An Open-label Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of REPLAGAL® in Treatment-naïve Chinese Subjects With Fabry Disease
Phase: PHASE3
Conditions: Fabry Disease
Sponsor: Takeda

For non-commercial use only

TAKEDA PHARMACEUTICALS 
Protocol: 
TAK-675-3001 
Title: 
An Open-label Study to Evaluate the Safety, Efficacy, and 
Pharmacokinetics of REPLAGAL® in Treatment-naïve Chinese 
Subjects with Fabry Disease 
Short Title: 
REPLAGAL® Study in Treatment-naïve Chinese Subjects  
Study Phase: 
Phase 3 
Drug: 
REPLAGAL® (agalsidase alfa) 
IND Number: 
Non-IND 
EUDRACT Number: 
2022-004246-35 
Sponsor: 
Takeda Development Center Americas, Inc.  
95 Hayden Ave, Lexington, MA 02421, USA 
Principal / Coordinating 
Investigator: 
 MD, PhD 
  
 
Protocol History: 
Amendment 2.0: 23 May 2023 
Amendment 1.0: 07 Feb 2022 
Original Protocol: 17 Mar 2021 (Final) 
Confidentiality Statement 
This document contains confidential and proprietary information of Takeda and is disclosed pursuant to 
confidentiality and non-disclosure obligations. This information should be used solely for the purposes for which 
it was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Takeda. 
For non-commercial use only

For non-commercial use only

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CONTACTS  
SAE Reporting 
In the event of a serious adverse event (SAE), the investigator should complete an SAE 
electronic Case Report Form (eCRF) in English or report via the paper safety report form (as 
back-up) within 24 hours of becoming aware of any SAE. The fax number and email address are 
provided in the Form Completion Instruction. 
Protocol and Safety-Related Questions or Concerns 
For protocol- or safety-related questions or concerns, the investigator must contact Takeda 
Clinical Research Physician or IQVIA medical monitor: 
, M.D., Ph.D. 
Takeda Clinical Research Physician 
Mobile: 
 
Email: 
 
 
, M.D., Ph.D. 
IQVIA 
 
Mobile: 
 
Email: 
 
 
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PRODUCT QUALITY COMPLAINTS 
Investigators are required to report investigational product quality complaints or non-medical 
complaints to Takeda within 1 business day. If requested, defective product(s) will be returned to 
the sponsor for inspection and analysis. 
A product quality complaint includes any instances where there is an allegation or report relating 
to Takeda licensed or investigational products, received in writing, electronically, or orally, 
which indicates an impact to a product’s strength, identity, safety, purity, or quality, or which 
suggests that the product did not meet the criteria defined in the regulatory applications, licenses, 
or marketing authorizations for the product. Examples of investigational product quality 
complaints include, but are not limited to, the following: 
Unit issues 
• Capsule fill empty or overage 
• Bottle/vial fill shortage or overage 
• Capsule/tablet damaged/broken 
• Syringe/vial cracked/broken 
• Syringe leakage 
• Missing components 
• Product discoloration 
• Device malfunction 
Labeling 
• Label missing 
• Leaflet or Instructions for Use 
missing  
• Label illegible 
• Incomplete, inaccurate, or 
misleading labeling 
• Lot number or serial number missing 
Packaging 
• Damaged packaging (eg, secondary, 
primary, bag/pouch) 
• Tampered seals 
• Inadequate or faulty closure 
• Missing components within package 
Foreign 
material 
• Contaminated product 
• Particulate in bottle/vial 
• Particulate in packaging 
 
Please report the product quality complaint using Clinical Trial Material Compliant Form via the 
email address: 
 
ctmcomplaint@takeda.com 
For instructions on reporting adverse events related to product complaints, see Appendix 3.4. 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ........................................................................................2 
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION .....................3 
CONTACTS .............................................................................................................................6 
PRODUCT QUALITY COMPLAINTS ................................................................................7 
TABLE OF CONTENTS ........................................................................................................8 
LIST OF IN-TEXT TABLES ...............................................................................................11 
LIST OF APPENDICES .......................................................................................................11 
1. PROTOCOL SUMMARY ................................................................................................12 
1.1 Synopsis ........................................................................................................................12 
1.2 Schedule of Activities ..................................................................................................17 
2. INTRODUCTION..............................................................................................................21 
2.1 Indication and Current Treatment Options .............................................................21 
2.2 Product Background and Clinical Information .......................................................23 
2.3 Study Rationale ...........................................................................................................25 
2.4 Benefit/Risk Assessment .............................................................................................25 
2.5 Compliance Statement ................................................................................................26 
3. OBJECTIVES AND ENDPOINTS ..................................................................................27 
3.1 Study Objectives ..........................................................................................................27 
3.1.1 Primary Objective ................................................................................................27 
3.1.2 Secondary Objectives ...........................................................................................27 
3.2 Study Endpoints ..........................................................................................................28 
4. STUDY DESIGN ................................................................................................................30 
4.1 Overall Design .............................................................................................................30 
4.2 Justification for Dose ..................................................................................................31 
4.3 Duration of Subject Participation and Study Completion Definition ....................31 
4.4 Sites and Regions .........................................................................................................31 
5. STUDY POPULATION ....................................................................................................32 
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5.1 Inclusion Criteria ........................................................................................................32 
5.2 Exclusion Criteria .......................................................................................................33 
5.3 Restrictions ..................................................................................................................34 
5.4 Reproductive Potential ...............................................................................................34 
5.4.1 Female Contraception ..........................................................................................34 
5.4.2 Male Contraception ..............................................................................................35 
6. STUDY INTERVENTION ................................................................................................36 
6.1 Investigational Product ...............................................................................................36 
6.1.1 Identity of Investigational Product .....................................................................36 
6.1.2 Blinding the Treatment Assignment ...................................................................36 
6.2 Administration of Investigational Product ...............................................................36 
6.2.1 Management of Infusion-related Reactions .......................................................36 
6.2.2 Interactive Response Technology for Investigational Product Management .36 
6.2.3 Allocation of Subjects to Treatment ...................................................................36 
6.2.4 Dosing ....................................................................................................................37 
6.2.5 Dose Modification .................................................................................................38 
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product ..............38 
6.3.1 Labeling .................................................................................................................38 
6.3.2 Packaging ..............................................................................................................38 
6.3.3 Storage ...................................................................................................................38 
6.3.4 Handling ................................................................................................................39 
6.4 Drug Accountability ....................................................................................................39 
6.5 Subject Compliance ....................................................................................................40 
6.6 Premedication and Prohibited Treatment ................................................................41 
6.6.1 Premedications ......................................................................................................41 
6.6.2 Prohibited Treatment ...........................................................................................41 
6.7 Protocol Considerations for Unavoidable Circumstances Such as the COVID-19 
Pandemic ......................................................................................................................41 
7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL .......................................................................43 
7.1 Discontinuation of Investigational Product ..............................................................43 
7.2 Reasons for Discontinuation ......................................................................................43 
7.3 Withdrawal from the Study .......................................................................................43 
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Contact/Visit .............44 
8. STUDY ASSESSMENTS AND PROCEDURES ............................................................45 
8.1 Study Periods ...............................................................................................................45 
8.1.1 Screening Period (Week -7 to Week -2) ..............................................................45 
8.1.2 Baseline Visit Period (Week -1) ...........................................................................46 
8.1.3 Treatment Period ..................................................................................................46 
8.1.3.1 REPLAGAL Infusion EOW (±4 days) from Week 0 Through Week 52 ......46 
8.1.3.2 Evaluation Visits at Week 8, 16, 28, 40, and 52 ...........................................46 
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8.1.4 Safety Follow-up Period (End of Study) .............................................................46 
8.1.5 Additional Care of Subjects after the Study ......................................................47 
8.2 Study Assessments .......................................................................................................47 
8.2.1 Demographic and Other Baseline Characteristics ............................................47 
8.2.1.1 Height and Weight .........................................................................................47 
8.2.1.2 Medical History ..............................................................................................47 
8.2.1.3 Prior and Concomitant Treatment...............................................................48 
8.2.1.4 Viral Testing ...................................................................................................48 
8.2.1.5 Confirmation of Study Eligibility .................................................................49 
8.2.2 Efficacy ..................................................................................................................49 
8.2.2.1 Estimated Glomerular Filtration Rate .........................................................49 
8.2.2.2 Brief Pain Inventory-Short Form .................................................................50 
8.2.2.3 Urine Protein/Creatinine Ratio ....................................................................50 
8.2.2.4 Echocardiography ..........................................................................................50 
8.2.2.5 Audiology Testing ..........................................................................................50 
8.2.3 Safety .....................................................................................................................51 
8.2.3.1 Physical Examination ....................................................................................51 
8.2.3.2 Adverse Events ...............................................................................................51 
8.2.3.3 Vital Signs .......................................................................................................51 
8.2.3.4 Clinical Laboratory Tests ..............................................................................52 
8.2.3.5 Pregnancy Test ...............................................................................................52 
8.2.3.6 Electrocardiogram .........................................................................................53 
8.2.3.7 Anti-drug Antibody Testing ..........................................................................53 
8.2.4 Other Assessments ................................................................................................53 
8.2.4.1 Pharmacodynamic Assessment: Plasma Globotriaosylsphingosine 
(Lyso-Gb3) Level ............................................................................................53 
8.2.4.2 Pharmacokinetic Assessment ........................................................................53 
8.2.5 Volume of Blood to Be Drawn from Each Subject ............................................54 
9. STATISTICAL CONSIDERATIONS .............................................................................56 
9.1 Statistical Analysis Process ........................................................................................56 
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee ...56 
9.3 Sample Size and Power Considerations ....................................................................56 
9.4 Statistical Analysis Set ................................................................................................56 
9.5 Efficacy Analyses .........................................................................................................57 
9.6 Safety Analyses ............................................................................................................57 
9.7 Pharmacokinetic Analyses .........................................................................................58 
10. REFERENCES .................................................................................................................60 
 
 
 
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LIST OF IN-TEXT TABLES 
Table 1. Schedule of Activities ..............................................................................................17 
Table 2. Intensive Pharmacokinetic Sampling Time Points ..............................................20 
Table 3. Sparse Pharmacokinetic Sampling Time Points ..................................................20 
Table 4. Objectives and Endpoints .......................................................................................28 
Table 5. Schedule for Recording of Vital Signs at Infusion ...............................................51 
 
LIST OF APPENDICES 
Appendix 1 
Regulatory, Ethical, and Study Oversight Considerations ........................63 
Appendix 2 
Clinical Laboratory Tests..............................................................................71 
Appendix 3 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .................................................................................................73 
Appendix 4 
Contraceptive Guidance ................................................................................83 
Appendix 5 
Scales and Assessments .................................................................................84 
Appendix 6 
Abbreviations .................................................................................................87 
Appendix 7 
Protocol History .............................................................................................90 
 
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1. PROTOCOL SUMMARY 
1.1 Synopsis 
Protocol number: TAK-675-3001 
Drug: REPLAGAL (agalsidase alfa) 
Title of the study: An Open-label Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of REPLAGAL® 
in Treatment-naïve Chinese Subjects with Fabry Disease 
Short title: REPLAGAL® Study in Treatment-naïve Chinese Subjects 
Study phase: 3 
Number of subjects (total and per treatment arm): 20 safety evaluable subjects in total (at least 25% are ≥7 to 
<18 years old) 
Principal/Coordinating Investigator: 
 
