A Multicenter, dOuble-blind, ranDomized, Placebo-controlled, Parallel-group Study to Determine the effIcacy and Safety of Lucerastat Oral Monotherapy in Adult Subjects With FabrY Disease
Phase: PHASE3
Conditions: Fabry Disease
Sponsor: Idorsia Pharmaceuticals Ltd.

 
 
TPL-100601_v03 
Lucerastat / ACT-434964 
Fabry disease 
Protocol ID-069A301 
 
MODIFY 
A Multicenter, dOuble-blind, ranDomized, placebo-controlled, parallel-group study 
to determine the effIcacy and safety of lucerastat oral monotherapy in adult subjects 
with FabrY disease. 
 
 
Study Phase: 
3 
EudraCT Number: 
2017-003369-85 
Status and version: 
Final Version 5 
Date: 
24 August 2021 
Document type: 
Global protocol 
Idorsia document number  
(Doc No.): 
D-21.234 
 
Confidentiality statement 
The information contained in this document, especially unpublished data, is the property of the sponsor of 
this study, Idorsia Pharmaceuticals Ltd. It is therefore provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your personnel, and an independent ethics committee 
or institutional review board. It is understood that this information will not be disclosed to others without 
written authorization from Idorsia Pharmaceuticals Ltd, except to the extent necessary to obtain informed 
consent from those persons to whom the study treatment may be administered. 
 
 
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SPONSOR CONTACT DETAILS 
Sponsor 
 
Idorsia Pharmaceuticals Ltd 
Hegenheimermattweg 91 
CH-4123 Allschwil 
Switzerland 
 
+41 58 844 00 00 
Clinical Trial Physician  
Contact details of the Clinical Trial Physician can 
be found in the Investigator Site File. 
Medical Emergency Hotline 
Toll phone number:  
Site-specific toll telephone numbers and toll-free 
numbers for the Medical Emergency Hotline can 
be found in the Investigator Site File. 
 
 
COORDINATING INVESTIGATOR 
Name / Title 
Address 
Dr. Derralynn Hughes, MD 
Department of Hematology,  
Royal Free London NHS 
Foundation Trust and University College London, 
London NW3 2PF, UK 
 
 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION 
Some study activities will be delegated to Contract Research Organizations (CROs). 
A list of site-specific contact details can be found in the Investigator Site File. 
 
 
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SIGNATURE PAGE FOR IDORSIA PHARMACEUTICALS LTD 
Hereinafter called Idorsia or sponsor 
Treatment name / number 
Lucerastat / ACT-434964 
Indication 
Fabry disease 
Protocol number, study acronym, study title 
ID-069A301, MODIFY 
A multicenter, double-blind, randomized, placebo-controlled, parallel-group study to 
determine the efficacy and safety of lucerastat oral monotherapy in adult subjects with 
Fabry disease. 
I approve the terms and conditions relating to this study as defined in this protocol. I 
confirm that the information contained in this protocol is consistent with the current 
risk-benefit evaluation of lucerastat, and with the ethical and scientific principles governing 
clinical research as set out in the Declaration of Helsinki and the International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. 
Title 
Name 
Date 
Director, Clinical 
Project Physician 
, MD 
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INVESTIGATOR SIGNATURE PAGE 
 
Treatment name / number 
Lucerastat / ACT-434964 
Indication 
Fabry disease 
Protocol number, study acronym, study title 
ID-069A301, MODIFY 
A multicenter, double-blind, randomized, placebo-controlled, parallel-group study to 
determine the efficacy and safety of lucerastat oral monotherapy in adult subjects with 
Fabry disease. 
I agree to the terms and conditions relating to this study as defined in this protocol and any 
other protocol-related documents. I fully understand that any changes instituted by the 
investigator(s) without previous agreement with the sponsor would constitute a protocol 
deviation, including any ancillary studies or procedures performed on study subjects (other 
than those procedures necessary for the well-being of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, 
and applicable regulations and laws. 
 
 
Principal 
Investigator 
Country 
Site 
number 
Town 
Date 
 
Signature 
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
SPONSOR CONTACT DETAILS ..................................................................................... 2 
COORDINATING INVESTIGATOR................................................................................ 2 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION .................................. 2 
NON-SUBSTANTIAL GLOBAL AMENDMENT 4 ...................................................... 18 
PROTOCOL SYNOPSIS ID-069A301 ............................................................................ 24 
PROTOCOL ..................................................................................................................... 40 
1 
BACKGROUND ........................................................................................................ 40 
1.1 
Fabry disease ............................................................................................... 40 
1.1.1 
Current treatment of Fabry disease .................................................. 41 
1.1.2 
Unmet medical need in Fabry disease ............................................. 41 
1.2 
Lucerastat ..................................................................................................... 42 
1.2.1 
Mechanism of action ........................................................................ 42 
1.2.2 
Nonclinical summary ....................................................................... 43 
1.2.3 
Clinical summary ............................................................................. 44 
1.2.4 
Lucerastat dose rationale ................................................................. 46 
1.3 
Rationale of the study .................................................................................. 46 
1.3.1 
Unmet medical need of subjects with Fabry disease ....................... 47 
1.3.2 
Substrate reduction therapy with lucerastat as a distinct 
treatment modality ........................................................................... 47 
1.3.3 
Potential of lucerastat to interfere with the mechanisms 
underlying key Fabry disease symptoms — neuropathic pain 
and gastrointestinal symptoms ......................................................... 47 
1.4 
Summary of known and potential risks and benefits ................................... 48 
2 
STUDY OBJECTIVES .............................................................................................. 49 
2.1 
Primary objective ......................................................................................... 49 
2.2 
Secondary objectives ................................................................................... 49 
2.3 
Other objectives ........................................................................................... 49 
3 
OVERALL STUDY DESIGN AND PLAN .............................................................. 50 
3.1 
Study design ................................................................................................ 50 
3.1.1 
Study periods ................................................................................... 50 
3.1.2 
Study duration and global end of the study ..................................... 53 
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3.1.3 
Sub-studies ....................................................................................... 53 
3.1.3.1 
Pharmacokinetic profile sub-study (all sites) ......................... 53 
3.1.3.2 
Exit interview sub-study (US and Canadian sites only) ......... 53 
3.2 
Overall study design rationale ..................................................................... 54 
3.3 
Study committee .......................................................................................... 55 
3.3.1 
Independent Data Monitoring Committee ....................................... 55 
4 
STUDY POPULATION ............................................................................................ 55 
4.1 
Selection of study population ...................................................................... 55 
4.2 
Rationale for the selection of the study population ..................................... 56 
4.3 
Inclusion criteria .......................................................................................... 57 
4.4 
Exclusion criteria ......................................................................................... 59 
4.5 
Contraception requirements for women of childbearing potential .............. 61 
4.5.1 
Definition of childbearing potential ................................................. 61 
4.5.2 
Highly effective methods of contraception ...................................... 61 
4.6 
Contraception requirements for fertile males .............................................. 62 
5 
TREATMENTS ......................................................................................................... 63 
5.1 
Study treatment ............................................................................................ 63 
5.1.1 
Investigational treatment and matching placebo: description .......... 63 
5.1.2 
Study treatment dosing and administration ..................................... 63 
5.1.3 
Treatment assignment ...................................................................... 64 
5.1.4 
Blinding ........................................................................................... 64 
5.1.5 
Unblinding ....................................................................................... 65 
5.1.5.1 
Unblinding for final analyses ................................................. 65 
5.1.5.2 
Unblinding for suspected unexpected serious adverse 
reactions .................................................................................. 65 
5.1.5.3 
Emergency procedure for unblinding ..................................... 65 
5.1.6 
Study treatment supply .................................................................... 66 
5.1.6.1 
Study treatment packaging and labeling ................................ 66 
5.1.6.2 
Study treatment distribution and storage ................................ 66 
5.1.6.3 
Study treatment dispensing .................................................... 66 
5.1.6.4 
Study treatment return and destruction .................................. 67 
5.1.7 
Study treatment accountability and compliance with study 
treatment .......................................................................................... 67 
5.1.7.1 
Study treatment accountability ............................................... 67 
5.1.7.2 
Study treatment compliance ................................................... 67 
5.1.8 
Study treatment dose adjustments and interruptions ....................... 68 
5.1.9 
Premature discontinuation of study treatment ................................. 69 
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5.1.10 
Study-specific criteria for interruption / premature 
discontinuation of study treatment ................................................... 70 
5.1.10.1 
Pregnancy ............................................................................... 70 
5.1.10.2 
Cardiovascular event .............................................................. 70 
5.1.10.3 
Renal function ........................................................................ 70 
5.1.10.4 
Cerebrovascular event ............................................................ 70 
5.2 
Previous and concomitant therapy ............................................................... 70 
5.2.1 
Definitions ....................................................................................... 70 
5.2.2 
Mandatory concomitant therapy ...................................................... 71 
5.2.3 
Allowed concomitant therapy .......................................................... 71 
5.2.3.1 
Angiotensin-converting enzyme inhibitor or angiotensin 
receptor blocker ...................................................................... 71 
5.2.3.2 
Pain medications ..................................................................... 71 
5.2.3.3 
Antidepressants used to treat depression ................................ 73 
5.2.4 
Forbidden concomitant therapy ....................................................... 73 
5.2.4.1 
Enzyme replacement therapy (agalsidase alfa, agalsidase 
beta) ........................................................................................ 73 
5.2.4.2 
Inhibitors of glucosyl ceramide synthase, 
-galactosidase A chaperone, investigational drugs .............. 74 
5.2.5 
Reporting of previous / concomitant therapy in the electronic 
case report form and electronic diary .............................................. 74 
5.2.5.1 
Fabry disease-specific therapies ............................................. 74 
5.2.5.2 
Pain medications ..................................................................... 75 
5.2.5.3 
Other therapies ....................................................................... 76 
6 
STUDY ENDPOINTS ............................................................................................... 76 
6.1 
Efficacy endpoints ....................................................................................... 76 
6.1.1 
Primary efficacy endpoint ................................................................ 76 
6.1.2 
Secondary efficacy endpoints .......................................................... 76 
6.1.3 
Efficacy estimands ........................................................................... 77 
6.1.4 
Other efficacy endpoints .................................................................. 79 
6.1.4.1 
Renal function endpoints ........................................................ 79 
6.1.4.2 
Echocardiography-based endpoints ........................................ 79 
6.1.4.3 
Pain medication endpoints based on daily entries in 
electronic diary ....................................................................... 79 
6.1.4.4 
Clinical symptoms endpoints based on data collected at 
site visits ................................................................................. 79 
6.1.4.5 
Treatment failure .................................................................... 80 
6.1.5 
Overview of efficacy endpoints ....................................................... 80 
6.2 
Safety endpoints .......................................................................................... 82 
6.3 
Quality of life endpoints .............................................................................. 83 
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6.4 
Pharmacokinetic endpoints .......................................................................... 83 
6.4.1 
Pharmacokinetic profile sub-study .................................................. 83 
6.5 
Biomarker endpoints .................................................................................... 83 
6.6 
Rationale for primary and secondary efficacy endpoints ............................ 84 
6.6.1 
Rationale for evaluating neuropathic pain at Month 6 .................... 84 
6.6.2 
Rationale for evaluating gastrointestinal symptoms (abdominal 
pain, diarrhea) at Month 6 ................................................................ 85 
6.6.3 
Rationale for evaluating plasma levels of 
globotriaosylceramide at Month 6 ................................................... 87 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS ............................................... 87 
7.1 
Study visits .................................................................................................. 87 
7.1.1 
Screening/re-screening ..................................................................... 88 
7.1.1.1 
Screening ................................................................................ 88 
7.1.1.2 
Re-screening ........................................................................... 88 
7.1.2 
Unscheduled visits ........................................................................... 89 
7.2 
Study assessments ........................................................................................ 95 
7.2.1 
Demographics / baseline characteristics .......................................... 95 
7.2.1.1 
Fabry disease history .............................................................. 96 
7.2.1.2 
Data to be collected for screening failure subjects ................. 97 
7.2.2 
Efficacy assessments ........................................................................ 97 
7.2.2.1 
Use of an electronic diary ....................................................... 97 
7.2.2.2 
Efficacy assessments collected on a daily basis in the 
electronic diary ....................................................................... 98 
7.2.2.3 
Brief Pain Inventory-Short Form ......................................... 100 
7.2.2.4 
Patient Global Impression of Severity .................................. 101 
7.2.2.5 
Patient Global Impression of Change ................................... 101 
7.2.2.6 
Center for Epidemiologic Studies Depression Scale 
Revised ................................................................................. 102 
7.2.2.7 
Echocardiography ................................................................. 102 
7.2.2.8 
Exit interview (US and Canada) ........................................... 103 
7.2.3 
Safety assessments ......................................................................... 104 
7.2.3.1 
Physical examination ............................................................ 104 
7.2.3.2 
Vital signs ............................................................................. 104 
7.2.3.3 
Weight and height ................................................................ 104 
7.2.3.4 
Electrocardiogram assessment ............................................. 105 
7.2.4 
Laboratory assessments ................................................................. 106 
7.2.4.1 
Type of laboratory ................................................................ 106 
7.2.4.2 
Laboratory tests .................................................................... 106 
7.2.5 
Quality of life assessments ............................................................ 109 
7.2.5.1 
36-Item Short Form Health Survey Version 2 ..................... 109 
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7.2.6 
Pharmacokinetic assessments ........................................................ 109 
7.2.6.1 
Pharmacokinetic assessments ............................................... 109 
7.2.6.2 
Sampling, labeling, storage and shipment ............................ 109 
7.2.6.3 
Bioanalysis ........................................................................... 109 
7.2.7 
Biomarker assessments .................................................................. 110 
7.2.7.1 
Biomarkers of Fabry disease and their metabolic 
precursors ............................................................................. 110 
7.2.7.2 
Other non-genetic research samples ..................................... 110 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL 
CARE ....................................................................................................................... 111 
8.1 
Study completion as per protocol .............................................................. 111 
8.2 
Premature withdrawal from study ............................................................. 111 
8.3 
Premature termination or suspension of the study ..................................... 112 
8.4 
Medical care of subjects after study completion / withdrawal from 
study ........................................................................................................... 112 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ........................ 112 
9.1 
Safety definitions ....................................................................................... 112 
9.1.1 
Definition of adverse events .......................................................... 112 
9.1.2 
Definition of serious adverse events .............................................. 113 
9.1.3 
Definition of suspected unexpected serious adverse reactions ...... 114 
9.1.4 
Intensity of adverse events ............................................................. 114 
9.1.5 
Relationship to study treatment ..................................................... 115 
9.1.6 
Relationship to protocol-mandated procedure ............................... 115 
9.2 
Time period and frequency for adverse event / serious adverse event 
assessment and follow-up .......................................................................... 115 
9.2.1 
Follow-up of adverse events .......................................................... 115 
9.2.2 
Follow-up of serious adverse events .............................................. 115 
9.3 
Reporting procedures ................................................................................. 115 
9.3.1 
Reporting of adverse events ........................................................... 115 
9.3.2 
Additional reporting procedure for serious adverse events ........... 116 
9.4 
Pregnancy .................................................................................................. 116 
9.4.1 
Reporting of pregnancy ................................................................. 116 
9.4.2 
Follow-up of pregnancy ................................................................. 117 
9.5 
Reporting of study treatment overdose, misuse, abuse and medication 
errors .......................................................................................................... 117 
9.6 
Study safety monitoring ............................................................................. 117 
10 STATISTICAL METHODS .................................................................................... 118 
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10.1 
Analysis sets .............................................................................................. 118 
10.1.1 
Screened Analysis Set .................................................................... 118 
10.1.2 
Full Analysis Set ............................................................................ 118 
10.1.3 
Modified Full Analysis Set ............................................................ 118 
10.1.4 
Modified Full Analysis Set-gastrointestinal symptoms ................. 118 
10.1.5 
Per-Protocol Analysis Set .............................................................. 118 
10.1.6 
Safety Set ....................................................................................... 119 
10.1.7 
Other analysis sets ......................................................................... 119 
10.1.8 
Usage of the analysis sets .............................................................. 119 
10.2 
Variables .................................................................................................... 119 
10.2.1 
Primary efficacy variable ............................................................... 119 
10.2.2 
Secondary efficacy variables ......................................................... 120 
10.2.2.1 
Change from baseline to Month 6 in the 11-point 
numerical rating scale score of “abdominal pain at its 
worst in the last 24 hours” in subjects with 
gastrointestinal symptoms at baseline .................................. 120 
10.2.2.2 
Change from baseline to Month 6 in the number of days 
with at least 1 stool of a Bristol Stool Scale consistency 
Type 6 or 7 in subjects with gastrointestinal symptoms at 
baseline ................................................................................. 120 
10.2.2.3 
Change from baseline to Month 6 in plasma 
globotriaosylceramide .......................................................... 121 
10.2.3 
Safety variables .............................................................................. 121 
10.3 
Description of statistical analyses .............................................................. 121 
10.3.1 
Overall testing strategy .................................................................. 121 
10.3.2 
Analysis of the primary efficacy variable ...................................... 122 
10.3.2.1 
Hypotheses ........................................................................... 122 
10.3.2.2 
Primary statistical analysis ................................................... 122 
10.3.2.3 
Handling of missing data ...................................................... 123 
10.3.2.4 
Sensitivity analyses for missing data .................................... 123 
10.3.2.5 
Supportive analyses .............................................................. 124 
10.3.2.6 
Sub-group analyses ............................................................... 127 
10.3.3 
Analysis of the secondary efficacy variables ................................. 128 
10.3.3.1 
Change from baseline to Month 6 in the 11-point 
numerical rating scale score of “abdominal pain at its 
worst in the last 24 hours” in subjects with 
gastrointestinal symptoms at baseline .................................. 128 
10.3.3.2 
Change from baseline to Month 6 in the number of days 
with at least 1 stool of a Bristol Stool Scale consistency 
Type 6 or 7 in subjects with gastrointestinal symptoms at 
baseline ................................................................................. 129 
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10.3.3.3 
Change from baseline to Month 6 in plasma 
globotriaosylceramide .......................................................... 130 
10.3.4 
Analysis of other efficacy variables ............................................... 131 
10.3.5 
Analysis of the safety variables ..................................................... 131 
10.3.5.1 
Adverse events ..................................................................... 132 
10.3.5.2 
Vital signs ............................................................................. 132 
10.3.5.3 
Electrocardiography ............................................................. 132 
10.3.5.4 
Laboratory data ..................................................................... 133 
10.3.6 
Analysis of other variables ............................................................ 133 
10.4 
Interim analyses ......................................................................................... 133 
10.5 
Sample size ................................................................................................ 133 
11 DATA HANDLING ................................................................................................. 134 
11.1 
Data collection, data transfer procedure and data access .......................... 134 
11.2 
Maintenance of data confidentiality .......................................................... 135 
11.3 
Database management ............................................................................... 135 
12 PROCEDURES AND GOOD CLINICAL PRACTICE .......................................... 136 
12.1 
Ethics and Good Clinical Practice ............................................................. 136 
12.2 
Independent Ethics Committee / Institutional Review Board ................... 136 
12.3 
Informed consent ....................................................................................... 137 
12.4 
Compensation to subjects and investigators .............................................. 137 
12.5 
Protocol adherence/compliance ................................................................. 137 
12.6 
Protocol amendments ................................................................................ 138 
12.7 
Essential documents and retention of documents ...................................... 138 
12.8 
Monitoring ................................................................................................. 139 
12.9 
Investigator Site File .................................................................................. 140 
12.10 
Audit .......................................................................................................... 140 
12.11 
Inspections ................................................................................................. 141 
12.12 
Reporting of study results and publication ................................................ 141 
13 REFERENCES ......................................................................................................... 142 
14 APPENDICES .......................................................................................................... 150 
 
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LIST OF TABLES 
 
Table 1 
eGFR-based study treatment dosing scheme ............................................ 63 
Table 2 
List of pain medications used in Fabry disease ......................................... 72 
Table 3 
Estimands for the primary and secondary efficacy objectives and 
analyses ..................................................................................................... 78 
Table 4 
Type of efficacy endpoints ........................................................................ 81 
Table 5 
Visit and assessment schedule: double-blind treatment period ................. 90 
Table 6 
Visit and assessment schedule: post-treatment observation period .......... 93 
Table 7 
Power to detect a treatment difference for continuous secondary 
endpoints analyzed on the mFAS-GIS for a range of deltas and SDs 
(n = 69 subjects) ...................................................................................... 134 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design .............................................................................................. 52 
Figure 2 
Fixed-sequence statistical testing strategy .............................................. 122 
 
LIST OF APPENDICES 
 
Appendix 1 
Individualized Pain Management Plan template ..................................... 150 
Appendix 2 
Bristol Stool Scale ................................................................................... 154 
Appendix 3 
Brief Pain Inventory-Short Form – English version (24 h) ..................... 156 
Appendix 4 
Patient Global Impression questionnaires ............................................... 159 
Appendix 5 
Center for Epidemiologic Studies Depression Scale Revised ................. 161 
Appendix 6 
36-Item Short Form Health Survey Version 2 ........................................ 163 
 
 
 
 
 
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LIST OF ABBREVIATIONS AND ACRONYMS 
α-GalA  
α-galactosidase A 
ACE  
Angiotensin-converting enzyme 
AE  
Adverse event 
ALT  
Alanine aminotransferase 
ANCOVA  
Analysis of covariance 
ARB  
Angiotensin receptor blocker 
AST  
Aspartate aminotransferase 
AUC  
Area under the plasma concentration-time curve 
AUC  
Area under the plasma concentration-time curve during one 
dosing interval 
AUC0-48  
Area under the plasma concentration-time curve from zero to 48 h 
after dosing 
AUC0-∞  
Area under the plasma concentration-time curve extrapolated to 
infinity 
AUC0-t  
Area under the plasma concentration-time curve from zero to time 
t of the last measured concentration above the limit of 
quantification 
b.i.d.  
Twice daily 
BLQ  
Below the limit of quantification 
BPI  
Brief Pain Inventory 
BPI-SF  
Brief Pain Inventory-Short Form 
BPI-SF3/5/9  
Brief Pain Inventory-Short Form item 3/5/9 
BSS  
Bristol Stool Scale 
CESD-R-20  
Center for Epidemiologic Studies Depression Scale Revised 
CFR  
Code of Federal Regulations (US) 
CHMP  
Committee for Medicinal Products for Human Use 
CI  
Confidence interval 
CKD-EPI  
Chronic Kidney Disease Epidemiology Collaboration 
Cmax  
Maximum observed plasma concentration 
CMH  
Cochran-Mantel-Haenszel 
COVID-19  
Coronavirus disease 2019 
CR  
Copy Reference 
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CRA  
Clinical Research Associate 
CRO  
Contract Research Organization 
CSR  
Clinical Study Report 
CTCAE  
Common Terminology Criteria for Adverse Events 
CTFG  
Clinical Trials Facilitation Group 
CTT  
Clinical Trial Team 
DBP  
Diastolic blood pressure 
DDI  
Drug-drug interaction 
DRG  
Dorsal root ganglia 
EC  
Ethics Committee 
eCDF  
Empirical cumulative distribution function 
ECG  
Electrocardiogra(m/phy) 
eCRF  
Electronic case report form 
eDiary  
Electronic diary 
eGFR  
Estimated glomerular filtration rate 
EMA  
European Medicines Agency 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
ePDF  
Empirical probability density function 
ERT  
Enzyme replacement therapy 
EU  
European Union 
FAS  
Full Analysis Set 
FD  
Fabry disease (Anderson-Fabry disease) 
FDA  
Food and Drug Administration 
FOS  
Fabry Outcome Survey 
FU  
Follow-up 
Gb3  
Globotriaosylceramide 
GCP  
Good Clinical Practice 
GCS  
Glucosylceramide synthase 
GI  
Gastrointestinal 
GLA  
Gene coding for α-galactosidase A 
GlcCer  
Glucosylceramide (Gb1) 
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GSL  
Glycosphingolipid 
HbA1c  
Hemoglobin A1c 
HR  
Heart rate 
i.v.  
Intravenous 
IB  
Investigator’s Brochure 
IBS  
Irritable bowel syndrome 
ICE  
Intercurrent event 
ICF  
Informed consent form 
ICH  
International Council for Harmonisation 
IDMC  
Independent Data Monitoring Committee 
IEC  
Independent Ethics Committee 
IMMPACT  
Initiative on Methods, Measurement, and Pain Assessment in 
Clinical Trials 
IPMP  
Individualized Pain Management Plan 
IRB  
Institutional Review Board 
IRT  
Interactive Response Technology 
ISF  
Investigator Site File 
J2R  
Jump to Reference 
Ki 
 
