs 
will be closely monitored and 
evaluated throughout the study. 
Non-investigational premedication 
with acetaminophen and one 
antihistamine will be administered 
to all participants to avoid IARs 
prior to each infusion, and 
dexamethasone and montelukast 
will be added to the premedication 
in participants experiencing IARs 
during the study. 
All participants will have their 
infusions in a clinical setting, with 
direct physician supervision where 
any reactions can be managed 
appropriately. 
In the unpublished data from 
Japanese post marketing 
surveillance study, shorter infusion 
duration was related to lower 
incidence of IARs as infusion 
duration was reduced in 
participants who tolerated longer 
infusions. By reducing infusion 
duration only when a participant 
tolerates longer infusion, the risk 
of IARs will be minimized. 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
AEs 
Common adverse reactions which 
occurred in ≥20% of patients 
treated with Fabrazyme and >2.5% 
compared to placebo are upper 
respiratory tract infection, chills, 
pyrexia, headache, cough, 
paresthesia, fatigue, peripheral 
edema, dizziness, and rash 6. 
The most common adverse 
reactions (>20%) in pediatric FD 
patients, ages 8 to 16 years, were 
headache, abdominal pain, 
pharyngitis, fever, nausea, 
vomiting, rhinitis, diarrhea, 
arthralgia, and dizziness 6. 
The incidence and severity of AEs 
will be monitored and evaluated 
throughout the study and will be 
managed per clinical judgment and 
institutional standard of care. 
Anaphylaxis is an AESI in this 
study. The incidence and severity 
of anaphylaxis will be closely 
monitored and evaluated 
throughout the study. 
Study Procedures 
Blood draws 
Blood draws have the potential to 
cause pain, bruising, erythema, 
bleeding, swelling of the site/vein, 
hematoma at the injection site, and 
fainting. 
Most symptoms are self-limiting 
and curtailed by use of appropriate 
measures. Blood will be drawn in 
aseptic conditions with the support 
of medically trained professionals. 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; IAR = infusion associated reaction. 
2.3.2 
Benefit Assessment  
The pivotal Phase 37 and extension study8 have demonstrated sustained clearance of GL3 from 
capillary endothelium in the heart, kidney, and skin, as well as from kidney cell types. Renal 
function remained stable in most participants. However, the effect of Fabrazyme treatment on 
kidney function was limited in some participants with advanced renal disease. The results also 
indicate that patients may achieve reduced pain and enhanced quality of life with ERT. In 
another double-blind, placebo-controlled study with more advanced disease, the rate of 
clinical events was substantially lower among Fabrazyme treated participants compared to 
placebo-treated participants, and this result was consistent across renal, cardiac, and 
cerebrovascular events. 
The results of these studies indicate that Fabrazyme treatment at 1.0 mg/kg Q2W provides 
clinical benefit in key clinical outcomes in patients with early and advanced FD. Because this 
condition is slowly progressive, early detection and treatment are critical to achieve the best 
outcomes. 
In the open label pediatric study, clearance of GL3 in superficial skin vascular endothelium 
was achieved in all participants who had accumulated GL3 at baseline. 
Since its approval in 2001, many clinical studies and observational data have been published 
detailing the clinical benefit of Fabrazyme in adults and children with FD 9, 10. 
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Fabrazyme-based ERT is a life-long treatment and patients require regular intravenous 
infusions every 2 weeks, which entails a significant burden for them to bear in addition to the 
symptoms of the disease 11. In this study, additionally to the benefit of continuing treatment 
with Fabrazyme free of charge during the study, the participants will have the opportunity to 
benefit from shorter infusions, which will decrease the time committed to treatment and 
potentially increase their quality of life. 
2.3.3 
Overall Benefit Risk Conclusion  
Taking into account the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with Fabrazyme are justified by the 
anticipated benefits that may be afforded to participants with FD. 
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3.0 OBJECTIVES, ENDPOINTS, AND ESTIMANDS  
Table 2 presents the primary, secondary, and exploratory objectives and corresponding 
Estimands or endpoints. 
Table 2 
Study Objectives and Estimands/Endpoints  
Objectives 
Estimand Description/Endpoints 
Primary 
 
• 
To investigate the safety and tolerability of the 
protocol to increase the rate of Fabrazyme 
infusion with reduced total time and volume of 
infusion 
Population: Participants with confirmed diagnosis of 
FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during the 
most recent 3 infusions. 
Treatment: Fabrazyme 1 mg/kg Q2W up to the rate 
tolerated (refer to Section 6.2), with oral 
premedications given 30 minutes prior to each 
infusion. 
Endpoint: % reduction of infusion duration from 
prestudy average of recent 3 infusions. 
Intercurrent events: A while-on-treatment approach 
will be applied, where the % reduction of infusion 
duration will be derived from the infusions actually 
received. Participants never observed to tolerate any 
infusion rate will be counted as having zero percent 
reduction. A treatment policy approach will be 
applied in case pre-medications are not given as 
described within the protocol. No action will be taken 
for this event for the analysis even when 
pre-medications are not given as described within the 
protocol. 
Summary measure: Median and quantiles of % 
reduction of infusion duration from prestudy average 
of recent 3 infusions. 
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Objectives 
Estimand Description/Endpoints 
 
Population: Participants with confirmed diagnosis of 
FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during the 
most recent 3 infusions. 
Treatment: Fabrazyme 1 mg/kg Q2W up to the rate 
tolerated (refer to Section 6.2), with oral 
premedications given 30 minutes prior to each 
infusion. 
Endpoint: Shortest infusion duration each participant 
tolerates. 
Intercurrent events: A while-on-treatment approach 
will be applied, the shortest infusion duration will be 
derived from the infusions actually received. 
Participants never observed to tolerate any infusion 
rate will be counted as having duration greater than 
the maximum observed in their treatment group. A 
treatment policy approach will be applied in case 
pre-medications are not given as described within the 
protocol. No action will be taken for this event for the 
analysis even when pre-medications are not given as 
described within the protocol. 
Summary measure: Median and quantiles of the 
shortest infusion duration each participant tolerates. 
Secondary 
 
• 
To investigate the proportion of participants 
achieving the shortest planned duration of 
infusion time (20 minutes for participants ≥30 kg 
and 30 minutes for participants <30 kg) without 
experiencing any or the second IAR 
Population: Participants with confirmed diagnosis of 
FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during the 
most recent 3 infusions. 
Treatment: Fabrazyme 1 mg/kg Q2W up to the rate 
tolerated (refer to Section 6.2), with oral 
premedications given 30 minutes prior to each 
infusion. 
Endpoint: Binary: Participant achieved the shortest 
planned duration of infusion time (20 minutes for 
participants ≥30 kg and 30 minutes for participants 
<30 kg) without experiencing any IAR. 
Intercurrent events: A while-on-treatment approach 
will be applied. Participants never observed to 
tolerate any infusion rate will be counted as not 
achieving the shortest planned duration. A treatment 
policy approach will be applied in case 
pre-medications are not given as described within the 
protocol. No action will be taken for this event for the 
analysis even when pre-medications are not given as 
described within the protocol. 
Summary measure: Number and % of participants 
achieving the endpoint. 
 
Population: Participants with confirmed diagnosis of 
FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during the 
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Objectives 
Estimand Description/Endpoints 
most recent 3 infusions. 
Treatment: Fabrazyme 1 mg/kg Q2W up to the rate 
tolerated (refer to Section 6.2), with oral 
premedications given 30 minutes prior to each 
infusion. 
Endpoint: Binary: Participant achieved the shortest 
planned duration of infusion time (20 minutes for 
participants ≥30 kg and 30 minutes for participants 
<30 kg) without experiencing a second IAR. 
Intercurrent events: A while-on-treatment approach 
will be applied. Participants never observed to 
tolerate any infusion rate will be counted as not 
achieving the shortest planned duration. A treatment 
policy approach will be applied in case 
pre-medications are not given as described within the 
protocol. No action will be taken for this event for the 
analysis even when pre-medications are not given as 
described within the protocol. 
Summary measure: Number and % of participants 
achieving the endpoint. 
• 
To investigate the proportion of participants 
achieving infusion duration shorter than 
90 minutes without experiencing any or the 
second IAR 
Population: Participants with confirmed diagnosis of 
FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during the 
most recent 3 infusions. 
Treatment: Fabrazyme 1 mg/kg Q2W up to the rate 
tolerated (refer to Section 6.2), with oral 
premedications given 30 minutes prior to each 
infusion. 
Endpoint: Binary: Participant achieved infusion 
duration shorter than 90 minutes without 
experiencing any IAR. 
Intercurrent events: A while-on-treatment approach 
will be applied. Participants never observed to 
tolerate any infusion rate will be counted as not 
achieving the required duration. A treatment policy 
approach will be applied in case pre-medications are 
not given as described within the protocol. No action 
will be taken for this event for the analysis even when 
pre-medications are not given as described within the 
protocol. 
Summary measure: Number and % of participants 
achieving the endpoint. 
 