Sites and Regions: 4 to 6 sites in China 
Study period (planned): 
2021-2024 
Clinical phase: 
3 
Objectives: 
Primary: The primary objective of this study is to assess the safety of REPLAGAL (0.2 mg/kg every other week 
[EOW] up to 52 weeks), by evaluating the incidence of serious treatment-emergent adverse events (TEAEs) over 
the study period, in treatment-naïve Chinese subjects with Fabry disease. 
Secondary: The secondary objectives are as follows:  
• 
To evaluate other safety parameters of REPLAGAL  
• 
To evaluate the efficacy of REPLAGAL on the renal parameter (ie, estimated glomerular filtration rate 
[eGFR])  
• 
To assess the efficacy of REPLAGAL on left ventricular mass index (LVMI) and left ventricular ejection 
fraction (LVEF) 
• 
To evaluate the efficacy of REPLAGAL on other renal variables, pain, and pharmacodynamic markers 
(plasma globotriaosylsphingosine [lyso-Gb3]) 
• 
To evaluate the change in hearing for subjects <18 years old 
• 
To evaluate the pharmacokinetics (PK) of REPLAGAL in treatment-naïve Chinese subjects with Fabry 
disease. 
Rationale: On 28 Aug 2020, REPLAGAL received approval of its New Drug Application from China’s National 
Medical Products Administration for the treatment of Fabry disease. As part of the approval requirements and 
post-authorization commitment, the China Health authority has requested that further efficacy and safety data be 
collected from Chinese patients with Fabry disease. For that, a Phase 3 interventional study was proposed. This 
study is intended to evaluate the safety, efficacy, and PK of REPLAGAL in treatment-naïve Chinese subjects with 
Fabry disease. 
Investigational product, dose, and mode of administration: 
The investigational product is REPLAGAL (agalsidase alfa), which will be supplied as a sterile, clear, colorless 
concentrate for dilution for intravenous (IV) infusion. REPLAGAL will be provided in single-use, 5 mL vials 
containing 3.5 mL of concentrate at a concentration of 1 mg/mL. 
REPLAGAL infusions will occur at the clinical site. Subjects will receive REPLAGAL at a dose of 0.2 mg/kg body 
weight administered as an IV infusion over 40 minutes (±10 minutes) EOW (±4 days), except on Day 1 (Week 0) 
and Week 28 visits where the length of infusion must be exactly 40 minutes to support the PK sampling. 
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Methodology: 
This is a China-only, Phase 3, multicenter, nonrandomized, open-label, single-arm study to evaluate the safety, 
efficacy, and PK of REPLAGAL in treatment-naïve Chinese subjects with Fabry disease. The study will consist of 
EOW treatment with 0.2 mg/kg IV infusion of REPLAGAL for up to 52 weeks. A total of 20 safety evaluable 
subjects aged ≥7 to ≤65 years are planned to be enrolled with at least 25% of the total eligible subjects in the age 
range of ≥7 to <18 years old. 
The study will include a screening period, a baseline visit period, a treatment period, and a safety follow-up 
period. Screening assessments will occur from Week -7 through Week -2. Baseline visit period will be at 
Week -1. After completion of baseline procedures and assessments, eligible subjects will receive 0.2 mg/kg IV 
infusions of REPLAGAL EOW (±4 days) from Day 1 (Week 0) up to Week 52 (end of treatment visit) during the 
treatment period. Evaluation visits will be performed at clinical site at Week 8 (±4 days), Week 16 (±4 days), 
Week 28 (±4 days), Week 40 (±7 days), and Week 52 (±7 days). Additionally, PK assessments will occur at 
Day 1 (Week 0) and Week 28 (±4 days). In order to ensure subjects’ safety, subjects will undergo a follow-up 
period of approximately 14 days (+7 days), after the completion of the treatment infusion (or the last infusion for 
early treatment discontinued subjects).  
Safety assessments include monitoring of adverse events (AEs), use of concomitant medication, clinical 
laboratory values, antibody formation, vital signs, physical examination, and electrocardiogram results.  
Efficacy assessments include measurements of eGFR, urine protein/creatinine ratio, LVMI, LVEF, and Brief Pain 
Inventory (BPI).  
For pediatric subjects (<18 years old at screening), additional assessment for hearing will be performed.  
Pharmacodynamic assessment includes plasma lyso-Gb3.  
Pharmacokinetic assessments will be completed by obtaining blood samples at pre-specified time points in the 
study. Ten subjects (5 adult subjects and 5 pediatric subjects) will provide intensive PK samples and other 
subjects will provide sparse PK samples. 
Inclusion and Exclusion Criteria:  
Each subject must participate in the informed consent process and provide written informed consent/assent before 
any procedures specified in the protocol are performed. 
Inclusion Criteria: 
The subject will not be considered eligible for the study without meeting all of the criteria below. 
1. Subject and/or legally authorized representative must voluntarily sign an Institutional Review 
Board/Independent Ethics Committee approved written informed consent form (ICF) after all relevant 
aspects of the study have been explained and discussed with the subject. For the subjects <18 years old, 
subjects will give assent AND their parent(s)/legally authorized representative should sign the ICF 
accordingly. 
2. The subject has confirmed diagnosis of Fabry disease as determined by the investigator, according to 
medical record including: 
• 
For male subject, Fabry disease is confirmed by a deficiency of α-galactosidase A (GLA) activity and a 
mutation in the GLA gene 
• 
For female subject, Fabry disease is confirmed by a mutation in the GLA gene. 
3. The subject is 7 to 65 years of age, inclusive, at screening. 
4. Female subjects of childbearing potential must have a negative pregnancy test at screening.  
5. Female subjects of childbearing potential must agree to use a medically acceptable method of contraception 
at all times during the study and for at least 14 days after the final investigational product infusion; the 
methods of acceptable contraception are listed in the protocol.  
6. The subject is deemed, as determined by the investigator, to have adequate general health to undergo the 
specified protocol-related procedures and to have no safety or medical contraindications for participation. 
7. The subject has not received any treatment (approved or investigational) specific to Fabry disease, such as 
enzyme replacement therapy, chaperone therapy, or substrate reduction therapy.  
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8. The adult subject (≥18 years old) must have an eGFR of 45 to 120 mL/min/1.73 m2 (inclusive). Serum 
creatinine is tested and the eGFR is calculated by central laboratory using the Chronic Kidney Disease 
Epidemiology equation. 
Exclusion Criteria: 
The subject will be excluded from the study if any of the following exclusion criteria are met. 
1. In the opinion of the investigator, the subject’s life expectancy is ≤5 years. 
2. The subject has undergone or is scheduled to undergo kidney transplantation or is currently on dialysis or 
has any signs or symptoms of end stage renal disease. 
3. The subject has a urine protein/creatinine ratio of >500 mg/g. 
4. The subject has a clinically relevant history of allergy or signs or symptoms of severe hypersensitivity, 
which in the investigator’s judgment, will substantially increase the subject’s risk if he or she participates in 
the study.  
5. In the opinion of the investigator, the subject has non-Fabry disease-related cause of end organ (renal, 
cardiovascular, central nervous system) dysfunction/failure or is receiving medications that may affect the 
rate of disease progression, as assessed by renal measures.  
6. The subject has a positive test result at screening for hepatitis B surface antigen with detectable hepatitis B 
viral DNA load, hepatitis C virus (HCV) antibody with confirmation by HCV ribonucleic acid polymerase 
chain reaction testing, or human immunodeficiency virus antibody. 
7. The subject has received prior treatment with any of the following medications, with the exception of non-
systemic use: 
• 
Chloroquine 
• 
Amiodarone 
• 
Monobenzone  
• 
Gentamicin 
8. The subject is pregnant or lactating. 
9. The subject has a body mass index >35 kg/m2. 
10. The subject is treated or has been treated with any investigational drug for indication other than Fabry 
disease within 30 days prior to study start. 
11. The subject and/or the subject’s parent(s)/legal guardian is unable to understand the nature, scope, and 
possible consequences of the study.  
12. The subject is unable to comply with the protocol, eg, uncooperative with protocol schedule, refusal to agree 
to all of the study procedures, inability to return for evaluations, or is otherwise unlikely to complete the 
study, as determined by the investigator. 
Maximum duration of subject participation in the study: 
The subject’s maximum duration of participation from screening to safety follow-up period is expected to be 
approximately 61 weeks (or 14.2 months).  
• 
Screening period: up to 6 weeks (42 days) 
• 
Baseline visit period: up to 1 week (7 days) 
• 
Treatment period: up to 52 weeks  
• 
Safety follow-up period: 2 weeks (14 days) 
Statistical analysis: 
Analysis Set 
The statistical analysis will include the following analysis sets: 
• 
The intent-to-treat (ITT) set will include all subjects who sign the ICF, are enrolled in the study, and 
have received at least 1 study drug infusion (full or partial). 
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• 
The modified intent-to-treat (mITT) set will include all enrolled subjects (all subjects from the ITT 
set) who have received at least 1 dose of investigational product and completed at least 1 post-baseline 
efficacy assessment of the endpoints. The mITT set will be used for efficacy analyses. 
• 
The safety set will include all subjects in the ITT set who receive at least 1 dose of REPLAGAL. The 
safety set will be used for the analysis of safety endpoints.  
• 
The per-protocol (PP) set will include all subjects in the mITT set excluding subjects with major 
protocol deviations. The PP set will be identified by a team consisting of, at a minimum, a physician and 
a statistician from Takeda. The PP set will be used for an efficacy sensitivity analysis. 
• 
The pharmacokinetic (PK) set will include all subjects in the ITT who receive at least 1 dose of 
investigational product and provide intensive or sparse PK samples. The intensive PK set will include 
subjects in the PK set who provide intensive sampling. Five adult subjects and 5 pediatric subjects will 
be included in this set. Pharmacokinetic parameters will be derived from the intensive PK set. 
Study Endpoints 
Primary Endpoint: 
• 
Serious TEAEs 
Secondary Endpoints: 
• 
TEAEs 
• 
Infusion-related reactions (IRRs) 
• 
Anti-drug antibody against agalsidase alfa assessment, including neutralizing antibody (NAb) status  
• 
Laboratory assessments 
• 
Vital signs 
• 
Electrocardiogram results 
• 
Change from baseline at Week 52 in renal function, assessed by eGFR  
• 
Change over time in eGFR 
• 
Change over time in LVMI and LVEF as measured by echocardiography 
• 
Change over time in urine protein/creatinine ratio  
• 
Change over time in pain as assessed by BPI-Short Form 
• 
Change over time in plasma lyso-Gb3 level 
• 
Change in hearing (audiology testing for subjects <18 years old at screening) 
• 
PK parameters 
Sample Size 
A sample size of 20 safety evaluable subjects is planned to be enrolled in this study to descriptively provide an 
estimate of the serious TEAE rate. No formal sample size calculations have been done and the sample size is 
based on feasibility. 
Efficacy Analyses 
Continuous variables will be summarized with descriptive statistics including the mean, standard deviation (SD), 
median, minimum and maximum. Categorical data will be summarized with the frequency and percentage of 
subjects falling within each category. Subsequently, longitudinal data will be analyzed using mixed-effects model 
for repeated measures, using both the mITT and PP sets (using the PP set will serve as a sensitivity analysis). 
The observed values, the change from baseline, the change over time, and the percentage change from baseline 
for the efficacy measurements (eGFR, urine protein/creatinine ratio, plasma lyso-Gb3, LVMI, and LVEF) will be 
summarized by sex and visit. Subject listings will be provided for clinical outcomes from the BPI-Short Form 
measurement. 
Audiology results will be produced at baseline and (if applicable) for each post-baseline evaluation visit. 
Audiology data will also be presented in the form of individual subject listings. 
Efficacy analyses will be based on the mITT set, with the PP set as a sensitivity analysis. 
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Safety Analyses 
Adverse events will be coded using the most recent version of Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Treatment-emergent AEs will be summarized for overall and by system organ 
class (SOC) and preferred term (PT). Analysis of AEs will be performed at both subject level and AE level. 
Similar displays will be provided for IRRs. The AEs will be summarized by severity, seriousness, and 
relationship to investigational product. 
Subjects will be counted once per SOC and once per PT. Multiple events of the same type will be combined for 
each subject and, when doing this, the worst severity or outcome for each event type will be presented for the 
analysis. When calculating event rates, the denominator will be the total population size, irrespective of dropouts 
over the course of follow-up.  
Tabular summaries of other safety endpoints (eg, vital signs, blood tests, concomitant medications [coded using 
the World Health Organization Drug Dictionary], anti-agalsidase alfa antibody status, and infusion information) 
will be produced at baseline and, if applicable, for each post-baseline evaluation visit. 
Changes in the results of physical examination from the baseline will be presented by visit and body system in the 
form of a shift table. 
The observed values and the change from baseline for electrocardiogram (ECG) parameters (PR, QRS, QT, QTc, 
and heart rate) will be summarized by visit. The number of subjects with normal and abnormal ECG results 
during the study period will be summarized by visit in the form of a shift table. 
Laboratory data will be listed by subject. Subjects with newly occurring abnormalities outside the normal range 
will be flagged, listed separately, and summarized. The mean change from baseline in laboratory values or a shift 
table also will be provided at each visit. Change from baseline will be calculated by subtracting the baseline value 
from the post-baseline value. 
Vital sign data will be listed by subject, and any newly occurring changes outside the reference range from 
baseline will be flagged. Mean changes from baseline for vital sign data will be summarized. Subjects with 
notable abnormal values will be identified and listed separately along with their values. 
The number and percentage of subjects reporting at least one use of concomitant medication during the study will 
be reported. Subject listings will be provided describing the reason(s) for study discontinuation. 
Antibody data, including NAbs, will also be presented in the form of individual subject listings. 
Safety data will be analyzed using the safety set. 
Pharmacokinetic Analyses 
Statistical analysis of PK data will be based on the PK set as well as the intensive PK set. 
For the PK set, individual concentrations will be listed and summarized by scheduled time points for all subjects 
and by age (eg, ≥18 years vs <18 years). For the intensive PK set, individual concentration will be summarized 
for all subjects and by age. Individual PK parameters of REPLAGAL will be listed and summarized by treatment 
for all subjects as well as by age with descriptive statistics (number, arithmetic mean, SD, coefficient of variation 
[CV], median, minimum, maximum, geometric mean, and CV of geometric mean). Pharmacokinetic parameter 
estimates will be computed, where appropriate, from individual serum-concentration time data using 
noncompartmental methods and actual times. Figures of individual and mean (±SD) concentration-time profiles 
of REPLAGAL will be generated based on nominal time points for all subjects and by age. 
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1.2 Schedule of Activities 
Table 1. Schedule of Activities 
Study Assessments  
and Procedures 
Screening 
Perioda 
 
Baseline 
Visit 
Periodb 
Treatment Periodc 
Safety Follow-up Period 
(End of Study) 
  
EOW REPLAGAL 
Infusion 
(±4 days; 
Week 0 through 
Week 52)d 
Evaluation Visite 
Telephone Contact/Visitf 
Week -7 
through 
 Week -2 
 
 
 (Week -1) 
 
Week 8 
(±4 days) 
Week 16 
(±4 days) 
Week 28 
(±4 days) 
Week 40 
(±7 days) 
Week 52 
(±7 days) 
EOT or Early 
Discontinuationg 
14 days 
(+7 days) from EOT or 
Last Infusion for 
Discontinued Subjects 
Informed consenth 
• 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria review 
• 
• 
 
 
 
 
 
 
 
Confirmation of Fabry diseasei 
• 
 
  
 
 
 
 
 
 
Demography 
• 
 
 
 
 
 
 
 
 
Medical history 
• 
 
 
 
 
 
 
 
 
Physical examination 
• 
 
 
 
• 
 
 
• 
 
Vital signsj 
• 
• 
• 
• 
• 
• 
• 
• 
 
Heightk 
• 
• 
 
• 
• 
• 
• 
• 
 
Weightl 
• 
• 
• 
• 
• 
• 
• 
• 
 
Audiology testingm 
 
• 
 
• 
• 
• 
• 
• 
 
Pain (BPI-Short Form) 
 
• 
 
• 
• 
• 
• 
• 
 
Dose calculationn 
 
 
• 
• 
• 
• 
• 
•g 
 
REPLAGAL infusiono 
 
 
• 
• 
• 
• 
• 
•g 
 
PK samplingp 
 
 
• 
 
 
• 
 
 
 
12-Lead ECG 
• 
• 
 
 
• 
 
 
• 
 
Echocardiographyq 
 
• 
 
 
• 
 
 
• 
 
eGFR calculationr 
• 
• 
 
• 
• 
• 
• 
• 
 
Pregnancy tests 
• 
• 
 
• 
• 
• 
• 
• 
 
Serum chemistryt 
• 
• 
 
• 
• 
• 
• 
• 
 
Hematologyu 
• 
• 
 
• 
• 
• 
• 
• 
 
Serum ADA and neutralizing 
antibodiesv 
 
• 
 
• 
• 
• 
• 
• 
 
Plasma lyso-Gb3w 
 
• 
 
• 
• 
• 
• 
• 
 
Urinalysisx 
• 
• 
 
• 
• 
• 
• 
• 
 
Urine protein/creatinine ratiox 
• 
• 
 
• 
• 
• 
• 
• 
 
Viral testingy 
• 
 
 
 
 
 
 
 
 
Review of AEs 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Prior/concomitant medications, and 
medical/surgical interventions 
• 
• 
• 
• 
• 
• 
• 
• 
• 
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ADA=anti-drug antibody; AE=adverse event; β-hCG=beta-human chorionic gonadotropin; BPI=Brief Pain Inventory; ECG=electrocardiogram; eGFR=estimated 
glomerular filtration rate; EOT=end of treatment; EOW=every other week; HCV=hepatitis C virus; IRR=infusion-related reaction; 
lyso-Gb3=globotriaosylsphingosine; PK=pharmacokinetic; SAE=serious adverse event 
a Screening procedures can be performed over multiple days within a period of up to 42 days following the subject’s (or the subject’s parent(s)/legally 
authorized representative) signature of the informed consent form. 
b All baseline procedures and evaluations must be completed prior to the first REPLAGAL infusion and will be performed at the clinical site. Serum chemistry, 
hematology, urinalysis, and ECG performed at screening within 7 days prior to baseline visit may be used as the baseline.  
c During the treatment period, all study assessments and procedures should be completed on the day(s) of the scheduled visit. 
d The REPLAGAL infusions are to be administered at the clinical site. 
e Procedures and evaluations to be performed at site visits will occur at the clinical site. 
f The safety follow-up period (end of study) is 14 days (+7 days) following EOT infusion (or the last infusion for discontinued subjects). During this period, 
there will be a telephone call/scheduled visit to query for AEs, SAEs, and concomitant medications. Subjects who experienced SAEs, or mild, moderate, or 
severe AEs may be requested to visit the clinical site for further examination. All AEs and SAEs that are not resolved at the time of this contact will be 
followed to closure. 
g For subjects who discontinue the study early, all EOT assessments and procedures should be completed except for dose calculation and REPLAGAL infusion. 
h Informed consent must be obtained prior to performing any study-related procedures. 
i Fabry disease diagnosis will be confirmed at screening by medical record. 
j The following vital signs will be collected at all study visits (screening and infusion visits): pulse, blood pressure, respiratory rate, and temperature. On 
infusion visits (EOW and evaluation visits), vital signs should be obtained as follows: 1) within 10 minutes prior to starting the infusion; 2) 20 minutes 
(±5 minutes) after the start of the infusion; 3) 10 minutes (±5 minutes) after completing the infusion; and 4) 30 minutes (±5 minutes) after completing the 
infusion. In the event that a scheduled infusion does not occur on an evaluation visit, the vital signs should still be collected. The vital signs that were taken 
within 10 minutes prior to the start of the expected infusion should be documented in the electronic case report form. If no IRRs are observed during the first 
3 infusions, the observation and vital signs after infusion can be omitted at the discretion of the investigator. 
k For subjects <18 years of age, height should be measured at screening, baseline, and every evaluation visit during the treatment period. For subjects ≥18 years 
of age at screening, height should be measured only at the baseline visit.  
l Weight will be measured at screening, baseline, and every visit during the treatment period, with any dosing adjustments completed prior to the dose 
administration. 
m Audiology testing is only applicable to subjects <18 years old. 
n The first dose of REPLAGAL will be based on the subject’s weight at baseline. A change of at least 5% in subject weight from baseline or the last weight used 
to calculate the dose will require a dose recalculation at the clinical site. 
o REPLAGAL (at a dose of 0.2 mg/kg body weight) will be administered as an intravenous infusion over 40 minutes (±10 minutes) EOW (±4 days) at the clinical 
site, except on Day 1 (Week 0) and at the Week 28 visit where the length of infusion must be exactly 40 minutes to support the PK sampling. All study 
procedures, assessments (except for post-infusion vital signs), and sample collections (except for post-infusion PK sample collection) should be completed 
prior to administering an infusion, except on Week 40 and 52 visits where REPLAGAL infusion should maintain the ±4 days window period while the 
evaluation procedures can be done within the ±7 days window period. If at all possible, missed infusions should be avoided. If a subject is not dosed within 
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21 days from the previous dose, the subject should receive the missed infusion as soon as possible. It may be acceptable to give the next infusion as early as 
7 days after the previous infusion. Subsequent infusions will return to the original schedule. 
p Sampling for PK assessments will be performed only at Week 0 and Week 28 and the PK assessments will be conducted in the Takeda-designated central 
laboratory. See Table 2 and Table 3 for PK sampling time points. 
q An echocardiogram performed within 14 days prior to baseline visit may be used as the baseline echocardiogram. Echocardiography will be read locally at the 
clinical site by the investigator or a qualified designee. 
r eGFR will be calculated using the Counahan–Barratt equation for subjects <18 years old and the Chronic Kidney Disease Epidemiology (CKD-EPI) 
Collaboration equation for subjects aged 18 years and older and will be conducted in the Takeda-designated central laboratory. 
s Female subjects of childbearing potential will have a pregnancy test administered at screening, baseline visit, and evaluation visits. Pregnancy testing will be 
performed using a urine test, and if needed, a serum β-hCG test. If the urine pregnancy test is negative, procedures will be completed; serum β-hCG testing is 
no longer required. If the urine test is positive, a blood sample will be collected for serum β-hCG testing and sent to either local laboratory or the central 
laboratory for analysis; no additional procedures should be completed until the result of the serum pregnancy test is available. Female subjects of childbearing 
potential must have a negative urine pregnancy test, or a negative serum β-hCG test when a urine test is positive to be eligible for the study. A positive serum 
β-hCG test would result in the subject being a screen failure or discontinued from the study. 
t Serum chemistry laboratory tests (see Appendix 2 for details) will be performed in the local laboratory unless otherwise specified. 
u Hematology laboratory tests include complete blood count (see Appendix 2 for details) will be performed in the local laboratory. 
v ADA samples will be collected at baseline visit and evaluation visits prior to infusion; any samples that are confirmed positive for ADA will also be tested for 
neutralizing antibodies. The test will be performed in the Takeda-designated central laboratory. 
w Plasma lyso-Gb3 will be assessed in the Takeda-designated central laboratory. 
x An early morning spot urine sample will be obtained to measure protein and creatinine levels. Measurement of urine protein/creatinine ratio will be performed 
as part of urinalysis (see Appendix 2 for details on urinalysis). 
y Tests for hepatitis B surface antigen with confirmation by hepatitis B viral DNA load, HCV antibody with confirmation by HCV ribonucleic acid polymerase 
chain reaction testing, and human immunodeficiency virus antibody will be performed in the local laboratory. 
 