Inhibition constant 
λZ 
 
Terminal disposition rate constant 
LacCer  
Lactosylceramide (Gb2) 
LVEF  
Left ventricular ejection fraction 
LVMI  
Left ventricular mass index 
lysoGb3  
Globotriaosylsphingosine 
MAP  
Mean arterial pressure 
MAR  
Missing at random 
MedDRA™  
Medical Dictionary for Regulatory Activities 
mFAS  
Modified Full Analysis Set 
mFAS-GIS  
Modified Full Analysis Set-gastrointestinal symptoms 
MI  
Multiple imputation 
MMRM  
Mixed model for repeated measures 
MNAR  
Missing not at random 
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NRS-11  
11-point numerical rating scale 
NSAID  
Non-steroidal anti-inflammatory drug 
NYHA  
New York Heart Association 
OCT2  
Organic cation transporter 2 
OLE  
Open-label extension 
ORc  
Common odds ratio 
PD  
Pharmacodynamic(s) 
PGIC  
Patient Global Impression of Change 
PGIC-DS  
Patient Global Impression of Change in Disease Severity 
PGIC-PS  
Patient Global Impression of Change in neuropathic Pain Severity 
PGIS-D  
Patient Global Impression of Severity of Disease 
PGIS-P  
Patient Global Impression of Severity of neuropathic Pain 
PI  
Principal investigator 
PK  
Pharmacokinetic(s) 
PPS  
Per-Protocol Analysis Set 
PRO  
Patient Reported Outcome 
PTOP  
Post-treatment observation period 
QoL  
Quality of life 
QS  
Quality System 
QTc  
Corrected QT 
QTcB  
QT corrected according to Bazett’s formula 
QTcF  
QT corrected according to Fridericia’s formula 
RSI  
Reference safety information 
SAE  
Serious adverse event 
SAF  
Safety Set 
SAP  
Statistical analysis plan 
SBP  
Systolic blood pressure 
SD  
Standard deviation 
SF-36v2  
36-Item Short Form Health Survey Version 2 
SIV  
Site initiation visit 
SNRI  
Serotonin-norepinephrine re-uptake inhibitor 
SOC  
System organ class 
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SRT  
Substrate reduction therapy 
SSRI  
Selective serotonin re-uptake inhibitor 
SUSAR  
Suspected unexpected serious adverse reaction 
t½  
Apparent terminal elimination half-life 
TCA  
Tricyclic antidepressant 
tmax  
Time to reach maximum observed plasma concentration 
TQT  
Thorough QT 
UACR  
Urine albumin-to-creatinine ratio 
ULN  
Upper limit of normal 
VHP  
Voluntary harmonization procedure 
 
 
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NON-SUBSTANTIAL GLOBAL AMENDMENT 4 
Rationale for the amendment  
This applies to global protocol ID-069A301 Version 4 dated 1 October 2020. The resulting 
amended global protocol is Version 5 dated 24 August 2021. 
In addition to this protocol and its amendments, a separate addendum to the protocol is in 
place to cover exceptional measures to ensure subject safety in the context of the 
COVID-19 pandemic and counteract any trial conduct disruption that may occur. The 
addendum applies to sites affected by the COVID-19 outbreak and is limited to the time 
during which such sites are affected.  
The main purpose of this fourth global amendment is to change the statistical analysis of 
the secondary endpoint, Change from baseline to Month 6 in the number of days with at 
least 1 stool of a Bristol Stool Scale (BSS) consistency Type 6 or 7, from a parametric 
analysis (assuming normality) to a non-parametric analysis. This change in analysis is 
warranted because blinded baseline data review suggests that the endpoint is not normally 
distributed.  
The necessity to make a change to this analysis method was discussed with the U.S. Food 
and Drug Administration (FDA); the change is restricted to the statistical analysis of the 
last secondary endpoint in the testing strategy and does not alter the study population and 
the primary and secondary objectives of the study.  
Changes to the protocol 
Two versions of the amended protocol will be prepared: 1) a clean version and 2) a Word 
comparison document showing deletions and insertions in comparison to the previous 
protocol version. 
Amended protocol sections 
The main sections of the protocol affected by this global amendment are listed below. 
Where applicable, the same changes have also been made to the corresponding sections of 
the protocol synopsis: 
Section 6.1.3  
Efficacy estimands 
Section 10.3.2.1 
Hypotheses 
Section 10.3.3.2 
Change from baseline to Month 6 in the number of days with at least 
1 stool of a Bristol Stool Scale consistency Type 6 or 7 in subjects 
with gastrointestinal symptoms at baseline 
Section 13 
 
 
References 
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Summary of previous amendments: 
Amendment 
Date 
Main reason(s) 
1 
12 April 
2018 
Non-substantial global amendment to address questions 
and comments received as part of the FDA review on 
9 March 2018 (items 1 and 2) and the VHP assessments on 
20 February 2018 (items 3 to 5) and 20 March 2018 
(item 6): 
1. The definition of neuropathic pain was split to improve 
readability and patient comprehension. The descriptor 
“numbness” was removed from the description as it was 
considered a distinct concept that does not necessarily 
describe neuropathic pain severity. The concept of 
intermittence was also added to the definition of 
neuropathic pain. 
2. A new patient global impression of severity scale to 
assess the overall severity of neuropathic pain was added. 
3. It was clarified that current guidelines for the diagnosis 
and treatment of Fabry disease were to be followed. 
4. A more explicit definition of the global end of the study 
was included. 
5. The process of the electronic diary (eDiary) data 
availability, transfer, encoding, and the measures taken to 
maintain privacy of the patient was clarified. 
6. Exclusion criteria were adjusted to emphasize that any 
subject at high risk of developing clinical signs of organ 
involvement within the time period of the study, as per 
investigator judgment would be excluded from the study. 
In addition, the following modifications were made: 
• The Discussion Guide for the Exit Interview was 
removed from the appendices as it is only relevant for 
the substudy conducted in the US and Canada. It was 
revised based on FDA recommendations and was 
submitted separately in those two countries. 
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• The time when the subject must definitively return the 
eDiary to the site personnel was clarified. 
• Reporting of change in intensity of an AE was 
clarified. 
• Footnote ‘h’ in Table 4 was corrected as it was not 
consistent with corresponding Section 7.2.4.2.1 of the 
protocol. 
• Footnote ‘a’ in Table 5 was removed as it was not 
consistent with Section 3.1.1, footnote ‘a’ of Table 4 
and protocol synopsis. 
• A typographical error in Table 5 was corrected (serum 
sampling moved from biomarker sampling line to 
research sampling line) as it was not consistent with 
Sections 7.2.7.1 and 7.2.7.2 of the protocol. 
• The sequence of site visit assessments was completed. 
• The stool sample collection was further clarified. 
• The nonclinical summary section was updated to detail 
the toxicological findings. 
2 
25 
October 
2018 
Substantial global amendment to remove some of the 
protocol restrictions following the release of the 
Investigator’s Brochure version 8 (October 2018): 
• The results of a clinical drug-drug interaction (DDI) 
study (ID-069-105) with the organic cation transporter 
2 (OCT2) inhibitor cimetidine led to the conclusion 
that lucerastat can be administered concomitantly with 
OCT2 inhibitors without need for dose adaptation. 
Therefore, respective protocol restrictions at study 
entry (exclusion criterion #15) and during the study 
(forbidden concomitant therapy) related to the use of 
OCT2 inhibitors have been removed. 
In addition, the following modifications were made:  
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• The “Current treatment of Fabry disease” section has 
been updated to reflect the approval of Galafold® 
outside of Europe; 
• The clinical summary section has been updated to 
include the results of the clinical DDI study with 
cimetidine; 
• The conditions under which barrier contraception can 
be used and the list of methods of contraception that 
are not considered as acceptable have been updated in 
line 
with 
the 
‘Recommendations 
related 
to 
contraception and pregnancy testing in clinical trials’ 
version 
15-09-2014 
from 
the 
Clinical 
Trials 
Facilitation Group; 
• The sequence of the Patient Global Impression 
questionnaire assessments was corrected; 
• The stool sample collection and shipment process was 
updated in line with the central laboratory manual and 
study-specific laboratory flowchart. 
3 
1 
October 
2020 
Global amendment to change the method used to analyze 
the primary endpoint using a dichotomous responder 
analysis, based on a reduction of at least 30% from baseline 
to Month 6 in modified Brief Pain Inventory-Short Form 
item 3 (BPI-SF3) score, to an analysis of the change from 
baseline to Month 6 in modified BPI-SF3 score. The 
dichotomous responder analysis will be documented to 
support and establish clinical relevance. The  change in the 
analysis of the modified BPI-SF3 score was agreed with 
the FDA. It was restricted to the primary statistical analysis 
and did not alter the study population and the primary 
objective of the study to determine the effect of lucerastat 
on neuropathic pain in subject with Fabry disease.  
In addition, the following modifications were made, 
including:  
• Improvements to statistical methodology as a result of 
FDA requests and advice, including: 
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− Efficacy estimands targeted by the primary and 
secondary analyses have been added; 
− A multiple testing procedure to control the study-
wise two-sided type I error at 0.05 or less has been 
added. Consequently, the two secondary endpoints 
based on gastrointestinal symptoms are no longer 
tested with a two-sided significance level of 0.10; 
− The number of subjects expected in the modified 
Full 
Analysis 
Set-gastrointestinal 
symptoms 
population has been clarified, including power 
estimates for a range of treatment effects; 
− The use of baseline/last/worst observation carried 
forward imputation methods for the primary and 
secondary endpoints analyses have been replaced 
by multiple imputation methods; 
− Multiple alternative definitions of the primary 
endpoint using different approaches of handling 
missing data have been removed; 
− Following the change from a responder to a 
continuous primary analysis method, the analysis 
for assessing the impact of rescue pain therapy has 
been added. This now replaces the responder 
analyses to assess the impact of data collected 
during the post-treatment observation period 
and/or after initiation of enzyme replacement 
therapy and/or after changes or initiation of 
significant rescue pain therapy; 
− As a responder analysis is no longer the primary 
analysis method, the related supportive analysis 
using logistic regression (also a responder analysis) 
has been removed; 
• To fulfill the clinical commitment made to the Irish 
Health Products Regulatory Authority at the time of 
clinical trial approval, the investigational treatment 
description was updated to specify the amount of 
lactose intake by the subjects. In addition, the 
exclusion criteria (8b and 11) were updated to 
emphasize the exclusion of subjects with galactose 
intolerance, total lactase deficiency, glucose-galactose 
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malabsorption, and subjects with hypersensitivity to 
lactose as lucerastat excipient;  
• The clinical summary section has been updated to 
include the results of the thorough QT study; 
• The exit interview section has been updated to 
incorporate FDA requirements; 
• The time windows for study assessments and study 
treatment 
dispensing 
have 
been 
revised 
to 
accommodate logistics at sites; 
• The recording of study treatment interruption in the 
electronic case report form has been further clarified; 
• The definition of re-tests and what is needed during 
unscheduled visits has been clarified. 
 