Population: Participants with confirmed diagnosis of 
FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during the 
most recent 3 infusions. 
Treatment: Fabrazyme 1 mg/kg Q2W up to the rate 
tolerated (refer to Section 6.2), with oral 
premedications given 30 minutes prior to each 
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Objectives 
Estimand Description/Endpoints 
infusion. 
Endpoint: Binary: Participant achieved infusion 
duration shorter than 90 minutes. without 
experiencing a second IAR. 
Intercurrent events: A while-on-treatment approach 
will be applied. Participants never observed to 
tolerate any infusion rate will be counted as not 
achieving the required duration. A treatment policy 
approach will be applied in case pre-medications are 
not given as described within the protocol. No action 
will be taken for this event for the analysis even when 
pre-medications are not given as described within the 
protocol. 
Summary measure: Number and % of participants 
achieving the endpoint. 
• 
To investigate the number and proportion of 
participants achieving each infusion duration 
planned in the study without experiencing any or 
the second IAR 
Population: Participants with confirmed diagnosis of 
FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during the 
most recent 3 infusions. 
Treatment: Fabrazyme 1 mg/kg Q2W up to the rate 
tolerated (refer to Section 6.2), with oral 
premedications given 30 minutes prior to each 
infusion. 
Endpoint: Binary, calculated separately for each 
infusion duration: Participant achieved infusion 
duration without experiencing any IAR. 
Intercurrent events: A while-on-treatment approach 
will be applied. Participants never observed to 
tolerate any infusion rate will be counted as not 
achieving the required duration for the infusion. A 
treatment policy approach will be applied in case 
pre-medications are not given as described within the 
protocol. No action will be taken for this event for the 
analysis even when pre-medications are not given as 
described within the protocol. 
Summary measure: For each infusion duration, 
number and % of participants achieving the endpoint. 
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Objectives 
Estimand Description/Endpoints 
 
Population: Participants with confirmed diagnosis of 
FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during the 
most recent 3 infusions. 
Treatment: Fabrazyme 1 mg/kg Q2W up to the rate 
tolerated (refer to Section 6.2), with oral 
premedications given 30 minutes prior to each 
infusion. 
Endpoint: Binary, calculated separately for each 
infusion duration: Participant achieved infusion 
duration without experiencing a second IAR. 
Intercurrent events: A while-on-treatment approach 
will be applied. Participants never observed to 
tolerate any infusion rate will be counted as not 
achieving the required duration for the infusion. A 
treatment policy approach will be applied in case 
pre-medications are not given as described within the 
protocol. No action will be taken for this event for the 
analysis even when pre-medications are not given as 
described within the protocol. 
Summary measure: For each infusion duration, 
number and % of participants achieving the endpoint. 
Exploratory 
 
• 
To investigate the influence of increased infusion 
rate on the immunogenicity and efficacy of 
Fabrazyme treatment 
• 
Changes of plasma lyso-GL3 from baseline to 
6 months follow-up 
• 
Change of the titer of ADA to Fabrazyme over 
6 months follow-up 
Safety 
 
• 
To investigate the influence of increased infusion 
rate on the safety of Fabrazyme treatment 
• 
Number, severity, and nature of AEs including 
IARs 
Abbreviations: ADA = anti-drug antibody, AE = adverse event; FD = Fabry disease; IAR = infusion associated reaction; 
lyso-GL3 = globotriaosylsphingosine; Q2W = every 2 weeks. 
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4.0 STUDY DESIGN  
4.1 
Overall Design  
This is a Phase 4, prospective, open label, single arm, interventional study, to be conducted in 
the US, to evaluate the safety and tolerability of Fabrazyme at approved dose of 1 mg/kg with 
increases in the infusion rate and reduced infusion volume. 
Up to 14 participants with FD will be enrolled to receive study intervention in 4 cohorts: 
• Cohort 1: 3 Fabrazyme experienced female participants (body weight ≥30 kg). 
• Cohort 2: 3 Fabrazyme experienced non-classic male participants (body weight ≥30 kg). 
• Cohort 3: 4 Fabrazyme experienced classic male participants (body weight ≥30 kg). 
• Cohort 4: 4 Fabrazyme experienced participants (body weight <30 kg). 
Classic FD is defined by αGAL level in dried blood spot or leukocyte below 3% of normal 
value and all others are considered as non-classic disease. 
The study schema is presented in Section 1.2. Screening will be performed up to 4 weeks prior 
to the first dose of study intervention. All 4 cohorts of this study will be enrolled 
simultaneously. Enrolled participants will receive treatment for up to 16 weeks (up to 
9 infusions) and have an End-of-Study Visit 28 weeks after the start of the treatment. 
Participants will undergo visits and study procedures as shown in Schedule of Activities 
(SoA) presented in Section 1.3. 
All participants will receive Fabrazyme infusions at dose of 1 mg/kg at the study site. The 
participants are not required to stay at the site after completion of the infusion, unless the 
Investigator considers it medically necessary. The infusion duration will shorten, and the 
infusion rate will rise with each successfully tolerated infusion (ie, an infusion completed 
within a duration not exceeding 120% of planned duration, without infusion associated 
reaction [IAR]), until reaches the minimum infusion duration of 20 minutes for participants in 
cohorts 1 to 3 (≥30 kg) and 30 minutes for participants in cohort 4 (<30 kg). Guidance for 
increasing the rate of infusion (and consequently decreasing the infusion duration) are 
presented in Section 6.2. When the participant successfully reaches the shortest infusion 
duration planned for the cohort which he/she belongs, he/she will be considered a treatment 
completer and will not receive any further infusion as part of the study, regardless of whether 
the treatment period reaches 16 weeks or not. 
All participants will also receive premedication with an antipyretic and antihistamine to avoid 
IARs prior to each infusion. Oral steroid and montelukast will also be administered as 
premedication for the participants that presents an IAR during the study. 
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4.2 
Scientific Rationale for Study Design  
A single arm design was selected as the main objective is to evaluate the safety and 
tolerability of increases in Fabrazyme infusion rate, and within a participant, the longer-lasting 
infusions might be used as the comparators for the shorter ones. An open label design was 
selected as all participants will receive the same intervention and the duration of the infusion 
decreases as the study progresses, which is automatically recognizable to the participants and 
study personnel. 
The population chosen for the study comprises the diversity of patients with FD already 
treated with Fabrazyme: women, men with classic and non-classic disease, and children. 
Standard clinical and laboratory procedures will be utilized in this study. All efficacy and 
safety-related measurements in this study are standard for participants with FD. All clinical 
and laboratory procedures in this study are standard and generally accepted. 
4.3 
Justification for Dose  
The dose selected for this study of 1 mg/kg body weight given every 2 weeks as an 
intravenous infusion is the recommended dose as per approved dosage regimen 6. 
Fabrazyme will be used according to the US package insert, except for infusion duration and 
rate, as the main objective of this study is to evaluate shorter infusion durations, and infusion 
volume. The volume of infusion to be used in this study (50 mL for participants <60 kg and 
100 mL for participants ≥60 kg) is within the range that was used in the Phase I/II study 12. 
4.4 
End of Study Definition  
The end of the study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if he/she has completed all periods of 
the study including the last scheduled visit. 
4.5 
End of Treatment Definition  
The end of treatment is defined when the participant successfully reaches the shortest infusion 
duration planned for the cohort which he/she belongs to or when the participant experiences a 
second IAR. At that point, the participant will not receive any further infusion as part of the 
study, regardless of whether the Study Intervention Period reaches 16 weeks or not (Figure 2 
and Figure 3). 
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4.6 
Study Stopping Criteria  
4.6.1 
Stopping Criteria for Individual Participants  
Criteria for discontinuing study intervention for an individual participant and the criteria for 
discontinuing the study for an individual participant are presented in Section 7.0. 
4.6.2 
Criteria for Stopping the Study  
While no specific criteria have been established for terminating the study prematurely, it 
remains within the Sponsor’s discretion to stop the study, at any time, either in its entirety or 
at any site. The Investigator may also stop the study at his/her site if he/she has safety 
concerns. If the Sponsor terminates the study for safety reasons, the Sponsor will promptly 
notify the Investigator. 
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5.0 STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria  
Participants are eligible to be included in the study only if all the following criteria apply: 
1. Participants with confirmed diagnosis of FD who are ≥2 and ≤65 years of age at the time 
of signing the informed consent form (ICF) or assent, if applicable. 
a. Cohort 1: female participants with body weight ≥30 kg who have been treated with 
Fabrazyme for at least 3 months without IARs during the most recent 3 infusions. 
b. Cohort 2: non-classic male participants with body weight ≥30 kg who have been 
treated with Fabrazyme for at least 3 months without IARs during the most recent 
3 infusions. 
c. Cohort 3: classic male participants with body weight ≥30 kg who have been treated 
with Fabrazyme for at least 3 months without IARs during the most recent 
3 infusions. 
d. Cohort 4: participants with body weight <30 kg who have been treated with 
Fabrazyme for at least 3 months without IARs during the most recent 3 infusions. 
Note: Classic FD is defined by αGAL level in dried blood spot or leukocyte below 3% 
of normal value. 
2. Women of childbearing potential must use a highly effective method of contraception 
through the study (refer to Appendix 4 in Section 10.4). 
 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. Female participants who are pregnant or breastfeeding. 
2. History of significant allergic disease or hypersensitivity to Fabrazyme or other medicinal 
products. 
3. Contraindication to Fabrazyme or any of the premedications or rescue medications 
(diphenhydramine, loratadine, cetirizine, fexofenadine, acetaminophen, montelukast, 
dexamethasone). 
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4. Any other medical condition considered to make the increased infusion rate not tolerable 
at the Investigator’s discretion. 
 
5.3 
Lifestyle Considerations  
No lifestyle observations are required in this study. 
5.4 
Screen Failures  
A screen failure occurs when a participant who consents to participate in the clinical study is 
not subsequently entered in the study. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be rescreened. 
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6.0 STUDY INTERVENTIONS AND CONCOMITANT 
THERAPY  
Study intervention is defined as any investigational interventions, marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. 
6.1 
Study Interventions Administered  
The study has a single arm. All participants will receive 1 mg/kg of body weight of 
Fabrazyme every 2 weeks at the study site until they reach the shortest infusion duration 
planned for the cohort they belong to, for up to 16 weeks. The infusion duration and rate will 
follow the flow presented in Section 6.2. 
The participants are not required to stay at the site after completion of the infusion, unless the 
Investigator considers it medically necessary. 
All participants will receive acetaminophen and one antihistamine as non-investigational 
prophylactic premedication, 30 minutes prior to each infusion. In case of IAR occurrence, 
participant will receive dexamethasone and montelukast as rescue medication, and both drugs 
will be given from this time forward as prophylactic premedication, together with 
acetaminophen and the antihistamine, 30 minutes prior to all further infusions. 
The study interventions are presented in Table 3 and Table 4 (for the possible antihistamines 
allowed as premedication). 
 