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Table 2. Intensive Pharmacokinetic Sampling Time Points 
Sampling time 
pointsa 
(from start of 
infusion) 
Pre-infusion 
During infusion  
End of Infusion 
Post-infusion  
0 min 
20 mins 
40 mins 
50 mins 
60 mins 
90 mins 
120 mins 
240 mins 
360 mins 
Window 
 
±1 min 
±1 min  
±2 mins 
±2 mins 
±2 mins 
±2 mins 
±2 mins 
±3 mins 
≥18 years old 
• 
  
• 
• 
• 
• 
• 
• 
• 
• 
<18 years old 
• 
  
• 
• 
• 
• 
• 
• 
•  
a Intensive serial PK should be collected in 5 pediatric subjects and 5 adult subjects to allow for accurate estimation of PK parameters including AUC0-t and Cmax. 
 
Table 3. Sparse Pharmacokinetic Sampling Time Points 
Sampling time pointsa 
(from start of infusion) 
Pre-infusion 
End of Infusion 
Post-infusion  
0 min 
40 mins 
120 mins 
Window 
 
±1 min 
±2 min 
≥18 years old 
• 
• 
• 
<18 years old 
• 
• 
• 
a A reduced/sparse PK sampling schedule will be allowed for subjects not providing intensive PK samples.
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2. INTRODUCTION 
2.1 Indication and Current Treatment Options  
Indication  
Fabry disease is a rare, lifelong, slowly progressive, X-linked glycosphingolipid storage disorder 
with a global incidence estimated at 1:50,000 male live births (Spada et al., 2006). There are an 
estimated 18,860 patients with Fabry disease in China mainland (Blue book of “Improve the 
availability of drug for rare disease in China”, 2019).  
Fabry disease results from a mutation in the α-galactosidase A (GLA) gene located on 
chromosome Xq22.1, which leads to a partial or full loss of the activity of the lysosomal enzyme 
GLA (Garman and Garboczi, 2004). More than 400 mutations have been identified in the GLA 
gene. These consist mainly of missense mutations, but nonsense mutations in addition to single 
amino acid deletions and insertions were also reported (Mehta et al., 2010). Most of these 
mutations are “private”, having been identified only in individual families (Mehta et al., 2010). 
As an X-linked disorder, females may inherit an X-linked Fabry mutation from either parent 
accounting for twice the number of carriers (heterozygotes) as males (hemizygotes). Female 
carriers are not necessarily asymptomatic (Eng et al., 2007).  
Alpha-galactosidase A is a lysosomal hydrolase enzyme that catalyzes the removal of terminal 
alpha-galactosyl moieties during the catabolism of glycolipids and glycoproteins. Partially active 
or deficient GLA results in abnormal accumulation of glycolipids (globotriaosylceramide [Gb3]) 
in cells throughout the body, including capillary endothelial, renal (podocytes, tubular cells, 
glomerular endothelial, mesangial, and interstitial cells), cardiac (cardiomyocytes and 
fibroblasts) and nerve cells. Abnormal Gb3 concentrations in membranous structures may impair 
intracellular trafficking processes, cellular activation, intercellular communication, and cellular 
homeostasis. This results in inflammatory changes and cytokine release, ultimately leading to 
apoptosis and eventual organ dysfunction and/or failure (Brady, 1967; Kahn, 1973; Kaye et al., 
1988; Desnick, 1995; deVeber et al., 1992; Schaefer et al., 2009). 
Fabry disease is characterized by a range of phenotypes that generally correlates with the degree 
of residual enzymatic activity. The threshold level of alpha-Gal A activity below which clinically 
significant Fabry disease occurs is thought to be 30 to 35 percent of the mean normal control 
(Schiffmann et al., 2016). Phenotype presentation becomes more evident during childhood and 
young adulthood (Eng et al., 2007), and as the patient advances in age organ function 
deterioration intensifies ultimately leading to organ failure and early death. Most patients display 
multiple clinical manifestations of the disease, many of which may occur before 10 years of age 
in males (Deegan et al., 2006). In females, GLA activity is most often higher than males (Arends 
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et al, 2017) and the onset of symptoms and time of diagnosis can be variable, occurring 
approximately 10 years later compared with males (Eng et al., 2007; Kruger et al., 2010). The 
clinical presentation of the disease varies widely among patients, but neuropathic pain and 
acroparesthesia are typically the first and most frequent symptoms to manifest. Other clinical 
manifestations of Fabry disease include angiokeratomas, gastrointestinal problems, proteinuria, 
progressive renal impairment leading to renal failure, hypertrophic cardiomyopathy with 
arrhythmias, corneal dystrophy, hypohydrosis, and microvascular cerebral events including 
transient ischemic attacks, stroke, and dolychoectasia (Schiffmann and Ries, 2005; Deegan et al., 
2006). Vital organs, especially the heart, kidneys, and brain, are progressively affected with 
advancing age (Ries and Schiffmann, 2005). As a consequence, physical and functional well-
being and quality of life (QoL) are significantly reduced in patients with Fabry disease compared 
with the general population and patients with other chronic non-genetic disorders (Gold et al., 
2002; Miners et al., 2002). 
Patients with Fabry disease have a shortened life expectancy with men and women affected by 
the disorder living 20 years (MacDermot et al., 2001b) and 15 years (MacDermot et al., 2001a; 
Barbey et al., 2004; Mehta et al., 2004) less than those in the general population, respectively. 
Prior to the introduction of enzyme replacement therapy (ERT) in 2001, the leading cause of 
death in patients with Fabry disease was renal disease (Mehta et al., 2009). Since then, 
significant improvements have been made in supportive care of renal function and cardiac 
disease is now the primary cause of death (Mehta et al., 2009; Waldek et al., 2009). 
Current Treatment Options 
Two ERT products have been approved for patients with a confirmed diagnosis of Fabry disease: 
agalsidase alfa (marketed under the trade name of REPLAGAL® in countries outside the United 
States [US] by Shire [now part of Takeda]) and agalsidase beta (FABRAZYME®; 
Sanofi Genzyme).  
The first approval of REPLAGAL as treatment for Fabry disease occurred in August 2001 in the 
European Union. As of 31 Jan 2023, REPLAGAL has been approved as treatment for Fabry 
disease in 70 countries.  
Migalastat (GALAFOLD) was granted approval in Europe in May 2016 and in the US in 2018 as 
the first chaperone therapy for the long-term treatment of Fabry disease in adults and adolescents 
aged 16 or older with an amenable mutation in GLA. 
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2.2 Product Background and Clinical Information 
Product Background 
Alpha-galactosidase A is a homodimer comprising 2 approximately 50 kDa subunits; GLA is 
targeted to its lysosomal site of action by mannose-6-phosphate (M6P) moieties, which bind to 
their cognate receptors in the Golgi directing the enzyme to the prelysosomal compartments. Any 
enzyme that escapes this routing system is secreted by the cell via the constitutive secretory 
pathway and is often recaptured by cell surface M6P receptors to be rerouted to the lysosome by 
the endocytic pathway (Kornfeld and Mellman, 1989). The M6P mediated lysosomal targeting is 
the key mechanism that made ERT a feasible treatment strategy for lysosomal storage diseases as 
it enables the targeting of exogenously administered lysosomal enzymes to the appropriate 
subcellular compartment for their optimal activity.  
REPLAGAL (agalsidase alfa) is human GLA produced by genetic engineering technology in a 
human cell line. REPLAGAL is manufactured using an aseptic filling process in a facility in 
compliance with current Good Manufacturing Practice and regulations. REPLAGAL is formulated 
as a sterile product suitable for parenteral administration. The formulation of REPLAGAL includes 
sodium phosphate as a buffering agent, polysorbate 20 as a stabilizing agent, and sodium 
chloride as an isotonic agent. 
REPLAGAL is intended for use as an ERT for patients with Fabry disease. Replacement of the 
absent or deficient enzyme contributes to the correction of the deficient enzymatic activity and 
allows for improved metabolism of the natural substrate of the enzyme.  
Over time, chronic replacement of the deficient enzyme could theoretically alter the natural 
history of Fabry disease, with concomitant improvements in renal and cardiac function, 
metabolism, neuropathic pain, and QoL. 
Clinical Information 
Clinical studies of REPLAGAL have been conducted in Australia, Brazil, Canada, Europe, Japan, 
Paraguay, and the US. The clinical development program was designed to evaluate the safety and 
efficacy of REPLAGAL in subjects with Fabry disease and includes early phase safety studies, 
placebo-controlled safety and efficacy studies, and open-label extension studies. Additionally, 
studies in special populations have been conducted: pediatric subjects, female subjects, dialysis 
and renal-transplant subjects, and 1 compassionate-use study. A manufacturing change led to 
additional studies, such as bioequivalence pharmacokinetic (PK)/pharmacodynamic (PD) studies. 
One open-label, treatment protocol study (HGT-REP-081) evaluating the long-term safety of 
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REPLAGAL in subjects with Fabry disease following a manufacturing change from roller bottle to 
bioreactor, animal-free process has been recently completed in Canada (2018).  
REPLAGAL has a well-established safety profile. The population exposed to REPLAGAL in clinical 
studies is considerable relative to the rarity of this genetic disease and represents an extensive 
clinical database to assess REPLAGAL in the treatment of Fabry disease. As of 31 Jan 2023, the 
population exposed to REPLAGAL in clinical studies included 779 subjects (641 subjects with 
Fabry disease and 138 healthy volunteers). The 641 subjects with Fabry disease included 567 
adult subjects and 74 pediatric subjects. The estimated cumulative worldwide exposure to 
REPLAGAL, based on commercial sales data from launch in 2001 through 03 Aug 2022, is 
approximately 46,233 person-years.  
REPLAGAL is generally safe and well-tolerated in the adult and pediatric Fabry populations, as 
evidenced by over 10 years of clinical and commercial data. In the integrated clinical study 
datasets (November 2009), REPLAGAL was administered to 153 adult patients for a median of 
1.3 years and to 24 pediatric patients (6 to ≤18 years of age) for a median of 1.8 years. Twenty 
(20) adult patients (13.1%) and 11 pediatric patients (45.8%) were treated for at least 4 years. 
Given the extent of exposure, most adult patients (151 patients; 98.7%) and all pediatric patients 
(100.0%) reported at least 1 adverse event (AE), and 56 (36.6%) adult patients and 5 (20.8%) 
pediatric patients reported at least 1 serious adverse event (SAE). Only 5 (3.3%) adult patients 
discontinued due to an AE; no pediatric patient discontinued due to an AE. For a more detailed 
safety profile of REPLAGAL, please refer the Investigator’s Brochure (IB). 
Data collected in clinical trials to-date indicate that REPLAGAL remains safe and well-tolerated 
during long-term use. As with other intravenously (IV) administered protein therapeutics, the 
identified and potential risks of treatment with REPLAGAL include occurrence of infusion-related 
reactions (IRRs), cardiac ischemic events and arrhythmias triggered by IRRs, and potential 
development of neutralizing antibodies (NAbs) that may compromise efficacy. Of these, IRRs 
are idiosyncratic and allergic-type hypersensitivity reactions which may be defined as any new 
signs or symptoms experienced by subjects during the infusion or any new events occurring on 
the first day of administration of pharmacologic or biologic agents. Infusion-related reactions are 
the most commonly observed adverse drug reactions associated with REPLAGAL and generally 
occur within the first 2 to 4 months after initiation of treatment with REPLAGAL. The clinical 
experience has indicated that IRRs can be mitigated with a combination of infusion-rate control 
and medications such as antihistamines, antipyretics or low-dose corticosteroids. Cardiac 
ischemic events and arrhythmias triggered by IRRs have been also reported as risks associated 
with REPLAGAL treatment in patients with pre-existing cardiac manifestations of Fabry disease. 
The majority of these events were mild in severity, nonserious, and resolved. Cardiac events 
triggered by IRRs are possibly due to the hemodynamic stress caused by infusion. Additionally, 
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there is no apparent evidence to date for a loss of efficacy due to NAbs against agalsidase alfa. 
Borderline immunoglobulin E antibody positivity not associated with anaphylaxis has been 
reported in clinical studies. 
The efficacy profile of REPLAGAL was evaluated in clinical studies and REPLAGAL received 
initial regulatory approval based on reduction of pain in patients with Fabry disease; additionally, 
the registration studies evaluated important clinical outcome benefits such as QoL, renal 
function, cardiac structure, and PD (Gb3) measures.  
In aggregate, data from randomized double-blind placebo-controlled trials, long-term treatment 
data from open-label extensions, open-label experiences in special populations, and post-
marketing experience demonstrate that treatment with REPLAGAL is an effective treatment that 
stabilizes and decreases the progression of renal and cardiac disease, demonstrates clinically 
meaningful results in measures of pain and QoL, and produces a sustained improvement in PD 
measures in patients with Fabry disease. 
2.3 Study Rationale 
On 28 Aug 2020, REPLAGAL received approval of its New Drug Application from China’s 
National Medical Products Administration for the treatment of Fabry disease. As part of the 
approval requirements and post-authorization commitment, the China Health authority has 
requested that further efficacy and safety data be collected from Chinese patients with Fabry 
disease. For that, a Phase 3 interventional study was proposed. This study is intended to evaluate 
the safety, efficacy, and PK of REPLAGAL in treatment-naïve Chinese subjects with Fabry 
disease. 
2.4 Benefit/Risk Assessment 
The cumulative clinical and post-marketing experience indicates that the benefit-risk profile of 
agalsidase alfa for the treatment of Fabry disease remains favorable and supported by the 
following: 
• A high disease burden with life-threatening/debilitating complications 
• Alternative treatments are limited and are also associated with significant adverse 
reactions 
• Demonstrated benefit in pain reduction, improvement or stabilization of cardiac and renal 
function, and reduction in accumulation of Gb3 
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• Well established safety profile with the main identified risks of IRRs, cardiac events 
triggered by IRRs, and immunogenicity. 
Always refer to the latest version of the REPLAGAL IB for the overall risk/benefit assessment and 
the most accurate and current information regarding the drug metabolism, PK, efficacy, and 
safety of REPLAGAL. 
2.5 Compliance Statement 
This study will be conducted in accordance with this protocol, the International Council for 
Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, 1996; ICH E6 R2, 2016), 
and applicable national and local regulatory requirements. 
The responsibilities of the study sponsor and investigator(s) are described fully in Appendix 1. 
 