 
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PROTOCOL SYNOPSIS ID-069A301 
TITLE 
A multi-center, double-blind, randomized, placebo-controlled, 
parallel-group study to determine the efficacy and safety of 
lucerastat oral monotherapy in adult subjects with Fabry 
disease. 
ACRONYM 
MODIFY 
OBJECTIVES 
Primary objective 
The primary objective of the study is to determine the effect of 
lucerastat on neuropathic pain in subjects with Fabry disease 
(FD). 
Secondary objectives 
• To determine the effects of lucerastat on gastrointestinal 
(GI) symptoms (abdominal pain and diarrhea) in subjects 
with FD and GI symptom(s) at baseline; 
• To confirm the effect of lucerastat on biomarkers of FD; 
• To determine the safety and tolerability of lucerastat in 
subjects with FD. 
Other objectives 
Other objectives are described in Section 2.3 of the core 
protocol.  
DESIGN 
This is a prospective, multicenter, double-blind, randomized, 
placebo-controlled, parallel-group, Phase 3 study. 
Approximately 99 adult subjects with FD exhibiting 
Fabry-associated pain of moderate to severe intensity will be 
randomized in a 2:1 ratio to either lucerastat (approximately 
66 subjects) or placebo (approximately 33 subjects).  
Treatment allocation will be stratified by sex and by specific 
background FD treatment at screening (subjects treated with 
enzyme replacement therapy ERT, also called “switch” 
subjects, as they will have to stop ERT at screening visit, vs 
subjects not treated with ERT at screening).  
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Subjects not treated with ERT at screening include: 
(i) “treatment-naïve” subjects who have never been treated 
with ERT. 
(ii) “pseudo-naïve” subjects who stopped ERT at least 
6 months prior to screening.  
Once randomized, subjects will enter a 6-month double-blind 
treatment period. 
The study comprises the following consecutive periods: 
Screening period: Lasts approximately 6–7 weeks; starts with 
the signing of the informed consent form (ICF; at the screening 
visit) and ends the day before subject randomization.  
Treatment period: Lasts approximately 6 months; Starts on 
the day of subject randomization (randomization visit) and 
ends at the End-of-Treatment (EOT) visit (Month 6).  
Post-treatment observation period (PTOP): Subjects who 
discontinue study treatment prematurely will enter into the 
PTOP which starts on the day after the last dose of study 
treatment, and ends at latest at the Month 6 PTOP visit.  
Post-treatment safety follow-up (FU) period: The FU period 
is applicable to all subjects except those who enter the 
open-label extension (OLE) study. It starts on the day after the 
last dose of study treatment: 
• For female and non-fertile male subjects: it includes 
1 safety 
FU 
telephone 
call 
(FU1) 
taking 
place 
approximately 1 month after the last dose of study 
treatment; 
• For fertile male subjects: it includes 2 safety FU telephone 
calls taking place approximately 1 month (FU1) and 
3 months (FU2) after the last dose of study treatment. 
Subjects who complete the 6-month double-blind treatment 
period will be proposed to enroll into an OLE study conducted 
under a separate protocol (provided the extension study 
protocol has been approved in the country/site by regulatory 
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authorities and Ethics Committees [ECs] / Institutional Review 
Boards [IRBs]). 
Subjects who discontinue study treatment prematurely for any 
reason should be subsequently treated according to local 
standard-of-care at the investigator’s discretion and will be 
followed in the PTOP until the originally scheduled 
Month 6 visit. 
PLANNED 
DURATION 
Approximately 3.5 years from first subject, first visit to last 
subject, last visit. 
The global end of the study corresponds to the last visit of the 
last subject: 
• If the last subject enters the OLE study, the global end of 
the study corresponds to the last subject’s EOT visit.  
• If the last subject does not enter the OLE study, the global 
end of the study corresponds to the last subject’s FU1 visit, 
FU2 visit, or to the last visit of the PTOP, whichever is last. 
SITES/COUNTRIES 
Approximately 58 sites in approximately 14 countries. 
INCLUSION 
CRITERIA 
Screening visit criteria 
1. Signed and dated ICF prior to any study-mandated 
procedure; 
2. Male or female subjects 18 years old and above; 
3. FD diagnosis confirmed with local genetic test results 
(i.e., presence of at least 1 mutation in GLA, the gene 
coding for α-galactosidase A α-GalA); 
4. Fabry-associated neuropathic pain, as defined by the 
subject, in the last 3 months prior to screening; 
5. ERT treatment status: 
a) Subject never treated with ERT; or 
b) Subject has not received ERT for at least 6 months prior 
to screening; or  
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c) Subject treated with ERT at the time of the screening 
visit and meeting all of the following criteria at the time of 
screening:  
i) ERT administration for the last 12 months; 
ii) Stable ERT dose regimen during the last 3 months; 
iii) Subject agrees to stop ERT administration at the 
screening 
visit 
for 
approximately 
8 months  
(6–7 weeks screening + 6 months of double-blind 
treatment). 
6. A woman of childbearing potential [see definition in 
Section 4.5.1 of the core protocol] is eligible only if the 
following applies: 
– Negative serum pregnancy test at screening and a 
negative urine pregnancy test at randomization; 
– Agreement to undertake monthly urine pregnancy tests 
during the study and up to at least 30 days after study 
treatment discontinuation; 
– Agreement to follow a highly effective contraception 
scheme as described in Section 4.5.2 of the core 
protocol from screening up to at least 30 days after 
study treatment discontinuation. 
7. A fertile male (physiologically capable of conceiving a 
child according to investigator judgment) who is sexually 
active with a woman of childbearing potential is eligible 
only if the following applies: 
– Agreement to use a condom during the treatment period 
(starting at randomization) and for up to 3 months after 
study treatment discontinuation; and 
– Agreement not to father a child during this period. 
Randomization visit criteria 
8. Adequate subject compliance with completion of an eDiary 
during the screening period; 
9. Subjects with moderate or severe neuropathic pain as 
determined from daily entries of the modified Brief Pain 
Inventory-Short Form item 3 (BPI-SF3) score of 
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“neuropathic pain at its worst in the last 24 hours” in the 
eDiary during the screening period. 
The definition of moderate to severe neuropathic pain at 
baseline is provided in Section 4.3 of the core protocol. 
EXCLUSION 
CRITERIA 
Screening visit criteria 
Disease/condition 
1. Pregnant / planning to become pregnant up to 30 days after 
study treatment discontinuation or lactating subject; 
2. Severe renal insufficiency defined as an estimated 
glomerular filtration rate (eGFR) per the Chronic Kidney 
Disease Epidemiology Collaboration creatinine equation 
< 30 mL/min/1.73 m2 at screening (as reported by the 
central laboratory); 
3. Subject on regular dialysis for the treatment of chronic 
kidney disease; 
4. Subject has undergone, or is on a waiting list for, or is 
scheduled 
to 
undergo 
kidney 
or 
other 
organ 
transplantation; 
5. Known and documented transient ischemic attack, stroke, 
unstable angina or myocardial infarction within 6 months 
prior to screening; 
6. Clinically significant unstable cardiac disease in the 
opinion of the investigator (e.g., uncontrolled symptomatic 
arrhythmia, New York Heart Association class III or IV 
congestive heart failure); 
7. Any other subject at high risk of developing clinical signs 
of organ involvement within the time period of the study, 
as per investigator judgment; 
8.  Any known factor or disease that might interfere with 
treatment compliance, study conduct or interpretation of 
the results such as: 
a) Other disease or condition associated with a pain 
component that could confound assessment of 
neuropathic 
pain 
(e.g., 
diabetic 
neuropathy, 
chemotherapy- 
or 
radiation-induced 
peripheral 
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neuropathy, chronic inflammatory demyelinating 
polyneuropathy); 
b) Other disease of the GI tract that could interfere with 
the 
assessment 
of 
GI 
symptoms 
in 
FD 
(e.g., inflammatory 
bowel 
disease, 
galactose 
intolerance, 
total 
lactase 
deficiency 
or 
glucose-galactose malabsorption); 
c) Documented poorly controlled diabetes mellitus 
(i.e., HbA1c > 8.0% at screening as reported by the 
central laboratory); 
d) Significant neurological disorder;  
e) Significant psychiatric disease; suicidal ideation at 
screening or history of suicide attempt or behavior 
within 6 months prior to screening as per investigator 
judgment; 
f) History of drug dependence (including opioids) or 
alcohol dependence;  
g) Inability to complete an eDiary on a daily basis. 
9.  Known concomitant life-threatening disease with a life 
expectancy < 18 months. 
Treatments 
10. Subject planned for imminent initiation of treatment with 
ERT; 
11. Known hypersensitivity to lucerastat or drug of the same 
chemical class of iminosugars (e.g., miglitol, miglustat, 
migalastat), or any of their excipients (including lactose); 
12. Initiation or treatment at an unstable dose within 4 weeks 
prior to screening with any of the following medications: 
a) Angiotensin-converting enzyme (ACE) inhibitor 
and/or angiotensin receptor blocker (ARB);  
b) Anti-epileptic;  
c) Tricyclic 
antidepressant 
(TCA) 
and/or 
other 
antidepressants 
belonging 
to 
the 
serotonin-norepinephrine re-uptake inhibitor (SNRI) 
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and selective serotonin re-uptake inhibitor (SSRI) 
classes. 
13. Planned or current treatment with another investigational 
treatment within 3 months prior to screening; 
14. Treatment with any inhibitor of the glucosylceramide 
synthase (GCS) (e.g., miglustat, lucerastat, eliglustat, 
ibiglustat/venglustat) 
or 
an 
α-GalA 
chaperone 
(e.g., migalastat) within 6 months prior to screening; 
Randomization visit criteria 
15. Treatment with ERT (agalsidase alfa, agalsidase beta) 
during the screening period. 
STUDY 
TREATMENTS 
Lucerastat is currently available for clinical study use as hard 
gelatin capsules containing 250 mg of lucerastat and inactive 
excipients (
 mg of lactose anhydrous and 
 mg of talc).  
Placebo capsules will be identical in appearance to the 
lucerastat capsules, and will contain inactive excipients 
(
 mg of lactose anhydrous and 
 mg of talc). 
The starting dose of the study treatment (lucerastat or matching 
placebo) will be based on the subject’s eGFR value (as 
reported by the central laboratory) at the screening visit as 
shown in Table 1 of the core protocol.  
During the study, the dose of the study treatment will be 
reduced if the subject’s eGFR (as reported by the central 
laboratory during scheduled or unscheduled visits) decreases 
and crosses the next lower eGFR boundary as shown in Table 1 
of the core protocol.  
Study treatment must be discontinued if one of the 
study-treatment stopping criteria is met [see Section 5.1.10 of 
the core protocol]. 
CONCOMITANT 
THERAPY 
Mandatory concomitant therapy 
Mandatory therapy includes any treatments required for 
contraception purposes in women of childbearing potential.  
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Allowed concomitant therapy 
Treatments considered necessary for the subject’s well-being 
and not categorized as forbidden concomitant medications are 
allowed during the study and must be documented in the 
medical charts. 
ACE inhibitor or ARB 
Subject must not have initiated ACE inhibitor or ARB therapy 
within 4 weeks prior to screening. ACE inhibitor or ARB 
therapy, if used by the subject, must be at a stable dose for at 
least 4 weeks prior to screening. During the study, initiation or 
dose adjustment is allowed based on investigator judgment. 
Pain medications 
During the study, the use of adjuvant pain medications, 
non-opioid and opioid analgesics is allowed if judged 
medically required by the investigator. 
Subject must not have initiated adjuvant pain medications 
(i.e., anti-epileptics, TCAs and SNRIs/SSRIs) within 4 weeks 
prior to screening. The dose regimen of adjuvant pain 
medications used chronically by the subject at screening must 
be stable for at least 4 weeks prior to screening. 
In the event of unbearable pain, rescue pain medications may 
be considered.  
An Individualized Pain Management Plan (IPMP) will be 
provided by the investigator/delegate to each subject with 
customized instructions regarding the use of pain medications 
during the study. The IPMP will list the pain medications 
ongoing at the screening visit that the subject should continue 
taking during the study. It will also include a list of new pain 
medication(s) or dose adjustment that should be made in the 
event of unbearable pain taking into account the subject’s 
background pain medication(s) and previous response to pain 
medication(s). The IPMP will be applicable starting at 
screening visit and until the EOT visit or the last visit of the 
PTOP (as applicable). 
Depending on the background pain medication(s) of the 
subject, and provided that the medication is not categorized as 
forbidden concomitant medication [Section 5.2.4], the rescue 
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pain medication(s) may include one or more of the following 
options: 
• Initiation or dose escalation of adjuvant pain medication(s) 
(i.e., anti-epileptics, TCAs, SNRIs, SSRIs); 
• Initiation or dose escalation of opioid analgesic drugs;  
• Initiation or dose escalation of non-opioid analgesics drugs 
(i.e., 
non-steroidal 
anti-inflammatory 
drug, 
topical 
analgesics). 
If, after the modification of pain treatment, the subject still 
suffers from unbearable pain, the investigator/delegate should 
discuss with the subject alternative therapeutic options 
including the possibility to (re-)initiate ERT treatment 
(if available at the site). 
Antidepressants used to treat depression 
Subject must not have initiated antidepressants (i.e., SNRIs, 
SSRIs, TCAs) within 4 weeks prior to screening. The doses of 
antidepressants used by the subject at screening must be stable 
for at least 4 weeks prior to screening. During the study, 
initiation or dose adjustment are allowed based on investigator 
judgment. 
Forbidden concomitant therapy 
ERT (agalsidase alfa, agalsidase beta) 
Subjects on ERT with neuropathic pain at screening (“switch”) 
must agree to stop ERT administration for about 8 months  
(6–7 weeks screening + 6 months of double-blind treatment).  
Recently published recommendations by the European Fabry 
Working Group have defined ERT stopping criteria which 
include the lack of response for 12 months when the sole 
“indication” for ERT is neuropathic pain, and the subject’s 
request to stop ERT Biegstraaten 2015. 
Subjects off ERT with neuropathic pain at screening (“naïve” 
or “pseudo-naïve”) who are planned for imminent initiation of 
treatment with ERT are not eligible for the study [see 
Section 4.4 of the core protocol], and initiation of ERT will 
therefore not be withheld for these subjects. 
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Although discouraged throughout the whole study, subjects 
may be allowed to (re-)initiate ERT treatment (if available at 
that site) if judged medically required due to significant FD 
progression (e.g., significant renal function deterioration or 
cardiac function deterioration) based on investigator judgment. 
Inhibitors of GCS, -GalA chaperone, investigational drugs 
The following concomitant therapies are forbidden from 
screening visit until the EOT visit or the last visit of the PTOP 
(as applicable): 
• Any inhibitor of GCS (e.g., miglustat, eliglustat); 
• Any -GalA chaperone (e.g., migalastat); 
• Any other investigational drug (e.g., ibiglustat/venglustat, 
pegunigalsidase alfa). 
ENDPOINTS 
Primary efficacy endpoint 
The primary efficacy endpoint is change from baseline to 
Month 6 in the “modified” BPI-SF3 score of “neuropathic pain 
at its worst in the last 24 hours”. 
Secondary efficacy endpoints 
• Change from baseline to Month 6 in the 11-point numerical 
rating scale (NRS-11) score of “abdominal pain at its worst 
in the last 24 hours” in subjects with GI symptoms at 
baseline. 
The definition of a subject considered to have GI symptoms at 
baseline is provided in Section 10.1.4 of the core protocol. 
• Change from baseline to Month 6 in the number of days 
with at least one stool of a Bristol Stool Scale (BSS) 
consistency Type 6 or 7 in subjects with GI symptoms at 
baseline; 
• Change 
from 
baseline 
to 
Month 6 
in 
plasma 
globotriaosylceramide (Gb3). 
Other efficacy endpoints 
Other efficacy endpoints are described in Section 6.1.4 of the 
core protocol. 
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Safety endpoints 
• Treatment-emergent adverse events (AEs) and serious 
AEs; 
• AEs leading to premature discontinuation of study 
treatment; 
• Change from baseline to each visit up to Month 6 in vital 
signs; 
• Treatment-emergent marked abnormalities for vital 
signs variables up to Month 6;  
• Change from baseline to each visit up to Month 6 and from 
pre-dose to 2 hours and 4 hours post dose at Month 1 in 
12-lead electrocardiogram (ECG) variables; 
• Treatment-emergent marked abnormalities for quantitative 
12-lead ECG variables up to Month 6; 
• Change from baseline to each visit up to Month 6 in 
laboratory variables [see list in Section 7.2.4.2 of the core 
protocol]; 
• Treatment-emergent marked abnormalities for selected 
laboratory variables up to Month 6. 
Other endpoints (quality of life, pharmacokinetic [PK], 
other biomarkers) 
Other endpoints are described in Sections 6.3, 6.4, and 6.5 of 
the core protocol. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 5 and Table 6 of 
the core protocol. 
STATISTICAL 
METHODOLOGY 
Analysis sets 
The Screened Analysis Set includes all subjects who have 
given informed consent to participate in the study and have a 
subject number. 
The Full Analysis Set (FAS) includes all subjects randomized 
to either lucerastat or placebo. Subjects will be evaluated 
according to their assigned study treatment and stratum 
information as recorded in the Interactive Response 
Technology system. 
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A modified FAS (mFAS) will be defined by including subjects 
from the FAS who took at least 1 dose of study treatment. 
The Per-Protocol Analysis Set includes all subjects from the 
mFAS without important protocol deviations occurring prior 
to Month 6, which could affect the analysis of the primary 
endpoint variable. 
The mFAS-gastrointestinal symptoms (mFAS-GIS) comprises 
all subjects from the mFAS who, during the 4 weeks prior to 
randomization, have experienced: 
• abdominal pain of moderate to severe intensity at baseline 
defined as an average abdominal pain intensity score 
≥ 3 on an NRS-11 scale; and/or 
• diarrhea at baseline defined as having at least 1 stool of a 
BSS consistency type 6 or 7 on at least 8 days. 
The Safety Set (SAF) includes all subjects who received at 
least 1 dose of study treatment (as recorded in the electronic 
case report form). Subjects will be analyzed based on the 
treatment received. In the event of accidental dispensation of 
both study treatments to the same subject, the subject will be 
counted as on lucerastat for the whole study. 
Other analysis datasets will be defined in the statistical analysis 
plan (SAP; or corresponding SAPs), e.g., PK set, sub-study 
sets, and subgroups of interest. 
Overall testing strategy 
Comparisons of lucerastat vs placebo will be conducted for the 
primary and secondary endpoints assessed at Month 6. 
The Type I error rate will be controlled at a two-sided alpha of 
5% for the testing of the four null hypotheses associated with 
the primary and secondary endpoint comparisons employing a 
fixed-sequence statistical testing strategy in the following 
order: 
1. Change from baseline to Month 6 in the “modified” 
BPI-SF3 score of “neuropathic pain at its worst in the last 
24 hours”. 
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2. Change from baseline to Month 6 in plasma Gb3. 
3. Change from baseline to Month 6 in the NRS-11 score of 
“abdominal pain at its worst in the last 24 hours” in subjects 
with GI symptoms at baseline. 
4. Change from baseline to Month 6 in the number of days 
with at least one stool of a BSS consistency Type 6 or 7 in 
subjects with GI symptoms at baseline. 
All available data will be used regardless of occurrence of 
intercurrent 
events 
such 
as 
premature 
treatment 
discontinuation or changes in background medication. 
Analysis of the primary efficacy variable 
Hypotheses for the primary endpoint are formulated in terms 
of the mean differences in change from baseline to Month 6. 
H0: Lucerastat - Placebo = 0 
is the null hypothesis that there is no difference between 
treatments. 
HA: Lucerastat - Placebo ≠ 0 
is the alternative hypothesis that a difference in change from 
baseline to Month 6 exists between treatments. 
The primary statistical analysis will be performed on the 
mFAS, according to the intent-to-treat approach. The null 
hypothesis will be tested at the two-sided alpha level = 0.05, 
using the following method: 
Missing data will be imputed applying a control-based multiple 
imputation assuming missing not at random using the Copy 
Reference approach [Carpenter 2013]. Instead of imputing a 
single value for each missing observation, a set of values is 
generated from the model, resulting in as many distinct 
complete datasets without missing data. The imputation model 
includes the baseline value, the two stratification factors (sex 
and ERT treatment status at screening) and all post-baseline 
monthly scores up to Month 6. Missing data for subjects from 
both treatment arms will be imputed using data from the 
placebo arm. This approach assumes that subjects with missing 
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data in the lucerastat arm have outcomes trending towards 
outcomes observed in the placebo arm, i.e., the imputations 
result in a treatment effect that gradually diminishes towards 
the placebo arm. 
An analysis of covariance model will be used to analyze this 
endpoint on each imputed dataset. The following terms will be 
included in the model: baseline value, the two stratification 
factors (sex and ERT treatment status at screening), and the 
treatment group. 
Uncertainty in the imputations will be reflected appropriately 
in the analysis by combining the results on each imputed 
dataset using Rubin’s methodology [Rubin 1987]. 
The mean difference in changes from baseline to Month 6 
between lucerastat and placebo together with its two-sided 
95% confidence interval and p-value will be reported. 
The robustness of inferences from the primary endpoint 
analysis to deviations from its underlying modelling 
assumptions will be explored using sensitivity analyses.  
A series of additional analyses based on the modified BPI-SF3 
score data will support the primary endpoint results by 
analyzing the primary endpoint variable using various other 
methods and assumptions. 
Sub-group analyses classifying subjects according to important 
baseline characteristics, will be performed to explore the 
consistency of treatment effect in a variety of relevant 
subgroups to support the efficacy evaluation of lucerastat in 
this indication. 
Analysis of the secondary efficacy variables 
The following secondary efficacy endpoint variables will be 
analyzed in the mFAS-GIS at a two-sided significance level of 
alpha = 0.05: 
• Change from baseline to Month 6 in the NRS-11 score of 
“abdominal pain at its worst in the last 24 hours” in 
subjects with GI symptoms at baseline; 
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• Change from baseline to Month 6 in the number of days 
with at least 1 stool of a BSS consistency Type 6 or 7 in 
subjects with GI symptoms at baseline.  
The following secondary efficacy endpoint variable: 
• Change from baseline to Month 6 in plasma Gb3 
will be analyzed in the mFAS at the two-sided significance 
level of alpha = 0.05. 
Sample size 
The planned sample size for this study is 99 subjects using a 
2:1 allocation ratio (66 lucerastat, 33 placebo) and is primarily 
based on a test for the mean difference between lucerastat and 
placebo in the change from baseline to Month 6 in the 
“modified” BPI-SF3 score.  
Assuming a clinically relevant difference of 2 points on the 
11-point scale (0−10) between lucerastat and placebo, a 
corresponding standard deviation of 3 points, a two-sided type 
I error of 5%, and equal group variances, 99 subjects will 
provide a power of 87.2% to detect a treatment difference 
between lucerastat and placebo on the primary endpoint. The 
calculations were conducted using East 6.5 based on a 
two-sided t-test for independent samples. 
STUDY 
COMMITTEE 
An Independent Data Monitoring Committee (IDMC) will 
have the overall responsibility for safeguarding the interests of 
subjects by monitoring safety and efficacy data obtained in the 
study and making appropriate recommendations based on the 
reported data, thus ensuring that the study is being conducted 
to the highest scientific and ethical standards.  
The IDMC will be fully operational prior to enrollment of the 
first subject into the study. The composition and operation of 
the IDMC will be described in an IDMC charter. 
SUB-STUDIES 
PK profile sub-study (all sites) 
A sub-study will be conducted at all sites to determine the PK 
profile of lucerastat at steady state in a subgroup of 
approximately 36 subjects with FD with either normal or 
subnormal 
renal 
function 
(i.e., screening 
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eGFR ≥ 60 mL/min/1.73 m2) or impaired renal function 
(i.e., screening eGFR < 60 mL/min/1.73 m2). If necessary, 
blood samples collected for PK may be used for the 
identification of potential metabolites of lucerastat in this 
population. Subjects consenting to this sub-study will have a 
12-hour PK profile performed at the Month 1 visit. 
Exit interview sub-study (US and Canadian sites only) 
An exit interview sub-study will be conducted in all 
English-speaking subjects at US and Canadian sites. 
The interviews will focus on gaining an understanding of what 
constitutes a meaningful change on the neuropathic pain and 
GI symptom (diarrhea and abdominal pain) questions from a 
subject perspective. 
Details on the analysis of the exit interview data are available 
in the Exit Interview Analysis Plan. 
STUDY EXTENSION Subjects who complete the 6-month double-blind treatment 
period will be proposed to enroll into an OLE study conducted 
under a separate protocol (provided the OLE study protocol has 
been approved in the country/site by regulatory authorities and 
ECs/IRBs at the time of enrollment). 
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PROTOCOL 
1 
BACKGROUND 
1.1 Fabry disease 
Fabry disease (FD) is a rare, pan-ethnic X-linked inherited glycosphingolipid (GSL) 
storage 
disorder 
caused 
by 
the 
deficiency 
of 
the 
lysosomal 
enzyme 
α-galactosidase A (α-GalA) [Germain 2010]. In FD, mutations in the gene coding for 
α-GalA (GLA gene), located on the X chromosome, are responsible for reduced expression 
and/or activity of α-GalA resulting in accumulation of globotriaosylceramide (Gb3), 
globotriaosylsphingosine (lysoGb3), and other neutral GSLs in lysosomes and other 
subcellular compartments. Progressive storage of these GSL molecules eventually leads to 
cellular dysfunction, associated with inflammation and/or fibrosis which results in 
multisystem disease, mainly affecting the kidneys, heart, and nervous system. 
Diagnosis of FD combines clinical presentation, α-GalA activity and GLA mutations, as 
defined in the most recent international guidelines [Schiffmann 2017]. 
There are 2 major phenotypes: a classic phenotype and a late-onset (also referred to as 
“atypical” or “non-classical”) phenotype Arends 2017.  
The classic phenotype is more severe due to little or no α-GalA activity. The first clinical 
symptoms (e.g., neuropathic pain, gastrointestinal [GI] symptoms, abnormal sweating) 
interfering with well-being and daily activities arise in childhood [Hopkin 2008]. In the 
absence of treatment, progressive damage to vital organ systems occurs in subjects with 
FD over several decades, resulting in end-stage renal disease and/or life-threatening 
cardiovascular or cerebrovascular complications, causing substantial morbidity, 
significantly impaired quality of life (QoL), and premature death [MacDermot 2001a, 
MacDermot 2001b].  
The late-onset phenotype is typically less severe and is observed in subjects with significant 
residual α-GalA activity. It is characterized by a more variable disease course, and disease 
manifestations may be limited to a single organ, e.g., the heart. 
As expected for an X-linked disorder, males with deleterious mutations have little or no 
residual α-GalA activity. Therefore, these male subjects usually experience the full 
spectrum of disease symptoms. In heterozygous female subjects with FD (carriers) who 
have a mutation in one copy of the GLA gene, random X inactivation effectively results in 
mosaic expression, with some cells exhibiting normal α-GalA activity and others with little 
or no α-GalA activity [Linhart 2007]. The severity of the disease is heterogeneous in 