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Table 3 
Study Interventions Administered 
Intervention Label 
Fabrazyme 
Acetaminophen 
Dexamethasone 
Montelukast 
Intervention Name 
Recombinant human αGAL 
(agalsidase beta) 
Acetaminophen 
Dexamethasone 
Montelukast 
Intervention Description 
Fabrazyme 1 mg/kg Q2W 
Acetaminophen 
Dexamethasone 
Montelukast 
Type  
Biological 
Drug 
Drug 
Drug 
Dose Formulation 
Lyophilized powder for 
reconstitution 
Tablet (for participants >12 
years old) or solution (for 
participants ≤12 years old) 
Tablet or solution 
(alternative only available 
for participants <16 years 
old) 
Tablet (for participants ≥15 
years old), chewable tablet 
(for participants up to 
14 years old) or oral granules 
(only for participants <6 
years old) 
Unit Dose Strength(s) 
Nominal value of 35 mg to have 5 
mg/mL (35 mg/7 mL) after 
reconstitution with 7.2 mL of sterile 
water for infusion 
650 mg (tablet), or any 
approved and commercially 
available solution 
7.5 mg (tablet) or any 
approved and commercially 
available solution 
10 mg (tablet), 5 mg 
(chewable tablet) or 4 mg 
(chewable tablet or oral 
granules) 
Dosage Level(s) 
1 mg/kg of body weight, Q2W 
According to age: 
>12 years: 650 mg 
12 years: 640 mg 
11 years: 480 mg 
9-10 years: 400 mg 
7-8 years: 320 mg 
4-6 years: 240 mg 
2-3 years: 160 mg 
Frequency: 30 minutes prior 
to each infusion 
According to age: 
Adult: 7.5 mg 
<16 years: 0.1 mg/kg, 
maximum of 5 mg 
Frequency: At an IAR and 
from this time forward, 30 
minutes prior to each new 
infusion 
According to age: 
≥15 years: 10 mg 
6-14 years: 5 mg 
<6 years: 4 mg 
Frequency: At an IAR and 
from this time forward, 30 
minutes prior to each new 
infusion 
 
Route of Administration 
IV infusion 
Oral 
Oral 
Oral 
Use 
Experimental intervention 
Prophylactic premedication 
Rescue and prophylactic 
premedication 
Rescue and prophylactic 
premedication 
IMP and NIMP/AMP 
IMP 
NIMP/AMP 
NIMP/AMP 
NIMP/AMP 
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Intervention Label 
Fabrazyme 
Acetaminophen 
Dexamethasone 
Montelukast 
Sourcing 
Provided centrally by the Sponsor 
Provided locally by the 
study site 
Provided locally by the 
study site 
Provided locally by the study 
site 
Packaging and Labeling 
Study intervention will be provided 
in a single vial per box (35 mg). 
Each box will be labeled as required 
per country requirement 
Packaged and labeled as 
required per country 
requirement 
Packaged and labeled as 
required per country 
requirement 
Packaged and labeled as 
required per country 
requirement 
Abbreviations: AMP = auxiliary medicinal product; IAR = infusion associated reaction; IMP = investigational medical product; IV = intravenous; 
NIMP = non-investigational medical product; Q2W = every 2 weeks; αGAL = α-galactosidase A. 
 
Table 4 
Possible Antihistamines Administered as Premedication 
Intervention Label 
Diphenhydramine 
Loratadine 
Cetirizine 
Fexofenadine 
Intervention Name 
Diphenhydramine 
Loratadine 
Cetirizine 
Fexofenadine 
Intervention Description 
Diphenhydramine 
Loratadine 
Cetirizine 
Fexofenadine 
Type  
Drug 
Drug 
Drug 
Drug 
Dose Formulation 
Tablet or solution (alternative only 
available for participants <12 years 
old) 
Tablet (for participants 
>6 years old) or 
chewable tablet (for 
participants between 2 to 
6 years old) 
Tablet (for participants 
>6 years old) or oral 
solution (for participants 
between 2 to 6 years old) 
Tablet (for participants 
>12 years old) or oral 
suspension (for participants 
between 2 to 12 years old) 
Unit Dose Strength(s) 
25 mg or 12.5 mg (tablet) or any 
approved and commercially 
available solution 
10 mg (tablet) or 5 mg 
(chewable tablet) 
 
5 mg (tablet) or 2.5 mg (oral 
solution of 1 mg/mL) 
180 mg (tablet) or 30 mg 
(oral suspension of 
30 mg/5 mL) 
Dosage Level(s) 
According to age: 
≥12 years: 25 mg 
<12 years: 12.5 mg 
Frequency: 30 minutes prior to each 
infusion 
According to age: 
Adults and children >6 
years old: 10 mg 
2 to 6 years age: 5 mg 
Frequency: 30 minutes 
prior to each infusion 
According to age: 
Adults and children >6 years 
old: 5 to 10 mg 
2 to 6 years age: 2.5 to 5 mg 
(2.5 mL to 5 mL) 
Frequency: 30 minutes prior 
to each infusion 
According to age: 
Adults and children >6 years 
old: 180 mg 
2 to 12 years age: 30 mg 
(5 mL) 
Frequency: 30 minutes prior 
to each infusion 
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Route of Administration 
Oral 
Oral 
Oral 
Oral 
Use 
Prophylactic premedication 
Prophylactic 
premedication 
Prophylactic premedication 
Prophylactic premedication 
IMP and NIMP/AMP 
NIMP/AMP 
NIMP/AMP 
NIMP/AMP 
NIMP/AMP 
Sourcing 
Provided locally by the study site 
Provided locally by the 
study site 
Provided locally by the 
study site 
Provided locally by the 
study site 
Packaging and Labeling 
Packaged and labeled as required 
per country requirement 
Packaged and labeled as 
required per country 
requirement 
Packaged and labeled as 
required per country 
requirement 
Packaged and labeled as 
required per country 
requirement 
Abbreviations: AMP = auxiliary medicinal product; IMP= investigational medical product; NIMP = non-investigational medical product. 
 
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6.2 
Infusion Duration Guideline  
The decrease in the infusion duration for participants in cohorts 1 to 3 (with ≥30 kg body 
weight) will follow the flow presented in Figure 2. The decrease in the infusion duration for 
participants in cohort 4 (with <30 kg body weight) will follow the flow presented in Figure 3. 
Please note that a participant is considered to tolerate the infusion duration when the infusion 
is completed within a duration not exceeding 120% of planned duration and no IAR is 
observed during the infusion. 
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Figure 2 
Guideline for Decreasing Infusion Duration for Participants ≥30 kg  
 
Abbreviations: IAR = infusion associated reaction. 
Note: IARs occurring during a single infusion are counted as one IAR. Only when an IAR occurs in relation to a 
separate infusion will it be considered as a second IAR. 
Note: When a second IAR occurs, the participant will discontinue study intervention and the previous highest 
rate tolerated by the participant will be considered as the maximum tolerated rate for this participant. 
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Figure 3 
Guideline for Decreasing Infusion Duration for Participants <30 kg  
 