 
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3. OBJECTIVES AND ENDPOINTS 
3.1 Study Objectives 
3.1.1 Primary Objective 
The primary objective of this study is to assess the safety of REPLAGAL (0.2 mg/kg every other 
week [EOW] up to 52 weeks), by evaluating the incidence of serious treatment-emergent adverse 
events (TEAEs) over the study period, in treatment-naïve Chinese subjects with Fabry disease. 
3.1.2 Secondary Objectives 
The secondary objectives are as follows:  
• To evaluate other safety parameters of REPLAGAL  
• To evaluate the efficacy of REPLAGAL on the renal parameter (ie. estimated glomerular 
filtration rate [eGFR]) 
• To assess the efficacy of REPLAGAL on left ventricular mass index (LVMI) and left 
ventricular ejection fraction (LVEF) 
• To evaluate the efficacy of REPLAGAL on other renal variables, pain, and PD markers 
(plasma globotriaosylsphingosine [lyso-Gb3]) 
• To evaluate the change in hearing for subjects <18 years old 
• To evaluate the PK of REPLAGAL in treatment-naïve Chinese subjects with Fabry disease. 
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3.2 Study Endpoints 
Table 4. Objectives and Endpoints 
Objective 
Endpoints 
Primary 
 
• 
To assess the safety of 
REPLAGAL, by evaluating the 
incidence of serious TEAEs 
over the study period, in 
treatment-naïve Chinese 
subjects with Fabry disease 
• 
Serious TEAEs 
Secondary 
 
• 
To evaluate other safety 
parameters of REPLAGAL  
• 
TEAEs 
• 
Infusion-related reactions  
• 
Anti-drug antibody against agalsidase alpha assessment, including 
neutralizing antibody status 
• 
Laboratory assessments 
• 
Vital signs 
• 
Electrocardiogram results 
• 
To evaluate the efficacy of 
REPLAGAL on the renal 
parameter (ie, eGFR) 
• 
Change from baseline at Week 52 in renal function, assessed by 
eGFR using the CKD-EPI equation for subjects ≥18 years old and 
Counahan–Barratt equation for subjects <18 years old 
• 
Change over time in eGFR 
• 
To assess the efficacy of 
REPLAGAL on LVMI and 
LVEF 
• 
Change over time in LVMI and LVEF as measured by 
echocardiography. 
• 
To evaluate the efficacy of 
REPLAGAL on other renal 
variables, pain, and PD 
markers (plasma lyso-Gb3) 
• 
Change over time in urine protein/creatinine ratio  
• 
Change over time in pain as assessed by BPI-Short Form 
• 
Change over time in plasma lyso-Gb3 level 
• 
To evaluate the change in 
hearing for subjects 
<18 years old 
• 
Change in hearing (audiology testing for subjects <18 years old at 
screening) 
• 
To evaluate the PK of 
REPLAGAL in treatment-naïve 
Chinese subjects with Fabry 
disease 
PK parameters include, but are not limited to, the following: 
• 
AUC0-last (min*U/mL): Area under the concentration-time curve 
from the time of dosing to the last measurable concentration 
• 
AUC0-∞ (min*U/mL): Area under the concentration-time curve 
from time zero extrapolated to infinity 
• 
CL (mL/min): Serum clearance of administered dose (Dose/AUC) 
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Table 4. Objectives and Endpoints 
Objective 
Endpoints 
• 
CL (mL/min/kg): Serum clearance of administered dose normalized 
for body weight  
• 
Cmax: Maximum concentration observed 
• 
t1/2 (min): Terminal elimination half-life, defined as the natural log 
of 2 divided by the terminal rate constant (ƛz) 
• 
tmax (min): Time of maximum observed concentration sampled 
post-dose 
• 
Vss (mL): Volume of distribution at steady state 
• 
Vss (%BW): Estimate of volume of distribution at steady state 
normalized for body weight 
• 
AUClast/dose (AUClast/[U/kg]): Area under the concentration-time 
curve at the last sample (AUClast) normalized for the dose of 
enzyme activity 
• 
AUC0-∞/dose (AUC0-∞/[U/kg]): Area under the concentration-time 
curve at infinity (AUC0-∞) normalized for the dose of enzyme 
activity 
• 
Cmax/dose (Cmax/[U/kg]): Maximum serum concentration (Cmax) 
normalized for the dose of enzyme activity 
AUC=area under the curve; BPI=Brief Pain Inventory; CKD-EPI=Chronic Kidney Disease Epidemiology; 
CL=serum clearance; Cmax=maximum concentration observed; eGFR= estimated glomerular filtration rate; 
LVEF=left ventricular ejection fraction; LVMI=left ventricular mass index; lyso-Gb3=globotriaosylsphingosine; 
PD=pharmacodynamic; PK=pharmacokinetic; t1/2=terminal elimination half-life; TEAE=treatment-emergent 
adverse event; tmax=time of maximum observed concentration; Vss=volume of distribution at steady state 
 
 
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4. STUDY DESIGN 
4.1 Overall Design 
This is a China-only, Phase 3, multicenter, nonrandomized, open-label, single-arm study to 
evaluate the safety, efficacy, and PK of REPLAGAL in treatment-naïve Chinese subjects with 
Fabry disease. The study will consist of EOW treatment with 0.2 mg/kg IV infusion of 
REPLAGAL for up to 52 weeks. A total of 20 safety evaluable subjects aged ≥7 to ≤65 years are 
planned to be enrolled with at least 25% of the total eligible subjects in the age range of ≥7 to 
<18 years old. 
The study will include a screening period, a baseline visit period, a treatment period, and a safety 
follow-up period. Screening assessments will occur from Week -7 through Week -2. Baseline 
visit period will be at Week -1. After completion of baseline procedures and assessments, 
eligible subjects will receive 0.2 mg/kg IV infusions of REPLAGAL EOW (±4 days) from Day 1 
(Week 0) up to Week 52 (end of treatment [EOT] visit) during the treatment period. Evaluation 
visits will be performed at clinical site at Week 8 (±4 days), Week 16 (±4 days), Week 28 
(±4 days), Week 40 (±7 days), and Week 52 (±7 days). Additionally, PK assessments will occur 
at Day 1 (Week 0) and Week 28 (±4 days). In order to ensure subjects’ safety, subjects will 
undergo a follow-up period of approximately 14 days (+7 days) after the completion of the 
treatment infusion (or the last infusion for early treatment discontinued subjects). The complete 
list of study procedures is presented in Table 1. 
In the event a monitor cannot visit the site in a timely manner due to unavoidable circumstances, 
such as the coronavirus disease (COVID-19) pandemic, alternative monitoring approaches such 
as remote source data verification or telephone contact may be used to ensure data quality and 
integrity and maintain subject safety. Alternative monitoring approaches should be used only 
where allowed by the local Health Authority and permitted by the institutional review board 
(IRB)/ethics committee (EC), if applicable. 
Safety assessments include monitoring of AEs, use of concomitant medication, clinical 
laboratory values, vital signs, antibody formation, physical examination, and electrocardiogram 
(ECG) results (Section 8.2.3). 
Efficacy assessments include measurements of eGFR, urine protein/creatinine ratio, LVMI, 
LVEF, and Brief Pain Inventory (BPI). For pediatric subjects (<18 years old at screening), 
additional assessment for hearing will be performed (Section 8.2.2). 
Pharmacodynamic assessment includes plasma lyso-Gb3 (Section 8.2.4.1). Pharmacokinetic 
assessments will be completed by obtaining blood samples at pre-specified time points in the 
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study (Section 8.2.4.2). Ten subjects (5 adult subjects and 5 pediatric subjects) will provide 
intensive PK samples and other subjects will provide sparse PK samples. 
4.2 Justification for Dose 
REPLAGAL (agalsidase alfa) 1 mg/mL concentrate solution for infusion is approved in 
70 countries worldwide as of 31 Jan 2023. REPLAGAL will be administered at the globally 
approved dose of 0.2 mg/kg EOW by IV infusion over 40 minutes (±10 minutes). This regimen 
of REPLAGAL has been approved and marketed in Europe and multiple other countries worldwide 
for the treatment of Fabry disease. 
4.3 Duration of Subject Participation and Study Completion Definition 
The subject’s maximum duration of participation from screening to safety follow-up period is 
expected to be approximately 61 weeks (or 14.2 months).  
• Screening period: up to 6 weeks (42 days) 
• Baseline visit period: up to 1 week (7 days) 
• Treatment period: up to 52 weeks  
• Safety follow-up period: 2 weeks (14 days) 
The study completion is defined as when the last subject in the study completes the final 
protocol-defined assessment(s). This includes the safety follow-up visit or contact, whichever is 
later (see Section 8.1.4 for the defined safety follow-up period for this protocol). 
The study is expected to be completed in approximately 28 months.  
4.4 Sites and Regions 
The study is planned to be conducted in 4 to 6 sites in China. 
 
 
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5. STUDY POPULATION 
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed. 
5.1 Inclusion Criteria 
The subject will not be considered eligible for the study without meeting all of the criteria below. 
1. Subject and/or legally authorized representative must voluntarily sign an Institutional 
Review Board/Independent Ethics Committee approved written informed consent form 
(ICF) after all relevant aspects of the study have been explained and discussed with the 
subject. For the subjects <18 years old, subjects will give assent AND their 
parent(s)/legally authorized representative should sign the ICF accordingly. 
2. The subject has confirmed diagnosis of Fabry disease as determined by the investigator, 
according to medical record including: 
• For male subject, Fabry disease is confirmed by a deficiency of GLA activity and a 
mutation in the GLA gene 
• For female subject, Fabry disease is confirmed by a mutation in the GLA gene.  
3. The subject is 7 to 65 years of age, inclusive, at screening. 
4. Female subjects of childbearing potential must have a negative pregnancy test at 
screening.  
5. Female subjects of childbearing potential must agree to use a medically acceptable 
method of contraception at all times during the study and for at least 14 days after the 
final investigational product infusion; the methods of acceptable contraception are listed 
in the protocol (Section 5.4.1).  
6. The subject is deemed, as determined by the investigator, to have adequate general 
health to undergo the specified protocol-related procedures and to have no safety or 
medical contraindications for participation. 
7. The subject has not received any treatment (approved or investigational) specific to 
Fabry disease, such as ERT, chaperone therapy, or substrate reduction therapy.  
8. The adult subject (≥18 years old) must have an eGFR of 45 to 120 mL/min/1.73 m2 
(inclusive). Serum creatinine is tested and the eGFR is calculated by central laboratory 
using the Chronic Kidney Disease Epidemiology (CKD-EPI) equation.  
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5.2 Exclusion Criteria 
The subject will be excluded from the study if any of the following exclusion criteria are met. 
1. In the opinion of the investigator, the subject’s life expectancy is ≤5 years. 
2. The subject has undergone or is scheduled to undergo kidney transplantation or is 
currently on dialysis or has any signs or symptoms of end stage renal disease. 
3. The subject has a urine protein/creatinine ratio of >500 mg/g. 
4. The subject has a clinically relevant history of allergy or signs or symptoms of severe 
hypersensitivity, which in the investigator’s judgment, will substantially increase the 
subject’s risk if he or she participates in the study.  
5. In the opinion of the investigator, the subject has non-Fabry disease-related cause of end 
organ (renal, cardiovascular, central nervous system) dysfunction/failure or is receiving 
medications that may affect the rate of disease progression, as assessed by renal 
measures.  
6. The subject has a positive test result at screening for hepatitis B surface antigen with 
detectable hepatitis B viral DNA load, hepatitis C virus (HCV) antibody with 
confirmation by HCV ribonucleic acid polymerase chain reaction testing, or human 
immunodeficiency virus antibody. 
7. The subject has received prior treatment with any of the following medications, with the 
exception of non-systemic use: 
• Chloroquine 
• Amiodarone 
• Monobenzone  
• Gentamicin 
8. The subject is pregnant or lactating. 
9. The subject has a body mass index >35 kg/m2. 
10. The subject is treated or has been treated with any investigational drug for indication 
other than Fabry disease within 30 days prior to study start. 
11. The subject and/or the subject’s parent(s)/legal guardian is unable to understand the 
nature, scope, and possible consequences of the study.  
12. The subject is unable to comply with the protocol, eg, uncooperative with protocol 
schedule, refusal to agree to all of the study procedures, inability to return for 
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evaluations, or is otherwise unlikely to complete the study, as determined by the 
investigator. 
5.3 Restrictions  
Not applicable. 
5.4 Reproductive Potential 
5.4.1 Female Contraception 
Sexually active females of childbearing potential should use an acceptable form of contraception. 
Females of childbearing potential must be advised to use acceptable contraceptives throughout 
the study period and for 14 days following the last infusion of investigational product. If used, 
hormonal contraceptives should be administered according to the package insert. Any female of 
childbearing potential who is not currently sexually active must agree to use acceptable 
contraception, as defined below, if she becomes sexually active during the study and for 14 days 
following the last infusion of investigational product. 
Female children and adolescent subjects should be either: 
• Premenarchal and either Tanner stage 1 or less than age 9 years, or 
• Of childbearing potential with a negative pregnancy test at the screening visit (see 
Section 8.2.3.5). Females of childbearing potential must agree to abstain from sexual 
activity that could result in pregnancy or agree to use acceptable methods of 
contraception. 
 
Female adult subjects should be either: 
• Post-menopausal (12 consecutive months of spontaneous amenorrhea and age ≥51 years), 
• Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or 
• Of childbearing potential with a negative pregnancy test at the screening visit (see 
Section 8.2.3.5). Females of childbearing potential must agree to abstain from sexual 
activity that could result in pregnancy or agree to use acceptable methods of 
contraception with signature in ICF. 
 
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Acceptable methods of contraception include the following: 
• Intrauterine devices plus condoms 
• Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam) 
• Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the screening visit, plus condoms. Note: If the subject becomes 
sexually active during the study, she should use one of the other acceptable methods 
noted above in addition to the hormonal contraceptive until it has been stabilized for 
30 days. 
 