female carriers, who, like male subjects and somehow unexpectedly, may develop 
life-threatening complications of the disorder. Up to 70% of female carriers develop 
FD-related symptoms, including neuropathic pain, GI symptoms, renal and cardiac disease, 
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and/or stroke [Schiffmann 2009]. In general, affected female carriers experience symptoms 
similar to hemizygous males with a delayed onset and slower progression compared to men 
[Linhart 2007]. 
1.1.1 Current treatment of Fabry disease 
The management of FD consists of conventional palliative management, enzyme 
replacement therapy (ERT), and chaperone therapy. 
Conventional management consists of pain medications, angiotensin-converting enzyme 
(ACE) inhibitors or angiotensin receptor blockers (ARBs) to protect the heart and kidney, 
antiarrhythmic agents, and anticoagulants to avoid thrombotic complications. Dialysis or 
renal transplantation are available for subjects experiencing end-stage renal failure. 
A recent review of the pharmacotherapy for neuropathic pain in Fabry adult subjects 
recommends 
using 
anti-epileptics 
(e.g., 
carbamazepine, 
gabapentin), 
tricyclic 
antidepressants 
(TCAs; 
e.g., amitriptyline), 
and 
other 
antidepressants 
of 
the 
serotonin-norepinephrine re-uptake inhibitor class (SNRIs; e.g., duloxetine, venlafaxine) 
as first-line therapy [Finnerup 2015, Politei 2016]. Non-opioid and opioid analgesic drugs 
are used as second- and third-line treatments, respectively. Due to the limited evidence 
with respect to the effectiveness of pain medication in FD, clinicians usually rely on local 
clinical experience or follow national and international guidelines for the management of 
neuropathic pain [Finnerup 2015]. 
Two injectable ERTs have been granted market authorization in at least 1 country for the 
treatment of FD: agalsidase alfa (Replagal®) and agalsidase beta (Fabrazyme®). However, 
their effectiveness in controlling all symptoms and complications of FD is limited (see 
below). Chaperone therapy is also available to improve the activity of some defective 
enzymes. In FD, migalastat (Galafold), an oral small molecule pharmacological 
chaperone, has been granted market authorization in at least 1 country for the treatment of 
subjects with amenable mutations. 
The most recent international guidelines provide the framework for screening, diagnosis 
and management of patients with FD [Biegstraaten 2015, Schiffmann 2017]. They include 
recommendations on the use of ERT, the discontinuation of ERT, the monitoring of 
Fabry-specific symptoms and organ diseases, and the use of adjunctive therapy. 
Recommendations for diagnosis and management of neuropathic pain in subjects with FD 
are also available [Politei 2016]. 
1.1.2 Unmet medical need in Fabry disease 
Despite ERT administration, a large proportion of subjects with FD still exhibit clinical 
symptoms, in particular neuropathic pain, which impact their daily life. Although an effect 
on neuropathic pain after 6 months of treatment with agalsidase alfa has been suggested in 
a placebo-controlled study [Schiffmann 2001], the totality of the data provided no clear 
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evidence that ERT treatment is associated with improvement in the “worst pain” Brief Pain 
Inventory (BPI) scores. While no other placebo-controlled study was performed to assess 
the effect of ERT on neuropathic pain, further data from the Fabry Outcome Survey (FOS) 
registry [Hoffmann 2005] and a comparative trial with agalsidase alfa or beta 
[Vedder 2007] showed little or no improvement in neuropathic pain with ERT in subjects 
with FD. 
The effects of ERT on different organs/systems in subjects with FD have been extensively 
evaluated [Eng 2001, Banikazemi 2007, Schiffmann 2001]. Overall, some limited 
improvements in renal function, cardiac mass, cerebrovascular complications, and QoL 
have been reported [Mehta 2009]. Long-term effects of ERT on risk of morbidity and 
mortality related to FD remain to be established even to this day [El Dib 2016]. 
ERT for FD has intrinsic limitations such as a very short half-life combined with a low 
tissue penetration, in particular in the nervous system [Murray 2007, Thurberg 2004, 
Thurberg 2009], and the development of antibodies to the infused protein in many subjects 
[Deegan 2012]. Inhibitory antibodies may compromise the efficacy of the treatment with 
ERT [Lenders 2016]. Furthermore, the intravenous (i.v.) route of administration for ERT 
is associated with an elevated risk of adverse events (AEs) and it can be inconvenient 
[Mehta 2009]. 
The oral administration of migalastat is restricted to subjects with amenable mutations 
only, which represent approximately 30% of all known GLA mutations [Galafold® SmPC]. 
In that population, the Phase 3 study results suggest that migalastat may provide some 
beneficial clinical effects, e.g., stabilizing renal function and decreasing left ventricular 
mass index (LVMI) [Germain 2016]. However, long-term data with the use of chaperone 
therapy in FD is tenuous. 
Overall, there is still an unmet medical need in the treatment of subjects with FD. The 
available therapies have not yet demonstrated long-term clinical benefit on the main 
symptoms such as neuropathic pain. In addition, their use is either restricted due to their 
mode of administration (i.v. infusion) and immunogenic potential or indicated only in a 
subset of subjects with FD. 
1.2 Lucerastat  
1.2.1 Mechanism of action 
Lucerastat is an iminosugar that has the potential to provide substrate reduction therapy 
(SRT) for the treatment of FD. The goal of SRT with lucerastat in FD is to inhibit the 
enzyme glucosylceramide synthase (GCS) that catalyzes the first committed step of GSL 
biosynthesis, thereby reducing the rate of synthesis of Gb3 to a level compatible with its 
residual clearance. The expected result is a reduction of net Gb3 load in tissues resulting 
in symptomatic improvement and a delayed progression towards end-stage organ failure. 
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1.2.2 Nonclinical summary 
Nonclinical pharmacology studies were performed in mice. Pharmacokinetic (PK), 
metabolism, and toxicology in vitro and in vivo studies were performed in mice, rats, 
rabbits and dogs. 
In summary, lucerastat dose dependently inhibits GCS at low micromolar concentrations, 
and reduces Gb3 storage and lysosomal staining in cultured FD subject fibroblasts, 
including fibroblasts from subjects with mutations associated with very low or no residual 
α-GalA activity [Welford 2017, Welford 2018]. In a mouse model of FD devoid of α-GalA 
activity oral lucerastat reduces Gb3 levels in the dorsal root ganglia (DRG) and in the 
kidney. In other mouse models of related GSL storage disorders such as Sandhoff disease, 
and GM1 gangliosidosis, lucerastat prolongs life span and improves clinical manifestations. 
In rats and dogs, hepatic elimination is negligible and the main route of elimination is renal 
excretion of unchanged lucerastat. In vitro studies showed that lucerastat is a substrate of 
organic cation transporter 2 (OCT2), but not of other kidney transporters. This observation 
triggered a clinical drug-drug interaction (DDI) study with the OCT2 inhibitor cimetidine 
in healthy male subjects [see Section 1.2.3]. 
Dermal findings of low severity were present in rats and dogs. They consisted of acanthosis 
(epidermal hyperplasia), along with hyperkeratosis and lymphoid cell infiltration, in rats at 
doses ≥ 1000 mg/kg/day given for 26 weeks and in dogs at doses ≥ 300 mg/kg/day given 
for up to 39 weeks. The changes were mild, reversible, without further consequences, and 
thus considered not adverse. As skin findings were observed both in rodents and in 
non-rodents, and these findings might be related to exaggerated pharmacodynamic (PD) 
effects, it is recommended that the skin be monitored in clinical studies. 
Embryo-fetal toxicity studies indicated that lucerastat has embryotoxic potential in rats and 
rabbits and teratogenic potential in rabbits at high doses inducing maternal toxicity.  
In rat fertility studies, lucerastat had no effects on female fertility, while male fertility was 
reduced at doses ≥ 500 mg/kg/day. The 26-week toxicity study in rats showed changes in 
sperm parameters and microscopic findings in the testes and epididymides. In CD-1 mice 
and dogs, no changes in sperm parameters (assessed in the 13-week mouse study and the 
4-week dog study) were seen. In addition, no histopathological effects in the testes were 
seen when lucerastat was administered for up to 13 weeks in mice and 39 weeks in dogs. 
Systemic exposure levels reached in mice and dogs were similar to or higher than those 
producing effects on the male reproductive system of rats. In the absence of changes in 
sperm parameters and microscopic findings in dogs and mice, the testicular toxicity 
observed in rats is considered unlikely to be relevant in man. 
More detailed information can be found in the Investigator’s Brochure (IB) [Lucerastat IB]. 
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1.2.3 Clinical summary 
A total of six Phase 1 studies have been completed, which overall enrolled 180 subjects: 
one single-ascending dose study (n = 39) and one multiple-ascending dose study (n = 37) 
in healthy male subjects, one study in subjects with different degrees of renal function 
impairment (n = 32), one exploratory Phase 1b study in subjects with FD (n = 14), one DDI 
study in healthy male subjects (n = 14), and one thorough QT (TQT) study in healthy 
subjects (n = 44). In the DDI study, lucerastat was administered concomitantly with the 
OCT2 inhibitor cimetidine at steady state. 
Across the six Phase 1 studies, lucerastat has been administered to 152 subjects including 
10 subjects with FD. It was found to be safe and well tolerated at all dose regimes evaluated 
(single oral doses up to 4000 mg, repeated oral doses up to 1000 mg twice daily [b.i.d.] for 
12 weeks [on top of ERT], and a single oral dose of 500 mg administered concomitantly 
with cimetidine at steady state). 
Overall, in the completed studies, there were 2 serious AEs (SAEs): One SAE of recurrent 
femoral thrombosis was reported in a subject with severe renal function impairment, and 
medical history of factor V Leiden gene mutation. Another SAE of re-occurrence of atrial 
fibrillation in the context of hypertrophic cardiomyopathy was reported in a subject with 
FD with a history of transient ischemic attack and atrial fibrillation. 
Among other AEs, there was one with alanine aminotransferase (ALT) 5  upper limit of 
normal (ULN) and aspartate aminotransferase (AST) 2.5  ULN in a healthy subject 
leading to study drug discontinuation and full resolution thereafter. Total bilirubin 
remained within normal range. Few subjects in both lucerastat and placebo groups reported 
medically irrelevant AEs of increased liver enzymes. 
After single dosing of lucerastat (range: 100–4000 mg) in healthy subjects, peak plasma 
drug concentrations were attained between 0.5 and 4.0 h, and the apparent terminal 
elimination half-life (t½) ranged from 3.6–16.9 h. Following repeated administration of 
lucerastat (range: 200–1000 mg b.i.d.), peak plasma concentration observed during the 
dosing interval were attained between 0.5 h and 4.0 h. The PK of lucerastat were 
proportional for the area under the plasma concentration-time curve (AUC) extrapolated to 
infinity (AUC0–∞) over the dose range tested after both single and multiple dosing. There 
was no relevant increase in exposure from Day 1 to Day 7, indicating absence of 
accumulation over time. The time to reach steady state was approximately 2 days. 
Renal clearance of unchanged lucerastat varied from 68–85% of oral clearance and mean 
renal excretion of unchanged lucerastat per daily dose from 68−85%. No clinically relevant 
food effect was observed. 
The PK results of 1000 mg b.i.d. obtained in subjects with FD were in line with those 
observed in healthy subjects. The PK profiles of lucerastat were similar in subjects with 
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mild renal function impairment when compared with healthy subjects. Plasma lucerastat 
concentrations were higher in subjects with moderate and severe renal function 
impairment. The t½ was longer in subjects with moderate (9.6 h) or severe renal function 
impairment (16.1 h) than in healthy subjects (7.0 h). Overall, this resulted in a 1.6- and 
3.2-fold increase in AUC0-∞ of lucerastat in subjects with moderate and severe renal 
function impairment, respectively, when compared with healthy subjects. 
In the DDI study with the OCT2 inhibitor cimetidine, 14 healthy male subjects received a 
single oral dose of 500 mg lucerastat (on Day 1), as well as a single oral dose of 500 mg 
lucerastat (on Day 6) administered concomitantly with cimetidine at steady state (multiple 
oral doses of 800 mg b.i.d. cimetidine from Day 3 to Day 9). Results from the DDI study 
demonstrated that cimetidine had only a weak effect on the exposure to lucerastat, i.e., the 
geometric mean (90% confidence interval [CI]) AUC0-∞ increased by 22% (16%; 27%) 
when lucerastat was administered concomitantly with cimetidine at steady state, as 
compared to lucerastat alone. Geometric mean (90% CI) maximum observed plasma 
concentration (Cmax) was almost unchanged (i.e., increased by 4% [8%; 17%]) and 
absorption was slower (i.e., time to reach Cmax [tmax] delayed by 1 h). Geometric mean t½ 
was not changed. These effects are considered as not clinically relevant. Based on this, 
lucerastat can be administered concomitantly with OCT2 inhibitors without need for dose 
adaptation. 
The TQT study was split into two parts: Part A was a double-blind, placebo-controlled 
study in healthy male subjects to determine the supratherapeutic dose of lucerastat to be 
used in Part B. Part B was a randomized, double-blind (for lucerastat), placebo-controlled, 
four-way crossover study including an open-label positive control in healthy male and 
female subjects to assess the effect of single therapeutic and supratherapeutic doses of 
lucerastat on the QT/QTc interval duration. In Part A, 6 subjects received a single oral dose 
of 2000 mg lucerastat on Day 1 and a single oral dose of 4000 mg lucerastat on Day 3, 
whereas 2 subjects received placebo both on Days 1 and 3. In Part B, 36 subjects were 
enrolled. Subjects received, in a random sequence, single oral doses of 1000 mg lucerastat 
(anticipated therapeutic dose), 4000 mg lucerastat (supratherapeutic dose), 400 mg 
open-label moxifloxacin (positive control to assess assay sensitivity), and placebo. Based 
on concentration-QTc analysis, a QTc according to Fridericia’s formula (QTcF) effect of 
clinical concern (i.e., above 10 ms) could be excluded up to lucerastat plasma 
concentrations of approximately 34 g/mL. The results constituted a negative TQT study, 
demonstrating that lucerastat up to a single dose of 4000 mg does not have any clinically 
relevant liability to prolong the QT interval or any clinically relevant effect on other ECG 
parameters. 
In the exploratory Phase 1b study, a marked change in biomarkers was observed in subjects 
with FD who received 1000 mg b.i.d. lucerastat on top of ERT, with a mean percentage 
change from baseline (standard deviation [SD]) of −49% (17), −33% (13), and −55% (10) 
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in plasma levels of glucosylceramide (GlcCer), lactosylceramide (LacCer), and Gb3, 
respectively, at Week 12.  
Urinary Gb3 was also decreased by 53% (21) at Week 12. 
There was no change in plasma GlcCer, LacCer or Gb3 in the control group. No significant 
changes were observed for plasma lysoGb3 in either group. The concomitant decrease in 
GlcCer, LacCer, and Gb3 confirms GCS inhibition and α-GalA substrate reduction with 
lucerastat in subjects with FD. 
More detailed information can be found in the IB [Lucerastat IB]. 
1.2.4 Lucerastat dose rationale 
Based on the nonclinical data from studies in wild-type mice and Fabry mice 
Lucerastat IB, it was hypothesized that achieving plasma drug concentrations equal to or 
above the inhibition constant (Ki) for inhibition of human GCS for at least 80% of the time 
during a 24 h dosing interval is needed to achieve relevant substrate reduction and 
subsequent decreases of plasma Gb3 levels in subjects with FD. The exploratory Phase 1b 
study in subjects with FD receiving ERT confirmed that treatment with a dose of lucerastat 
1000 mg b.i.d. for 12 weeks was adequate, resulting in (i) plasma lucerastat concentration 
above the Ki for 98% of the time of a dosing interval, (ii) marked and favorable PD effects 
(e.g., a decrease in plasma Gb3 level of 55%), and (iii) good safety and tolerability 
[Lucerastat IB].  
The nonclinical and clinical safety data and the resulting safety margins / exposure ratios 
are considered to adequately support the safe use of lucerastat at doses up to 1000 mg b.i.d. 
in long-term clinical studies in subjects with FD, taking into account the limited and/or 
species-specific toxicity in animals, the reversibility of the findings, and the severity of the 
disease. 
Based on available nonclinical and clinical data, a dosing regimen of lucerastat 1000 mg 
b.i.d. is considered adequate to potentially achieve a clinical benefit while maintaining 
long-term safety and tolerability in subjects with FD. 
In subjects with moderate renal function impairment increased systemic exposure was 
observed, hence dose adjustment is required in this population see Section 5.1.2. 
1.3 Rationale of the study 
The rationale for this Phase 3 study is based on (i) the recognition of an unmet medical 
need of subjects with FD, (ii) the use of SRT with lucerastat as a distinct oral treatment 
modality for all subjects regardless of their FD mutation, and (iii) the potential of lucerastat 
to reduce the net Gb3 load in tissues to alleviate key symptoms of the disease and delay 
progression towards end-stage organ failure. 
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1.3.1 Unmet medical need of subjects with Fabry disease 
As available therapies have not yet demonstrated clear long-term clinical benefit there is 
still a high unmet medical need in FD [see Section 1.1.2]. Additionally, the use of existing 
therapies is restricted, either due to their mode of administration and immunogenic 
potential, or due to a treatment modality from which only a subset of subjects with specific 
FD mutations can benefit. 
1.3.2 Substrate reduction therapy with lucerastat as a distinct treatment modality  
SRT may be achieved using small-molecule GCS inhibitors such as oral lucerastat, which 
can be administered daily and lacks the immunogenic potential of recombinant enzymes 
(i.e., ERT). 
SRT with lucerastat has the potential to produce the desired PD effect regardless of the 
subject’s GLA mutation, including mutations associated with very low or no residual 
α-GalA activity [see Section 1.2.2].  
SRT with lucerastat was demonstrated in the exploratory Phase 1b study in subjects with 
FD receiving ERT, as shown by a fast and marked reduction in the plasma concentration 
of the biomarkers GlcCer, LacCer and Gb3 [see Section 1.2.3 and Lucerastat IB]. 
In addition, SRT with marketed drugs (miglustat, eliglustat) has proven effective and safe 
for the treatment of subjects with type 1 Gaucher disease, another GSL storage disorder. 
1.3.3 Potential of lucerastat to interfere with the mechanisms underlying key 
Fabry disease symptoms — neuropathic pain and gastrointestinal symptoms 
Typical manifestations of pain and acroparesthesia affecting subjects with FD are thought 
to result from poor perfusion of the peripheral nerves and lysosomal accumulation of GSL 
in neurons, DRG and spinal cord, in the form of lamellar inclusions, which may contribute 
to the atrophy of small unmyelinated nerves [Kaye 1988]. Subjects with FD have severely 
enlarged DRG [Godel 2017], which may be due to Gb3 accumulation mediating direct 
neurotoxic effects and decreased neuronal blood supply [Møller 2007, Godel 2017]. The 
DRG are intensely vascularized organs with high permeability between blood and nervous 
tissue and, therefore, are expected to be exposed to lucerastat concentrations similar to 
those in blood [Godel 2016]. SRT with lucerastat was able to reduce Gb3 storage levels in 
the DRG in a mouse model of FD devoid of α-GalA activity Lucerastat IB.  
Hence, a therapeutic intervention such as SRT with lucerastat would be expected to reduce 
Gb3 accumulation in neurons, DRG and spinal cord, and mitigate neuropathic pain, one of 
the most frequent debilitating symptoms of FD, which poorly responds to current 
pharmaceutical treatments Alegra 2012, Markham 2016. 
Although the pathophysiology of GI manifestations in FD is not fully understood, it is 
postulated that almost all the cells and tissues contributing to intestinal function and 
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structure may be affected [Keshav 2006]. Neuropathy, vasculopathy, and myopathy are 
generally considered to be a major cause of GI symptoms; these alterations are thought to 
be due to Gb3 accumulation in the vegetative neurons of the autonomic plexus, in the 
smooth muscle cells as well as in the vascular endothelium [Buda 2013]. Similar to 
neuropathic pain, a therapeutic intervention such as SRT with lucerastat would be expected 
to reduce Gb3 in the GI tract, and may also alleviate GI symptoms of FD, e.g., abdominal 
pain and diarrhea. 
1.4 Summary of known and potential risks and benefits 
The potential benefits of lucerastat administration, for subjects participating in this study, 
include a decrease (in frequency and/or intensity) of FD symptoms such as neuropathic 
pain, GI symptoms (diarrhea, constipation, abdominal pain), and an improvement of their 
QoL. 
The potential risks for subjects participating in this study are related to those based on the 
nonclinical findings of the study treatment [see Section 1.2.2], discontinuation of ERT see 
Section 5.2.3.1, and risks and discomforts associated with some of the study tests and 
procedures see Section 7.2. 
There is potential risk in both placebo and lucerastat treatment groups that FD symptoms 
or condition may not get better or may get worse. It should be noted that during the shortage 
of the ERT agalsidase beta supply between June 2009 and January 2012, no increase in 
clinical event incidence [Smid 2011] and only mild decrease in renal function 
[Weidemann 2014, Lenders 2016] could be observed in subjects with FD receiving a 
reduced dose of agalsidase beta. 
In this study, the most invasive procedure repeated at each visit will be blood sampling. 
All test procedures (e.g., blood sampling, electrocardiogram [ECG], echocardiography) are 
part of the routine standard-of-care of subjects with FD, although their frequency may be 
higher in the study. The use of the electronic diary (eDiary) carries no to little risk to the 
subjects. 
The following measures will contribute to minimize the risks for the subjects participating 
in the study, in particular those who discontinue ERT at screening: 
• Exclusion of subjects at high risk of developing clinical signs of organ involvement 
within the time period of the study (as per investigator judgment), including subjects 
with substantial organ damage and severe complications of FD [see Section 4.4]; 
• Maintenance of the background pain medications such as anti-epileptics and TCAs [see 
Section 5.2.3.2]; 
• Individualized Pain Management Plan (IPMP) set up at the screening visit for each 
subject [see Section 5.2.3.2.2]; 
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• Close follow-up of the subjects throughout the study with daily collection of symptoms 
via an eDiary and with four site visits scheduled during the 6-month treatment period 
see Section 7.1; 
• Monitoring of safety and efficacy data by an Independent Data Monitoring Committee 
(IDMC) [see Section 3.3.1]; 
• Study-specific criteria for stopping study treatment [see Section 5.1.10]; 
• Study-specific study treatment dose adjustment in the event of a decrease in estimated 
glomerular filtration rate (eGFR) see Section 5.1.2; 
• Possibility to (re-)initiate ERT if judged medically required due to significant FD 
progression [see Section 5.2.4.1]. 
It is the investigator’s responsibility to continuously monitor the risk-benefit ratio of the 
study on an individual subject level, and to take the appropriate measures to ensure the 
subjects’ well-being. 
2 
STUDY OBJECTIVES 
The overall objective of this study is to determine the clinical efficacy of lucerastat oral 
monotherapy and to further evaluate its safety and tolerability in adult subjects with FD 
over a period of 6 months. 
2.1 Primary objective 
The primary objective of the study is to determine the effect of lucerastat on neuropathic 
pain in subjects with FD. 
2.2 Secondary objectives 
• To determine the effects of lucerastat on GI symptoms (abdominal pain and diarrhea) 
in subjects with FD and GI symptom(s) at baseline; 
• To confirm the effect of lucerastat on biomarkers of FD; 
• To determine the safety and tolerability of lucerastat in subjects with FD. 
2.3 Other objectives 
• To evaluate the effect of lucerastat on renal function and cardiac parameters in subjects 
with FD; 
• To evaluate the effect of lucerastat on depression in subjects with FD; 
• To evaluate the effect of lucerastat on QoL in subjects with FD; 
• To document the PK of lucerastat in subjects with FD. 
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3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
This is a prospective, multicenter, double-blind, randomized, placebo-controlled, 
parallel-group, Phase 3 study. 
Approximately 99 adult subjects with FD exhibiting Fabry-associated pain of moderate to 
severe intensity will be randomized in a 2:1 ratio to either lucerastat (approximately 
66 subjects) or placebo (approximately 33 subjects).  
Treatment allocation will be stratified by sex and by specific background FD treatment at 
screening (subjects treated with ERT also called “switch” subjects, as they will have to 
stop ERT at screening visit, vs subjects not treated with ERT at screening). Subjects not 
treated with ERT at screening include (i) “treatment-naïve” subjects who were never 
treated with ERT and (ii) “pseudo-naïve” subjects who stopped ERT at least 6 months prior 
to screening.  
The study will be conducted at approximately 58 sites in approximately 14 countries. 
Once randomized, the subject will enter a 6-month double-blind treatment period 
see Section 3.1.1.  
All English speaking subjects in the US and Canada will participate in an exit interview as 
soon as possible after the end of study treatment phase or End-of-Treatment (EOT) visit, 
ideally within 2 weeks. 
3.1.1 Study periods 
The study comprises the following consecutive periods: 
Screening period: Lasts approximately 6–7 weeks; starts with the signing of the informed 
consent form (ICF; at the screening visit) and ends the day before subject randomization. 
Treatment period: Lasts approximately 6 months. Starts on the day of subject 
randomization (randomization visit) and ends at the EOT visit (Month 6). It will consist of 
site visits at Month 1, Month 3, Month 5 and Month 6 and telephone call visits at Month 2 
and Month 4. 
The EOT visit will take place at Month 6 (or earlier in the event of premature 
discontinuation). 
Whenever possible, the EOT visit should take place 1 day after the last dose of study 
treatment but no later than 7 days after the last dose of study treatment.  
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Post-treatment observation period (PTOP): Subjects who discontinue study treatment 
prematurely will enter into the PTOP, which starts on the day after the last dose of study 
treatment, and ends at latest at the Month 6 PTOP visit.  
During this period, all assessments except PK will be performed. They will be performed 
at the time of the originally scheduled visits [Table 6]. 
Post-treatment safety follow-up (FU) period: The FU period is applicable to all subjects 
except those who enter the open-label extension (OLE) study. It starts on the day after the 
last dose of study treatment: 
• For female and non-fertile male subjects: it includes 1 safety FU telephone call (FU1) 
taking place approximately 1 month after the last dose of study treatment; 
• For fertile male subjects: it includes 2 safety FU telephone calls taking place 
approximately 1 month (FU1) and 3 months (FU2) after the last dose of study 
treatment. 
Subjects who complete the 6-month double-blind treatment period will be proposed to 
enroll into an OLE study conducted under a separate protocol (provided the OLE study 
protocol has been approved in the country/site by regulatory authorities and Ethics 
Committees [ECs] / Institutional Review Boards [IRBs]). 
Subjects who discontinue study treatment prematurely for any reason should be 
subsequently treated according to local standard-of-care at the investigator’s discretion and 
will be followed in the PTOP until the originally scheduled Month 6 visit. 
For an individual subject, the End-of-Study (EOS) is defined as follows: 
• For subjects who enter the OLE study, the EOS corresponds to the EOT visit; 
• For all other subjects, the EOS corresponds to the FU1 visit, FU2 visit or to the last 
visit of the PTOP, whichever is last. 
The visit schedule and protocol-mandated procedures will be performed according to the 
tables of assessments [Table 5 and Table 6] and are described in Section 7.1. 
The overall study design is depicted in [Figure 1]. 
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Figure 1 
Study design  
 