Abbreviations: IAR = infusion associated reaction. 
Note: IARs occurring during a single infusion are counted as one IAR. Only when an IAR occurs in relation to a 
separate infusion will it be considered as a second IAR. 
Note: When a second IAR occurs, the participant will discontinue study intervention and the previous highest 
rate tolerated by the participant will be considered as the maximum tolerated rate for this participant. 
6.3 
Preparation, Handling, Storage, and Accountability  
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention. 
Guidance about reconstitution and dose preparation for Fabrazyme are provided in 
Appendix 2 (Section 10.2). 
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Only participants enrolled in the study may receive study intervention, and only authorized 
study site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator and 
authorized study site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
The Investigator, a member of the study site staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study intervention using the Drug 
Accountability Form. These forms must be available for inspection at any time. 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual. 
6.4 
Measures to Minimize Bias: Randomization and Blinding  
This is a single arm and open label study. No randomization or blinding will be implemented. 
The study intervention kits dispensing will not be managed within Interactive Response 
Technology. To minimize bias, the participant number will be assigned sequentially in the 
electronic case report form (eCRF) as the participants are enrolled into the study. 
6.5 
Study Intervention Compliance  
The prescribed dosage, timing, and mode of administration may not be changed. Any 
departures from the intended regimen must be recorded in the eCRF. 
Participants exhibiting poor compliance as assessed by visit attendance for their infusions 
should be counseled on the importance of good compliance to the study dosing regimen. 
Non-compliance is defined as taking less than 80% of study intervention during any 
evaluation period (visit to visit). 
Participants will be dosed at the study site and receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents. The dose of study 
intervention and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study intervention. 
A record of the quantity of study intervention administered to each participant must be 
maintained and reconciled with study intervention and compliance records. The date, time of 
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start and stop of each infusion, as well as the dose and total volume infused, will also be 
recorded. 
6.6 
Dose Modification  
Dose modifications are not planned or allowed in this study. Any dose deviation must be 
recorded in the eCRF. 
6.7 
Continued Access to Study Intervention After the End of the Study  
The Sponsor will not be responsible for study intervention provision after the end of the 
treatment phase and after the end of the study. Continuing treatment after the end of the Study 
Intervention Period will be at the discretion of Investigator or treating physician. 
The Sponsor will not provide any additional care to participants after they leave the study 
because such care should not differ from what is normally expected for participants with FD. 
6.8 
Treatment of Overdose  
Any dose of study intervention greater than the planned and approved dose will be considered 
an overdose. 
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
• Contact the medical monitor immediately. 
• Evaluate the participant to determine, in consultation with the medical monitor, whether 
study intervention should be interrupted or whether the dose should be reduced. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
intervention can no longer be detected systemically (depending on study intervention 
half-life). 
• Document the quantity of the excess dose as well as the duration of the overdose. 
6.9 
Concomitant Therapy  
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
• For vaccines (if applicable) include brand name and manufacturer (plus lot number if 
available) 
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Administration of live or inactivated vaccines is allowed (eg, inactivated influenza vaccines or 
severe acute respiratory syndrome coronavirus 2 vaccines). 
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins, recreational drugs, and dietary or herbal supplements) that may interfere with the 
study in the opinion of the Investigator and the Sponsor within 7 days (or 14 days if the drug 
is a potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
intervention until completion of the follow-up visit. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Non-investigational premedication with acetaminophen and an antihistaminic will be 
administered to avoid IARs prior to each infusion. Dexamethasone and montelukast may also 
be administered as premedication in participants who have experienced an IAR (refer to 
Section 6.1). All premedications must be recorded as concomitant medication. 
6.9.1 
Rescue Medicine  
In case of IAR occurrence, participant will receive dexamethasone and montelukast as rescue 
medication, and both drugs will be given from this time forward as prophylactic 
premedication, together with acetaminophen and the antihistamine, 30 minutes prior to all 
further infusions. Both drugs are described in Section 6.1. 
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7.0 DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
Discontinuation of specific study sites or of the study as a whole are detailed in 
Section 10.1.11. 
7.1 
Discontinuation of Study Intervention  
It may be necessary for a participant to permanently discontinue study intervention. If study 
intervention is permanently discontinued, the participant will remain in the study to be 
evaluated 12 and 28 weeks after the start of the treatment (ie, Visit 8 [Week 12] and Visit 11, 
End-of-Study [Week 28], see the SoA in Section 1.3 for data to be collected). 
If a participant who does not meet enrollment criteria is inadvertently enrolled, that participant 
must be discontinued from study intervention and the Sponsor, or Sponsor designee, must be 
contacted. An exception may be granted in rare circumstances for which there is a compelling 
safety reason to allow the participant to continue. In these rare cases, the Investigator must 
obtain documented approval from the Sponsor, or Sponsor designee, to allow the participant 
to continue in the study. 
The participant will be permanently discontinued from the study intervention under the 
following circumstances: 
• Participant’s own request. 
• Pregnancy. 
• Any significant AE/SAE that in the opinion of the Investigator necessitates the 
participant’s being withdrawn. 
• When a second IAR occurs (IARs occurring during a single infusion are counted as one 
IAR. Only when an IAR occurs in relation to a separate infusion it will be considered 
as a second IAR). 
• Specific request from Sponsor. 
• Any other information, if in the Investigator’s opinion suggests that taking part in the 
study may not be in the participant’s best interest. 
• Any major medical finding (eg, abnormal liver function) that in the opinion of the 
Investigator necessitates the participant's being withdrawn. 
Participants who discontinue study intervention will not be replaced, except in the cases where 
the participant was enrolled in error. 
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7.2 
Participant Discontinuation/Withdrawal from the Study  
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or 
compliance, or administrative reasons. This is expected to be uncommon. 
If participants no longer wish to take the study intervention, they will be encouraged to remain 
in the study to be evaluated 12 and 28 weeks after the start of the treatment. 
The participant will be permanently discontinued from the study intervention and the study at 
that time. 
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the study site study records. 
Participants who voluntarily withdraw are termed dropouts. Dropouts and participants 
withdrawn due to protocol violations will not be replaced. 
7.3 
Lost to Follow-up  
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The study site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls, and if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
• Study site personnel, or an independent third-party, will attempt to collect the vital status 
of the participant within legal and ethical boundaries for all participants enrolled, 
including those who did not get study intervention. Public sources may be searched for 
vital status information. If vital status is determined as deceased, this will be documented 
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and the participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information. 
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8.0 STUDY ASSESSMENTS AND PROCEDURES  
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers 
or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention. 
Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
All screening evaluations must be completed and reviewed at Day 1 to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the timeframe defined in the SoA (Section 1.3). 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 55 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples. 
8.1 
Collection of Demographic Characteristics  
Demographic parameters including but not limited to age, gender, race/ethnicity, and duration 
of Fabrazyme treatment before entering the study will be collected at the Screening Visit 
(refer to SoA in Section 1.3). 
Race and ethnicity are typically collected in clinical studies of Fabry disease. Although there 
is no evidence so far that race/ethnicity may influence the safety and tolerability of faster 
infusions of Fabrazyme, which are the outcomes investigated in this study, this possibility 
cannot be ruled out. Gathering data on ethnicity will be informative when interpreting the 
results from this study and will make it easier to compare the findings with those of other 
studies. 
8.2 
Body Weight Measurements  
The amount of Fabrazyme to be administered is dependent on the participant's weight. Before 
each infusion, the participant must be weighed. If weighing is not possible before each 
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infusion preparation, the site may use the participant's weight obtained for the previous 
infusion, within 1 month of the date of the infusion. 
8.3 
Efficacy Assessments  
Efficacy data will be collected for exploratory purposes, at the planned time points specified 
in the SoA (Section 1.3). 
8.3.1 
Plasma Lyso-GL3 Marker  
Levels of Lyso-Gb3 will be assessed in the plasma by a central laboratory using standardized 
and validated methods in addition to applicable calibrated equipment. 
Refer to the Laboratory Manual for details regarding collection, processing, storage, and 
shipment. 
8.4 
Safety Assessments  
8.4.1 
Vital Signs  
Body temperature, heart rate, respiratory rate, and blood pressure will be assessed before and 
1 hour after the completion of each infusion. 
Blood pressure and heart rate measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
Blood pressure and heart rate measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
Three readings of blood pressure and heart rate will be taken. The first and second readings 
should be rejected. The third reading should be recorded. 
8.4.2 
Clinical Safety Laboratory Tests  
There are no clinical safety laboratory tests planned for this study. 
During the study, laboratory exams may be requested at the Investigator’s discretion 
according to the individual needs of each participant. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline or 
are no longer considered clinically significant by the Investigator or medical monitor. 
If clinically significant values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor notified. 
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If laboratory values from non-protocol-specified laboratory tests performed at the institution’s 
local laboratory require a change in participant management or are considered clinically 
significant by the Investigator (eg, SAE or AE or dose modification), then the results must be 
recorded. 
8.5 
Adverse Events, Serious Adverse Events, and Other Safety Reporting  
The definitions of AEs and SAEs can be found in Section 10.3. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study intervention/ study (see 
Section 7.0). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.5.1 
Time Period and Frequency for Collecting AE and SAE Information  
All AEs and SAEs will be collected from the signing of the ICF until the last scheduled visit 
at the time points specified in the SoA (Section 1.3). 
All SAEs and AESIs will be recorded and reported to the Sponsor or designee immediately 
and under no circumstance should this exceed 24 hours of the Investigator’s awareness of the 
event, as indicated in Section 10.3. The Investigator will submit any updated SAE or AESI 
data to the Sponsor or designee within 24 hours of their awareness of the updated information. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion 
of the study participation. However, if the Investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she considers the 
event/cause of death to be reasonably related to the study intervention or study participation, 
the Investigator must promptly notify the Sponsor or designee. 
The method of recording, evaluating, and assessing causality of AE, AESI and SAE and the 
procedures for completing and transmitting safety reports are provided in Section 10.3. 
8.5.2 
Method of Detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs, AESIs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
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8.5.3 
Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and adverse events of special interest 
(AESI) (as defined in Section 8.5.6) will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is provided in Section 10.3. 
8.5.4 
Regulatory Reporting Requirements for SAEs  
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRBs)/Independent Ethics 
Committees (IECs), and Investigators. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then 
file it along with the study documents and will notify the IRB/IEC, if appropriate according to 
local requirements. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
8.5.5 
Pregnancy  
Details of all pregnancies in female participants will be collected after the start of study 
intervention and until end of study. 
If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor or designee within 24 hours of learning of the 
female participant pregnancy and should follow the procedures outlined in Section 10.3. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in an 
aborted fetus, stillbirth, or neonatal death]) the Investigator will report according to the SAE 
reporting procedures described in Section 10.3. 
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The participant will be followed to determine the outcome of the pregnancy (eg, until delivery 
of baby). The Investigator will collect follow-up information on the participant and the 
neonate, and the information will be forwarded to the Sponsor or designee. 
Any post study pregnancy-related SAE considered reasonably related to the study intervention 
by the Investigator will be reported to the Sponsor as described in Section 8.5.4. While the 
Investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
8.5.6 
Adverse Events of Special Interest  
Adverse events of special interest are events of scientific and medical interest specific to the 
further understanding of the safety profile of the study treatment and require close monitoring 
and rapid communication by the Investigators to the Sponsor. For this study, the following 
events are considered AESIs: 
• Infusion associated reaction: 
o In this study, IAR is defined as AEs listed below or any other AEs that the 
Investigator considers related to Fabrazyme infusion, occurring on same day as 
infusion and only after infusion has begun. IARs will be considered separate only 
when they are occurring in separate infusions. IARs occurring at multiple time 
points during a single infusion will be considered as a single IAR. 
▪ Chills 
▪ Fever/body temperature increased (objective sign/measurement) 
▪ Feeling hot/cold (subjective symptom only) 
▪ Nausea 
▪ Vomiting 
▪ Hypertension (following age-appropriate ranges) 
▪ Acute hypotension (following age-appropriate ranges) 
▪ Flushing 
▪ New or worsening (if paresthesia at baseline) paresthesia during infusion or 
on same day after infusion completion 
▪ New or worsening (if fatigue at baseline) fatigue during infusion or on 
same day after infusion completion 
▪ New or worsening (if pain at baseline) pain during infusion or on same day 
after infusion completion 
▪ New or worsening (if dyspnea at baseline) dyspnea during infusion or on 
same day after infusion completion 
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▪ New or worsening (if abdominal pain at baseline) abdominal pain during 
infusion or on same day after infusion completion 
▪ Headache 
▪ Pruritis 
▪ Chest discomfort 
▪ Urticaria 
▪ Dizziness/lightheadedness 
▪ Decreased alertness/level of consciousness 
▪ Tachycardia (using age-appropriate ranges) 
▪ Hypoxia (oxygen saturation decreased from baseline) during infusion or on 
same day after infusion completion 
▪ Throat tightness 
▪ Acute facial edema 
▪ Acute rhinitis or nasal congestion during infusion or on same day after 
infusion completion 
▪ Acute bronchospasm/wheezing 
▪ Tachypnea (using age-appropriate reference ranges) during infusion or on 
same day after infusion completion 
▪ Palpitations (subjective) 
• Anaphylaxis: 
Anaphylaxis is highly likely when any one of the following 2 criteria are fulfilled 13:  
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) and 
at least one of the following: 
o Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow, hypoxemia) 
o Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence) 
o Severe gastrointestinal symptoms (eg, severe crampy abdominal pain, repetitive 
vomiting), especially after exposure to non-food allergens  
2. Acute onset of hypotensiona or bronchospasmb or laryngeal involvementc after exposure to 
a known or highly probable allergend for that patient (minutes to several hours), even in 
the absence of typical skin involvement. 
a. Hypotension defined as a decrease in systolic blood pressure greater than 30% 
from that person's baseline, OR 
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i. 
Infants and children under 10 years: systolic blood pressure less than 
(70 mmHg + [2 x age in years]) 
ii. 
Adults and children over 10 years: systolic blood pressure less than 
90 mmHg. 
b. Excluding lower respiratory symptoms triggered by common inhalant allergens or 
food allergens perceived to cause “inhalational” reactions in the absence of 
ingestion. 
c. Laryngeal symptoms include stridor, vocal changes, odynophagia. 
d. An allergen is a substance (usually a protein) capable of triggering an immune 
response that can result in an allergic reaction. Most allergens act through an 
immunoglobulin E (IgE) mediated pathway, but some non-allergen triggers can act 
independent of IgE (for example, via direct activation of mast cells). 
All AESIs will be recorded in the eCRF before the next infusion began. An AESI can be 
serious or non-serious and will be reported as detailed in Section 10.3. 
8.6 
Pharmacokinetics  
Pharmacokinetics parameters are not evaluated in this study. 
8.7 
Pharmacodynamics  
Plasma lyso-GL3 will be evaluated as a pharmacodynamic biomarker in this study. As plasma 
lyso-GL3 is also being used in this study as a surrogate endpoint of efficacy that is reasonably 
likely to predict clinical benefit, details are reported in Section 8.3.1. 
8.8 
Genetics  
Genetics are not evaluated in this study. 
8.9 
Biomarkers  
Plasma lyso-GL3 will be evaluated as a pharmacodynamic biomarker in this study. As plasma 
lyso-GL3 is also being used in this study as a surrogate endpoint of efficacy that is reasonably 
likely to predict clinical benefit, details are reported in Section 8.3.1. 
8.10 Immunogenicity Assessments  
Antibodies to Fabrazyme will be evaluated in serum samples collected from all participants 
according to the SoA (Section 1.3). These samples will be tested by the Sponsor or Sponsor’s 
designee. 
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Serum samples will be screened for antibodies binding to Fabrazyme and the titer of 
confirmed positive samples will be reported. Other analyses may be performed to verify the 
stability of antibodies to Fabrazyme and/or further characterize the immunogenicity of 
Fabrazyme. 
The detection and characterization of antibodies to Fabrazyme will be performed using a 
validated assay method by or under the supervision of the Sponsor. Antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of the study 
interventions. Samples may be stored for a maximum of 15 years (or according to local 
regulations) following the last participant’s last visit for the study at a facility selected by the 
Sponsor to enable further analysis of immune responses to Fabrazyme. 
8.11 Health Economics  
Health economics parameters are not evaluated in this study. 
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9.0 STATISTICAL CONSIDERATIONS  
The statistical analysis plan (SAP) will be finalized prior to database lock, and it will include a 
more technical and detailed description of the statistical analyses described in this section. 
This section is a summary of the planned statistical analyses of the endpoints including 
primary, secondary, and exploratory endpoints. 
9.1 
Statistical Hypotheses  
There are no statistical hypotheses. 
9.1.1 
Multiplicity Adjustment  
Multiplicity adjustment is not applicable. 
9.2 
Analysis Sets  
- 
Enrolled Analysis Set: All participants who sign the ICF. 
- 
Intent-to-Treat Analysis Set: All participants who were enrolled and allocated to study 
treatment. 
- 
Safety Analysis Set: All participants who receive any amount of study treatment 
(Fabrazyme). The Safety Analysis Set will be used for all safety analyses. 
9.3 
Statistical Analyses  
9.3.1 
General Considerations  
All analyses, summaries, and listings will be performed using SAS® software (version 9.4 or 
higher) unless otherwise noted. All details regarding the statistical analysis and the preparation 
of tables, listings and figures will be described in the SAP. 
The analysis of complete data for the study will be performed when all the participants have 
either completed the study or discontinued early from the study, all data from the study are in 
the database, and the database is locked. 
In general, descriptive statistics of efficacy and safety parameters (result and change from 
baseline) by scheduled visits will be provided on observed cases, ie, inclusion of only 
participants having non-missing assessments at a specific visit. The data will be summarized 
per cohort and by pooled cohorts as described in Sections 9.3.2, 9.3.3 and 9.3.4, and where 
appropriate, per infusion duration. 
The observation period of safety data will be as follows: 
• Pre-treatment period: The pre-treatment observation period is defined from the signed 
informed consent up to the first dose of study intervention. 
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• Treatment Emergent (TE) period: The TE period is defined as the time from the first dose 
of study intervention to the last dose of study intervention + follow-up period. 
The following descriptive statistics will be used as applicable to summarize the study data 
unless otherwise specified: 
• Continuous data will be summarized using the number of observations available (n, mean, 
standard deviation [SD], minimum, median, 1st quartile, 3rd quartile, and maximum). 
Additionally, for the absolute change or percent change from baseline analysis, a 95% 
confidence interval (CI) will be provided. 
• Categorical data will be summarized using count and percentage (the percentage of 
participants in each category relative to the total number of participants in the relevant 
analysis set or relative to the total number of participants in the relevant analysis set, with 
assessments available [where appropriate]) in each category. A 95% CI will be provided 
for the binary endpoint as appropriate. The change from baseline in distribution for the 
categorical endpoint will be presented with a shift table; number and percentage of 
participants will be provided. 
Baseline definition: Unless otherwise specified, baseline is defined as the last observed value 
of the parameter of interest prior to the first intake of Fabrazyme in the study period (this 
includes unscheduled visits). 
9.3.2 
Primary Endpoint Analysis  
Table 5 
Primary Endpoint Analysis  
Endpoint 
Statistical Analysis Methods 
% Reduction of infusion duration from prestudy 
average of recent 3 infusions in participants with 
confirmed diagnosis of FD, age 2 to 65 years, 
Fabrazyme-experienced, treated for at least 3 months 
without IARs during recent 3 infusions. 
The primary endpoint will be analyzed using 
descriptive statistic, focusing on median and quantiles 
of % reduction of infusion duration from prestudy 
average of recent 3 infusions (pooled all cohorts). 
Shortest infusion duration tolerated by each 
participant in participants with confirmed diagnosis 
of FD, age 2 to 65 years, Fabrazyme-experienced, 
treated for at least 3 months without IARs during 
recent 3 infusions. 
The primary endpoint will be analyzed using 
descriptive statistic, focusing on median and quantiles 
of the shortest infusion duration tolerated by each 
participant (pooled all cohorts). 
Abbreviations: FD = Fabry disease; IAR = infusion associated reaction. 
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9.3.3 
Secondary Endpoints Analysis  
Table 6 
Secondary Endpoint Analysis  
Endpoint 
Statistical Analysis Methods 
Participants achieving the shortest planned duration 
of infusion time (20 minutes for participants ≥30 kg 
and 30 minutes for participants < 30 kg) without 
experiencing a second IAR. 
The secondary endpoints will be analyzed using 
descriptive statistics (cohort 1 to 4). 
Participants achieving infusion duration shorter than 
90 minutes without experiencing a second IAR. 
Participants achieving the shortest planned duration 
of infusion time (20 minutes for participants ≥30 kg 
and 30 minutes for participants < 30 kg) without 
experiencing any IAR. 
Participants achieving infusion duration shorter than 
90 minutes without experiencing any IAR. 
Participants achieving each infusion duration without 
experiencing any IAR. 
Participants achieving each infusion duration without 
experiencing a second IAR. 
Abbreviations: IAR = infusion associated reaction. 
9.3.4 
Exploratory Endpoints Analysis  
Table 7 
Exploratory Endpoint Analysis  
Endpoint 
Statistical Analysis Methods 
Changes of plasma lyso-GL3 from baseline to 
6 months follow-up 
The exploratory endpoints will be analyzed using 
descriptive statistics (cohort 1 to 4). 
Changes of the titer of ADA to Fabrazyme from 
baseline to 6 months follow-up 
Abbreviations: ADA = anti-drug antibody; lyso-GL3 = globotriaosylsphingosine. 
9.3.5 
Safety Analysis  
Safety endpoints include treatment-emergent adverse events, AESI (IARs and anaphylaxis), 
and vital signs. 
For applicable safety variables, both the actual value and the change from the baseline value 
will be summarized at each visit using the n, mean, SD, median, minimum value, and 
maximum value. AEs and IARs will be summarized by frequency counts and percentage. 
Duration of exposure to study intervention and number of injections will be summarized 
descriptively. 
All safety analyses will be performed on the Safety Analysis Set. 
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9.4 
Interim Analysis  
No formal interim analysis will be conducted. 
9.5 
Sample Size Determination  
There is no sample size calculation. The chosen sample size is based on feasibility 
considerations. 
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10.0 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations  
10.1.1 
Regulatory and Ethical Considerations  
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
international ethical guidelines. 
• Applicable ICH GCP guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, ICF, and other relevant documents (eg, advertisements) 
must be submitted to an IRB/IEC by the Investigator and reviewed and approved by the 
IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC. 
• 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 study site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and 
all other applicable local regulations. 
After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative. The study will not start at any study 
site at which the Investigator has not signed the protocol. 
10.1.2 
Adequate Resources  
The Investigator is responsible for supervising any individual or party to whom the 
Investigator delegates study-related duties and functions conducted at the study site. 
If the Investigator/institution retains the services of any individual or party to perform study-
related duties and functions, the Investigator/institution should ensure this individual or party 
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is qualified to perform those study-related duties and functions and should implement 
procedures to ensure the integrity of the study-related duties and functions performed and any 
data generated. 
10.1.3 
Financial Disclosure  
Investigators and sub investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
10.1.4 
Insurance  
Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the participants in this study. The terms of the insurance will be kept in the study 
files. 
10.1.5 
Informed Consent Process  
The Investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the participant or their legally authorized representative and answer all 
questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants (or their legally 
authorized representatives) and the participant’s legal guardian (for children under 16 years 
old) will be required to provide assent, if applicable, and sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy, and data 
protection requirements, where applicable, and the IRB/IEC or study site. 
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. 
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. Participants who reach legal age of majority after study initiation 
must reconfirm their participation in the study by giving signed informed consent. 
A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative. 
10.1.6 
Data Protection  
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
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names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant who will be required to give consent for their data to be 
used as described in the informed consent. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.7 
Committees Structure  
No study committee is involved in this study. 
10.1.8 
Dissemination of Clinical Study Data  
The results of the study should be reported within 1 year from the end of the clinical study. 
Irrespective of the outcome, the Sponsor will submit to any relevant database a summary of 
the results of the clinical study within 1 year from the end of the global clinical study. It shall 
be accompanied by a summary written in a manner that is understandable to laypersons. 
10.1.9 
Data Quality Assurance  
• All participant data relating to the study will be recorded on printed or eCRFs 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 case report form (CRF). 
• Guidance on completion of CRFs will be provided in CRF Completion instruction. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Quality tolerance limits will be predefined in the monitoring plan to identify systematic 
issues that can impact participant safety and/or reliability of study results. These 
predefined parameters will be monitored during the study, and important deviations from 
the quality tolerance limits and remedial actions taken will be summarized in the clinical 
study report. 
• Monitoring details describing strategy, including definition of study critical data items and 
processes (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 non-compliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the monitoring plan. 
• The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
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• The Sponsor assumes accountability for actions delegated to other individuals (eg, 
contract research organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after study completion 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. 
10.1.10 
Source Documents  
The Investigator/institution should maintain adequate and accurate source documents and 
study records that include all pertinent observations on each of the study site’s participants. 
Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, should not obscure the original entry, 
and should be explained if necessary (eg, via an audit trail). 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
Definition of what constitutes source data and its origin can be found in ICH GCP Integrated 
Addendum E6 (R2) Section 1.51 and Section 4.9. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized study 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. 
10.1.11 
Study and Site Start and Closure  
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first study site open and will be the study start date. 
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Study/Site Termination 
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 the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to: 
For study termination: 
• Discontinuation of further study intervention development. 
For study 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. 
10.1.12 
Publication Policy  
The data generated by this study are confidential information of the Sponsor. The Sponsor will 
make the results of the study publicly available. The publication policy with respect to the 
Investigator and study site will be set forth in the Clinical Trial Agreement. 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
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multicenter studies only in their entirety and not as individual study site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
 