5.4.2 Male Contraception 
Not applicable. 
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6. STUDY INTERVENTION 
6.1 Investigational Product 
6.1.1 Identity of Investigational Product 
The investigational product is REPLAGAL, which will be supplied as a sterile, clear, colorless 
concentrate for dilution for IV infusion. REPLAGAL will be provided in single-use, 5 mL vials 
containing 3.5 mL of concentrate at a concentration of 1 mg/mL. 
Additional information is provided in the current REPLAGAL IB. 
6.1.2 Blinding the Treatment Assignment 
Not applicable. 
6.2 Administration of Investigational Product 
REPLAGAL infusions will occur at the clinical site. Subjects will receive REPLAGAL at a dose of 
0.2 mg/kg body weight administered as an IV infusion over 40 minutes (±10 minutes) EOW 
(±4 days), except on Day 1 (Week 0) and Week 28 visits where the length of infusion must be 
exactly 40 minutes to support the PK sampling. Refer to the instruction manual provided 
separately from this protocol that outlines all operating procedures to be followed for this study 
including drug reconstitution and the required subject assessments before, during, and after 
infusion of investigational product. 
6.2.1 Management of Infusion-related Reactions 
For guidance on the management of IRRs, see Appendix 3.1. 
6.2.2 Interactive Response Technology for Investigational Product Management 
An interactive response technology (IRT) will be used for investigational product management 
tasks including investigational product supply management, inventory management and supply 
ordering, investigational product expiration tracking, destruction at site tracking, and return of 
investigational product. Please refer to the instruction manual provided separately from this 
protocol that outlines the operating procedures regarding the IRT. 
6.2.3 Allocation of Subjects to Treatment  
This is an open-label, non-randomized study where all subjects will be enrolled to receive 
REPLAGAL at 0.2 mg/kg EOW. Subject numbers are assigned to all subjects as they consent to 
take part in the study. Within each site (numbered uniquely within a protocol), the subject 
number is assigned according to the sequence of subject presentation for study participation. 
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6.2.4 Dosing 
REPLAGAL will be administered at a dose of 0.2 mg/kg body weight as an IV infusion over 
40 minutes (±10 minutes) EOW (±4 days), except on Day 1 (Week 0) and Week 28 visits where 
the length of infusion must be exactly 40 minutes to support the PK sampling. The first dose of 
REPLAGAL will be based on the subject’s weight at baseline.  
The appropriate dose calculation is obtained as follows: multiply the subject’s weight in 
kilograms by 0.2 mg/kg. (Round up or down to the 1/10th decimal place from the 1/100th 
decimal place using >0.05 to round up). This will give the number of milliliters of drug required 
since the concentration is 1 mg/mL. A change in subject weight of ≥5% from baseline or the last 
weight used to recalculate the dose will require a recalculation of the dose by the clinical site. 
REPLAGAL will be provided in single-use, 5 mL vials containing 3.5 mL of concentrate at a 
concentration of 1 mg/mL. To determine the number of vials required, divide number of 
milliliters determined above by 3.5 mL. Round up to the whole number and this is the number of 
vials required to withdraw the number of milliliters needed. 
DOSE CALCULATION EXAMPLE for a subject weighing 68 kg:  
• 68 kg × 0.2 mg/kg = 13.6 mg of REPLAGAL 
(subject weight × 0.2 mg/kg required per protocol = subject total dose of REPLAGAL) 
Since the concentration is 1 mg per mL, 13.6 mg = 13.6 mL 
• 13.6 mL ÷ 3.5 mL = 3.9 vials 
(subject dose ÷ total volume per vial = number of vials required)  
The subject would need 3 full vials and a partial amount of the fourth vial. 
All study procedures, assessments (except for post-infusion vital signs), and sample collection 
(except for post-infusion PK sample collection) should be completed prior to administering an 
infusion, except on Week 40 and 52 visits where REPLAGAL infusion should maintain the ±4 days 
window period while the evaluation procedures can be done within the ±7 days window period. 
Ideally, investigational product infusions should occur on the same day of the week, EOW (ie, 
every 14 days), but may occur every 14 days (±4 days) of the target day in order to facilitate 
subject scheduling. If at all possible, missed infusions should be avoided. If a subject is not 
dosed within 21 days from the previous dose, the subject should receive the missed infusion as 
soon as possible. It may be acceptable to give the next infusion as early as 7 days after the 
previous infusion. Subsequent infusions will return to the original schedule. 
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6.2.5 Dose Modification 
The first dose of REPLAGAL will be based on the subject’s weight at baseline. A change of at 
least 5% in subject weight from baseline or the last weight used to recalculate the dose will 
require a dose recalculation at the clinical site. Weight will be measured at every infusion visit, 
as specified in the Schedule of Activities (Table 1), with any dosing adjustments completed prior 
to the dose administration. 
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product 
6.3.1 Labeling 
Investigational product labels will contain information necessary to meet the applicable 
regulatory requirements. 
6.3.2 Packaging 
Investigational product will be packaged in the following labeled containers: single-use, 5 mL 
vials containing 3.5 mL of concentrate at a concentration of 1 mg/mL.  
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor. 
6.3.3 Storage 
REPLAGAL will be provided by the sponsor (or designee) to the clinical sites in a temperature-
controlled, monitored container. The vials should be stored in a refrigerator at 2-8°C (36-46°F). 
A minute amount of fine particulate matter, causing the solution to appear slightly hazy, may be 
present during storage. 
Investigational product must be stored in a locked refrigerator, or in a refrigerator in a locked 
room, with access limited to authorized study personnel. 
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within the established temperature range. The sponsor, or designee, must 
be notified of any temperature that fall out of the accepted range. Detailed guidance on storage 
requirements and issue reporting will be outlined in the Infusion and Pharmacy Manuals.  
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room. 
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6.3.4 Handling 
REPLAGAL should be handled as follows: 
• REPLAGAL vials should be stored in a refrigerator at 2-8°C (36-46°F). A minute amount 
of fine particulate matter, causing the solution to appear slightly hazy, may be present 
during storage. 
• REPLAGAL is intended for IV use only. 
• REPLAGAL for subject administration should be prepared by slowly mixing the 
appropriate amount of REPLAGAL into 100 mL of normal saline (0.9% sodium chloride) 
suitable for IV administration. 
• Once diluted into normal saline, the solution should be rocked gently, but not shaken.  
• Investigational product should be prepared on the day of infusion. As the product does 
not contain preservatives, REPLAGAL should be used as soon as possible after diluting 
with normal saline. Do not store above 25°C (77°F). It is recommended that infusion of 
the product be initiated within 24 hours of dilution. 
• The diluted REPLAGAL must be administered via an IV line that contains a standard filter. 
• Do not mix with or administer in conjunction with other drug solutions. 
• REPLAGAL vials are intended for one time use only (3.5 mL maximum). Remaining drug 
product (overfill or unused drug) left in a vial after withdrawing the subject’s assigned 
dose is NOT to be used for subsequent doses. 
6.4 Drug Accountability 
Investigators, or designee, will be provided with sufficient amounts of the investigational product 
to carry out this protocol for the agreed number of subjects. The investigator or designee will 
acknowledge receipt of the investigational product, documenting shipment content and 
condition. Accurate records of all investigational product received, dispensed, used, returned, 
and/or destroyed must be maintained as detailed further in this section. The investigator has 
overall responsibility for administering/dispensing the investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form. 
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The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. 
No investigational product stock or returned inventory from a Takeda-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer. 
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records. 
With the written agreement of the sponsor, at the end of the study all unused stock and 
empty/used investigational product packaging may be destroyed at the site or a local facility. In 
this case, destruction records identifying what was destroyed, when and how, must be obtained 
with copies provided to the sponsor. Destruction of investigational products must be in 
accordance with local, state, and national laws.  
In the event that a site is not allowed to destroy investigational product, all unused stock and 
empty/used investigational product packaging are to be sent to a nominated contractor on behalf 
of the sponsor. Investigational product being returned to the sponsor’s designated contractors 
must be counted and verified by clinical site personnel and the sponsor (or designated contract 
research organization [CRO]). Contact the sponsor for authorization to return any investigational 
product prior to shipment. Shipment of all returned investigational product must comply with 
local, state, and national laws. 
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction. 
6.5 Subject Compliance 
For this study, REPLAGAL is administered under controlled conditions at a clinical site; therefore, 
subject compliance with investigational product is anticipated to be high assuming 10% to 20% 
drop-out rate based on previous REPLAGAL trials.  
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6.6 Premedication and Prohibited Treatment 
6.6.1 Premedications 
Subjects experiencing a mild IRR may be premedicated with an antipyretic (eg, acetaminophen) 
and/or an antihistamine (eg, diphenhydramine) for subsequent infusions. Subjects experiencing a 
moderate or severe IRR may be premedicated with both an antihistamine and a corticosteroid 
(eg, diphenhydramine and hydrocortisone) in addition to acetaminophen for subsequent 
infusions. Premedication with ranitidine as a protective agent for the intestinal mucosa (in 
conjunction with hydrocortisone) may also be considered. If subsequent infusions continue 
without incident, then tapering of premedications may also be considered. If the subject 
experiences 3 additional IRRs of any severity despite premedication, blood should be drawn for 
anti-agalsidase alfa antibody testing just prior to the next infusion. 
6.6.2 Prohibited Treatment 
The following medications and treatments are prohibited at any time prior and throughout the 
course of the study: 
1. FABRAZYME (agalsidase beta) and its biosimilars 
2. GLYSET (miglitol) 
3. GALAFOLD (migalastat) 
4. Any investigational product for treatment of Fabry disease 
The following medications should not be administered at any time during this study because 
these substances have the potential to inhibit intracellular GLA: 
1. Chloroquine 
2. Amiodarone 
3. Monobenzone  
4. Gentamicin 
6.7 Protocol Considerations for Unavoidable Circumstances Such as the COVID-19 
Pandemic 
On a temporary basis, in order to maintain subject safety, confidentiality, and study integrity in 
the context of healthcare delivery challenges presented by unavoidable circumstances, such as 
the COVID-19 pandemic, subjects who may be impacted should contact clinical sites and 
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investigators to determine the best course of action. Depending on the impact, in some cases it 
may be possible to arrange for alternative solutions as permitted by local regulations. Any 
decision on procedural changes should be made on a case-by-case basis by the principal 
investigator in consultation with the study team and the medical monitor, while maintaining 
subject safety and confidentiality as the priority. 
Missing data, remote visits, changes to assessment approaches, and altered visit windows during 
unavoidable circumstances such as the COVID-19 public health emergency may affect the study 
results. Thus, it is important to identify all protocol deviations and altered data collection or 
assessment methods. Any protocol deviations, missing visits, or missing assessments related to 
COVID-19 restrictions will be recorded and reported in the clinical study report. 
The following procedural changes may be considered: 
• If necessary, informed consent (and assent if applicable) from a potential or current study 
subject may be obtained via electronic informed consent capabilities, or an electronic 
face-to-face consent interview when potential subjects are unable to travel to the site. 
• Subjects who discontinued from screening due to COVID-19-related factors but were 
otherwise qualified to participate in the study may be rescreened if the medical monitor 
agrees. 
• Remote checks instead of site visits (if appropriate) may be performed as a safety check 
on subject well-being. 
• Transfer to clinical sites away from risk zones to complete required visits. 
 
 
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7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
7.1 Discontinuation of Investigational Product 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 52 (Table 1) will be performed as completely as possible. Whenever possible, all 
discontinued subjects should also undergo the protocol-specified safety follow-up 14 days 
(+7 days) after the last dose/infusion. Comments (spontaneous or elicited) or complaints made by 
the subject must be recorded in the source documents. The reason for discontinuation, date of 
discontinuation of the investigational product, and the total amount of investigational product 
administered must be recorded in the source documents.  
7.2 Reasons for Discontinuation 
The primary reason for discontinuation must be determined by the investigator and recorded in 
the subject’s source document and the appropriate eCRF.  
Reasons for discontinuation include, but are not limited to: 
• Adverse event 
• Protocol deviation 
• Withdrawal by subject (by a parent(s) or legal guardian for pediatric subjects) 
• Lost to follow-up 
• Lack of efficacy 
• Death 
• Pregnancy 
• Other (If “Other” is selected, the investigator must specify in the eCRF)  
 
7.3 Withdrawal from the Study 
Withdrawal from the study means that the subject is no longer taking study treatment and does 
not return for further study visits. A subject may withdraw from the study at any time and for any 
reason without prejudice to his/her future medical care by the physician or at the institution, or 
may be withdrawn at any time at the discretion of the investigator or sponsor (eg, in the interest 
of subject safety). The investigator is encouraged to discuss withdrawal of a subject with the 
medical monitor when possible. Subjects who discontinue or withdraw will not be replaced. 
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7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Contact/Visit 
A minimum of 3 documented attempts must be made to contact any subject (or their legally 
authorized representative) who is lost to follow-up at any time point prior to the last scheduled 
contact (in person or by phone or video). These contact attempts should be documented in the 
medical record.   
 