Randomization 2:1 
 
 
 
 
 
 
 
 
 
 
        
EOT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOS 
 
 
 
 
Lucerastat  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   (Patient eDiary daily completion) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  V1                         V2                   V3                  V4                        V5                         V6                 V7                     V8   V9*   V10** 
                                                                          (phone)                                            (phone)                                              (phone)(phone) 
                                D1                  M1                   M2                      M3                       M4                  M5                        M6 FU1      FU2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
ScreeningPeriod 
6 to 7 weeks 
 
                                         Double-blind treatment Period 
 
                                   6 Months 
 
 
 
 
 
Follow-up 
Period 
     1 to 3 
months  
  
      
     12-hour PK profile                                                                                                                 Exit interview  
                                                                                                                                                  (US/Canada)***      
  
 
 
 
                                           V3PTOP           V4PTOP               V5PTOP                 V6PTOP           V7PTOP              V8PTOP    
                                                                    (phone)                                                (phone)                                                    
                                                M1                  M2                         M3                         M4                    M5                           M6   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                         Post-treatment observation Period 
 
                                   Up to 6 Months 
 
 
 
 
 
      
* All subjects not entering the OLE study 
** Only fertile male subjects not entering the OLE study 
*** Exit interview conducted as soon as possible after the end of study treatment phase (or EOT visit), ideally within 2 
weeks  
D = day; EOS = End-of-Study; EOT = End-of-Treatment; FU = follow-up (telephone); M = Month; OLE = open-label 
extension; PK = pharmacokinetics; PTOP = post-treatment observation period; V = Visit. 
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3.1.2 Study duration and global end of the study 
The study starts with the first subject, first visit and ends with the last subject, last visit. 
The study is expected to last approximately 3.5 years. 
The duration of individual participation in the study is expected to be about 9 months for a 
female subject and between 9 and 11 months for a male subject. 
The global end of the study corresponds to the last visit of the last subject: 
• If the last subject enters the OLE study, the global end of the study corresponds to the 
last subject’s EOT visit.  
• If the last subject does not enter the OLE study, the global end of the study corresponds 
to the last subject’s FU1 visit, FU2 visit, or to the last visit of the PTOP, whichever is 
last. 
3.1.3 Sub-studies 
As part of this protocol, the following sub-studies will be performed: 
3.1.3.1 Pharmacokinetic profile sub-study (all sites) 
The purpose of the PK sub-study is to further characterize the PK profile of lucerastat. 
It will be conducted at all sites to determine the PK profile of lucerastat at steady state in a 
subgroup of approximately 36 subjects with FD with either normal or subnormal renal 
function (i.e., screening eGFR ≥ 60 mL/min/1.73 m2) or impaired renal function 
(i.e., screening eGFR < 60 mL/min/1.73 m2). If necessary, blood samples collected for PK 
may be used for the identification of potential metabolites of lucerastat in this population. 
The enrollment in the sub-study will be managed by the Interactive Response Technology 
(IRT) system and will continue in each of the eGFR subgroups until 18 subjects 
(12 subjects randomized to lucerastat and 6 randomized to placebo) are enrolled in each 
subgroup. If the PK sub-study is not fully enrolled when the recruitment target at overall 
study level (i.e., 108 subjects) is reached, the PK sub-study will not continue recruiting. 
Subjects consenting to this sub-study will have a 12-hour PK profile performed at the 
Month 1 visit. Further details on PK sampling and collection are available in 
Section 7.2.6.2. PK profile endpoints are defined in Section 6.4.1. 
3.1.3.2  Exit interview sub-study (US and Canadian sites only) 
The purpose of the exit interview sub-study is to further explore what constitutes 
meaningful changes on the neuropathic pain and GI symptom (diarrhea and abdominal 
pain) questions from a subject perspective. 
The exit interview sub-study will be conducted in all English-speaking subjects at US and 
Canadian sites. 
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Details on the analysis of the exit interview data are available in the Exit Interview Analysis 
Plan. 
Subjects will be contacted by a Contract Research Organization (CRO) to set an interview 
date as soon as possible after the end of study treatment phase (or EOT visit), ideally within 
2 weeks. All interviews will be conducted via telephone and will take approximately 
45 minutes to complete. 
More details are available in the sub-study Protocol and Discussion Guide for the Exit 
Interview which have been developed separately. 
3.2 Overall study design rationale 
Neuropathic pain and GI symptoms are important clinical manifestations of FD. 
In the absence of regulatory guidelines specific to the development of treatment for FD at 
the time of the first protocol version, the methodology used in the study to assess the effect 
of lucerastat on neuropathic pain and GI symptoms has been based whenever applicable 
on the Committee for Medicinal Products for Human Use (CHMP) guideline for 
neuropathic pain [CHMP 2007] (later replaced by the CHMP guideline on pain 
[CHMP 2017], and FDA guidance on chronic pain [FDA 2014], irritable bowel syndrome 
(IBS) [FDA 2012], and Patient Reported Outcome (PRO) [FDA 2009]. In particular, those 
guidelines recommend the use of a randomized, double-blind study design when assessing 
subject symptoms using a PRO. In 2019, FDA issued a draft FDA guidance on 
development of drugs for FD treatment [FDA 2019]. The overall study design and endpoint 
chosen are in line with this guidance. 
Due to a high and variable placebo response rate in pain trials (i.e., a systematic tendency 
for efficacy measures to show an improvement from baseline to endpoint of the trial 
irrespective of treatment allocation) placebo controlled superiority trials are necessary 
CHMP 2017, FDA 2012. 
Both the FDA and the CHMP [FDA 2014] and [CHMP 2017] recommend at least a 
3-month duration for studies evaluating analgesia in a chronic pain condition. With its 
mode of action, lucerastat is being developed as a disease-modifying drug for subjects with 
FD. It is postulated that the potential effects of lucerastat on the established clinical 
symptoms of neuropathic pain will result from its PD effect, i.e., the reduction of Gb3 and 
lysoGb3 storage in the DRG and peripheral nerves [see Section 1.3]. This “de-bulking” 
effect is likely to require a longer time period of treatment than drugs having a direct central 
analgesic effect. In a mouse model of FD, the effect of oral lucerastat on the storage of 
α-GalA substrates including Gb3 in DRG was greater after 20 weeks of treatment 
(48% reduction) compared to 10 weeks of treatment (27% reduction) Lucerastat IB. In 
subjects with FD who received 1000 mg b.i.d. lucerastat on top of ERT, there was a fast 
onset of the effect of lucerastat on plasma levels of FD biomarkers with a mean percentage 
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change from baseline (SD) of −50% (14), −38% (8), and −39% (14) in plasma levels of 
GlcCer, LacCer, and Gb3, respectively, at Week 4 Lucerastat IB. Based on those data, it 
is expected that the effect would already be measurable at Month 6. 
Temporary interruption of ERT for a maximum of 8 months in subjects with neuropathic 
pain is acceptable for the following reasons: 
• FD is a slowly progressive disease with respect to clinical signs and symptoms, and 
organ function impairment [see Section 1.1]. Therefore, significant clinical worsening 
of organ disease in subjects who discontinue ERT is not expected within the time frame 
of the study; 
• ERT stopping criteria recommended by the European Fabry Working Group include 
the lack of response when the sole “indication” for ERT is neuropathic pain, and the 
subject’s request to stop ERT [Biegstraaten 2015]; 
• Possibility to (re-)initiate ERT if judged medically required due to significant FD 
progression [see Section 5.2.4.1]. 
In addition, several measures are implemented for safeguarding the interests of study 
subjects as described in Section 1.4. 
The choice of the stratification factors (sex and ERT treatment status at screening) was 
primarily based on (i) the difference in the age of onset and neuropathic pain history 
observed between male and female subjects Mehta 2004, Deegan 2006 and (ii) the 
possibility that the time-course of the placebo-corrected effect of lucerastat on neuropathic 
pain may be different between “switch” subjects and “pseudo-naïve” / “treatment-naïve” 
subjects. 
3.3 Study committee 
3.3.1 Independent Data Monitoring Committee 
An IDMC will have overall responsibility for safeguarding the interests of subjects by 
monitoring safety and efficacy data obtained in the study and making appropriate 
recommendations based on the reported data, thus ensuring that the study is being 
conducted to the highest scientific and ethical standards. The IDMC will be fully 
operational prior to enrollment of the first subject into the study. The composition and 
operation of the IDMC will be described in an IDMC charter. 
4 
STUDY POPULATION 
4.1 Selection of study population 
In general, diagnosis of FD combines clinical presentation, α-GalA activity and GLA 
mutations, as defined in the most recent international guidelines [Schiffmann 2017. This 
study will specifically enroll adult male and female subjects with a diagnosis of FD, as 
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confirmed by the presence of at least one GLA gene mutation, with Fabry-associated 
neuropathic pain in the last 3 months prior to screening. 
Neuropathic pain in FD usually feels like burning, shocks or shooting pain, tingling, pins 
and needles, stabbing, and/or numbness in the hands and feet. The patient may experience 
constant pain of variable intensity. He/she may also get attacks of intense, excruciating 
pain that starts in the hands and feet and spreads out to other parts of the body. Pain may 
occur randomly. It may also be triggered by heat or cold, weather change, being sick or 
having a fever, and/or physical activity Biegstraaten 2012, Politei 2016, Üceyler 2014. 
The subjects will have to present with moderate to severe neuropathic pain resulting in an 
average modified BPI-Short Form item 3 (BPI-SF3) of “neuropathic pain at its worst in the 
last 24 hours” ≥ 4 as reported on an 11-point numerical rating scale (NRS-11) during the 
last 4 weeks preceding randomization.  
Participation in the study will be proposed to subjects with FD for whom continuation or 
initiation of ERT is not medically indicated, as determined by the investigator, based on 
the medical history of the subject and in accordance with local or international treatment 
guidelines [Biegstraaten 2015, Politei 2016, Schiffmann 2017]. Subjects at high risk of 
developing clinical signs of organ involvement within the time period of the study, 
including subjects with substantial organ damage and severe complications of FD are not 
eligible for the study Section 4.4 
Subjects who are currently treated with ERT must agree to stop ERT at the screening visit 
(i.e., “switch” subjects). Subjects who are “treatment-naïve” (i.e., no ERT received at any 
time in the past), or “pseudo-naïve” (i.e., no ERT received in the last 6 months prior to 
screening) must not be planned for imminent initiation of ERT at the time of enrolment. 
Subjects with significant medical conditions or therapies for such conditions: 
cardiovascular, renal or cerebrovascular and subjects with any disease that could interfere 
with the interpretation of the study results (e.g., disease with pain components) are not 
eligible to enter the study [see Section 4.4]. 
In order to minimize the rate of screening failures, the site is encouraged to perform 
pre-screening activities by, e.g., reviewing subject charts. Subjects with any of the chronic 
conditions mentioned in the exclusion criteria list [see Section 4.4] should not be 
considered for screening. 
4.2 Rationale for the selection of the study population 
The targeted FD study population is homogeneous with regards to FD-associated 
neuropathic pain (as defined by the subject) in the last 3 months prior to screening, and the 
presence of moderate to severe neuropathic pain during the 4 weeks preceding 
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randomization as determined from daily entries of the modified BPI-SF3 score in an 
eDiary. 
Published guidelines on pain recommend studying the efficacy in a population that is 
homogeneous with respect to either diagnosis or pain intensity and to stratify according to 
baseline disease characteristics [CHMP 2017].  
The inclusion of subjects with moderate to severe pain (i.e., worst pain intensity score 
≥ 4 reported on an NRS-11) is in line with the recommendations of the CHMP guidelines 
[CHMP 2017] and justified by the higher placebo effect expected in a population with mild 
pain (i.e., worst pain intensity score < 4 reported on an NRS-11). Furthermore, mild 
neuropathic pain typically causes the least interference with “function” and most often only 
requires mild analgesic treatment (e.g., acetaminophen) [Cleeland 2002]. Therefore, 
subjects with mild neuropathic pain will be excluded from the study. 
The goal of MODIFY is to determine the effect of lucerastat as an oral monotherapy in 
subjects with FD. At the time of screening, subjects could either be off ERT or on ERT but 
willing to stop it. Indeed, a significant proportion of subjects with FD still exhibit 
symptoms of neuropathic pain despite long-term treatment with ERT. The European Fabry 
Working Group has published a recommendation for cessation of ERT in patients with FD 
[Biegstraaten 2015]. Consensus criteria to stop ERT include the lack of response for 1 year 
when the sole “indication” for ERT is neuropathic pain, non-compliance for more than 
50% of the ERT infusions, and the patient’s request to stop ERT. Subjects on ERT at 
screening can only be enrolled if they fulfil the neuropathic pain inclusion criteria despite 
exposure to ERT for at least 12 months.  
The age range (i.e., 18 years or above) of the study population is representative of the 
general adult FD population. 
Subjects with major cardiovascular, renal, cerebrovascular medical complications or other 
diseases with pain components are excluded since they could potentially be at greater risk 
of experiencing side effects, and/or their conditions could interfere with evaluation of the 
treatment effect, study assessment and interpretation of study results.  
4.3 Inclusion criteria 
For inclusion in the study, the subject must fulfill all the following inclusion criteria at the 
specified study visits. It is not permitted to waive any of the criteria for any subject: 
Screening visit criteria 
1. Signed and dated ICF prior to any study-mandated procedure; 
2. Male or female subjects 18 years old and above; 
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3. FD diagnosis confirmed with local genetic test results (i.e., presence of at least 
1 mutation in GLA, the gene coding for α-GalA); 
4. Fabry-associated neuropathic pain, as defined by the subject, in the last 3 months prior 
to screening; 
5. ERT treatment status: 
a) Subject never treated with ERT; or  
b) Subject has not received ERT for at least 6 months prior to screening; or 
c) Subject treated with ERT at the time of the screening visit, and meeting all of the 
following criteria at the time of screening: 
i) ERT administration for the last 12 months; 
ii) Stable ERT dose regimen during the last 3 months; 
iii) Subject agrees to stop ERT administration at the screening visit for 
approximately 8 months (6–7 weeks screening + 6 months of double-blind 
treatment). 
6. A woman of childbearing potential [see definition in Section 4.5.1] is eligible only if 
the following applies: 
• Negative serum pregnancy test at screening and a negative urine pregnancy test at 
randomization; 
• Agreement to undertake monthly urine pregnancy tests during the study and up to 
at least 30 days after study treatment discontinuation; 
• Agreement to follow a highly effective contraception scheme as described in 
Section 4.5.2 from screening up to at least 30 days after study treatment 
discontinuation. 
7. A fertile male (physiologically capable of conceiving a child according to investigator 
judgment) who is sexually active with a woman of childbearing potential is eligible 
only if the following applies: 
• Agreement to use a condom during the treatment period (starting at randomization) 
and for up to 3 months after study treatment discontinuation; and 
• Agreement not to father a child during this period. 
Randomization visit criteria 
8. Adequate subject compliance with completion of an eDiary during the screening 
period; 
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9. Subjects with moderate or severe neuropathic pain as determined from daily entries of 
the modified BPI-SF3 score of “neuropathic pain at its worst in the last 24 hours” in 
the eDiary during the screening period. 
Moderate or severe neuropathic pain during the screening period is defined as an average 
modified BPI-SF3 score of “neuropathic pain at its worst in the last 24 hours” ≥ 4 as 
determined from daily entries in an eDiary during the 4 weeks preceding randomization. 
Adequate subject compliance with completion of the eDiary is defined as the availability 
of the modified BPI-SF3 score of at least 4 days per week, in at least 3 out of the 4 weeks 
preceding randomization. 
4.4 Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria at the specified study visits. 
It is not permitted to waive any of the criteria for any subject: 
Screening visit criteria 
Disease/condition 
1. Pregnant / planning to become pregnant up to 30 days after study treatment 
discontinuation or lactating subject; 
2. Severe renal insufficiency defined as an eGFR per the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) creatinine equation < 30 mL/min/1.73 m2 at 
screening (as reported by the central laboratory); 
3. Subject on regular dialysis for the treatment of chronic kidney disease; 
4. Subject has undergone, or is on a waiting list for, or is scheduled to undergo kidney or 
other organ transplantation; 
5. Known and documented transient ischemic attack, stroke, unstable angina or 
myocardial infarction within 6 months prior to screening; 
6. Clinically significant unstable cardiac disease in the opinion of the investigator 
(e.g., uncontrolled symptomatic arrhythmia, New York Heart Association [NYHA] 
class III or IV congestive heart failure); 
7. Any other subject at high risk of developing clinical signs of organ involvement within 
the time period of the study, as per investigator judgment; 
8. Any known factor or disease that might interfere with treatment compliance, study 
conduct or interpretation of the results such as: 
a) Other disease or condition associated with a pain component that could confound 
assessment of neuropathic pain (e.g., diabetic neuropathy, chemotherapy- or 
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radiation-induced peripheral neuropathy, chronic inflammatory demyelinating 
polyneuropathy); 
b) Other disease of the GI tract that could interfere with the assessment of GI symptoms 
in FD (e.g., inflammatory bowel disease, galactose intolerance, total lactase deficiency 
or glucose-galactose malabsorption); 
c) Documented poorly controlled diabetes mellitus (i.e., HbA1c > 8.0% at screening as 
reported by the central laboratory); 
d) Significant neurological disorder; 
e) Significant psychiatric disease; suicidal ideation at screening or history of suicide 
attempt or behavior within 6 months prior to screening as per investigator judgment; 
f) History of drug dependence (including opioids) or alcohol dependence; 
g) Inability to complete an eDiary on a daily basis. 
9.  Known concomitant life-threatening disease with a life expectancy < 18 months. 
Treatments 
10. Subject planned for imminent initiation of treatment with ERT; 
11. Known hypersensitivity to lucerastat or drug of the same chemical class of iminosugars 
(e.g., miglitol, miglustat, migalastat), or any of their excipients (including lactose); 
12. Initiation or treatment at an unstable dose within 4 weeks prior to screening with any 
of the following medications: 
a) ACE inhibitor and/or ARB; 
b) Anti-epileptic;  
c) TCA and/or other antidepressants belonging to SNRI and selective serotonin 
re-uptake inhibitor (SSRI) classes. 
13. Planned or current treatment with another investigational treatment within 3 months 
prior to screening; 
14. Treatment with any inhibitor of GCS (e.g., miglustat, lucerastat, eliglustat, 
ibiglustat/venglustat) or an α-GalA chaperone (e.g., migalastat) within 6 months prior 
to screening; 
Randomization visit criteria 
15. Treatment with ERT (agalsidase alfa, agalsidase beta) during the screening period. 
In addition, the investigator/delegate must verify that the subject does not fulfill the 
exclusion criteria checked at the screening visit (as applicable).  
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4.5 Contraception requirements for women of childbearing potential  
4.5.1 Definition of childbearing potential 
A woman is considered to be of childbearing potential unless she meets at least 1 of the 
following criteria: 
• Previous bilateral salpingectomy, bilateral salpingo-oophorectomy or hysterectomy; 
• Postmenopausal (defined as 12 consecutive months with no menses without an 
alternative medical cause [ICH M3 definition]); 
• Premature ovarian failure (confirmed by a specialist), XY genotype, Turner syndrome, 
uterine agenesis; 
The reason for not being of childbearing potential will be recorded in the electronic case 
report form (eCRF) and hospital charts. 
4.5.2 Highly effective methods of contraception 
Women of childbearing potential [see definition in Section 4.5.1] must follow a highly 
effective [CTFG 2014] contraception scheme from screening up to at least 30 days after 
study treatment discontinuation as follows: 
1. Two methods of contraception, one from Group 1 and one from Group 2, defined as 
follows: 
– Group 1: Oral, implantable, intravaginal, transdermal, or injectable hormonal 
contraceptives. If a hormonal contraceptive is chosen from this group, it must be 
taken for at least 1 month prior to randomization; 
– Group 2: Partner’s use of a condom (preferred method), female condom, cervical 
cap or diaphragm. Cervical cap and diaphragm must be used in combination with a 
spermicide. In countries where spermicide is not available/authorized, cap and 
diaphragm must not be used. 
OR 
2. Intrauterine device or intrauterine hormone-releasing system; 
OR 
3. Sterilization of the male partner with documented post-vasectomy confirmation of the 
absence of sperm in the ejaculate; 
OR 
4. Tubal sterilization (tubal occlusion / ligation at least 6 weeks prior to screening); 
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OR 
5. True abstinence from intercourse with a male partner only when this is in line with the 
preferred lifestyle of the subject and if locally accepted as a reliable method of 
contraception. 
The following methods are not allowed as methods of contraception for this study: 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
• Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• Withdrawal (coitus interruptus) 
• Spermicides only 
• Lactational amenorrhea method 
• Combination of female condom and male condom 
• Use of only Group 2 “barrier contraception method” (see above) 
The methods of birth control used (including non-pharmacological methods) must be 
recorded in the eCRF and hospital charts. 
To ensure compliance, the study personnel must remind women of childbearing potential 
at each visit to use the methods of contraception defined for this study. The reminders must 
be documented in the hospital chart. 
4.6 Contraception requirements for fertile males 
A fertile male is defined as physiologically capable of conceiving child according to the 
investigator’s judgment. 
Fertile male subjects participating in the study who are sexually active with women of 
childbearing potential must agree to use a condom during the treatment period and for up 
to 3 months after study treatment discontinuation and agree to not father a child during this 
period.  
To ensure compliance, the study personnel must remind the subjects of the contraception 
requirements at each visit, and ensure the reminders are documented in the hospital chart. 
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5 
TREATMENTS 
5.1 Study treatment 
5.1.1 Investigational treatment and matching placebo: description  
Lucerastat is available for clinical study use in hard gelatin capsules containing 250 mg of 
lucerastat and inactive excipients (
 mg of lactose anhydrous and 
 mg of talc).  
Matching placebo capsules will contain inactive excipients (
 mg of lactose anhydrous 
and 
 mg of talc). 
The maximum amount of lactose ingested by a subject enrolled in the placebo group will 
be 
 mg per dose and 
 mg per day. 
5.1.2 Study treatment dosing and administration  
Subjects will take either lucerastat or matching placebo orally b.i.d. 
The starting dose of the study treatment (lucerastat or matching placebo) will be based on 
the subject’s eGFR value (as reported by the central laboratory) at the screening visit as 
shown in Table 1.  
During the study, the dose of the study treatment will be reduced if the subject’s eGFR (as 
reported by the central laboratory during scheduled or unscheduled visits) decreases and 
crosses the next lower eGFR boundary as shown in Table 1. Upon receipt of the eGFR 
results from the central laboratory, the investigator/delegate will contact the subject to 
provide instruction if a dose adjustment is required. The date of the contact with the 
subjects and the reduced dose will be collected in the eCRF. 
Study treatment must be discontinued if one of the study-treatment stopping criteria is met 
see Section 5.1.10. 
Table 1 
eGFR-based study treatment dosing scheme 
eGFR 
(mL/min/1.73 m2) 
Dose regimen 
(oral) 
Number of capsules per dosing 
≥ 60 
1000 mg b.i.d. 
4 
≥ 45 and < 60 
750 mg b.i.d. 
3 
≥ 30 and < 45 
500 mg b.i.d. 
2 
≥ 15* and < 30 
250 mg b.i.d. 
1 
* study treatment must be stopped if eGFR < 15 mL/min/1.73m2 or in the event that the acute kidney injury CTCAE 
grade 2 or above is met, [see Section 5.1.10]. 
b.i.d. = twice daily; CTCAE = Common Terminology Criteria for Adverse Events; eGFR = estimated glomerular 
filtration rate. 
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Subjects will be instructed to start taking the study treatment on the evening of the 
randomization visit. Thereafter, the subject should take each study treatment dose in the 
morning and evening irrespective of food intake. It is preferable that the study treatment 
be taken each day (morning and evening) at approximately the same time.  
Subjects will be instructed not to take study treatment in the morning of study visit days. 
On the day of the study visits, study treatment must be administered only after the 
completion of the pre-dose assessments as indicated in Table 5. 
If a dose is missed, it should be taken as soon as possible. However, the missed dose should 
be skipped if it is almost time for the next dose. 
To ensure compliance, the study personnel must remind subjects at each visit of the study 
treatment intake requirements. The reminders must be documented in the hospital chart. 
5.1.3 Treatment assignment 
A total of 99 eligible subjects will be randomized in a 2:1 ratio to lucerastat or placebo, 
stratified by sex (male, female) and by ERT treatment status at screening (treated, 
“pseudo-naïve” / “treatment-naïve”). 
At the randomization visit, and after having verified that the subject meets all inclusion 
criteria and none of the exclusion criteria, the investigator/delegate contacts the IRT system 
to randomize the subject. 
The investigator/delegate will report the screening visit eGFR value of the subject (as 
reported by the central laboratory) in the IRT system. The IRT system assigns a 
randomization number to the subject and assigns the treatment kit numbers, which match 
the treatment arm assigned per the randomization list. The number of treatment kits 
assigned to the subject will depend on the study treatment dose established for the subject 
see Section 5.1.2. 
The IRT system is handled by an external independent vendor which will generate the 
randomization list. 
5.1.4 Blinding 
This study will be performed in a double-blind fashion. The investigator, study personnel, 
subjects, Clinical Research Associates (CRAs), sponsor personnel, and vendor/CRO 
personnel involved in the conduct of the study will remain blinded to the study treatment 
received by the subjects during the double-blind treatment period until study closure. 
To ensure adequate supply of study treatment, the IRT vendor personnel responsible for 
clinical study supply distribution and the sponsor individuals contributing to clinical supply 
distribution will need to be unblinded at subject level and depot level, respectively. These 
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persons will be clearly identified, their unblinding will be documented in the trial master 
file, and they will not take part in any Clinical Trial Team (CTT) meetings after study 
set-up has been completed. 
Until the time of unblinding for final data analysis, the randomization list is kept strictly 
confidential, and accessible only to IRT vendor and sponsor authorized persons 
(i.e., Pharmaceutical Development group, Bioanalytical Laboratory group), who are not 
involved in the conduct of the study. 
The investigational treatment and its matching placebo are indistinguishable, and all 
treatment kits will be packaged in the same way. 
To minimize the possibility of systematic unblinding, the results of the biomarker [see list 
in Section 7.2.7.1] and PK data will not be communicated to the investigator, study 
personnel, subjects, CRAs, any sponsor or vendor/CRO personnel involved in the conduct 
of the study. Results will be transferred by the central laboratory (for biomarkers) and the 
sponsor Bioanalytical Laboratory group (for PK data) to the sponsor and CRO personnel 
involved in the conduct of the study only after database lock. 
5.1.5 Unblinding  
5.1.5.1 Unblinding for final analyses 
Full randomization information will be made available for data analysis only after database 
lock, in accordance with the sponsor’s Quality System (QS) documents.  
5.1.5.2 Unblinding for suspected unexpected serious adverse reactions 
If a suspected unexpected serious adverse reaction (SUSAR) see definition in 
Section 9.1.3 occurs in a subject participating in the study, the sponsor’s Global Drug 
Safety department will request the unblinding of the treatment assignment in order to meet 
regulatory reporting requirement. 
The treatment assignment will not be communicated to site personnel, subjects, sponsor 
CTT or any vendor/CRO personnel involved in the conduct of the study. 
Unblinded SUSAR information will be reported to respective health authorities and 
Independent ECs (IECs) / IRBs only. SUSARs will be notified to investigators in a blinded 
fashion. 
5.1.5.3 Emergency procedure for unblinding 
The investigator, study personnel, subjects, CRAs, sponsor personnel, and any CRO 
personnel involved in the conduct of the study must remain blinded to the subject’s 
treatment assignment.  
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The identity of the study treatment may be revealed only if the subject experiences an 
emergency medical event, the management of which would require knowledge of the 
blinded treatment assignment. In this case, the decision to unblind resides solely with the 
investigator and the investigator can receive the unblinded treatment assignment through 
the IRT system. Whenever possible, and provided it does not interfere with (or does not 
delay) any decision in the best interest of the subject, the investigator is invited to discuss 
the intended unblinding with the sponsor personnel. 
The occurrence of any emergency unblinding during the study must be clearly justified and 
explained by the investigator. In all cases, the sponsor personnel must be informed about 
the emergency unblinding as soon as possible before or after the unblinding. 
The circumstances leading to unblinding must be documented in the hospital charts, the 
Investigator Site File (ISF) and in the eCRF. 
5.1.6 Study treatment supply 
Manufacturing, labeling, packaging, and supply of study treatment will be conducted 
according to Good Manufacturing Practice, GCP, and any local or national regulatory 
requirements. 
All study treatment supplies are to be used only in accordance with this protocol, and not 
for any other purpose. 
5.1.6.1 Study treatment packaging and labeling 
Study treatment is provided as capsules in childproof bottles. 
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located. 
5.1.6.2 Study treatment distribution and storage 
Study treatment supplies must be kept in an appropriate, secure area and stored according 
to the conditions specified on the label and in the IB [Lucerastat IB]. 
5.1.6.3 Study treatment dispensing 
The subjects will receive sufficient study treatment to cover the period up to the next 
scheduled visit. Subjects are asked to return all used, partially used, and unused study 
treatment bottles at each visit. Should the treatment bottle dispensed at a scheduled visit be 
lost or damaged, a replacement bottle or kit can be requested via the IRT system. 
In exceptional circumstances, the investigator/delegate may contact the IRT system shortly 
prior to the scheduled visit (with the exception of the randomization visit see 
Section 5.1.3) to obtain the treatment kit number(s) to be dispensed at the visit. 
The protocol-mandated study treatment dispensing procedures may not be altered without 
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prior written approval from the sponsor. In exceptional circumstances (e.g., if the subject 
lost the study treatment between two visits, or if the subject is unable to return to the site 
due to a medical emergency / hospitalization at another hospital), unscheduled dispensing 
and delivery of study treatment may occur outside of a scheduled visit. An accurate study 
treatment record of the date and amount of study treatment dispensed to each subject must 
be available at the site for inspection at any time. 
5.1.6.4 Study treatment return and destruction 
The protocol-mandated study treatment return procedures may not be altered without prior 
written approval from the sponsor. On an ongoing basis and/or on termination of the study, 
the CRA will collect used and unused treatment kits, which will be sent to the warehouse, 
where the sponsor personnel or a deputy will check treatment reconciliation. In certain 
circumstances, used and unused study treatment containers may be destroyed at the site 
once study treatment accountability is finalized and has been checked by the sponsor 
personnel or the deputy, and written permission for destruction has been obtained from the 
sponsor. 
5.1.7 Study treatment accountability and compliance with study treatment 
5.1.7.1 Study treatment accountability 
The inventory of study treatment dispensed to and returned by the subject (i.e., study 
treatment accountability) must be performed by site personnel on the day of the visit and 
before dispensing further study treatment. It is to be recorded by site personnel on the study 
treatment dispensing and accountability log and in the eCRF, and checked by the CRA 
during site visits and at the end of the study. The study treatment accountability log in the 
eCRF will include at least the following information for each study treatment unit (i.e., 
bottle) dispensed to the subject: 
• Dispensed bottle ID number; 
• Date dispensed / number of capsules dispensed (pre-populated in eCRF); 
• Date returned / number of capsules returned. 
All study treatment supplies, including partially used or empty bottles must be retained at 
the site until it is verified by the CRA. 
If the subject omits to bring the remaining study treatment to a study visit, he/she must be 
instructed to not take any capsules from the remaining study treatment bottle and to return 
it at the next visit. 
5.1.7.2 Study treatment compliance 
Treatment compliance will be assessed based on eDiary data. 
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The study treatment compliance with the prescribed study treatment dose regimen will be 
assessed by the sponsor based on eDiary data. On each day, subjects will be asked to enter 
in the eDiary the number of capsules taken in the morning and evening. The subjects will 
receive a reminder alarm (through the device) to take their morning and evening doses of 
study medication. 
For each time interval between two visits (i.e., “period”), the eDiary based study treatment 
compliance will be calculated by the sponsor using the following formula: 
eDiary based study treatment compliance = Total number of times the subject took study 
treatment at the prescribed dose regimen during the period / Total number of times the 
study treatment should have been taken at the prescribed dose regimen during the period 
 100 
The prescribed starting dose corresponds to the dose assigned to the subject by the IRT 
system at randomization visit. In the event of study treatment adjustment 
see Section 5.1.2, the prescribed dose corresponds to the new study treatment dose. 
The starting date of the new study treatment dose will be the date when the 
investigator/delegate contacts the subject to provide him/her instructions for study 
treatment adjustment. 
The period is defined as the number of days between visit n (or date of first study treatment 
intake if randomization visit) and visit n+1 (or date of last study treatment intake if EOT 
visit). 
The number of times the study treatment should have been taken at the prescribed dose 
regimen in a given period is calculated as follows: 
• Number of days in the period  2 
Study treatment interruption(s) will be ignored when calculating the study treatment 
compliance based on the eDiary. 
Between visits, study treatment compliance based on the eDiary is expected to be at least 
80%. The sponsor will inform the site staff and CRA about any compliance values below 
80%. Compliance values below 80% without a medical justification (e.g., AE) and not 
related to an eDiary completion issue will be considered as a protocol deviation, which will 
be reported as such to the sponsor by the CRA. In such cases, the investigator must discuss 
and clarify the reasons for non-compliance with the subject and take appropriate actions to 
avoid re-occurrence. 
5.1.8 Study treatment dose adjustments and interruptions 
Study treatment dose adjustment, other than described in Section 5.1.2 is prohibited.  
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Study treatment may be temporarily interrupted in response to an AE, or other reasons 
(e.g., diagnostic or therapeutic procedure, study treatment forgotten).  
If study treatment is interrupted by the subject for any reason, he/she must immediately 
inform the investigator.  
Interruptions of study treatment must be kept as short as possible. 
All study treatment interruptions of at least 2 consecutive days and/or due to an AE must 
be recorded in the eCRF. 
5.1.9 Premature discontinuation of study treatment  
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator, or sponsor personnel. The main reason (e.g., AE, lack of efficacy, study 
terminated by sponsor) must be documented in the eCRF. 
A subject has the right to prematurely discontinue study treatment at any time, without any 
justification, by withdrawing from study treatment only or by withdrawing from any further 
participation in the study (i.e., premature withdrawal from the study [see Section 8.2]). 
Although a subject is not obliged to give his/her reason for prematurely withdrawing from 
the treatment or the study, it is recommended that the investigator makes a reasonable effort 
to ascertain the reason(s), while fully respecting the subject’s rights. 
The investigator must discontinue study treatment for a given subject if, on balance, he/she 
believes that continued administration would be contrary to the best interests of the subject. 
Study-specific criteria for discontinuation of study treatment are described in 
Section 5.1.10. 
A subject who prematurely discontinues study treatment is NOT considered as withdrawn 
from the study and will be followed in the PTOP, provided that the subject’s consent for 
this participation in the study has not been withdrawn. Assessments including safety 
follow-up that are to be performed at each site visit are described in Section 7.1, 
Table 5 and Table 6. 
A subject who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the study. 
Subjects who die or are lost to follow-up are also considered as withdrawn from the study. 
Withdrawal from the study and follow-up medical care of subjects withdrawn from the 
study are described in Sections 8.2 and 8.4, respectively. 
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5.1.10 Study-specific criteria for interruption / premature discontinuation of study 
treatment 
5.1.10.1 Pregnancy 
If a subject becomes pregnant while on study treatment, study treatment must be 
permanently discontinued. The investigator/delegate must counsel the subject and discuss 
the risks of continuing with the pregnancy and the possible effects on the fetus. 
5.1.10.2 Cardiovascular event 
Subjects must be permanently discontinued from study treatment at any time during the 
study in the event of heart failure leading to in-patient hospitalization or prolongation of 
ongoing hospitalization. 
5.1.10.3 Renal function 
Subjects must be permanently discontinued from study treatment at any time during the 
study if eGFR < 15 mL/min/1.73m2 or in the event of acute kidney injury Common 
Terminology 
Criteria 
for 
Adverse 
Events 
(CTCAE) 
grade 
2 
or 
above 
(i.e., creatinine > 2  baseline creatinine, creatinine > 4.0 mg/dL or 353.6 µmol/L, 
hospitalization 
indicated, 
life-threatening 
consequences, 
dialysis 
indicated) 
[CTCAE 2010].  
5.1.10.4 Cerebrovascular event 
Subjects must be permanently discontinued from study treatment at any time during the 
study in the event of stroke CTCAE grade 3 or above (i.e., severe neurological deficit, 
life-threatening consequences, urgent intervention indicated) [CTCAE 2010].  
5.2 Previous and concomitant therapy 
5.2.1 Definitions 
A previous therapy is any treatment for which the end date is prior to the signature of the 
ICF. 
A therapy that is study-concomitant is any treatment that is ongoing or initiated after the 
signature of the ICF, or initiated up to 30 days after study treatment discontinuation. 
A therapy that is study treatment-concomitant is any treatment that is either ongoing at the 
start of study treatment or is initiated during the study treatment period. 
Local 
or 
international 
treatment 
guidelines 
[Biegstraaten 2015; 
Politei 2016; 
Schiffmann 2017] for the management of subjects with FD will apply whenever relevant 
to the study. These guidelines include the use of ERT and adjunctive therapies. 
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5.2.2 Mandatory concomitant therapy 
Mandatory therapy includes any treatments required for contraception purposes in women 
of childbearing potential. 
5.2.3 Allowed concomitant therapy 
Treatments considered necessary for the subject’s well-being and not categorized as 
forbidden concomitant medications are allowed during the study and must be documented 
in the medical charts.  
5.2.3.1 Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker  
Subject must not have initiated ACE inhibitor or ARB therapy within 4 weeks prior to 
screening. ACE inhibitor or ARB therapy, if used by the subject, must be at a stable dose 
for at least 4 weeks prior to screening. During the study, initiation or dose adjustment are 
allowed based on investigator judgment. 
5.2.3.2 Pain medications 
During the study, the use of adjuvant pain medications, non-opioid and opioid analgesics 
is allowed if judged medically required by the investigator. Initiation or dose adjustment 
of pain medications should be done as described in Section 5.2.3.2.2. 
5.2.3.2.1 Pain medications used in Fabry disease 
A list of pain medications used in FD is provided in Table 2. 
Subject must not have initiated adjuvant pain medications (i.e., anti-epileptics, TCAs and 
SNRIs/SSRIs) within 4 weeks prior to screening. The dose regimen of adjuvant pain 
medications used chronically by the subject at screening must be stable for at least 4 weeks 
prior to screening. 
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Table 2 
List of pain medications used in Fabry disease 
Categories 
Pain medications 
Adjuvant pain medications 
• 
Anti-epileptics: 
e.g., carbamazepine, 
gabapentin, 
phenytoin, 
pregabalin, oxcarbazepin, lamotrigine, topiramate; 
• 
TCAs: e.g., amitriptyline, nortriptyline; 
• 
Other antidepressants (SNRIs/SSRIs): e.g., duloxetine, venlafaxine. 
Non-opioid analgesics 
• 
NSAIDs: 
e.g., 
acetylsalicylic 
acid 
/ 
aspirin, 
paracetamol/acetaminophen, 
ibuprofen, 
naproxen, 
diclofenac, 
metamizole; 
• 
Topical analgesics: e.g., lidocaine, prilocaine, capsaicin. 
Opioid analgesic 
• 
“Weak” opioids: e.g., codeine, dihydrocodeine; 
• 
“Strong” opioids: e.g., morphine, oxycodone, tramadol, fentanyl, 
methadone, hydromorphone, mepiridine. 
NSAID = non-steroidal anti-inflammatory drug; SNRI = serotonin-norepinephrine re-uptake inhibitor; SSRI = selective 
serotonin re-uptake inhibitor; TCA = tricyclic antidepressant. 
 