 
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10.2 Appendix 2: Reconstitution, Dose Preparation and Storage of 
Reconstituted Solution of Fabrazyme  
The instructions presented below were extracted from Fabrazyme US label 6, when applicable. 
Sterile Water for Injection, USP, and 0.9% Sodium Chloride Injection, USP, for the 
reconstitution and dilution are provided by the study site. 
Vials are for single use only. Discard any unused product. 
Avoid shaking or agitating this product. Do not use filter needles during the preparation of the 
infusion. 
10.2.1 
Reconstitution and Dilution (Using Aseptic Technique)  
1. Allow Fabrazyme vials and diluent to reach room temperature prior to reconstitution 
(approximately 30 minutes). The number of 35 mg vials needed is based on the 
participant’s body weight (kg) and the recommended dose of 1 mg/kg. 
Select a number of 35 mg vials so that the total number of mg is equal to or greater 
than the participant’s number of kg of body weight. 
2. Reconstitute each 35 mg vial of Fabrazyme by slowly injecting 7.2 mL of Sterile 
Water for Injection, USP down the inside wall of each vial. Roll and tilt each vial 
gently. Each vial will yield a 5 mg/mL clear, colorless solution (total extractable 
amount per vial is 35 mg, 7 mL). 
3. Visually inspect the reconstituted vials for particulate matter and discoloration. Do not 
use the reconstituted solution if there is particulate matter or if it is discolored. 
4. The reconstituted solution should be further diluted with 0.9% Sodium Chloride 
Injection, USP to a total volume based on participant weight specified in Table 8 
below. Prior to adding the volume of reconstituted Fabrazyme required for the 
participant dose, remove an equal volume of 0.9% Sodium Chloride Injection, USP 
from the infusion bag. 
Table 8 
Total Infusion Volume Based on Participant Weight  
Participant Weight (kg) 
Maximum Total Volume (mL) 
<60 
50 
≥60 
100 
Participant dose (in mg) ÷ 5 mg/mL = Number of mL of reconstituted Fabrazyme 
required for participant dose. 
Example: Participant dose = 80 mg. 80 mg ÷ 5 mg/mL = 16 mL of Fabrazyme. 
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Slowly withdraw the reconstituted solution from each vial up to the total volume 
required for the participant dose. Inject the reconstituted Fabrazyme solution directly 
into the Sodium Chloride solution. Do not inject in the airspace within the infusion 
bag. Discard any vial with unused reconstituted solution. 
5. Gently invert infusion bag to mix the solution, avoiding vigorous shaking and 
agitation. 
6. Do not infuse Fabrazyme in the same intravenous line with other products. 
7. Administer Fabrazyme using an in-line low protein binding 0.2 μm filter. 
10.2.2 
Storage of Reconstituted Solution  
Use reconstituted and diluted solutions of Fabrazyme immediately. If immediate use is not 
possible, the reconstituted and diluted solution may be stored for up to 24 hours at 2°C to 8°C 
(36°F to 46°F). 
 