 
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8. STUDY ASSESSMENTS AND PROCEDURES 
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent (and assent if applicable) 
from the subject (as per local requirements). There must be documentation of consent (and assent 
if applicable) as per local requirements indicating that the subject is aware of the investigational 
nature of the study and the required procedures and restrictions, prior to performing any study-
related procedures. 
8.1 Study Periods 
See Table 1 for the schedule of study activities. Study assessments are detailed in Section 8.2. 
8.1.1 Screening Period (Week -7 to Week -2) 
The duration of the screening period is up to 42 days where study subjects will undergo all 
procedures listed for the screening period in Table 1. The screening period can occur over 
multiple days to allow for the evaluation of subject’s eligibility for inclusion in the study. 
Written informed consent, and assent if applicable, to participate in the study will be obtained by 
the investigator from each subject before the performance of any protocol-specific procedure. 
The screening period starts when subjects sign informed consent/assent.  
At screening, each subject will be reviewed for eligibility against the study inclusion/exclusion 
criteria. Subjects who do not meet the study entrance criteria will not be allowed to participate in 
the study, and the reason(s) for the subject’s ineligibility will be documented. 
A screen failure is a subject who has given informed consent but who fails to meet the inclusion 
and/or exclusion criteria and has not been administered investigational product(s). 
Subjects who fail screening due to a single laboratory test result that does not meet eligibility 
criteria may have that laboratory test repeated at the discretion of the investigator. This will 
include a repeat of only the failed assessment rather than a repeat of all screening assessments 
(rescreening). In these cases, a new Subject Identification Code (SIC) is not required. The repeat 
of a single screening assessment is allowed only once. A repeat assessment must take place 
within 42 days of the initial screening for any subject requiring repeat of a screening assessment.  
If this timeframe is exceeded, then all screening assessments must be repeated and the subject 
assigned a new SIC. Exemptions may be provided if the timeframe is exceeded due to 
administrative reasons. 
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Subjects who still do not meet eligibility criteria may not have the laboratory test repeated a 
second time unless a justification can be provided.  
8.1.2 Baseline Visit Period (Week -1) 
Study subjects will undergo all procedures listed for the baseline visit in Table 1 prior to 
receiving the first infusion of REPLAGAL. Subject eligibility will be confirmed at baseline on the 
basis of review of the study entrance criteria (see Section 8.2.1.5). Subjects should not proceed to 
treatment period unless they continue to meet all inclusion/exclusion criteria at the baseline visit. 
The reason(s) for the subject’s ineligibility for the study will be documented. Screening 
assessment for serum chemistry, hematology, urinalysis, and ECG may be used as baseline if 
assessment is performed within 7 days prior to baseline. 
8.1.3 Treatment Period 
8.1.3.1 REPLAGAL Infusion EOW (±4 days) from Week 0 Through Week 52 
The treatment period will be up to 52 weeks during which subjects will receive EOW (±4 days) 
IV infusions of REPLAGAL at the clinical site. The first dose of REPLAGAL will be based on the 
subject’s weight at baseline. A change in subject weight of ≥5% from baseline or the last weight 
used to recalculate the dose will require a recalculation of the dose by the clinical site. 
8.1.3.2 Evaluation Visits at Week 8, 16, 28, 40, and 52 
At evaluation visits, all study procedures, assessments (except for post-infusion vital signs), and 
sample collection (except for post-infusion PK sample collection on Week 28) outlined in 
Table 1 should be completed prior to administering an infusion, except on Week 40 and 52 visits 
where REPLAGAL infusion should maintain the ±4 days window period while the evaluation 
procedures can be done within the ±7 days window period. If REPLAGAL is discontinued, 
regardless of the reason, the evaluations listed for Week 52 will be performed as completely as 
possible. Subject may visit the clinical site at schedules other than the scheduled visits for 
assessments as clinically warranted; these will be recorded as unscheduled visit. Unscheduled 
visit(s) will be recorded in the eCRF. 
8.1.4 Safety Follow-up Period (End of Study) 
The safety follow-up period (end of study) is 14 days (+7 days) after EOT infusion (or the last 
infusion for early treatment discontinued subjects). During this period, there will be a telephone 
call/scheduled visit to query for AEs, SAEs, and concomitant medications. Subjects who 
experienced SAEs or mild, moderate, or severe AEs may be requested to report to the clinical 
site for further examination. All AEs and SAEs that are not resolved at the time of this contact 
will be followed to closure (see Appendix 3.2). 
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8.1.5 Additional Care of Subjects after the Study 
No aftercare is planned for this study. 
8.2 Study Assessments 
Detailed descriptions of subject procedures and evaluations required for this protocol are 
described in this section. The timing for the performance of these evaluations is specified in the 
Schedule of Activities (Table 1). 
8.2.1 Demographic and Other Baseline Characteristics 
Subject demographic information including gender, age, and race will be collected prior to the 
subject receiving the first dose of investigational product.  
8.2.1.1 Height and Weight 
Height and weight will be measured and recorded in the subject’s source documents.  
For subjects <18 years of age at screening, height should be measured at screening, baseline, and 
every evaluation visit during the treatment period.  
For subjects ≥18 years of age at screening, height should be measured only at the baseline visit. 
Weight is a critical measurement as it determines the dosing of REPLAGAL. Weight will be 
measured at screening, baseline, and every visit during the treatment period, as specified in the 
Schedule of Activities (Table 1), with any dosing adjustments completed prior to the dose 
administration (Section 6.2.5). 
BMI should be calculated by the investigator using the weight and height measured during the 
baseline visit and will be recorded in the source documents as well as in EDC. 
8.2.1.2 Medical History 
Medical history (including documentation of diagnosis of Fabry disease) will be collected and 
recorded in the subject’s source documents. Medical history will include a review of the 
subject’s medical status and documentation of current and prior medical/surgical procedures. The 
subject will be queried on the following: 
• Relevant intercurrent illness and chronic disease update 
• Disease-specific review of symptoms concerning to the following organs and systems: 
• Head, neck, and thyroid 
• Eyes, ears, nose, and throat 
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• Chest and lungs 
• Heart 
• Lymph nodes 
• Abdomen 
• Anorectal 
• Genitourinary 
• Skin 
• Musculoskeletal 
• Endocrine 
• Neurological 
• Other 
8.2.1.3 Prior and Concomitant Treatment 
All non-study treatment including, but not limited to, herbal treatments, vitamins, behavioral 
treatment, or non-pharmacological treatment, such as psychotherapy, received within 30 days 
prior to screening period through the end of the safety follow-up period must be recorded in the 
subject’s source document and on the appropriate eCRF page. 
Prior treatment includes all treatment received within 30 days prior to the screening period 
through the date of the first dose of investigational product. Prior treatment information must be 
recorded on the subject’s source documentation and on the appropriate eCRF page. 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the follow-up period, inclusive. Concomitant treatment 
information must be recorded in the subject’s source document and on the appropriate eCRF 
page.  
8.2.1.4 Viral Testing 
Viral testing will be performed at screening to ensure that subjects do not present with viral 
infections that might compromise their ability to safely complete the study and confound later 
interpretation of the study findings. Viral tests include hepatitis B surface antigen with 
confirmation by hepatitis B viral DNA load, HCV antibody with confirmation by 
HCV-ribonucleic acid polymerase chain reaction testing, and human immunodeficiency virus 
(HIV) antibody. 
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8.2.1.5 Confirmation of Study Eligibility 
At screening, each subject will be reviewed for eligibility against the study inclusion/exclusion 
criteria. Subjects who do not meet the study entrance criteria will not be allowed to participate in 
the study, and the reason(s) for the subject’s ineligibility will be documented; the subject will be 
considered a screen failure (see Section 8.1.1).  
Subject eligibility will be confirmed at baseline on the basis of review of the study entrance 
criteria. Subjects should not be administered study medication unless they continue to meet all 
inclusion/exclusion criteria at the time of dosing. For any subjects who do not continue to meet 
the study entrance criteria, the reason(s) for the subject’s ineligibility for the study will be 
documented and the subject will be considered a screen failure. 
An Eligibility Form and required supporting documentation, as allowed by local regulations, 
should be sent to the sponsor’s medical monitor or designee as soon as the baseline procedures 
are completed for confirmation of patient eligibility. Confirmation of patient eligibility by the 
sponsor’s medical monitor or designee is required before first dose administration. 
8.2.2 Efficacy 
8.2.2.1 Estimated Glomerular Filtration Rate 
For subjects ≥18 years old, the serum creatinine is tested and eGFR is calculated by a 
Takeda-designated central laboratory from serum creatinine using the CKD-EPI equation. The 
CKD-EPI equation, expressed as a single equation, is: 
eGFR = 141 × min(Scr/κ,1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] 
Where, Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 for 
females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the 
maximum of Scr/κ or 1. 
For subjects <18 years old, the serum creatinine is tested and eGFR is calculated by a 
Takeda-designated central laboratory from serum creatinine using the Counahan–Barratt 
equation. The Counahan–Barratt equation, expressed as a single equation, is: 
eGFR = (0.43 × height in cm)/Scr 
Where, Scr is serum creatinine (mg/dL). 
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8.2.2.2 Brief Pain Inventory-Short Form  
The BPI-Short Form is a validated self-report measure that includes valid scales of pain intensity 
and pain related interference with various domains of functioning (see Appendix 5). The 
instrument is well validated in cancer pain populations and was used to characterize pain in 
subjects with terminal illnesses. Using a 1-week frame of reference, pain intensity “on average”, 
“at its worst”, “at its least”, and “pain right now”, are measured on separate 10-point numerical 
rating scales. Similar rating scales are used to estimate the degree to which pain interferes with 
general activity, mood, walking ability, normal work, sleep, relations with other people, and 
enjoyment of life. These 7 scales can be summed to generate an overall index of functional 
interference due to pain. Pain at worst will be the primary variable for assessing improvement in 
neuropathic pain. Subjects must be 12 years of age or older to complete the BPI-Short Form 
assessment on their own. Prior to 12 years of age, the subject’s parent(s)/legally authorized 
representative will complete this with the subject. The inventory is to be completed in its entirety 
prior to infusions at baseline, Weeks 8, 16, 28, 40, and 52 visits. No questions should be omitted 
at the discretion of the investigator and the form should not be modified in any way to include 
the name provided by the author. 
8.2.2.3 Urine Protein/Creatinine Ratio 
An early morning spot urine sample will be obtained to measure protein and creatinine levels. 
Measurement of urine protein/creatinine ratio will be performed as part of urinalysis (see 
Appendix 2 for details on urinalysis). 
8.2.2.4 Echocardiography 
Echocardiography will be used to assess cardiac LVMI and LVEF. Echocardiography will be 
performed in accordance with the clinical site’s standard practice(s) at time points specified in 
the Schedule of Activities (Table 1). An echocardiogram performed within 14 days prior to 
baseline visit may be used as the baseline echocardiogram. Echocardiography will be read 
locally at the clinical site by the investigator or a qualified designee. 
8.2.2.5 Audiology Testing 
For subjects <18 years old, audiology testing will be performed. Audiology testing will include 
pure tone conduction and bone conduction for each ear using 4 different pure tone frequencies 
(500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz) and will be performed at visits specified in the 
Schedule of Activities (Table 1). Any changes in threshold will be categorized as conductive, 
sensorineural, or unknown. 
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8.2.3 Safety 
8.2.3.1 Physical Examination 
A full physical examination will be performed by the investigator with a thorough review of 
body systems. Physical examinations will include a review of the subject’s general appearance as 
well as evaluation of the body systems including, but not limited to, endocrine, head and neck, 
cardiovascular, eyes, abdomen, ears, genitourinary, nose, skin, throat, musculoskeletal, chest and 
lungs, and neurological. Abnormalities identified at the screening visit and at subsequent study 
visits will be recorded in the subject’s source documents. All subsequent physical examinations 
should assess clinically significant changes from the baseline physical examination (defined as 
the assessment before first dose of study drug). Physical examination information should be 
entered on the Physical Examination eCRF, including interpretation of Normal; Abnormal, Not 
Clinically Significant; or Abnormal, Clinically Significant. 
8.2.3.2 Adverse Events 
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events will be collected from the time informed consent is signed. See Appendix 3 for 
AE definitions (including TEAEs, SAEs, IRRs), assessment, collection time frame, and reporting 
procedures.  
8.2.3.3 Vital Signs 
The following vital signs will be collected at all study visits: pulse, blood pressure, respiratory 
rate, and temperature. On visits where a subject is scheduled to receive an infusion, vital signs 
should be recorded as outlined in Table 5. In the event that a scheduled infusion does not occur 
at one of these visits, vital signs should still be collected. The vital signs that were taken within 
10 minutes prior to the start of the expected infusion should be documented in the eCRF. 
If there are no IRRs reported during the first 3 infusions, the observation and vital signs after 
infusion can be omitted at the discretion of the investigator. 
The investigator will assess whether a change from baseline visit in vital signs is clinically 
significant, and whether the change should be considered and recorded as an AE.  
Table 5. Schedule for Recording of Vital Signs at Infusion 
Timing Relative to Infusion 
Schedule of Assessments 
Start of Infusion 
Within 10 minutes prior to start of infusion 
During Infusion 
20 minutes (±5 minutes) after start of infusion 
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Table 5. Schedule for Recording of Vital Signs at Infusion 
Timing Relative to Infusion 
Schedule of Assessments 
After Infusiona 
10 minutes (±5 minutes) after completing the infusion 
30 minutes (±5 minutes) after completing the infusion 
a If there are no infusion-related reactions during the first 3 infusions, the observation and vital signs after 
infusion can be omitted at the discretion of the investigator. 
8.2.3.4 Clinical Laboratory Tests 
All clinical laboratory tests will be performed according to the laboratory’s standard procedures. 
Reference ranges will be supplied by the laboratory and used to assess the results for clinical 
significance and out-of-range changes which may be associated with, or constitute, an AE. The 
investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value is not clinically significant or clinically significant. Abnormal clinical 
laboratory values, which are unexpected or not explained by the subject’s clinical condition, 
may, at the discretion of the investigator or sponsor, be repeated as soon as possible until 
confirmed, explained, or resolved. 
A complete list of the clinical laboratory tests (serum chemistry, hematology, and urinalysis) to 
be performed is provided in Appendix 2. 
8.2.3.5 Pregnancy Test 
Female subjects of childbearing potential will have a pregnancy test administered at screening, 
baseline visit, and evaluation visits outlined in Table 1.  
At screening, pregnancy testing will be performed using a urine test, and if needed, a serum 
beta-human chorionic gonadotropin (β-hCG) test. The urine pregnancy test should be 
administered by the site before any other screening procedures (except for signature of informed 
consent) are completed. If the urine pregnancy test is negative, screening procedures will be 
completed as outlined in Table 1; serum β-hCG testing is no longer required. If the urine test is 
positive, a blood sample will be collected for serum β-hCG testing and sent to either local 
laboratory or the central laboratory for analysis; no additional screening procedures should be 
completed until the result of the serum pregnancy test is available. Female subjects of 
childbearing potential must have a negative urine pregnancy test, or a negative serum β-hCG test 
when a urine test is positive at screening to be eligible for the study. A positive serum β-hCG test 
would result in the subject being a screen failure.  
At baseline, the urine pregnancy test should be administered by the site before any other baseline 
procedures are completed. If the urine test is positive, a blood sample will be collected for serum 
β-hCG testing and sent to either local laboratory or the central laboratory for analysis; no 
additional baseline procedures will be completed until the result of the serum pregnancy test is 
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available. If the serum β-hCG result is positive, the subject will not be dosed with REPLAGAL and 
would be considered a screen failure or discontinued from the study.  
At all other visits during the treatment period, a urine pregnancy test will be performed prior to 
the completion of any study procedures. If the urine test is positive, a blood sample will be 
collected for serum β-hCG testing and sent to either local laboratory or central laboratory for 
analysis; the subject will not receive any additional investigational product infusions until the 
result of the serum pregnancy test is available. If the serum β-hCG result is positive, no 
additional doses of the investigational product are to be administered. For details on pregnancy 
reporting, see Appendix 3.8. 
8.2.3.6 Electrocardiogram 
Twelve-lead ECGs will be performed in accordance with the clinical site’s standard practice(s) at 
time points specified in the Schedule of Activities (Table 1). The ECG recordings will be read 
locally at the clinical site by the investigator or a qualified designee. The ECGs will include 
assessment of heart rate, sinus rhythm, atrial or ventricular hypertrophy, and assessment of PR, 
QRS, QT, and corrected QT intervals. Identification of any clinically significant findings and/or 
conduction abnormalities will be recorded in the eCRF. 
8.2.3.7 Anti-drug Antibody Testing 
Blood samples will be collected for all subjects for the determination of anti-agalsidase alfa 
antibodies prior to the subject receiving the REPLAGAL infusion at time points specified in the 
Schedule of Activities (Table 1). Blood samples collected for anti-agalsidase alfa antibody 
determination will be evaluated at a Takeda-designated central laboratory. These samples will be 
analyzed for anti-REPLAGAL binding antibodies. Confirmed positive samples will undergo 
assessment for NAbs. Sample collection, processing, and shipping instructions will be detailed in 
the study laboratory manual provided by the laboratory. 
8.2.4 Other Assessments 
8.2.4.1 Pharmacodynamic Assessment: Plasma Globotriaosylsphingosine (Lyso-Gb3) Level 
Blood samples will be collected for plasma lyso-Gb3 assessment prior to the subject receiving 
the REPLAGAL infusion at time points specified in the Schedule of Activities (Table 1). Plasma 
lyso-Gb3 will be analyzed at a Takeda-designated central laboratory using a validated assay. 
8.2.4.2 Pharmacokinetic Assessment 
Subjects to be enrolled in this study will provide either intensive or sparse PK samples. Blood 
samples for PK analysis will be collected at Day 1 (Week 0) and Week 28 visits (Table 1). The 
intensive and sparse PK blood sample collection time points are presented in Table 2 and 
Table 3. The PK sample analysis will be conducted in the Takeda-designated central laboratory. 
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The intensive PK set will enable the accurate estimation of PK parameters including AUC0-t and 
Cmax. Five adult subjects and 5 pediatric subjects will provide the full set of serial PK samples 
(intensive sampling). Other subjects will follow a reduced/sparse PK sampling schedule (total 
of 3 samples: predose - 0 min, end of infusion - 40 min, and 120 min after start of infusion) 
(sparse sampling). Subject weight, REPLAGAL dose (in mg) administered, date and time of start 
and end of infusion, and date and time of PK samples will be collected. Pharmacokinetic 
parameters will be determined in subjects providing intensive PK using noncompartmental 
analysis and include, but are not limited to, the following: 
• AUC0-last (min*U/mL): Area under the concentration-time curve from the time of dosing 
to the last measurable concentration 
• AUC0-∞ (min*U/mL): Area under the concentration-time curve from time zero 
extrapolated to infinity 
• CL (mL/min): Serum clearance of administered dose (Dose/AUC) 
• CL (mL/min/kg): Serum clearance of administered dose normalized for body weight  
• Cmax: Maximum concentration observed 
• t1/2 (min): Terminal elimination half-life, defined as the natural log of 2 divided by the 
terminal rate constant (ƛz) 
• tmax (min): Time of maximum observed concentration sampled post dose 
• Vss (mL): Volume of distribution at steady state 
• Vss (%BW): Estimate of volume of distribution at steady state normalized for body 
weight 
• AUClast/dose (AUClast/[U/kg]): Area under the concentration-time curve at the last sample 
(AUClast) normalized for the dose of enzyme activity 
• AUC0-∞/dose (AUC0-∞/[U/kg]): Area under the concentration-time curve at infinity 
(AUC0-∞) normalized for the dose of enzyme activity 
• Cmax/dose (Cmax/[U/kg]): Maximum serum concentration (Cmax) normalized for the dose 
of enzyme activity 
 
8.2.5 Volume of Blood to Be Drawn from Each Subject 
The amount of blood to be collected for each assessment tested at the Takeda-designated 
laboratory is provided in the central laboratory manual. The amount of blood to be collected for 
each assessment tested at the local laboratory follows each selected site’s requirement. The 
amount of blood to be drawn may vary according to the instructions provided by the 
manufacturer or laboratory for an individual assessment. When more than 1 blood assessment is 
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to be done at the time point/period, if they require the same type of tube, the assessments may be 
combined. 
 
 
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9. STATISTICAL CONSIDERATIONS 
9.1 Statistical Analysis Process 
The study will be analyzed by the sponsor or its designee.  
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused, and spurious data will be addressed. 
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock. 
All statistical analyses will be performed using SAS® (SAS Institute, Cary, NC 27513) 
version 9.4 or higher. 
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee 
No interim analysis, adaptive design, or data monitoring committee is planned for this study. 
9.3 Sample Size and Power Considerations 
A sample size of 20 safety evaluable subjects is planned to be enrolled in this study to 
descriptively provide an estimate of the serious TEAE rate. No formal sample size calculations 
have been done and the sample size is based on feasibility.  
9.4 Statistical Analysis Set 
The statistical analysis will include the following analysis sets: 
• The intent-to-treat (ITT) set will include all subjects who sign the ICF, are enrolled in 
the study, and have received at least 1 study drug infusion (full or partial). 
• The modified intent-to-treat (mITT) set will include all enrolled subjects (all subjects 
from the ITT set) who have received at least 1 dose of investigational product and 
completed at least 1 post-baseline efficacy assessment of the endpoints. The mITT set 
will be used for efficacy analyses.  
 
 
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• The safety set will include all subjects in the ITT set who receive at least 1 dose of 
REPLAGAL. The safety set will be used for the analysis of safety endpoints.  
• The per-protocol (PP) set will include all subjects in the mITT set excluding subjects 
with major protocol deviations. The PP set will be identified by a team consisting of, at a 
minimum, a physician and a statistician from Takeda. The PP set will be used for an 
efficacy sensitivity analysis. 
• The pharmacokinetic (PK) set will include all subjects in the ITT who receive at least 
1 dose of investigational product and provide intensive or sparse PK samples. The 
intensive PK set will include subjects in the PK set who provide intensive sampling. 
Five adult subjects and 5 pediatric subjects will be included in this set. Pharmacokinetic 
parameters will be derived from the intensive PK set. 
 