5.2.3.2.2 Rescue medications for unbearable pain 
In the event of unbearable pain, rescue pain medications may be considered. An IPMP will 
be provided by the investigator/delegate to each subject with customized instructions 
regarding the use of pain medications during the study. 
The IPMP will list the pain medications ongoing at the screening visit that the subject 
should continue taking during the study. It will also include a list of new pain medication(s) 
or dose adjustment that should be made in the event of unbearable pain taking into account 
the subject’s background pain medication(s) and previous response to pain medication(s). 
The IPMP will be applicable starting at screening visit and until the EOT visit or the last 
visit of the PTOP (as applicable). The IPMP will also include instructions regarding the 
need to contact the investigator/delegate. The investigator/delegate and the subject will 
sign the IPMP at the screening visit and a copy of the IPMP will be given to the subject.  
A sample of the IPMP template is provided as Appendix 1. 
Depending on the background pain medication(s) of the subject, and provided that the 
medication is not categorized as forbidden concomitant medication [Section 5.2.4], the 
rescue pain medication(s) may include one or more of the following options: 
• Initiation or dose escalation of adjuvant pain medication(s) (i.e., anti-epileptics, TCAs, 
SNRIs, SSRIs); 
• Initiation or dose escalation of opioid analgesic drugs;  
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• Initiation or dose escalation of non-opioid analgesics drugs (i.e., non-steroidal 
anti-inflammatory drugs [NSAIDs], topical analgesics). 
The subject will be prescribed the rescue pain medication(s) listed in his/her IPMP. In the 
event of pain worsening that is not bearable, the subject will be instructed to: 
• Apply the IPMP agreed with his/her investigator/delegate at the time of the screening 
visit; 
• Contact his/her investigator/delegate as soon as possible. 
The investigator/delegate will advise the subject on pain treatment adjustment in the event 
of unbearable pain and will document the discussion in the hospital charts. 
If, after the modification of pain treatment, the subject still suffers from unbearable pain, 
the investigator/delegate should discuss alternative therapeutic options with the subject, 
including the possibility to (re-)initiate ERT treatment (if available at the site). 
Details on the pain medications taken for unbearable pain will be collected in the eDiary 
see Section 5.2.5.2. 
5.2.3.3 Antidepressants used to treat depression 
Subject must not have initiated antidepressants (i.e., SNRIs, SSRIs, TCAs) within 4 weeks 
prior to screening. The doses of antidepressants used by the subject at screening must be 
stable for at least 4 weeks prior to screening. 
During the study, initiation or dose adjustment are allowed based on investigator judgment. 
5.2.4 Forbidden concomitant therapy 
5.2.4.1 Enzyme replacement therapy (agalsidase alfa, agalsidase beta) 
Subjects on ERT with neuropathic pain at screening (“switch”) must agree to stop ERT 
administration for about 8 months (6–7 weeks screening + 6 months of double-blind 
treatment). Recently published recommendations by the European Fabry Working Group 
have defined ERT stopping criteria which include the lack of response for 12 months when 
the sole “indication” for ERT is neuropathic pain, and the subject’s request to stop ERT 
Biegstraaten 2015. 
Subjects off ERT with neuropathic pain at screening (“naïve” or “pseudo-naïve”) who are 
planned for imminent initiation of treatment with ERT are not eligible for enrollment in 
the study see Section 4.4, and initiation of ERT will therefore not be withheld for these 
subjects. 
Although discouraged throughout the whole study, subjects may be allowed to (re-)initiate 
ERT treatment (if available at that site) if judged medically required due to significant FD 
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progression (e.g., significant renal function deterioration or cardiac function deterioration) 
based on investigator judgment. In such case, the subject may continue taking the study 
treatment.  
5.2.4.2 Inhibitors of glucosyl ceramide synthase, -galactosidase A chaperone, 
investigational drugs 
To avoid concomitant administration of medications that would either compete with 
lucerastat as they have a similar mechanism of action or have an uncertain effect on 
neuropathic pain in subjects with FD, the following concomitant therapies are forbidden 
from screening visit until the EOT visit or the last visit of the PTOP (as applicable):  
• Any inhibitor of GCS (e.g., miglustat, eliglustat); 
• Any -GalA chaperone (e.g., migalastat); 
• Any other investigational drug (e.g., ibiglustat/venglustat, pegunigalsidase alfa). 
If a subject takes any of the forbidden medications listed in Section 5.2.4, the 
investigator/delegate must contact the sponsor to discuss further follow-up actions 
including stopping/interrupting study treatment as appropriate. 
5.2.5 Reporting of previous / concomitant therapy in the electronic case report 
form and electronic diary 
5.2.5.1 Fabry disease-specific therapies 
Any previous administration (at any time prior to screening) of ERT (i.e., agalsidase alfa 
[Replagal], agalsidase beta [Fabrazyme]) will be recorded in the eCRF. 
For treatments received in the last 12 months prior to screening, start/end dates of 
administration, reason for discontinuation and dose regimen if known, will be recorded in 
the eCRF. 
For treatments stopped before the last 12 months prior to screening, start/end dates, dose 
regimen, and reason for discontinuation if available in the hospital chart will be reported 
in the eCRF. 
In addition, history of ERT infusion reactions including anaphylactic and allergic reactions 
will be collected in the eCRF. 
ERT infusion reactions [Fabrazyme® USPI, Replagal SmPC] include: 
• Life-threatening anaphylactic and severe allergic reactions; 
• Localized angioedema (including swelling of the face, mouth, and throat); 
• Bronchospasm; 
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• Generalized urticaria, rash, pruritus, flushing; 
• Dysphagia; 
• Hypotension, hypertension; 
• Tachycardia, bradycardia; 
• Dyspnea, chest discomfort, chest pain, peripheral edema; 
• Nasal congestion, throat tightness; 
• Nausea, vomiting, abdominal pain, diarrhea; 
• Paresthesia, pain in extremity, myalgia; 
• Pyrexia, feeling hot or cold, chills, sweating, hives; 
• Headache, dizziness/lightheadedness; 
• Fatigue, somnolence. 
If ERT therapy is (re-)initiated during the course of the study see Section 5.2.4.1, the date 
of each ERT infusion, dose and detailed reason for (re-)initiation will be recorded in the 
eCRF (e.g., treatment-emergent renal or cardiac signs and symptoms fulfilling 
class I criteria recommendation to initiate ERT [Biegstraaten 2015]).  
Other therapies (experimental or not) used to treat FD (e.g., inhibitor of GCS 
[e.g., miglustat, eliglustat, ibiglustat/venglustat], -GalA chaperone [e.g., migalastat], or 
ERT e.g., pegunigalsidase alfa / PRX-102, moss-aGal) in the past 12 months will be 
recorded in the eCRF. For each therapy, the start/end dates, route of administration, and 
reason for discontinuation will be recorded. In addition, dose and frequency of 
administration should be recorded if available. 
5.2.5.2 Pain medications 
Previous pain medications [see Section 5.2.3.2 for definitions] if discontinued less than 
30 days prior to signing the ICF and pain medication ongoing at the screening visit must 
be recorded in the eCRF. The generic name, start dates and end dates (if applicable) of 
administration, route, dose regimen, and indication will be recorded in the eCRF. 
Starting at the screening visit, the subject will be asked on a daily basis to record the use 
of pain medication (e.g., dose regimen, initiation of a new medication) in the eDiary 
see Section 7.2.2.1 for more detail on the eDiary until the EOT visit or the last visit of 
the PTOP (as applicable). 
Pain medications taken by the subject during the FU period after he/she has returned the 
eDiary will be collected in the eCRF. 
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5.2.5.3 Other therapies 
The use of other (i.e., not covered in Sections 5.2.5.1 and 5.2.5.2) study-concomitant 
therapy (including contraceptives and traditional and alternative medicines, e.g., plant-, 
animal-, or mineral-based medicines) will be recorded in the eCRF. 
Any other previous therapy must be recorded in the eCRF if discontinued less than 30 days 
prior to signing of the ICF. 
The generic name, start/end dates of administration, route, dose regimen, and indication 
will be recorded in the eCRF. 
6 
STUDY ENDPOINTS 
6.1 Efficacy endpoints 
6.1.1 Primary efficacy endpoint 
The primary efficacy endpoint is: 
• Change from baseline to Month 6 in the “modified” BPI-SF3 score of “neuropathic 
pain at its worst in the last 24 hours”. 
This endpoint is determined from subject daily scoring of neuropathic pain intensity in an 
eDiary [see Section 7.2.2.1]. 
The rules used to derive the baseline and Month 6 modified BPI-SF3 scores are described 
in Section 10.2.1. 
6.1.2 Secondary efficacy endpoints 
The secondary efficacy endpoints are: 
• Change from baseline to Month 6 in the NRS-11 score of “abdominal pain at its worst 
in the last 24 hours” in subjects with GI symptoms at baseline. 
This endpoint is determined from subject daily scoring of abdominal pain intensity in an 
eDiary [see Section 7.2.2.1]. 
The rules used to derive the baseline and Month 6 average abdominal pain NRS-11 scores 
are described in Section 10.2.2.1. 
The definition of a subject considered to have GI symptoms at baseline is provided in 
Section 10.1.4. 
• Change from baseline to Month 6 in the number of days with at least 1 stool of a Bristol 
Stool Scale (BSS) consistency Type 6 or 7 in subjects with GI symptoms at baseline. 
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This endpoint is determined from subject’s daily reporting of bowel movement and stool 
consistency scoring in an eDiary [see Section 7.2.2.1]. 
The rules used to derive the baseline and Month 6 number of days with at least 1 stool with 
BSS Type 6 or 7 are described in Section 10.2.2.2. 
The definition of a subject considered to have GI symptoms at baseline is provided in 
Section 10.1.4. 
• Change from baseline to Month 6 in plasma Gb3. 
6.1.3 Efficacy estimands 
The estimands targeted by the primary and secondary efficacy objectives and analyses are 
defined in Table 3. 
A broad treatment policy strategy will be applied for all estimands defined in Table 3, i.e., 
all collected endpoint data are used in the analyses regardless of occurrence of any 
intercurrent events (ICEs). Expected ICEs are premature treatment discontinuation as well 
as use of other medications.  
FD medications (e.g., ERT) are forbidden by the protocol as they are not part of the 
treatment condition of interest [see definition in Table 3]. However, considering that 
forbidden medications could be taken in clinical practice, data collected during use of 
forbidden medications will be included in the analyses.  
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Table 3 
Estimands for the primary and secondary efficacy objectives and analyses 
Estimand 
Target 
population 
Treatment 
condition of 
interest 
Endpoint 
Strategy for addressing 
intercurrent events 
Population-level 
summary 
Primary 
Estimand 
Adult subjects 
with FD as defined 
by the inclusion 
and exclusion 
criteria in section 
4.3 and 4.4  
Lucerastat (dose 
ranging from 250 
mg to 1000 mg b.i.d. 
based on subject’s 
eGFR value) as 
monotherapy which 
will be compared to 
placebo. 
Change from 
baseline to Month 6 
in the modified 
BPI-SF3 score of 
“neuropathic pain at 
its worst in the last 
24 hours”. 
Treatment policy, i.e., all 
collected endpoint data are 
used regardless of 
premature treatment 
discontinuation or use of 
other medication (e.g., pain 
medication, ERT). 
Mean change 
from baseline to 
Month 6, 
summarized as 
the difference 
between 
lucerastat and 
placebo. 
Secondary 
Estimand 
#1 
Adult subjects 
with FD as defined 
by the inclusion 
and exclusion 
criteria in section 
4.3 and 4.4. 
Lucerastat (dose 
ranging from 250 
mg to 1000 mg b.i.d. 
based on subject’s 
eGFR value) as 
monotherapy which 
will be compared to 
placebo. 
Change from 
baseline to Month 6 
in plasma Gb3. 
Treatment policy, i.e., all 
collected endpoint data are 
used regardless of 
premature treatment 
discontinuation or use of 
other medication (e.g., pain 
medication, ERT). 
Mean change 
from baseline to 
Month 6, 
summarized as 
the difference 
between 
lucerastat and 
placebo. 
Secondary 
Estimand 
#2 
Adult subjects 
with FD as defined 
by the inclusion 
and exclusion 
criteria in section 
4.3 and 4.4 with 
GI symptoms at 
baseline. 
Lucerastat (dose 
ranging from 250 
mg to 1000 mg b.i.d. 
based on subject’s 
eGFR value) as 
monotherapy which 
will be compared to 
placebo. 
Change from 
baseline to Month 6 
in the NRS-11 score 
of “abdominal pain 
at its worst in the 
last 24 hours”. 
Treatment policy, i.e., all 
collected endpoint data are 
used regardless of 
premature treatment 
discontinuation or use of 
other medication (e.g., pain 
medication, ERT, GI 
symptomatic treatments). 
Mean change 
from baseline to 
Month 6, 
summarized as 
the difference 
between 
lucerastat and 
placebo. 
Secondary 
Estimand 
#3 
Adult subjects 
with FD as defined 
by the inclusion 
and exclusion 
criteria in section 
4.3 and 4.4 with 
GI symptoms at 
baseline. 
Lucerastat (dose 
ranging from 250 
mg to 1000 mg b.i.d. 
based on subject’s 
eGFR value) as 
monotherapy which 
will be compared to 
placebo. 
Change from 
baseline to Month 6 
in the number of 
days with at least 1 
stool of a Bristol 
Stool Scale 
consistency Type 6 
or 7. 
Treatment policy, i.e., all 
collected endpoint data are 
used regardless of 
premature treatment 
discontinuation or use of 
other medication (e.g., 
medication used to 
treat/prevent diarrhea). 
Win ratio of 
change from 
baseline to Month 
6 between 
lucerastat and 
placebo. 
b.i.d. = twice daily; BPI-SF3 = Brief Pain Inventory – Short Form item 3; eGFR = estimated glomerular filtration rate; ERT = enzyme 
replacement therapy; FD = Fabry disease; Gb3 = globotriaosylceramide; GI = gastrointestinal; NRS-11 = 11-point numerical rating 
scale.
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6.1.4 Other efficacy endpoints 
6.1.4.1 Renal function endpoints 
• Subject eGFR slope from baseline to Month 6; 
• Changes from baseline to Month 6 in urine albumin-to-creatinine ratio (UACR). 
Of note, long-term outcome of lucerastat on renal function parameters will be further 
assessed in the OLE study (separate protocol). 
6.1.4.2 Echocardiography-based endpoints 
• Change from baseline to Month 6 in LVMI, posterior wall thickness, left ventricular 
mean wall thickness, left ventricular ejection fraction (LVEF), left ventricular end 
diastolic and end systolic volumes, left atrial volume, as measured by 
echocardiography. 
Of note, long-term outcome of lucerastat on echocardiography parameters will be further 
assessed in the OLE study (separate protocol). 
6.1.4.3 Pain medication endpoints based on daily entries in electronic diary 
• Subject mean weekly dose of opioid analgesics from baseline up to Month 6. 
Doses of opioids will be converted to equianalgesic dose of oral morphine; 
• Use of significant rescue pain therapy from baseline up to Month 6. 
Significant rescue pain therapy is defined as any initiation or dose escalation of 
anti-epileptics, TCAs, SNRIs/SSRIs, or opioid analgesic drugs as recorded in the 
eDiary; 
• Total number of days on significant rescue pain therapy from baseline up to Month 6. 
6.1.4.4 Clinical symptoms endpoints based on data collected at site visits 
• Change from baseline to Month 6 in the subject’s rating of item 5 score of the BPI-SF 
(“pain on the average in the last 24 hours”); 
• Change from baseline to Month 6 in the total score of the subject’s rating of item 9 of 
the BPI-SF (7 pain interference questions: “general activity”, “mood”, “walking 
ability”, “normal work”, “relation with other people”, “sleep”, “enjoyment of life”);  
• Change from baseline to Month 6 in the subject’s rating of severity of neuropathic pain 
severity as measured by the Patient Global Impression of Severity of neuropathic Pain 
(PGIS-P); 
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• Subject rating of change in the overall severity of neuropathic pain since study 
treatment start as measured by the Patient Global Impression of Change (PGIC) in 
neuropathic Pain Severity (PGIC-PS) at Month 6; 
• Change from baseline to Month 6 in the subject’s rating of disease severity as measured 
by the Patient Global Impression of Severity of Disease (PGIS-D); 
• Subject rating of change in disease severity since study treatment start as measured by 
the PGIC in Disease Severity (PGIC-DS) at Month 6; 
• Change from baseline to Month 6 in the total score of the subject’s rating of the Center 
for Epidemiologic Studies Depression Scale Revised (CESD-R-20). 
6.1.4.5 Treatment failure 
• Time to treatment failure from baseline up to Month 6. 
Treatment failure is defined as: 
• Initiation or re-initiation of ERT; or 
• Permanent study treatment discontinuation for any reason. 
6.1.5 Overview of efficacy endpoints 
Table 4 provides a list of the study efficacy endpoints.  
 