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10.3 Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting for Study 
Intervention  
10.3.1 
Definition of AE  
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant administered a 
medicinal product and which does not necessarily have a causal relationship with that product. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention/treatment, whether considered related to the study 
intervention/treatment. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific judgment of 
the Investigator (ie, not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New condition detected or diagnosed after study intervention administration even though it may 
have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or 
a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as 
an AE or SAE if they fulfil the definition of an AE or SAE. Lack of efficacy or failure of 
expected pharmacological action also constitutes an AE or SAE. 
 
Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
that are associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
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• 
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if 
the surgery/procedure is being performed for a pre-existing condition and the surgery/procedure 
has been pre-planned prior to study entry. However, if the pre-existing condition deteriorates 
unexpectedly during the study (eg, surgery performed earlier than planned), then the 
deterioration of the condition for which the elective surgery/procedure is being done will be 
considered an AE. 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen. 
10.3.2 
Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of 
the criteria listed: 
a. Results in death 
• 
For SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate CRF. 
b. Is life-threatening 
• 
The term life-threatening in the definition of serious refers to an event in which the participant 
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. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
In general, hospitalization signifies that the participant has been admitted (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. Complications 
that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether hospitalization 
occurred or was necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(eg, sprained ankle) that may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
• 
The term congenital anomaly/birth defect means there is suspect that exposure to a medical 
product prior to conception or during pregnancy may have resulted in an adverse outcome in the 
child. 
f. Is a suspected transmission of any infectious agent via an authorized medicinal product 
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g. Other situations: 
• 
Medical or scientific judgment should be exercised by the Investigator in deciding whether SAE 
reporting is appropriate in other situations such as significant medical events that may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious. 
o 
Examples of such events include invasive or malignant cancers, intensive treatment for 
allergic bronchospasm, blood dyscrasias, convulsions or development of intervention 
dependency or intervention abuse. 
10.3.3 
Recording and Follow-Up of AE and/or SAE  
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) related 
to the event. 
• 
The Investigator will then record all relevant AE/SAE information. 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor or designee in lieu of completion of the applicable/required report form. 
• 
There may be instances when copies of medical records for certain cases are requested by the 
Sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before submission to 
the Sponsor or designee. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
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Assessment of Intensity 
The intensity of an AE is an estimate of the relative severity of the event made by the Investigator 
based on his or her clinical experience and familiarity with the literature. The following definitions 
are to be used to rate the severity of an AE: 
• 
Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
• 
Moderate: Minimal, local, or non-invasive intervention indicated; limiting age-appropriate 
instrumental Activities of Daily Living (ADL). Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc. 
• 
Severe: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling, limiting self-care ADL. Self-care ADL 
refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden.  
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. The Investigator will use clinical judgment to determine the 
relationship. 
• 
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration, will be 
considered and investigated. 
• 
For causality assessments, events assessed as having a reasonable possibility of being related 
to study intervention will be considered "related." Events assessed as having no reasonable 
possibility of being related to study intervention will be considered "unrelated." 
• 
The Investigator will also consult the product prescribing information, for marketed products, 
in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor or designee. However, it is very 
important that the Investigator always makes an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor or designee. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
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Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-up period, 
the Investigator will provide the Sponsor or designee with a copy of any postmortem findings 
including histopathology. 
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The Investigator will submit any updated SAE data to the Sponsor or designee within 24 hours 
of the Investigator’s awareness of the information. 
10.3.4 
Reporting of SAEs  
SAE Reporting to the Sponsor or Designee via an Electronic Data Collection System 
• 
The primary mechanism for reporting an SAE to the Sponsor or designee will be the 
electronic data collection system. The study site will enter the event into the electronic data 
collection system within 24 hours of the Investigator’s awareness of the event. 
• 
If the electronic system is unavailable, then the study site will use the paper SAE report form 
(see next section) to report the event and will enter the event into the electronic data 
collection system as soon as the system becomes available. 
• 
After the study is completed at a given study site, the electronic data collection system will be 
taken offline to prevent the entry of new data or changes to existing data. 
• 
If a study site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection system has been taken 
offline, then the study site can report this information on a paper SAE report form (see next 
section) to the Sponsor or designee. 
• 
Contacts for SAE reporting can be found in eCRF Completion Guidelines. 
 
SAE Reporting to the Sponsor or Designee via Paper SAE Report Form 
• 
The backup mechanism for reporting an SAE to the Sponsor or designee will be the paper 
SAE report form. The study site will submit the SAE report form, via email, within 24 hours 
of the Investigator’s awareness of the event. Facsimile transmission may be utilized as an 
alternative mode of submission, if necessary. 
• 
Notification of SAE information via telephone does not replace the need for the Investigator 
to complete, sign and submit the paper SAE report form to the Sponsor or designee within 
24 hours of the Investigator’s awareness of the event. 
• 
Email for SAE reporting via paper report form: phv_iab16602_so@iqvia.com. 
 