9.5 Efficacy Analyses 
Continuous variables will be summarized with descriptive statistics including the mean, standard 
deviation (SD), median, minimum and maximum. Categorical data will be summarized with the 
frequency and percentage of subjects falling within each category. Subsequently, longitudinal 
data will be analyzed using mixed-effects model for repeated measures, using both the mITT and 
PP sets (using the PP set will serve as a sensitivity analysis). 
The observed values, the change from baseline, the change over time, and the percentage change 
from baseline for the efficacy measurements (eGFR, urine protein/creatinine ratio, plasma 
lyso-Gb3, LVMI, and LVEF) will be summarized by sex and visit. 
Subject listings will be provided for clinical outcomes from the BPI-Short Form measurement. 
Audiology results will be produced at baseline and (if applicable) for each post-baseline 
evaluation visit. 
Audiology data will also be presented in the form of individual subject listings. 
Efficacy analyses will be based on the mITT set, with the PP set as a sensitivity analysis. 
9.6 Safety Analyses 
Adverse events will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities coding dictionary. Treatment-emergent AEs will be summarized for overall and by 
system organ class (SOC) and preferred term (PT). Analysis of AEs will be performed at both 
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subject level and AE level. Similar displays will be provided for IRRs. The AEs will be 
summarized by severity, seriousness, and relation to investigational product. 
Subjects will be counted once per SOC and once per PT. Multiple events of the same type will 
be combined for each subject and, when doing this, the worst severity or outcome for each event 
type will be presented for the analysis. When calculating event rates, the denominator will be the 
total population size, irrespective of dropouts over the course of follow-up.  
Tabular summaries of other safety endpoints (eg, vital signs, blood tests, concomitant 
medications [coded using the World Health Organization Drug Dictionary], anti-agalsidase alfa 
antibody status, and infusion information) will be produced at baseline and, if applicable, for 
each post-baseline visit. 
Changes in the results of physical examination from the baseline will be presented by visit and 
body system in the form of a shift table. 
The observed values and the change from baseline for ECG parameters (PR, QRS, QT, QTc, and 
heart rate) will be summarized by visit. The number of subjects with normal and abnormal ECG 
results during the study period will be summarized by visit in the form of a shift table. 
Laboratory data will be listed by subject. Subjects with newly occurring abnormalities outside 
the normal range will be flagged, listed separately, and summarized. The mean change from 
baseline in laboratory values or a shift table also will be provided at each visit. Change from 
baseline will be calculated by subtracting the baseline value from the post-baseline value. 
Vital sign data will be listed by subject, and any newly occurring changes outside the reference 
range from baseline will be flagged. Mean changes from baseline for vital sign data will be 
summarized. Subjects with notable abnormal values will be identified and listed separately along 
with their values. 
The number and percentage of subjects reporting at least one use of concomitant medication 
during the study will be reported. Subject listings will be provided describing the reason(s) for 
study discontinuation. 
Antibody data, including NAbs, will also be presented in the form of individual subject listings. 
Safety analyses will be based on the safety set. 
9.7 Pharmacokinetic Analyses 
Statistical analysis of PK data will be based on the PK set as well as the intensive PK set. 
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For the PK set, individual concentrations will be listed and summarized by scheduled time points 
for all subjects and by age (eg, ≥18 years vs <18 years). For the intensive PK set, individual 
concentration will be summarized for all subjects and by age. Individual PK parameters of 
REPLAGAL will be listed and summarized by treatment for all subjects as well as by age with 
descriptive statistics (number, arithmetic mean, SD, coefficient of variation [CV], median, 
minimum, maximum, geometric mean, and CV of geometric mean). Pharmacokinetic parameter 
estimates will be computed, where appropriate, from individual serum-concentration time data 
using noncompartmental methods and actual times. Figures of individual and mean (±SD) 
concentration-time profiles of REPLAGAL will be generated based on nominal time points for all 
subjects and by age. 
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Barbey, F., Hayoz, D., Widmer, U., and Burnier, M. 2004. Efficacy of enzyme replacement 
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Gold, K. F., Pastores, G. M., Botteman, M. F., Yeh, J. M., Sweeney, S., Aliski, W., and Pashos, 
C. L. 2002. Quality of life of patients with Fabry disease. Qual Life Res, 11:317-27. 
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Kaye, E. M., Kolodny, E. H., Logigian, E. L., and Ullman, M. D. 1988. Nervous system 
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Kornfeld, S. and Mellman, I. 1989. The biogenesis of lysosomes. Annu Rev Cell Biol, 5:483-525. 
Kruger, R., Bruns, K., and Grunhage, S. 2010. Determination of globotriaosylceramide in plasma 
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MacDermot, K. D., Holmes, A., and Miners, A. H. 2001a. Anderson-Fabry disease: clinical 
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MacDermot, K. D., Holmes, A., and Miners, A. H. 2001b. Anderson-Fabry disease: clinical 
manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet, 
38:750-60. 
Mehta, A., Beck, M., Eyskens, F., Feliciani, C., Kantola, I., Ramaswami, U., Rolfs, A., Rivera, 
A., Waldek, S. and Germain, D. P. 2010. Fabry disease: a review of current management 
strategies. QJM : monthly journal of the Association of Physicians, 103:641-59. 
Mehta, A., Clarke, J. T., Giugliani, R., Elliott, P., Linhart, A., Beck, M., and Sunder-Plassmann, 
G.; FOS Investigators. 2009. Natural course of Fabry disease: changing pattern of causes of 
death in FOS - Fabry Outcome Survey. J Med Genet, 46:548-52. 
Mehta, A., Ricci, R., Widmer, U., Dehout, F., Garcia de Lorenzo, A., Kampmann, C., Linhart, 
A., Sunder-Plassmann, G., Ries, M., and Beck, M. 2004. Fabry disease defined: baseline clinical 
manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest, 34:236-42. 
Miners, A. H., Holmes, A., Sherr, L., Jenkinson, C., and MacDermot, K. D. 2002. Assessment of 
health-related quality-of-life in males with Anderson Fabry disease before therapeutic 
intervention. Qual Life Res, 11:127-33. 
Ries, M. and Schiffmann, R. 2005. Fabry disease: angiokeratoma, biomarker, and the effect of 
enzyme replacement therapy on kidney function. Arch Dermatol, 141;904-5; author reply 905-6. 
Schaefer, R. M., Tylki-Szymanska, A., and Hilz, M. J. 2009. Enzyme replacement therapy for 
Fabry disease: a systematic review of available evidence. Drugs, 69:2179-205. 
Schiffmann, R. and Ries, M. 2005. Fabry's disease - an important risk factor for stroke. Lancet, 
366:1754-6. 
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Schiffmann R., Fuller M., Clarke L. A., and Aerts J. M. 2016. Is it Fabry disease? Genet Med, 
18:1181-5. 
Spada, M., Pagliardini, S., Yasuda, M., Tukel, T., Thiagarajan, G., Sakuraba, H., Ponzone, A., 
and Desnick, R. J. 2006. High incidence of later-onset Fabry disease revealed by newborn 
screening. Am J Hum Genet, 79:31-40. 
Waldek, S., Patel, M. R., Banikazemi, M., Lemay, R., and Lee, P. 2009. Life expectancy and 
cause of death in males and females with Fabry disease: findings from the Fabry Registry. Genet 
Med, 11:790-6. 
 
 
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Appendix 1 Regulatory, Ethical, and Study Oversight Considerations 
Appendix 1.1 Regulatory and Ethical Considerations 
This study is conducted in accordance with current applicable regulations including ICH E6, and 
all updates, as well as local ethical and legal requirements.  
Compliance with these regulations and guidelines also constitutes compliance with the ethical 
principles described in the Declaration of Helsinki. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate. 
Appendix 1.2 Sponsor’s Responsibilities 
Good Clinical Practice Compliance 
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, current ICH GCP Guidelines, as well as all applicable national 
and local laws and regulations. 
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, source documents, and eCRFs in accordance with current GCP and the 
respective local and national government regulations and guidelines. Records and data may 
additionally be reviewed by auditors or by regulatory authorities. 
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site. 
Indemnity/Liability and Insurance 
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines. 
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to applicable parties as necessary. 
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Public Posting of Study Information 
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information. The timing for study registration and results summary posting must be 
in accordance with applicable local and national requirements. 
Submission of Summary of Clinical Study Report to Competent Authorities of Member 
States Concerned and Ethics Committees 
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of study 
completion date for pediatric studies and within 1 year for non-pediatric studies as per guidance. 
Study Suspension, Termination, and Completion 
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. 
Appendix 1.3 Investigator’s Responsibilities 
Good Clinical Practice Compliance 
The investigator must undertake to perform the study in accordance with ICH GCP Guidelines 
E6 (1996) and E6 R2 (2017) and applicable regulatory requirements and guidelines. 
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period. 
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study. 
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If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study. 
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with ICH Guidance E3 (1995).  
Protocol Adherence and Investigator Agreement 
The investigator and any sub-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol. 
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations. 
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement. 
Documentation and Retention of Records 
Case Report Forms 
Electronic case report forms are completed for each subject and should be handled in accordance 
with instructions from the sponsor. 
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded into eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log. 
The CRA/study monitor will verify the contents against the source data per the monitoring plan. 
If the data are unclear or contradictory, queries are sent for corrections or verification of data. 
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The eCRFs should be approved by the investigator per study specifications and the sponsor’s 
data delivery requirements.  
Recording, Access, and Retention of Source Data and Study Documents 
Original source data to be reviewed during this study will include, but are not limited to, 
subject’s medical file and original clinical laboratory reports. 
All key data must be recorded in the subject’s source documents. 
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media. 
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF 
entries against the source documents. The ICF includes a statement by which the subject agrees 
to the monitor/auditor from the sponsor or its representatives, national or local regulatory 
authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, appointment 
books, original laboratory reports, X-rays etc). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US Food and 
Drug Administration [FDA], European Medicines Agency [EMA], UK Medicines and 
Healthcare products Regulatory Agency) or an auditor. 
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor. 
Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site. 
Financial Disclosure 
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
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following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998). 
Appendix 1.4 Data Management Considerations 
Data Collection 
The investigators’ authorized site personnel must enter the information required by the study 
eCRF Completion Guidelines or similar for all data requiring transcription of the source. A study 
monitor will visit each site in accordance with the monitoring plan and review the eCRF data 
against the source data for completeness and accuracy. Discrepancies between source data and 
data entered in the eCRF will be addressed by qualified site personnel. When a data discrepancy 
warrants correction, the correction will be made by authorized site personnel. Data collection 
procedures will be discussed with the site at the site initiation visit and/or at the investigator’s 
meeting. 
Data Management 
Data are to be entered into a clinical database as specified in the Takeda data management plan 
or similar. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database. 
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner. 
Appendix 1.5 Ethical Considerations 
Informed Consent 
It is the responsibility of the investigator to obtain written informed consent and assent from all 
study subjects prior to any study-related procedures including screening assessments. All consent 
and assent documentation must be in accordance with applicable regulations and GCP. Each 
subject or the subject’s legally authorized representative, as applicable, is requested to sign and 
date the subject informed consent form or a certified translation if applicable, after the subject 
has received and read (or been read) the written subject information and received an explanation 
of what the study involves, including but not limited to: the objectives, potential benefits and 
risk, inconveniences, and the subject’s rights and responsibilities. A copy of the informed 
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consent and assent documentation (ie, a complete set of subject information sheets and fully 
executed signature pages) must be given to the subject or the subject’s legally authorized 
representative, as applicable. This document may require translation into the local language. 
Signed consent and assent forms must remain in each subject’s study file and must be available 
for verification at any time. 
Pediatric subjects reaching the legal age during the study, ie, turning 18 years old (legal age in 
China is 18 years old) should sign an ICF at the earliest feasible opportunity additionally to the 
one provided by their parent(s)/legally authorized representative at the beginning of the study. 
Within the source documents, site personnel should document instruction of and understanding 
by the parent(s)/legally authorized representative/caregiver of the safe, responsible 
administration of investigational product to the study subject. 
Institutional Review Board or Ethics Committee 
It is the responsibility of the investigator to submit this protocol, the informed consent document 
(approved by the sponsor or their designee), relevant supporting information and all types of 
subject recruitment information to the IRB/EC for review, and all must be approved prior to site 
initiation. 
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement. 
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval. 
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue. If required by local law, substantial amendments to the protocol must also 
be approved by the appropriate regulatory agency prior to implementation. 
The investigator is responsible for keeping the IRB/EC apprised of the progress of the study and 
of any changes made to the protocol at least annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC. The investigator must also 
keep the local IRB/EC informed of any serious and significant AEs as required by IRB/EC 
procedures. 
Privacy and Confidentiality 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
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After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market REPLAGAL; national or local regulatory authorities; and the IRB/EC which gave approval 
for the study to proceed. The sponsor and/or its representatives accessing the records and data 
will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities. Subjects are assigned a unique 
identifying number; however, their initials and date of birth may also be collected, if permitted 
under local laws governing privacy.  
The results of studies containing subjects’ unique identifying number, relevant medical records, 
and possibly initials and dates of birth, where allowed per local law, may be transferred to, and 
used in, other countries which may not afford the same level of protection that applies within the 
countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities. 
Study Results/Publication Policy 
The term “Publication” shall mean any paper, article, manuscript, report, poster, internet posting, 
presentation slides, abstract, outline, video, instructional material, presentation (in the form of a 
written summary), or other public disclosure of the study results, in printed, electronic, oral, or 
other form. The parties understand and agree that participation in the study may involve a 
commitment to publish the data from all sites participating in the study in a cooperative 
publication with other investigators prior to publication or oral presentations of the study results 
on an individual basis. The site agrees not to publish or present the site’s study results until such 
time as either the aggregate multisite study results are published in a cooperative publication or 
for a period of one (1) year after termination or completion of the study at all participating sites, 
whichever shall first occur. After that time, the site may publish the site’s study results in 
scientific journals or present the study results at symposia or other professional meetings in 
accordance with the following provisions: 
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
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from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented. 
At least sixty (60) days prior to submitting an abstract, manuscript, or other document for 
publication, a copy of the proposed publication will be provided to the sponsor by the site for 
review. Upon the sponsor’s request, the site agrees to remove any and all confidential 
information (expressly excluding study results) identified in the publication and to delay such 
submission or presentation for an additional sixty (60) day period in order to allow the sponsor 
time to file any patent application(s). All publications of the study results shall appropriately 
reference the multisite study publication, if any, or the fact that the study results are a subset of 
data resulting from a larger multisite study. 
Takeda is committed to transparent dissemination of all scientific, technical and medical 
manuscripts generated from Shire-supported research. Therefore, after January 1, 2018, Takeda 
will require the submission of all Takeda-supported research manuscripts to journals that offer 
public availability via Open Access (including publisher platforms/repositories and self-
archiving). Open Access refers to the free at point of entry, online availability of published 
research output with, where available, rights of re-use according to an End User License. 
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) Recommendation for the Conduct, Reporting, Editing and Publication of Scholarly 
Work in Medical journals. Participation as an investigator does not confer any rights to 
authorship of publications. 
 