 
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Table 4 
Type of efficacy endpoints 
Primary endpoint 
Change from baseline to Month 6 in the “modified” BPI-SF3 score 
of “neuropathic pain at its worst in the last 24 hours”. 
Secondary endpoints 
Change from baseline to Month 6 in the NRS-11 score of 
“abdominal pain at its worst in the last 24 hours” in subjects with 
GI symptoms at baseline. 
Change from baseline to Month 6 in the number of days with at least 
one stool of a BSS consistency Type 6 or 7 in subjects with GI 
symptoms at baseline. 
Change from baseline to Month 6 in plasma Gb3. 
Other efficacy endpoints 
 
Renal function endpoints 
Subject eGFR slope from baseline to Month 6. 
 
Change from baseline to Month 6 in UACR. 
Echocardiography-based endpoints 
Change from baseline to Month 6 in LVMI, posterior wall 
thickness, left ventricular mean wall thickness, LVEF, left 
ventricular end diastolic and end systolic volumes, left atrial volume 
as measured by echocardiography. 
Pain medication endpoints based 
on daily entries in eDiary 
Subject mean weekly dose of opioid analgesics from baseline up to 
Month 6. 
 
Use of significant rescue pain therapy from baseline up to Month 6.  
 
Total number of days on significant rescue pain therapy from 
baseline up to Month 6. 
Clinical symptoms endpoints based 
on data collected at site visits 
Change from baseline to Month 6 in the subject’s rating of item 5 
score of the BPI-SF (“pain on the average in the last 24 hours”). 
 
Change from baseline to Month 6 in the total score of the subject’s 
rating of item 9 of the BPI-SF (7 pain interference questions: 
“general activity”, “mood”, “walking ability”, “normal work”, 
“relation with other people”, “sleep”, “enjoyment of life”). 
 
Change from baseline to Month 6 in the subject’s rating of severity 
of neuropathic pain severity as measured by the PGIS-P. 
Subject rating of change in the overall severity of neuropathic pain 
since study treatment start as measured by the PGIC-PS at Month 6. 
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Change from baseline to Month 6 in the subject’s rating of disease 
severity as measured by the PGIS-D. 
 
Subject rating of change in disease severity since study treatment 
start as measured by the PGIC-DS at Month 6. 
 
Change from baseline to Month 6 in the total score of the subject’s 
rating of the CESD-R-20. 
Treatment failure 
Time to treatment failure from baseline up to Month 6. 
BSS = Bristol Stool Scale; BPI-SF3/5/9 = Brief Pain Inventory - Short Form item 3/5/9; CESD-R-20 = Center for 
Epidemiologic Studies Depression Scale Revised; eGFR = estimated glomerular filtration rate; Gb3 = 
globotriaosylceramide; GI = gastrointestinal; LVEF = left ventricular ejection fraction; LVMI = left ventricular mass 
index; NRS-11 = 11-point numerical rating scale; PGIC-DS = Patient Global Impression of Change in Disease 
Severity; PGIS-D = Patient Global Impression of Severity of Disease; PGIC-PS = Patient Global Impression of 
Change in neuropathic Pain Severity; PGIS-P = Patient Global Impression of Severity of neuropathic Pain; UACR = 
urine albumin-to-creatinine ratio. 
 
6.2 Safety endpoints 
• Treatment-emergent AEs and SAEs; 
• AEs leading to premature discontinuation of study treatment;  
• Change from baseline to each visit up to Month 6 in vital signs. 
Vital signs include systolic blood pressure (SBP), diastolic blood pressure (DBP), mean 
arterial pressure (MAP), heart rate (HR), and body weight; 
• Treatment-emergent markeda abnormalities for vital signs up to Month 6; 
• Change from baseline to each visit up to Month 6 and from pre-dose to 2 hours and 
4 hours post dose at Month 1 in 12-lead ECG variables. 
ECG variables include HR, PR, QRS, QT, corrected QT (QTc) and morphological 
abnormalities as defined by the ECG provider; 
• Treatment-emergent markeda abnormalities for quantitative 12-lead ECG variables up 
to Month 6; 
• Change from baseline to each visit up to Month 6 in laboratory variables [see list in 
Section 7.2.4.2]; 
• Treatment-emergent markeda abnormalities for selected laboratory variables up to 
Month 6. 
                                                 
a The selection of marked abnormalities considered for the analyses will be based on standard definitions and described 
in the SAP. 
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6.3 Quality of life endpoints 
• Change from baseline up to Month 6 in subject rating of the 36-Item Short Form Health 
Survey Version 2 (SF-36v2) domain and component scores. 
6.4 Pharmacokinetic endpoints 
• Trough plasma concentration of lucerastat at each visit up to Month 6. 
6.4.1 Pharmacokinetic profile sub-study 
The plasma PK parameters of lucerastat will be derived by non-compartmental analysis of 
the plasma concentration-time data from PK samples collected at Month 1 in a subset of 
subjects: 
• AUC during one dosing interval (AUCτ) in a subset of subjects; 
• Cmax during one dosing interval in a subset of subjects; 
• tmax during one dosing interval; 
• The terminal disposition rate constant (λZ) and the t½. 
The measured individual plasma concentrations of lucerastat will be used to directly obtain 
Cmax and tmax. AUCτ will be calculated according to the linear trapezoidal rule using the 
measured concentration-time values above the limit of quantification during one dosing 
interval. The PK parameters will be calculated based on the actual blood sampling time 
points.  
For mean value calculations, all values below the limit of quantification (BLQ) will be set 
to zero. If > 50% of the values at a given time point are BLQ, no mean value will be 
calculated. Mean concentration-time profiles will be generated using these criteria. 
AUCτ, Cmax, and t½ are assumed to be log-normally distributed [Julious 2000]. 
If necessary, blood samples collected for determination of lucerastat plasma concentrations 
will be used for identification of possible metabolites. Results of metabolite investigations 
will be reported separately from the Clinical Study Report (CSR). 
6.5 Biomarker endpoints 
• Change from baseline to each visit up to Month 6 in plasma Gb3, lysoGb3 and their 
metabolic precursors (GlcCer and LacCer); 
• Change from baseline to each visit up to Month 6 in urinary Gb3 and lysoGb3. 
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6.6 Rationale for primary and secondary efficacy endpoints 
6.6.1 Rationale for evaluating neuropathic pain at Month 6 
Neuropathic pain is a major symptom of subjects with FD, being one of the earliest, most 
common, and most disabling clinical manifestations, impacting QoL of both male and 
female subjects with FD [Gold 2002, Hoffmann 2005, Eng 2007]. Subjects may 
experience permanent pain of variable intensity as well as pain attacks or crises 
Biegstraaten 2012, Politei 2016, Üceyler 2014. In the Fabry Registry, neuropathic pain 
has been reported in 62% of male and 41% of female subjects [Eng 2007]. Subjects with 
FD with neuropathic pain have also a higher risk of developing clinical complications 
(kidney, heart, hypoacousia) and depression [Gold 2002, Cole 2007, Bolsover 2014, 
Kaminsky 2014]. Neuropathic pain is not adequately managed by conventional pain 
medications or by ERT [see Section 1.1.2]. 
Demonstration of a clinically meaningful improvement in neuropathic pain symptom to 
establish drug effectiveness has been acknowledged by the FDA in their draft guidance on 
development of drugs for FD treatment [FDA 2019]. In the absence of regulatory 
guidelines specific to the development of treatment for FD at the time of the first version 
of the protocol, the methodology used in the study to assess the effect of lucerastat on 
neuropathic pain has been based whenever applicable on the CHMP guideline for 
neuropathic pain [CHMP 2007], and FDA guidance on chronic pain [FDA 2014], and 
PROs [FDA 2009]. 
While both the FDA and the CHMP recommend at least a 3-month duration for studies 
evaluating analgesia in a chronic pain condition [FDA 2014, CHMP 2017], it is postulated 
that the potential effects of lucerastat on the established clinical symptoms of neuropathic 
pain would already be measurable at Month 6 [see Section 3.2].  
Pain intensity has been reported to be higher during pain attacks and crises as compared to 
chronic pain Üceyler 2014. The frequency of pain attacks and crises may vary from daily 
occurrence to once a year. About 30–40% of subjects with FD who have neuropathic pain 
experience pain attacks or pain crises 1–4 times a month Üceyler 2014. Therefore, the 
baseline and Month 6 values will be derived from the subject’s neuropathic pain data 
collected over a period of 4 weeks [see Section 10.2.1], i.e., a time duration reasonably 
long enough to capture a true reflection of the subject’s score accounting for the variability 
of neuropathic pain intensity in subjects with FD. 
Published guidelines on neuropathic pain [CHMP 2007] and chronic pain [FDA 2014] 
recommend assessing the efficacy of treatment on pain preferably using uni-dimensional 
pain scales (e.g., NRS-11) as primary outcome. 
The BPI-SF is a frequently used, self-administered questionnaire, developed to assess the 
severity and impact of pain [Cleeland 2002]. The BPI-SF has become one of the most 
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widely used measurement tools for assessing clinical pain and is one of the recommended 
regular assessments to be performed in the two global FD registries Hernberg-Ståhl 2006, 
fabrydisease.org. The 24-hour recall period of the BPI-SF items is considered an 
appropriate time period for assessing pain intensity in line with the FDA and CHMP 
guidelines [CHMP 2017, FDA 2014]. 
In clinical studies, the BPI-SF item “pain at its worst in the last 24 hours” (BPI-SF3) has 
been used to assess pain severity and its use is supported by the Initiative on Methods, 
Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations for 
assessing pain in clinical trials [Dworkin 2005]. While the BPI-SF3 is a well-documented 
instrument to assess pain in general, it is not specific to neuropathic pain in FD. Therefore, 
a “modified” BPI-SF3 including a definition of neuropathic pain will be used in this study 
see Section 7.2.2.2.1. 
As per CHMP guideline on pain [CHMP 2017], the weekly averages of the daily 
measurement compared to baseline are commonly used as the primary efficacy variable in 
long term studies. The responder analysis should be provided in addition to the primary 
efficacy analyses with 30% or 50% reduction in pain intensity compared to baseline for 
chronic pain conditions. The benchmark commonly used to define the clinical relevance of 
changes in pain intensity is based on the clinically important differences in 11-point pain 
intensity scales following the recommendation of the IMMPACT consensus on the clinical 
significance of change across pain states and the CHMP guideline on neuropathic pain 
Farrar 2001, CHMP 2007, Dworkin 2008, Farrar 2010. In 15 chronic pain (including 
diabetic peripheral neuropathy) clinical trials, a decrease of 30% in pain intensity scale was 
associated with the categories “much improved” or “very much improved” in a 7-point 
PGIC regardless of the underlying disease, treatment administered and subject’s age or sex 
[Farrar 2001, Farrar 2010].  
6.6.2 Rationale for evaluating gastrointestinal symptoms (abdominal pain, 
diarrhea) at Month 6 
GI involvement is one of the earliest clinical manifestations and the second most common 
sign after neuropathic pain reported in childhood [Eng 2007, Hoffmann 2007a]. GI 
symptoms were reported in up to 52% of adult subjects with FD [Hoffmann 2007a]. 
GI symptoms in FD are somewhat similar to those associated with functional disorders 
such as IBS [Keshav 2006]. Abdominal pain and diarrhea are the most frequent GI 
symptoms, affecting 32% and 20% respectively of adult patients with FD, while 
constipation has been reported in 13% of patients [Hoffmann 2007a]. Gender differences 
have been reported in the FOS with diarrhea being more frequently reported by male 
(25.9%) than female (16.7%) patients and constipation more frequently reported by female 
(16.7%) than male (8.6%) patients [Hoffmann 2007a]. GI symptoms are not adequately 
managed by ERT [see Section 1.1.2]. 
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In the absence of regulatory guidelines specific to the development of treatment for FD at 
the time of the first version of the protocol, the methodology used in the study to assess the 
effect of lucerastat on GI symptoms has been based on the IBS [FDA 2012] and PRO 
[FDA 2009] guidance. According to the draft FDA guidance on development of drugs for 
FD treatment [FDA 2019], drug effectiveness can be established with the demonstration of 
clinically meaningful improvement in GI symptoms (abdominal pain, diarrhea, 
constipation). 
Similarly to the neuropathic pain symptom, it is postulated that the potential effects of 
lucerastat on GI symptoms (abdominal pain and diarrhea) result from the reduction of Gb3 
and lysoGb3 storage in the GI tract see Section 1.3. As for neuropathic pain, it is expected 
that the effect of lucerastat on GI symptoms would already be measurable at Month 6 in 
those subjects who had the corresponding symptom at baseline. Similar to neuropathic 
pain, GI symptoms may vary in frequency and intensity. Some subjects with FD describe 
a cyclic pattern of alternating diarrhea and constipation interspersed with periods of 
quiescence and normal bowel movements, making diagnosis and management particularly 
difficult [Keshav 2006]. Therefore, the baseline and Month 6 values will be derived from 
the subject’s abdominal pain and diarrhea data collected over a period of 4 weeks [see 
Sections 10.2.2.1 and 10.2.2.2], i.e., a time duration reasonably long enough to capture a 
true reflection of the subject’s score accounting for the variability of diarrhea and 
abdominal pain symptoms in subjects with FD. 
Published IBS guidelines [FDA 2012, CHMP 2014] recommend assessing the efficacy of 
treatment on abdominal pain intensity in subjects with moderate to severe abdominal pain 
by using uni-dimensional pain scales (e.g., NRS-11) that ask subjects to rate their 
abdominal pain at its worst in the last 24 hours on a daily basis. This is also in line with the 
recommendation from the IMMPACT consensus conference [Dworkin 2005]. The criteria 
used to define a subject with moderate to severe abdominal pain at baseline are consistent 
with the published IBS guidelines [FDA 2012]. The abdominal pain intensity rating scale 
used in this study see Section 7.2.2.2.2 has been previously tested in a cognitive 
debriefing / usability testing study conducted in subjects with FD. 
Published IBS guidelines [FDA 2012] recommend assessing the efficacy of treatment on 
diarrhea in subjects with diarrhea by using the BSS to assess the number and consistency 
of the stools on a daily basis. The BSS provides a visual and verbal description of stool 
consistency and form and is considered an appropriate instrument for capturing stool 
consistency in IBS trials [Lewis 1997]. The criteria used to define a subject with diarrhea 
at baseline are consistent with the published IBS guidelines [FDA 2012]. The questions 
used to assess the number and consistency of the stools in this study see Section 7.2.2.2.3 
have been previously tested in a cognitive debriefing / usability testing study conducted in 
subjects with FD. 
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6.6.3 Rationale for evaluating plasma levels of globotriaosylceramide at Month 6 
Changes in plasma levels of Gb3 will be evaluated in this study as a marker of the PD 
effect of SRT with lucerastat in subjects with FD.  
In the exploratory Phase 1b study in subjects with FD receiving ERT, lucerastat treatment 
was associated with a fast, marked and consistent reduction in plasma Gb3 concentration 
[see Section 1.2.3 and Lucerastat IB]. In this study, it is expected that plasma Gb3 levels 
will be reduced in the lucerastat arm compared to the placebo arm after 6 months, in both 
ERT “treatment-naïve” / “pseudo-naïve” subjects and “switch” subjects. 
Gb3 concentrations are highly elevated in plasma, urine and target organs of subjects with 
FD as a direct result of the reduced or absent -GalA activity caused by mutations of the 
GLA gene. In subjects with FD, ERT gives rise to a 50% reduction of plasma Gb3 relative 
to baseline after 3–6 months of treatment, and no further reduction after longer periods of 
treatment Bekri 2006. 
Plasma lysoGb3, which probably originates from Gb3, is also elevated in subjects with FD, 
but is not favored as a PD marker for this study due to the smaller FD induced absolute 
increase than Gb3 [Van Breemen 2011]. In subjects with FD, the reduction in plasma 
lysoGb3 achieved with ERT in subjects with FD is quantitatively much lower than that 
achieved in plasma Gb3 [Van Breemen 2011]. 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS 
7.1 Study visits 
The study visits and their respective time windows are listed in Table 5 and Table 6.  
In the event of premature discontinuation of study treatment, the EOT visit must take place 
as soon as possible and no later than 7 days after the last dose of study treatment. In such 
case, all assessments planned at the Month 6 visit must be performed at the EOT visit. 
Subjects who prematurely discontinue study treatment for any reason will not be replaced. 
An exit interview will be conducted by telephone as soon as possible after the end of the 
study treatment phase (or EOT visit), ideally within 2 weeks in English-speaking subjects 
at US and Canadian sites. 
Safety follow-up information will be collected during the FU1 visit (all subjects) and FU2 
visit (only in fertile males) via telephone call. At the FU1 visit, safety follow-up 
information includes use of concomitant therapy, AE/SAEs, result of pregnancy test, and 
reporting of pregnancy (as needed) in female subjects or male subjects’ female partners. 
Fertile male subjects will be reminded to continue using contraception until at least 
3 months following EOT. At the FU2 visit, safety follow-up information includes reporting 
of pregnancy (as needed) in male subjects’ female partners. 
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For subjects followed in the PTOP, safety follow-up information may also be collected 
during a site visit if it coincides with the originally scheduled visits. 
7.1.1 Screening/re-screening 
7.1.1.1 Screening 
The date of the screening visit is the date when the ICF is signed see Section 12.3 for 
informed consent procedure. 
The subjects who agree to participate in the study and the investigator/delegate must sign 
the ICF prior to any study-related assessment or procedure. 
If the signing of ICF and performance of the first study-specific procedures or assessments 
take place on the same day, it must be clear from the source documents that informed 
consent was obtained prior to any study-specific procedures being performed. If a 
study-specific procedure or assessment has been performed as part of routine assessments 
on the day of the screening visit and the results are available prior to the subject signing 
the ICF, such procedure or assessment may be used and does not have to be repeated (e.g., 
vital signs). In such cases, it must be clear from the source documents when and for which 
reason the assessment was done prior to the signing of the ICF. 
For convenience reasons, study-specific procedures or assessments can take place on 
different days during the screening period. 
After the ICF has been signed, the investigator/delegate contacts the IRT system to get a 
subject number allocated to the subject. 
Subjects who have signed the ICF when the enrollment target has been met may still be 
randomized. 
7.1.1.2 Re-screening 
Subjects who did not meet the criteria for participation in the study (i.e., screen failure) 
may be re-screened once if the reason for non-eligibility was transient (e.g., abnormal 
laboratory test, insufficient wash-out period of a forbidden medication, insufficient time 
window for allowed medications or previous medical events, having received ERT in the 
last 6 months). If the reason for non-eligibility is the absence of moderate to severe 
neuropathic pain (i.e., inclusion criteria #9 not met), re-screening is permitted only after 
1 month. 
A new ICF must be signed prior to re-screening the subject if more than 3 months have 
elapsed since the first ICF signature. Re-screened subjects will be assigned the same 
subject number as for the initial screening. 
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7.1.2 Unscheduled visits 
Unscheduled visits may be performed at any time during the study and will be recorded in 
the eCRF. Physical examination, vital signs, ECG and laboratory assessments must be 
performed at each unscheduled visit. PK and biomarker sampling should not be performed 
during unscheduled visits. Other assessments are performed at the discretion of the 
investigator. 
After an unscheduled visit, the regular scheduled study visits must continue according to 
the planned visit and assessment schedule. 
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Table 5 
Visit and assessment schedule: double-blind treatment period 
PERIODS 
 
Name 
SCREENING 
TREATMENT PERIOD 
FOLLOW-UP PERIOD Unscheduled 
 
Duration 6 to 7 weeks 
6 months 
Up to 3 months 
NA 
VISITS 
Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
U1  
 
Name 
Screening 
Randomization Month 
1 
Month 
2 
(phone) 
Month 
3 
Month 
4 
(phone) 
Month 5 
Month 
6 or 
EOTa  
FU1b 
FU2b 
Unscheduled 
 
Time 
window 
Day −49 
[max] / 
Day −42 
[min] to 
Day −1 
Day 1 
Day 21 
to Day 
38 
Day 54 
to Day 
68 
Day 
84 to 
Day 
98 
Day 
115 to 
Day 
129 
Day 145 to Day 
159 
Day 
169 
to Day 
197  
30 to 37 days 
after last 
study 
treatment 
dose 
91 to 105 
days 
after last 
study 
treatment 
dose 
Any day 
between ICF 
signature 
and EOS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Xc 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
FD history and 
treatment 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Previous & 
concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
IPMPd 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
(X) 
eDiary 
training/retraining 
X 
X 
X 
X 
X 
X 
X 
Xa 
 
 
 
Pain medication use 
** 
 X (collected daily in eDiary)a  → 
Xe 
 
 
Physical examination 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
Vital signs (BP, HR, 
body weight) 
X (+ height) 
X 
X 
 
X 
 
 X 
X 
 
 
X 
12-lead ECG 
(trough)* 
X 
X 
Xf 
 
X 
 
 X 
X 
 
 
X 
Echocardiography* 
 
X 
 
 
 
 
 
X 
 
 
(X) 
Laboratory tests 
(urine, blood) fasted 
state * 
X (+stoolg) 
Xh 
X 
 
X 
 
 X 
X 
 
 
X 
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(X) = optional. * collected by vendor. ** collected in eDiary. *** only reported to sponsor Global Drug Safety. 
a After completion of the Month 6 visit, those subjects will be proposed to enroll in a separate OLE study. Subjects who prematurely discontinue SD prior to the 
Month 6 visit should have an EOT visit scheduled not later than 7 days after the last dose of SD. In such case, all assessments planned at the Month 6 visit must 
be performed at the EOT visit. Those subjects will also have a safety follow-up and will enter into the PTOP [see Table 6]. eDiary retraining is not required at 
EOT if subject does not enter into the PTOP. The subject will return the eDiary to the site personnel at the EOT visit or at the last PTOP visit (whichever is 
last). 
b Visit(s) performed by telephone by the investigator only for subjects who do not enter the separate OLE study. For those subjects, the EOS corresponds to the FU1 
visit, FU2 visit or to the last visit of the PTOP, whichever is last.  
Pregnancy testi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
Biomarker sampling 
(urine/plasma at 
trough)* 
X- 
X 
X 
 
X 
 
X 
X 
 
 
 
Research biomarker 
sampling 
(urine/plasma/serum 
at trough)* 
 
X 
 
 
 
 
 
X 
 
 
 
PK sampling 
(trough)* 
 
 
X 
 
X 
 
X 
X 
 
 
 
PK profile sampling 
(sub-study)* 
 
 
Xj 
 
 
 
 
 
 
 
 
Neuropathic pain 
NRS-11 (modified 
BPI-SF3)** 
 X (collected daily in eDiary)a → 
 
 
 
Abdominal pain 
NRS-11** 
 X (collected daily in eDiary)a  → 
 
 
 
Stool number& 
consistency ** 
 X (collected daily in eDiary)a  → 
 
 
 
BPI-SF (Complete)** 
 
X 
X 
 
X 
 
X 
X 
 
 
 
PGIS-D, PGIS-P, 
PGIC-DS & 
PGIC-PS** 
 
X 
(only PGIS-D & 
PGIS-P) 
X 
 
X 
 
X 
X 
 
 
 
SF-36** 
 
X 
 
 
 
 
 
X 
 
 
 
CESD-R-20** 
 
X 
 
 
 
 
 
X 
 
 
 
Exit interview 
(sub-study)*k 
 
 
 
 
 
 
 
X 
 
 
 
SD dispensing/return 
 
X 
X 
 
X 
 
X 
X 
 
 
(X) 
SAEs/AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy report*** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
X 
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c If the GLA gene mutation is not known (i.e., male subject diagnosed based on residual -GalA activity), the gene mutation will be determined by the site locally 
at the screening visit. 
d IPMP will be applicable starting at screening visit and until EOT visit or the last visit of the PTOP (as applicable). 
e Pain medications taken by the subject during the FU period after he/she has returned the eDiary will be collected in the eCRF. 
f At the Month 1 visit, 2 additional ECGs will be performed 2 and 4 hours after SD administration.  
g Stool samples will be collected only in subjects presenting diarrhea symptoms at the screening visit. 
h -GalA activity will be measured at the screening and randomization visits only. 
i Serum pregnancy test at screening visit. Urinary pregnancy tests at all other visits and performed at home on a monthly basis between the visits until the FU1 visit. 
Result of the pregnancy tests are not collected in the eCRF. 
j Subset of subjects: blood samples to be drawn prior to study treatment administration (pre-dose), and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 6 h, 8 h, 10 h, and 
12 h thereafter. 
k Exit phone interviews conducted in US and Canadian subjects ideally within 2 weeks after the Month 6 or EOT visit. 
l Only pregnancy of female partner of male subjects. 
 