 
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10.4 Appendix 4: Contraceptive and Barrier Guidance and Collection of 
Pregnancy Information  
10.4.1 
Definitions  
Woman of childbearing potential (WOCBP) 
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: 
a) Documented hysterectomy. 
b) Documented bilateral salpingectomy. 
c) Documented bilateral oophorectomy. 
NOTE: Documentation can come from the study site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female: 
a) 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. 
b) Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the non-estrogen hormonal 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 enrollment. 
Pregnancy testing: 
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within the screening period before the first dose of study 
intervention. 
• If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive. 
10.4.2 
Collection of Pregnancy Information  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
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appropriate form and submitted to the Sponsor or designee within 24 hours of learning of a 
participant’s pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate, and the information will be forwarded to the Sponsor or designee. Generally, 
follow-up will not be required for longer than 6 to 8 weeks beyond the estimated delivery 
date. Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
will be reported as an AE or SAE. If the outcome of the pregnancy meets the criteria for 
immediate classification as an SAE (ie, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly [including that in an aborted fetus, stillbirth, or neonatal death]), the 
Investigator will report according to the SAE reporting procedures described in 
Section 10.3. 
• Any post study pregnancy-related SAE considered reasonably related to the study 
treatment by the Investigator will be reported to the Sponsor or designee as described in 
Section 10.3. While the Investigator is not obligated to actively seek this information in 
former participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
 
 
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10.5 Appendix 5: Abbreviations and Definitions  
Abbreviation 
Definition 
ADL 
Activities of Daily Living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CRF 
Case report form 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
ERT 
Enzyme replacement therapy 
FDA 
Food and Drug Administration 
FD 
Fabry disease 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GL3 
Globotriaosylceramide 
HRT 
Hormone replacement therapy 
IAR 
Infusion associated reaction 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgE 
Immunoglobulin E 
IRB 
Institutional Review Board 
Lyso-GL3 
Globotriaosylsphingosine 
Q2W 
Every 2 weeks 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SoA 
Schedule of activities 
TE 
Treatment emergent 
USP 
United States Pharmacopeia 
WOCBP 
Women of childbearing potential 
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Abbreviation 
Definition 
α-GAL 
α-galactosidase A 
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10.6 Appendix 6: Protocol Amendment History  
Amendment 1.0 (20-May-2024) 
Overall Rationale for the Amendment: 
This Amendment 1.0 (Protocol version 2.0) was developed to adjust the study design. Key 
adjustments include: 
• Removal of sequential enrollment, based on the observation that infusion durations 
shortenings for the initial 4 participants in cohorts 1 and 2 were well tolerated, and the 
risk for cohorts 3 and 4 is deemed low. 
• Cohort 5, which previously consisted of ERT-naïve participants and posed the highest 
risk of not tolerating an infusion duration shorter than 120 minutes, has been excluded 
from the study. 
• Removal of new targets for infusion duration in line with removal of sequential 
enrollment. 
• Removal of formal interim analysis, of which main purpose was to calculate new 
targets for infusion duration, in line with removal of sequential enrollment. 
• Addition of 3 additional options for antihistamine as premedication. 
• Addition of anaphylaxis as an adverse event of special interest. 
• Clarification that participants are not required to remain at the site after infusion unless 
medically necessary. 
• Addition of notes on body weight measurements. 
Additionally, although not described in the below table, the address of Sanofi office 
headquarters was updated. Minor editorial changes were also made, without impacting the 
content previously presented. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
3.0 Objectives, Endpoints 
and Estimands 
 
The second primary estimands 
involving the enzyme replacement 
therapy (ERT)-naïve population 
was deleted.  
The population attribute of all 
secondary estimands were adjusted 
to remove the mention on 
ERT-naïve population. 
The intercurrent event attribute for 
all endpoints was adjusted to add 
“A treatment policy approach will 
be applied in case pre-medications 
are not given as described within 
the protocol. No action will be 
taken for this event for the analysis 
even when pre-medications are not 
given as described within the 
protocol.” 
Cohort 5, previously composed of 
ERT-naïve participants, was removed 
from the study as a way to mitigate with 
participant enrollment delay. ERT-naïve 
patients are considered to have the highest 
risk of not tolerating shorter infusions. 
This cohort is removed to minimize 
increase of risk related to making 
enrollment of cohorts 2-4 parallel. 
 
Changes in intercurrent event attribute was 
made to explicitly add full clarity on 
management of endpoints in case 
pre-medications are not given as described 
within the protocol. 
1.1 Synopsis 
4.1 Overall Design 
The description and flow of the 
staged enrollment was removed 
(together with Figure 2) and the 
following sentence was added “All 
4 cohorts of this study will be 
enrolled simultaneously.” 
Initial data shows that infusion duration 
shortening is very well tolerated and 
participants can reach 20-minute duration 
without experiencing a single infusion 
associated reaction (IAR). Considering 
this, and that cohort 5 (treatment-naïve 
patients, which has the highest risk of not 
tolerating shorter infusions) was removed 
from the study, the risk for the remaining 
cohorts (2, 3, and 4) not tolerating these 
shorter infusions is relatively low. 
Therefore, the study will proceed to enroll 
all cohorts simultaneously. 
1.1 Synopsis 
4.1  Overall Design 
The number of participants was 
reduced from 18 to 14, and cohort 
5 description was deleted. 
Cohort 5, previously composed of 
ERT-naïve participants, was removed 
from the study as a way to mitigate with 
participant enrollment delay. ERT-naïve 
patients are considered to have the highest 
risk of not tolerating shorter infusions. 
This cohort is removed to minimize 
increase of risk related to making 
enrollment of cohorts 2 to 4 parallel. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
4.1 Overall Design 
The below paragraph was edited 
(deleted text in strikethrough, 
additions in bold): 
“The infusion duration will 
shorten, and the infusion rate will 
rise with each successfully 
tolerated infusion (ie, an infusion 
completed within a duration not 
exceeding 120% of planned 
duration, without IAR), until 
reaches the minimum infusion 
duration of 20 minutes for 
participants in cohorts 1 to 3 
(≥30 kg) and 30 minutes for 
participants in cohort 4 (<30 kg) 
or, in later cohorts, the new target 
infusion duration determined based 
on the results in earlier cohorts.” 
As initial data shows that infusion duration 
shortening is very well tolerated and 
participants can reach 20-minute duration 
without experiencing a single IAR, it is 
reasonable to assume that the previously 
defined calculations for new targets for 
infusion in cohorts 3 and 4 may not be 
necessary. Hence, the target infusion 
durations in this study are kept 20 minutes 
for cohorts 1 to 3 and 30 minutes for 
cohort 4, without further adjustment. 
 
A threshold was added to determine if an 
infusion is tolerated in the cases in which 
the actual infusion duration is greater than 
the planned duration. 
1.1 Synopsis 
The below paragraph was edited 
(deleted text in strikethrough, 
additions in bold): 
“Non-investigational prophylactic 
premedication with acetaminophen 
(160 mg to 650 mg, depending on 
age) and one antihistamine 
(diphenhydramine 25 mg or 
12.5 mg, or loratadine 10 mg or 
5 mg, or cetirizine 5 mg or 
2.5 mg, or fexofenadine 180 mg 
or 30 mg - doses will depend 
depending on age) will be 
administered to all participants to 
avoid IARs, 30 minutes prior to 
each infusion.” 
Additional antihistaminic options have 
been included in the protocol as 
premedication. This allows the 
Investigators to select from the four 
available H1 blockers. 
1.3 Schedule of Activities 
Added a cross reference to the new 
Section 8.2 on the notes for line 
“Vital signs and weight”. 
To allow sites to easily identify more 
details on weight measurements. 
2.1 Study Rationale 
The term “unpublished” was 
removed when referring to data 
from Japanese post-marketing 
surveillance study, and the 
appropriate reference from 
published literature was added. 
Adequate literature reference added to 
support the data described. 
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Section # and Name 
Description of Change 
Brief Rationale 
2.3.1 Risk Assessment 
The following information was 
added in the mitigation strategy for 
AEs: 
“Anaphylaxis is an AESI in this 
study. The incidence and severity 
of anaphylaxis will be closely 
monitored and evaluated 
throughout the study”. 
Also, the mention to 
diphenhydramine was changed to 
“one antihistaminic” in the 
mitigation strategy text for IARs. 
Anaphylaxis was added as an AESI per 
FDA’s comment, not based on a new 
safety signal. 
 