 
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Appendix 2 Clinical Laboratory Tests 
The following clinical laboratory assessments will be performed (unless otherwise specified, 
these assessments will be performed in the local laboratory): 
Chemistry 
 
• 
Sodium (Na+) 
• 
Potassium (K+) 
• 
Chloride (Cl-) 
• 
Bicarbonate 
• 
Total calcium (Ca2+) 
• 
Magnesium (Mg2+) 
• 
Phosphate 
• 
Creatinine (Takeda-designated central laboratory) 
• 
Blood urea nitrogen 
• 
Glucose 
• 
Albumin 
• 
Total bilirubin 
• 
Alkaline phosphatase 
• 
Alanine aminotransferase 
• 
Aspartate aminotransferase 
• 
Triglycerides 
• 
Cholesterol (total, low density lipoprotein, high 
density lipoprotein) 
 
Hematology 
 
Complete blood count 
• 
Leukocytes 
• 
Erythrocytes 
• 
Hematocrit [Hct] 
• 
Hemoglobin [Hb] 
• 
Platelets 
• 
Lymphocytes 
• 
Neutrophils 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes/leukocytes (%) 
• 
Eosinophils/leukocytes (%) 
• 
Monocytes/leukocytes (%) 
• 
Basophils/leukocytes (%) 
• 
Neutrophils/leukocytes (%) 
 
 
Urinalysis 
 
• 
Standard urinalysis (turbidity, color, pH, specific gravity, protein, glucose, ketones, bilirubin, occult blood, 
leukocytes, erythrocytes, bacteria, casts, crystals) 
• 
Urine protein/creatinine ratio (early morning spot urine) 
 
Viral Testing 
Other Tests 
• 
Hepatitis B surface antigen (HBsAg) 
• 
Hepatitis B virus DNA 
• 
Serum anti-drug antibody (ADA) and 
neutralizing antibodies (Takeda-designated 
central laboratory) 
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• 
Hepatitis C virus (HCV) antibody with 
confirmation by HCV ribonucleic acid 
polymerase chain reaction testing 
• 
Human immunodeficiency virus (HIV) antibody 
• 
Plasma lyso-Gb3 (Takeda-designated central 
laboratory) 
 
 
Pregnancy test 
 
• 
Serum β-hCG test (local laboratory or the central 
laboratory) 
• 
Urine pregnancy test 
 
 
 
 
 
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Appendix 3 Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting 
Appendix 3.1 Adverse Event Definitions 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this investigational product or medicinal product. An AE can therefore be any unfavorable 
and unintended sign (including a clinically significant laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
causality is suspected (ICH Guidance E2A 1995). 
Treatment-emergent Adverse Event 
A treatment-emergent adverse event (TEAE) is defined as any event emerging or manifesting at 
or after the initiation of treatment with an investigational product or medicinal product or any 
existing event that worsens in either intensity or frequency following exposure to the 
investigational product or medicinal product until the end of the safety follow-up period. 
Serious Adverse Event 
A serious adverse event (SAE) is any untoward clinical manifestation of signs, symptoms or 
outcomes (whether considered related to investigational product or not) and at any dose: 
• Results in death. 
• Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject 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 was more severe. 
• Requires inpatient hospitalization or prolongation of hospitalization. Note: 
Hospitalizations that are the result of elective or previously scheduled investigations 
procedures or surgery for pre-existing conditions and have not worsened after initiation 
of treatment should not be classified as SAEs.  
For example, an admission for a previously scheduled ventral hernia repair would not be 
classified as an SAE; however, complication(s) resulting from a hospitalization for an 
elective or previously scheduled surgery that meet(s) serious criteria must be reported as 
SAE(s). 
• Results in persistent or significant disability/incapacity. 
• Results in a congenital abnormality/birth defect. 
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• Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition. Examples of such medical events include: 
Bronchospasm associated with anaphylaxis requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in 
inpatient hospitalization; or the development of drug dependency or drug abuse. 
Reviewed and confirmed seroconversion for human immunodeficiency virus (HIV), 
hepatitis A virus (HAV), hepatitis B virus, hepatitis C virus (HCV), hepatitis E virus 
(HEV), or parvovirus B19 (B19V). 
 
Infusion-related Reaction 
An IRR will be defined as an event that:  
1. Begins either during or within 24 hours after the start of the infusion 
2. Is judged as related to treatment with the investigational product.  
An IRR can be serious or nonserious. Adverse events that are considered IRRs will be noted as 
such in the subject’s source documentation. Other AEs which occur prior to the infusion, along 
with AEs associated with protocol-defined testing and assessments (eg, laboratory testing and 
physical examinations), which were performed prior to the infusion, will not be considered as 
IRRs. 
A list of the most common IRRs that have been reported in patients with Fabry disease during 
REPLAGAL infusions is included in the current version of the REPLAGAL IB. 
Management of Infusion-related Reactions 
The management of IRRs should be based on the severity of the reaction, and at the discretion of 
the investigator. If mild or moderate acute infusion reactions occur, medical attention must be 
sought immediately, and appropriate actions instituted. The infusion can be temporarily 
interrupted (5 to 10 minutes) until symptoms subside and the infusion may then be restarted, or 
the infusion rate can be slowed. Some mild and transient effects may not require medical 
treatment or discontinuation of the infusion.  
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Oral or IV pretreatment with antihistamines and/or corticosteroids, from 1 to 24 hours prior to 
infusion, may prevent subsequent reactions in those cases where symptomatic treatment was 
previously required. Pretreatment of infusion reactions is left to the clinical judgment of the 
investigator. 
If further analysis of IRRs is necessary, additional clinical laboratory samples may be collected 
at the discretion of the investigator and in consultation with the study medical monitor. 
Unexpected Adverse Event 
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety Information 
(RSI). “Unexpected” also refers to the AEs that are mentioned in the IB and/or prescribing 
information as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the product but are not specifically mentioned as occurring with the particular 
product under investigation.  
The expectedness of AEs will be determined by the sponsor using the IB as the RSI. This 
determination will include considerations such as the number of AEs previously observed, but 
not on the basis of what might be anticipated from the pharmacological properties of a product. 
Suspected Unexpected Serious Adverse Reaction  
Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any suspected adverse 
reaction to investigational product (ie, including active comparators) that is both serious and 
unexpected.  
The event(s) must meet all of the following: 
• Suspected adverse reaction 
• Serious 
• Unexpected 
• Assessed as related to investigational product 
 
Symptoms of the Disease Under Study 
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected disease progression and are part of the efficacy or 
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effectiveness data collected in the study. Significant worsening of symptoms should be recorded 
as an AE. 
Pre-existing conditions prior to randomization or initiation of study medication are described in 
the medical history, and those that manifest with the same severity, frequency, or duration after 
drug exposure, are not to be recorded as AEs. However, when there is an increase in the severity, 
duration or frequency of a pre-existing condition, the event must be described in the AE eCRF. 
Clinical Laboratory and Other Safety Assessment 
A change in the value of a clinical laboratory parameter, physical examination finding, vital sign 
measure, or ECG assessment can represent an AE if the change is clinically relevant or if, during 
administration of investigational product, a shift of a parameter is observed from a value in the 
normative range to a value that is outside the normal range and considered clinically significant, 
or a further waning of an already clinically significant value. When evaluating such changes, the 
extent of deviation from the reference range, the duration until return to the reference range, 
either while continuing administration or after the end of administration with the investigational 
product, and the range of variation of the respective parameter within its reference range, should 
also be considered. 
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel), vital sign, or ECG values which were not present at the 
pretreatment evaluation observed closest to the start of investigational product, further 
investigations should be performed until the values return to within the reference range or until a 
plausible explanation (eg, concomitant disease or expected disease evolution) is found for the 
abnormal values. 
The investigator should assess, based on the above criteria and the clinical condition of the 
subject, whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE. 
The ECG assessment is conducted and reported by the local laboratory.  
Appendix 3.2 Collection of Adverse Events 
All AEs/SAEs are collected from the time the informed consent document is signed until the 
defined follow-up period stated in Section 8.1.4. This includes events occurring during the 
screening phase of the study, regardless of whether or not investigational product is 
administered.  
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All AEs/SAEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to baseline), regardless of whether the subject is still 
participating in the study. Closure indicates that an outcome is reached, stabilization achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 
event is otherwise explained. 
Appendix 3.3 Assessment of Adverse Events 
Severity Categorization 
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity is captured as a new event. 
Worsening medical conditions, signs or symptoms present prior to initiation of investigational 
product, must be recorded as new AEs. 
For example, if a subject reports mild intermittent dyspepsia prior to initiation of dosing with the 
investigational product, and the dyspepsia becomes severe and more frequent after first dose a 
new AE of severe dyspepsia (with the appropriate date of onset) should be documented in the 
source and appropriate eCRF. 
The medical assessment of severity is determined by using the following definitions: 
• Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
• Moderate: A type of AE that is usually alleviated with specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research subject. 
• Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
 
Relationship Categorization 
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as 
“not related”. Otherwise, if there is any valid reason, even if undetermined or untested, for 
suspecting a possible cause-and-effect relationship between the investigational product and the 
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occurrence of the AE, then the AE should be considered “related”. The causality assessment 
must be documented in the source. 
The following additional guidance may be helpful: 
Table A1. Adverse Event Relationship Categorization 
Related 
The temporal relationship between the event and the administration of the investigational 
product is compelling enough and/or follows a known or suspected response pattern to that 
product, and the event cannot be explained by the subject’s medical condition, other 
therapies, or accident. 
Not related 
The event can be readily explained by other factors such as the subject’s underlying medical 
condition, concomitant therapy, or accident and no plausible temporal or biologic 
relationship exists between the investigational product and the event. 
 
Outcome Categorization 
The outcome of AEs must be documented in the source during the course of the study. Outcomes 
are as follows: 
• Fatal 
• Not Recovered/Not Resolved 
• Recovered/Resolved 
• Recovered/Resolved With Sequelae 
• Recovering/Resolving 
• Unknown 
 
Appendix 3.4 Safety Reporting 
Reference Safety Information 
The RSI for this study is the IB which the sponsor has provided under separate cover to all 
investigators. 
Reporting Procedures 
The investigator should complete an SAE electronic Case Report Form (eCRF) in English or 
report via the paper safety report form (as back-up in case transmission of an SAE is not 
feasible) within 24 hours of becoming aware of any SAE. It is applicable to all initial and follow-
up SAE reports. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors (see Appendix 3.9) unless they result in an SAE. 
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The CRO/Takeda medical monitor should receive notification once there is new or update on 
SAE eCRF or paper SAE report form. 
Appendix 3.5 Serious Adverse Event Collection Time Frame 
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in Section 8.1.4 and 
must be reported to the Takeda Global Patient Safety Evaluation Department and the 
CRO/Takeda medical monitor within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Takeda Global 
Patient Safety Evaluation Department within 24 hours of the reported first becoming aware of 
the event. 
Appendix 3.6 Serious Adverse Event Onset and Resolution Dates 
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively. 
In addition, any signs or symptoms reported by the subject after signing the informed consent 
form or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate. 
Appendix 3.7 Fatal Outcome 
Any SAE that results in the subject’s death (eg, the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded. 
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of withdrawn should not be selected solely as a result of the 
subject’s death. 
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Appendix 3.8 Pregnancy 
All pregnancies are reported from the time informed consent is signed until the defined 
follow-up period stated in Section 8.1.4. 
Any report of pregnancy for any female study subject must be reported to Takeda Global Patient 
Safety Evaluation Department within 24 hours of the first awareness of the event using the paper 
Pregnancy Report Form. The fax number and e-mail address are provided in the Form 
Completion Instruction.  
A copy of the Takeda Pregnancy Report Form (and any applicable follow-up reports) must also 
be sent to the CRO/Takeda medical monitor using the details specified in the emergency contact 
information section of the protocol. The pregnant female study subject must be withdrawn from 
the study. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days and 1 year 
post-partum. 
Pregnancy complications such as abortion/miscarriage, or congenital abnormality are considered 
SAEs and must be reported according to the SAE reporting procedure. 
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE according to the SAE reporting procedure as well as the Takeda 
Pregnancy Report Form. The test date of the first positive serum/urine β-hCG test or ultrasound 
result will determine the pregnancy onset date. 
Appendix 3.9 Abuse, Misuse, Overdose and Medication Error 
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Appendix 3.1.  
Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category. 
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• Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society 
• Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol) 
• Overdose – Intentional or unintentional intake of a dose of investigational product higher 
than the protocol-prescribed dose 
• Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below. 
 
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. 
Medication errors should be collected/reported for all products under investigation. 
The administration and/or use of an expired investigational product, errors relating to rate of 
drug administration dilution, use of inappropriate diluent, and longer than recommended time 
frames within which drug must be used after dilution should be considered as a reportable 
medication errors. 
All investigational product provided to pediatric subjects should be supervised by the 
parent(s)/legally authorized representative/caregiver. 
Appendix 3.10 Urgent Safety Measures 
An urgent safety measure is an immediate action taken, which is not defined by the protocol, in 
order to protect subjects participating in a clinical trial from immediate harm, these do not 
constitute de facto deviation from the protocol. Urgent safety measures may be taken by the 
sponsor or clinical investigator, and may include any of the following: 
• Immediate change in study design or study procedures 
• Temporary or permanent halt of a given clinical trial or trials 
• Any other immediate action taken in order to protect clinical trial subjects from 
immediate hazard to their health and safety 
 
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The investigator may implement urgent safety measures to protect study subjects from 
immediate hazard to their health or safety. The measures should implement immediately and 
does not require prior authorization from the sponsor. In the event(s) of an apparent direct hazard 
to the subject, the investigator will notify the sponsor immediately by phone and confirm 
notification to the sponsor in writing as soon as possible, and within 1 calendar day after the 
change is implemented. The sponsor will also ensure the responsible EC(s) and relevant 
competent authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations. 
Appendix 3.11 Regulatory Agency, Institutional Review Board, Ethics Committee and Site 
Reporting 
The sponsor/CRO is responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable (serious) adverse drug reactions to regulatory authorities, 
investigators and ECs/institutions as applicable, in accordance with national regulations in the 
countries where the study is conducted. The sponsor/CRO will also prepare an expedited report 
for other safety issues where these might materially alter the current benefit-risk assessment of 
an investigational medicinal product or that would be sufficient to consider changes in the 
investigational medicinal products administration or in the overall conduct of the trial. 
In addition, the sponsor is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the TAK-675 program. 
The investigator is responsible for notifying the local IRB/EC of all safety reports or significant 
safety findings that occur at his or her site as required by IRB/EC procedures and applicable 
national regulations (see Appendix 1.5). 
 
 
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Appendix 4 Contraceptive Guidance  
Female subjects: 
Female subjects of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described below. 
Highly Effective Contraceptive Methods That Are User Dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulationb  
• 
Oral  
• 
Intravaginal  
• 
Transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral  
• 
Injectable  
Highly Effective Contraceptive Methods That Are User Independenta 
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
Bilateral tubal occlusion 
Vasectomized partnerc 
Sexual abstinenced 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies.  
b Hormonal contraception may be susceptible to interaction with the investigational product, which may reduce 
the efficacy of the contraceptive method. In this case, 2 highly effective methods of contraception should be 
utilized during the treatment period and for at least 30 days  after the last dose of investigational product. 
c A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the female of childbearing potential and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. 
d Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the investigational product. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the subject. 
 
 
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Appendix 5 Scales and Assessments 
The following scales/assessments will be utilized in this study: 
Full Title of Scale/Assessment 
Brief Pain Inventory (BPI)-Short Form  
 
A separate master file containing each scale/assessment listed above will be provided to the site.  
 
 
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Brief Pain Inventory-Short Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 6 Abbreviations  
Abbreviation 
Definition 
ADA 
anti-drug antibody 
AE  
adverse event 
AUC 
area under the curve 
AUC0-∞ 
area under the concentration-time curve from time zero 
extrapolated to infinity 
AUC0-last 
area under the concentration-time curve from the time of 
dosing to the last measurable concentration 
β-hCG 
beta-human chorionic gonadotropin 
BPI 
Brief Pain Inventory 
BW 
body weight 
CFR 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology 
CL 
serum clearance 
Cmax 
maximum concentration observed 
COVID-19 
coronavirus disease 
CRF 
case report form 
CRO 
contract research organization 
CV 
coefficient of variation 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form  
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EOT 
end of treatment 
EOW 
every other week 
ERT 
enzyme replacement therapy 
FDA 
Food and Drug Administration  
GCP 
Good Clinical Practice 
GLA 
α-galactosidase A 
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Abbreviation 
Definition 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IRB 
institutional review board 
IRR 
infusion-related reaction 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IV 
intravenous(ly)  
LVEF 
left ventricular ejection fraction 
LVMI 
left ventricular mass index 
lyso-Gb3 
globotriaosylsphingosine 
M6P 
mannose-6-phosphate 
mITT 
modified intent-to-treat 
NAb 
neutralizing antibody 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PP 
per protocol  
PT 
preferred term 
QoL 
quality of life 
RSI 
reference safety information 
SAE 
serious adverse event  
SAP 
statistical analysis plan 
SD 
standard deviation 
SIC 
Subject Identification Code 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
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Abbreviation 
Definition 
t1/2 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
tmax 
time of maximum observed concentration 
UK 
United Kingdom 
US 
United States 
Vss 
volume of distribution at steady state 
 
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