Additional antihistaminic options have 
been included in the protocol as 
premedication. This allows the 
Investigators to select from the four 
available H1 blockers. 
4.1  Overall Design 
6.1  Study Interventions 
Administered 
The following sentence was added: 
“The participants are not required 
to stay at the site after completion 
of the infusion, unless the 
Investigator considers it medically 
necessary.” 
To clarify that participants are not required 
to remain at the site following the 
completion of the infusion, unless the 
Investigator deems it medically necessary. 
4.2  Scientific Rationale 
for Study Design 
The below paragraphs were edited 
(deleted text in strikethrough, 
additions in bold): 
The population chosen for the 
study is wide, comprisesing the 
diversity of patients with Fabry 
Disease (FD) already treated with 
Fabrazyme: women, men with 
classic and non-classic disease, 
and children. patients already 
treated with Fabrazyme, and ERT-
naïve patients. The enrollment and 
treatment will have a staged 
enrollment. The study will start 
with the demographic segment 
with the lowest risk of 
experiencing IARs (ie, female 
participants and non classic male 
participants) and the portion with 
highest risk (ie, ERT naïve 
participants) will be the last cohort 
to be enrolled. 
Standard statistical, clinical, and 
laboratory procedures will be 
utilized in this study. 
Cohort 5, previously composed of ERT-
naïve participants, was removed from the 
study as a way to mitigate with participant 
enrollment delay. ERT-naïve patients are 
considered to have the highest risk of not 
tolerating shorter infusions. This cohort is 
removed to minimize increase of risk 
related to making enrollment of cohorts 2 
to 4 parallel. 
Also, initial data shows that infusion 
duration shortening is very well tolerated 
and participants can reach 20-minute 
duration without experiencing a single 
IAR. Considering this, and that cohort 5 
(which had the highest risk of not 
tolerating shorter infusions) was removed 
from the study, the risk for the remaining 
cohorts (2, 3, and 4) not tolerating these 
shorter infusions is relatively low. 
Therefore, the study will proceed to enroll 
all cohorts simultaneously. 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
4.5 End of Treatment 
Definition 
The below paragraphs were edited 
(deleted text in strikethrough, 
additions in bold): 
The end of treatment is defined 
when the participant successfully 
reaches the shortest infusion 
duration planned for the cohort 
which he/she belongs to or when 
the participant experiences a 
second IAR. At that point, the 
participant will not receive any 
further infusion as part of the 
study, regardless of whether the 
Study Intervention Period reaches 
16 weeks or not. 
 The Study Intervention Period will 
be completed in the absence of 
IAR at Week 10, or at the latest at 
Week 16  (Figure 2 and Figure 3). 
Correction on end of treatment definition, 
as in the absence of any IAR during the 
treatment period, if the current infusion 
duration for the participant ≥30 kg is 
120 minutes (the shortest possible initial 
duration), then he/she would complete the 
treatment at Week 8; if the current 
infusion duration for the participant 
<30 kg is 90 minutes (the shortest possible 
initial duration), then he/she would 
complete the treatment at Week 6. 
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Section # and Name 
Description of Change 
Brief Rationale 
4.6.2 Criteria for Stopping 
the Study 
The paragraphs were edited 
(deleted text in strikethrough, 
additions in bold): 
“While no specific criteria have 
been established for terminating 
the study prematurely, it remains 
within the Sponsor’s discretion 
to stop the study, at any time, 
either in its entirety or at any 
site. The Investigator may also 
stop the study at his/her site if 
he/she has safety concerns. If the 
Sponsor terminates the study for 
safety reasons, the Sponsor will 
promptly notify the Investigator. 
As detailed in Section 4.1, the 
duration of the Fabrazyme 
infusions given during the study 
will gradually decrease and the 
infusion rate will gradually 
increase, up to a minimum duration 
.that may be calculated during the 
study (ie, new targets for infusion 
duration). 
The study will be stopped without 
enrolling remaining cohorts if any 
of the following scenarios 
involving the new target infusion 
duration occur: 
• In case the new target 1 for 
infusion duration is not shorter than 
90 minutes. 
• In case the new target 2 for 
infusion duration is not shorter than 
90 minutes. 
• In case the new target 3 for 
infusion duration is not shorter than 
90 minutes.” 
As initial data shows that infusion duration 
shortening is very well tolerated and 
participants can reach 20-minute duration 
without experiencing a single IAR, it is 
reasonable to assume that the previously 
defined calculations for new targets for 
infusion in cohorts 3 and 4 may no longer 
be necessary. Consequently, there is no 
specific criteria for stopping the study 
related to these new targets. 
5.1 Inclusion Criteria 
Criterion 1 e. “Cohort 5: ERT-
naïve participants” was deleted. 
Cohort 5, previously composed of 
ERT-naïve participants, was removed 
from the study as a way to mitigate with 
participant enrollment delay. ERT-naïve 
patients are considered to have the highest 
risk of not tolerating shorter infusions. 
This cohort is removed to minimize 
increase of risk related to making 
enrollment of cohorts 2 to 4 parallel. 
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Section # and Name 
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria 
Criterion 3 was adjusted (additions 
in bold): 
“3. Contraindication to Fabrazyme 
or any of the premedications or 
rescue medications 
(diphenhydramine, loratadine, 
cetirizine, fexofenadine, 
acetaminophen, montelukast, 
dexamethasone). 
Adjustment to reflect the new 
antihistaminic options included in the 
protocol as premedication. This allows the 
Investigators to select from the four 
available H1 blockers. 
6.1  Study Interventions 
Administered 
The paragraphs were edited 
(deleted text in strikethrough, 
additions in bold): 
“All participants will receive 
acetaminophen and 
diphenhydramine one 
antihistamine as non-
investigational prophylactic 
premedication, 30 minutes prior to 
each infusion. In case of IAR 
occurrence, participant will receive 
dexamethasone and montelukast as 
rescue medication, and both drugs 
will be given from this time 
forward as prophylactic 
premedication, together with 
acetaminophen and the 
antihistamine, 30 minutes prior to 
all further infusions. 
All The study interventions are 
presented in Table 3 and Table 4 
(for the possible antihistamines 
allowed as premedication).” 
Table 4 containing details of 
possible antihistamines 
administered as premedication 
(including diphenhydramine, 
loratadine, cetirizine and 
fexofenadine) was added. 
Additional antihistaminic options have 
been included in the protocol as 
premedication. This allows the 
Investigators to select from the four 
available H1 blockers. 
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Section # and Name 
Description of Change 
Brief Rationale 
6.2 Infusion Duration 
Guideline 
Previous Figure 4 (current Figure 
3) Guideline for Decreasing 
Infusion Duration for Participants 
<30 kg was updated, removing the 
mention of naïve participants. 
 
The below sentence was adjusted 
(deleted text in strikethrough, 
additions in bold): 
“Please note that a participant is 
considered to tolerates the 
infusion duration when the 
infusion is completed within a 
duration not exceeding 120% of 
planned duration and no IAR is 
observed during the infusion. 
Cohort 5, previously composed of 
ERT-naïve participants, was removed 
from the study as a way to mitigate with 
participant enrollment delay. ERT-naïve 
patients are considered to have the highest 
risk of not tolerating shorter infusions. 
This cohort is removed to minimize 
increase of risk related to making 
enrollment of cohorts 2 to 4 parallel. 
 
A threshold was added to determine if an 
infusion is tolerated in the cases in which 
the actual infusion duration is greater than 
the planned duration. 
 
6.9  Concomitant Therapy 
Changed the word 
“diphenhydramine” to “an 
antihistaminic” in the paragraph 
about non-investigational 
premedication. 
Additionally, the below sentence 
was edited (additions in bold): 
“Dexamethasone and montelukast 
may also be administered as 
premedication in participants who 
have experienced an IAR (refer to 
Section 6.1).” 
Additional antihistaminic options have 
been included in the protocol as 
premedication. This allows the 
Investigators to select from the four 
available H1 blockers. 
 
Clarification – no change was made in the 
conduct previously established. 
6.9.1 Rescue Medicine 
The below sentence was edited 
(additions in bold): 
In case of IAR occurrence, 
participant will receive 
dexamethasone and montelukast as 
rescue medication, and both drugs 
will be given from this time 
forward as prophylactic 
premedication, together with 
acetaminophen and the 
antihistamine, 30 minutes prior 
to all further infusions. 
Clarification – no change was made in the 
conduct previously established. 
8.2  Body Weight 
Measurements 
Addition of a new section, 
explaining that the amount of 
Fabrazyme to be administered is 
dependent on the participant's 
weight, and if weighing is not 
possible before each infusion 
preparation, the site may use the 
participant's weight obtained for 
the previous infusion, within 1 
month of the date of the infusion. 
Section added to describe in more details 
weight measurements and permit the use 
of a previous measurement to prepare the 
current infusion for a participant. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.5.6 Adverse Events of 
Special Interest 
Anaphylaxis was added as an 
adverse event of special interest, 
with a definition according to the 
World Allergy Organization 
Anaphylaxis Guidance 2020. 
Anaphylaxis was added as an AESI per 
FDA’s comment, not based on a new 
safety signal. 
9.3.1 General 
Considerations 
The following paragraph was 
deleted: 
“Two interim analyses will be 
conducted: the first is when cohorts 
1 and 2 completes the study and the 
second is when cohorts 3 and 4 
completes the study.” 
Additionally, the following change 
was made in the text about 
categorical data (deleted text in 
strikethrough, additions in bold): 
“The change from baseline in 
distribution value for the 
categorical endpoint will be 
presented with a shift table; 
number and percentage of 
participants will be provided.” 
As all cohorts will now enroll 
simultaneously, there is no longer a 
requirement for interim analysis. 
 
 
 
 
Correction. 
9.3.2 Primary Endpoint 
Analysis 
The endpoint “% Reduction of 
infusion duration from initial 120 
minutes in participants with 
confirmed diagnosis of FD, age 2 
to 65 years, ERT-naïve” and the 
correspondent statistical analysis 
method was deleted from Table 4 
Primary Endpoint Analysis. 
All mentions to ERT-naïve or 
Cohort 5 were removed from the 
other primary endpoints. 
Cohort 5, previously composed of ERT-
naïve participants, was removed from the 
study as a way to mitigate with participant 
enrollment delay. ERT-naïve patients are 
considered to have the highest risk of not 
tolerating shorter infusions. This cohort is 
removed to minimize increase of risk 
related to making enrollment of cohorts 2 
to 4 parallel. 
9.3.3 Secondary 
Endpoints Analysis 
9.3.4 Exploratory 
Endpoints Analysis 
All mentions to Cohort 5 were 
removed from the statistical 
analysis methods. 
Cohort 5, previously composed of ERT-
naïve participants, was removed from the 
study as a way to mitigate with participant 
enrollment delay. ERT-naïve patients are 
considered to have the highest risk of not 
tolerating shorter infusions. This cohort is 
removed to minimize increase of risk 
related to making enrollment of cohorts 2 
to 4 parallel. 
9.3.5 Safety Analysis 
Anaphylaxis was added as an 
adverse event of special interest 
(AESI). 
Anaphylaxis was added as an AESI per 
FDA’s comment, not based on a new 
safety signal. 
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Section # and Name 
Description of Change 
Brief Rationale 
9.4 Interim Analysis 
The paragraphs were edited 
(deleted text in strikethrough, 
additions in bold): 
“Two interim analyses will be 
conducted. First interim analysis 
will take place after cohort 1 and 2 
complete the Study Intervention 
Period. Second interim analysis 
will take place after cohort 3 and 4 
complete the Study Intervention 
Period. 
The detailed plan of interim 
analyses will be specified in the 
SAP. 
The first interim analysis outcome 
will determine the enrollment and 
infusion rate of cohorts 3 and 4. 
The second interim analysis will 
determine the enrollment of 
cohort 5. 
No formal interim analysis will 
be conducted.” 
As all cohorts will now enroll 
simultaneously, there is no longer a 
requirement for interim analysis of which 
main purpose was to calculate new targets 
for infusion duration. 
 
 
 
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11.0 REFERENCES  
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