-GalA = α-galactosidase A; AE = adverse event; BP = blood pressure; BPI-SF = Brief Pain Inventory-Short Form; CESD-R-20 = Center for Epidemiologic Studies 
Depression Scale Revised; ECG = electrocardiogram; eCRF = electronic case report form; EOS = End-of-Study; EOT = End-of-Treatment; FD = Fabry disease; 
FU = follow-up; GI = gastrointestinal; HR = heart rate; ICF = informed consent form; IPMP = Individual Pain Management Plan; NRS-11 = 11-point numerical 
rating scale; OLE = open-label extension; PGIC-DS = Patient Global Impression of Change in Disease Severity; PGIC-PS = Patient Global Impression of 
Change in Pain Severity; PGIS-D = Patient Global Impression of Severity of Disease; PGIS-P= Patient Global Impression of Severity of neuropathic Pain; 
PK = pharmacokinetic(s); PTOP = post-treatment observation period; SAE = serious adverse event; SD = study drug; SF-36 = Short Form Health Survey. 
 
 
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Table 6 
Visit and assessment schedule: post-treatment observation period 
VISITS 
Number 
3PTOP 
4PTOP 
5PTOP 
6PTOP 
7PTOP 
8PTOP 
 
Name 
Month 1PTOP 
Month 2PTOP 
(phone) 
Month 3PTOP 
Month 4PTOP 
(phone) 
Month 5PTOP 
 
Month 6PTOP or 
End of PTOP 
 
Time 
window 
Day 21 to Day 38 
Day 54 to Day 68 
Day 84 to Day 98 Day 115 to Day 129 Day 145 to Day 159 
Day 169 
to Day 197  
Concomitant therapy 
X 
X 
X 
 X 
 X 
X 
IPMPa 
X 
X 
X 
 X 
 X 
X 
eDiary training/retraining 
X 
X 
X 
X 
X 
 
Pain medication use ** 
 X (collected daily in eDiary)b → 
Physical examination 
X 
 
X 
 
X 
X 
Vital signs (BP, HR, body 
weight) 
X 
 
X 
 
X 
X 
12-lead ECG* 
X 
 
X 
 
X 
X 
Echocardiography* 
 
 
 
 
 
X 
Laboratory tests (urine, 
blood) fasted state * 
X 
 
X 
 
X 
X 
Biomarker sampling 
(urine/plasma)* 
X 
 
X 
 
X 
X 
Research biomarker 
sampling 
(urine/plasma/serum)* 
 
 
 
 
 
X 
Neuropathic pain NRS-11 
(modified BPI-SF3)** 
 X (collected daily in eDiary)b  → 
 
Abdominal pain NRS-11** 
 X (collected daily in eDiary)b  → 
 
Stool number& consistency 
** 
 X (collected daily in eDiary)b  → 
 
BPI-SF (Complete)** 
X 
 
X 
 
X 
X 
PGIS-D, PGIS-P, PGIC-DS 
& PGIC-PS** 
X 
 
X 
 
X 
X 
SF-36** 
 
 
 
 
 
X 
CESD-R-20** 
 
 
 
 
 
X 
SAEs/AEs 
X 
X 
X 
X 
X 
X 
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*collected by vendor. ** collected in eDiary. 
a IPMP will be provided to the subject at the screening visit and will be applicable until Month 6 (or last PTOP) visit. 
b The subject will return the eDiary to the site personnel at the EOT visit or at the last PTOP visit (whichever is last). 
 
AE = adverse event; BP = blood pressure; BPI-SF = Brief Pain Inventory-Short Form; CESD-R-20 = Center for Epidemiologic Studies Depression Scale Revised; 
ECG = electrocardiogram; EOT = End-of-Treatment; HR = heart rate; IPMP = Individual Pain Management Plan; NRS-11 = 11-point numerical rating scale; 
PGIC-DS = Patient Global Impression of Change in Disease Severity; PGIC-PS = Patient Global Impression of Change in Pain Severity; PGIS-D = Patient 
Global Impression of Severity of Disease; PGIS-P= Patient Global Impression of Severity of neuropathic Pain; PTOP = post-treatment observation period; 
SAE = serious adverse event; SF-36 = Short Form Health Survey. 
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7.2 Study assessments 
The study assessments are listed in Table 5 and Table 6. The assessments that are 
mandatory during a visit are marked with an ‘X’. Optional assessments are marked with an 
‘(X)’. 
All study assessments performed during study visits (scheduled or unscheduled) are done 
by the investigator/delegate and are recorded in the eCRF, unless otherwise specified. 
In exceptional circumstances, the investigator/delegate may perform some assessments 
shortly prior to or after the scheduled visit (with the exception of the randomization visit) 
as long as it is within protocol-defined visit time window. 
All PROs collected on a daily basis (e.g., evening diary) or during a site visit will be 
recorded in an eDiary see Section 7.2.2.1 for more details. 
During site visits, subjects should complete the site visit PROs preferably at the beginning 
of the visit. Whenever feasible, the following order of assessments is preferred: SF-36v2™, 
BPI-SF, PGIS-P, PGIC-PS, PGIS-D, PGIC-DS, CESD-R-20, physical examination / vital 
signs, ECG, blood/urine/PK/biomarker sampling. 
If the principal investigator (PI) delegates any study procedure/assessment e.g., ECG, 
echocardiography, blood sampling to an external facility, he/she should inform the sponsor 
to whom these tasks are delegated. The set-up and oversight will be agreed upon with the 
sponsor. The supervision of any external facilities remains the responsibility of the PI. 
Calibration certificates / evidence of equipment maintenance for the below-listed 
equipment used to perform study assessments must be available unless the equipment is 
provided by the sponsor. Calibration certificates / evidence of equipment maintenance of 
other equipment must be available as per local requirements. 
Equipment for which calibration certificates are needed: 
• Temperature measurement devices for study treatment storage area and laboratory 
sample storage (e.g., freezer); 
• ECG recorder; 
• Echocardiography device. In addition, prior to the start of the study, each site must be 
qualified by the central echocardiography laboratory [see Section 7.2.2.7]. 
7.2.1 Demographics / baseline characteristics 
Demographic and baseline characteristic data to be collected on all subjects include: age, 
sex, race, and ethnicity (if allowed in the country). Relevant medical history / current 
medical conditions other than those related to FD (e.g., chronic and ongoing acute 
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conditions, serious past conditions) present before signing of the ICF will be recorded in 
the eCRF. Where possible, main diagnoses and not symptoms will be recorded. 
7.2.1.1 Fabry disease history 
Relevant FD medical history of special interest will be captured in the eCRF and includes: 
• Date and type of first known FD symptom (neuropathic pain, GI, skin, cardiac, kidney, 
cerebrovascular, eye, ear, bone, respiratory); 
• Date of FD diagnosis; 
• Diagnostic method (GLA gene mutation, -GalA activity). If -GalA was measured, 
sample type (e.g., plasma, leukocytes, dried blood spots), date of laboratory test, value, 
corresponding normal ranges and unit will be collected; 
• GLA gene mutation, date of genetic test, and testing method used.  
If the GLA gene mutation is not known (i.e., male subject diagnosed based on residual 
-GalA activity), the gene mutation will be determined by the site locally at the screening 
visit.  
An independent expert geneticist will be appointed by the sponsor to review and categorize 
in a blinded fashion the FD genetic mutations present at screening and reported by the 
investigator in the eCRF. 
• Incident case (yes/no/not known). An incident case is defined as a subject diagnosed in 
the absence of known family history of FD cases; 
• Neuropathic pain symptoms: 
– Date of first neuropathic pain symptom; 
– Type of neuropathic pain symptom(s): chronic pain, pain crisis/attacks, other; 
– Pain triggering factors: heat or cold, weather change, being sick or having fever, 
diet, stress, tiredness, physical activity, other; 
– Type of pain medication used to treat neuropathic pain in the last 12 months: 
anti-epileptics, TCAs, SNRIs, SSRIs, non-opioid analgesics (NSAIDs, topical 
analgesics), opioid analgesics. 
• Other FD-related symptoms and complications: 
– Other neurological symptoms excluding neuropathic pain: heat intolerance, cold 
intolerance, hearing loss, tinnitus, vertigo, depression; 
– GI symptoms: diarrhea, abdominal pain / postprandial pain, abdominal discomfort, 
bloating, vomiting, nausea, constipation, early satiety, poor weight gain; 
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– Eyes: corneal verticillata, corneal opacities, corneal dystrophy, lenticular opacities, 
retinal vein tortuosity, conjunctival vessel disorder; 
– Kidney: microalbuminuria, proteinuria, renal impairment; 
– Heart: heart valve insufficiency, arrhythmias, tachycardia, bradycardia, atrial 
fibrillation, atrial flutter, PR interval shortened, QTc prolonged, left ventricular 
hypertrophy, right ventricular hypertrophy, angina pectoris, myocardial infarction, 
coronary artery disease, heart failure (current NYHA class should be provided); 
– Respiratory: dyspnea at rest, dyspnea exertional, chronic cough, wheezing, chronic 
obstructive lung disease; 
– Cerebrovascular: transient ischemic attacks, ischemic stroke, white matter lesions; 
– Bones: osteoporosis, osteopenia; 
– Skin: angiokeratoma, anhydrosis, hypohydrosis, hyperhydrosis, acanthosis, 
hyperkeratosis, skin peeling. 
• Historical data on serum creatinine (µmol/L or mg/dL) (if available) within the 2 years 
prior to screening (e.g., 2 values per year 6 months apart from each other). 
7.2.1.2 Data to be collected for screening failure subjects 
• A minimal set of screening failure information is required to ensure transparent 
reporting of screening failure subjects. 
For subjects who failed screening, the following data will be recorded in the eCRF: 
• Age, sex, race, and ethnicity (if allowed in the country); 
• Inclusion criteria not met and/or exclusion criteria met; 
• FD history [see Section 7.2.1.1]; 
• FD-specific therapies [see Section 5.2.5.1]; 
• SAEs. 
7.2.2 Efficacy assessments 
7.2.2.1 Use of an electronic diary 
All PROs collected on a daily basis and during a site visit will be recorded in an eDiary. 
The data from the eDiary will be automatically transferred to the eDiary vendor’s central 
server. Once the data have been transferred to the vendor’s central server, the site staff, the 
eDiary vendor, and sponsor representatives can access them in a view-only mode. More 
details on eDiary data transfer procedures and data access are provided in Section 11.1. 
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Each subject will be provided with a portable eDiary with a touch screen interface. The 
subjects will be trained by study personnel at the time the subject is given access to the 
eDiary device (i.e., during the screening visit). A training version of the eDiary will be 
available to support the training session. The training version of the eDiary will allow a 
subject to complete every questionnaire he/she will encounter during the study, and to 
practice until he/she feels comfortable with the eDiary. Subjects must be re-trained during 
subsequent site visits or telephone calls if needed. 
The subject will complete the eDiary according to the protocol schedule. The subject 
should preferably complete the eDiary at approximately the same time every evening for 
those questionnaires collected on a daily basis (“evening diary”). Reminders will be 
programmed for scheduled diary entries (like the evening diary) and will occur when the 
diary is due for completion but data has not yet been entered. The subject will be instructed 
to bring his/her eDiary at the site in order to complete the site visit PROs (i.e., SF-36v2™, 
BPI-SF, PGIS-P, PGIC-PS, PGIS-D, PGIC-DS, CESD-R-20).  
When the subject has completed all the screens belonging to a diary (e.g., evening diary) 
or a site visit PRO (e.g., BPI-SF), he/she will have to confirm his/her answers. Once the 
subject will submit the confirmation screen, he/she will no longer be able to access or 
change the data entered in that diary or PRO. 
The subject will return the eDiary to the site personnel at the EOT visit or at the last PTOP 
visit (whichever is last). 
7.2.2.2 Efficacy assessments collected on a daily basis in the electronic diary 
7.2.2.2.1 Assessment of neuropathic pain  
Subjects will be asked to rate on a daily basis their neuropathic pain in the eDiary starting 
at the Screening visit until the Month 6 visit (Month 6 PTOP visit if subject is in the PTOP). 
Subjects will rate their neuropathic pain intensity on an NRS-11 (0 – no neuropathic pain 
to 10 – neuropathic pain as bad as you can imagine) to respond to the modified BPI-SF3 in 
the eDiary:  
The following question is about the neuropathic pain you may have because of your Fabry 
disease.  
This type of pain usually feels like burning, shocks or shooting, stabbing, tingling, and/or 
pins and needles in your hands and feet. You may have constant or intermittent pain with 
variable intensity. You may also get attacks of intense, excruciating pain that starts in the 
hands and feet and spreads to other parts of the body.  
Your pain may occur randomly. It may also be triggered by heat or cold, weather change, 
being sick or having a fever, diet, stress, tiredness and/or physical activity. 
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“Please rate your neuropathic pain (e.g., pain that feels like burning, shocks or shooting, 
stabbing, tingling, and/or pins and needles) in your hands and feet by selecting the number 
that best describes your neuropathic pain at its WORST in the last 24 hours.” 
Risk minimization of potential bias 
Subjects must not receive any of the following information:  
• Pain intensity randomization criterion (inclusion criterion #9 [Section 4.3]); 
• Computation rules and time windows used to derive the baseline modified BPI-SF3 
scores [see Section 10.2.1]; 
• Individual baseline modified BPI-SF3 score. 
The investigator and medical staff should not communicate any of the above information 
to the subject or any other parties who could be potentially in contact with the subject (e.g., 
subject’s general practitioner). 
7.2.2.2.2 Assessment of abdominal pain intensity 
The subjects will be asked to rate on a daily basis their abdominal pain in the eDiary starting 
at the screening visit until the Month 6 visit (Month 6 PTOP visit if subject is in the PTOP). 
Subjects will rate their abdominal pain intensity on an NRS-11 (0 – no pain to 10 – worst 
imaginable pain) to respond to the following question in the eDiary:  
• “Please rate your abdominal pain by selecting the number that best describes your 
abdominal pain at its WORST in the last 24 hours.” 
7.2.2.2.3 Assessment of number and consistency of bowel movements  
The subjects will be asked to record on a daily basis the number and consistency of bowel 
movements starting at the Screening visit until the Month 6 visit (Month 6 PTOP visit if 
subject is in the PTOP). 
The subject will answer the following question in the eDiary: 
• “How many bowel movements did you have in the last 24 hours?” 
The subject will then have to indicate the BSS type of each bowel movement [Appendix 2]. 
The BSS Appendix 2] is a medical aid designed to classify the form of human feces into 
seven categories. It provides a visual and verbal description of stool consistency and form.  
The use of the BSS is not covered by a license. 
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7.2.2.2.4 Risk minimization for missing data 
A series of measures will be implemented to minimize the risk of missing data entered on 
a daily basis by the subject: 
• Data will be collected in an eDiary: when compared with collecting PRO on paper 
diary, electronic data collection has been shown to dramatically increase subject 
compliance Lauritsen 2004; 
• The subject will be trained on the use of the eDiary during the screening visit; 
• The first 2 weeks of the screening period will allow the subject to fully familiarize 
themselves with the eDiary. Data collected during that time period will not be used for 
the setting of the baseline scores; 
• The subjects will get audible and visual alarms and reminders to complete the diary on 
a daily basis; 
• Data are transferred from the eDiary to the eDiary vendor’s central server on a nightly 
basis see Section 11.1 allowing the site staff, the sponsor and the eDiary CRO to 
remotely monitor the compliance of the subject; 
• The site staff, and the sponsor will get e-mail alerts in the event of subject 
non-compliance. The study staff with the support of the eDiary vendor and the sponsor 
will ensure the subject is advised and re-trained (if needed) to limit the number of days 
with incomplete data collection. The main reason for not completing the diary will be 
collected and documented in the hospital charts; 
• In the event of technical failure of the eDiary (excluding lack of eDiary recharging by 
the subject), a back-up plan includes provisioning all sites with back up eDiary and 
overnight shipment of the replacement eDiary to the subject. 
In the event of premature study treatment discontinuation, the subject is requested (to the 
extent of possibility) to continue completing the eDiary until the originally scheduled 
Month 6 visit. 
7.2.2.3 Brief Pain Inventory-Short Form 
The full BPI-SF questionnaire will be completed by the subject at the randomization visit 
and at each subsequent site visit until the Month 6 visit (Month 6 PTOP visit if subject is 
in the PTOP). The questionnaire will be administered in an electronic format using the 
eDiary see Section 7.2.2.1.  
The BPI-SF is a validated, self-administered questionnaire, developed to assess the severity 
and impact of pain. The BPI-SF provides a direct and comprehensive means of measuring 
pain intensity, location of pain, and the extent to which pain interferes with the subject’s 
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daily activities. The BPI was originally designed to assess pain in cancer subjects but has 
proven to work in other painful conditions including neuropathic pain and FD 
[Cleeland 2002]. 
The BPI-SF allows subjects to rate the severity of their pain (4 questions assessed on an 
NRS-11) and the degree to which their pain interferes with common dimensions of feeling 
and function (7 questions assessed on an NRS-11). Location of pain is also indicated on a 
body scheme by the subject.  
A sample of the BPI-SF (in English) is provided in Appendix 3.  
The sponsor has been granted a license agreement for the use of the BPI-SF.  
7.2.2.4 Patient Global Impression of Severity  
Two PGIS questionnaires will be completed by the subject at the randomization visit and 
at each subsequent site visit until the Month 6 visit (Month 6 PTOP visit if subject is in the 
PTOP): a PGIS-D and a PGIS-P. The questionnaires will be administered in an electronic 
format using the eDiary. 
The PGIS questionnaires are self-administered 1-item questionnaire designed to assess 
subject’s impression of disease severity (PGIS-D) and neuropathic pain severity (PGIS-P). 
Subjects will rate the overall severity of the disease and neuropathic pain symptoms over 
the past 7 days on a 4-point scale (1–4) scored as: “none”, “mild”, “moderate”, or “severe”. 
Samples of the PGIS-D and PGIS-P questionnaires are provided in Appendix 4. 
7.2.2.5 Patient Global Impression of Change  
Two PGIC questionnaires will be completed by the subject starting at Month 1, and at each 
subsequent site visit until the Month 6 visit (Month 6 PTOP visit if subject is in the PTOP): 
a PGIC-DS and a PGIC-PS. The questionnaires will be administered in an electronic format 
using the eDiary. 
The PGIC questionnaires are self-administered 1-item questionnaires designed to assess 
subject’s impression of change since study treatment start in disease severity (PGIC-DS) 
and neuropathic pain severity (PGIC-PS). Subjects will rate their change since they started 
study treatment in the overall severity of the disease symptoms (PGIC-DS) and change in 
the overall severity of neuropathic pain (PGIC-PS) on 7-point scales (1 to 7) scored as: 
“very much improved,” “much improved,” “minimally improved,” “no change,” 
“minimally worse,” “much worse,” or “very much worse”. 
Samples of the PGIC-DS and PGIC-PS questionnaires are provided in Appendix 4. 
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7.2.2.6 Center for Epidemiologic Studies Depression Scale Revised 
The CESD-R-20 will be completed by the subject at the randomization visit and 
Month 6 (Month 6 PTOP visit if subject is in the PTOP). The questionnaire will be 
administered in an electronic format using the eDiary. 
The CESD was created in 1977 [Radloff 1977] and revised in 2004 (CESD-R-20 
[Eaton 2004]). This self-report scale is well known and remains one of the most widely 
used instruments in the field of psychiatric epidemiology. 
The 20 items in the CESD-R-20 scale measure symptoms of depression in nine different 
groups as defined by the American Psychiatric Association Diagnostic and Statistical 
Manual, fifth edition.  
The total CESD-R-20 score is calculated as a sum of responses to all 20 questions. A score 
equal to or above 16 indicates a person at risk of clinical depression. 
A sample of the CESD-R-20 (in English) is provided in Appendix 5.  
The use of the CESD-R-20 is not covered by a license. 
7.2.2.7 Echocardiography 
A central echocardiography vendor (see echocardiography manual for contact details) will 
be used for all protocol-mandated echocardiographies, including re-tests, and 
echocardiographies performed at unscheduled visits. 
A re-test may be performed if the result for an echocardiography is missing (e.g., 
unreadable echocardiography) or to repeat an abnormal echocardiography. A re-test does 
not need to be reported as an unscheduled visit see Section 7.1.2.  
Standard 2D/Doppler echocardiographies will be collected at the randomization visit, and 
Month 6 (Month 6 PTOP visit if subject is in the PTOP). Echocardiographies will be 
acquired by trained sonographers/technicians using the echocardiography Image 
Acquisition Guidelines. The sonographers/technicians will have to be qualified by the 
central echocardiography vendor prior to any acquisition of echocardiographies in a study 
subject. Whenever possible, the same sonographer/technician should acquire all 
echocardiographies performed in one subject. The site personnel will electronically 
transmit the echocardiographies to the central echocardiography vendor for central reading. 
The overview of the assessment criteria and read procedures used by the echocardiography 
vendor will be described in a charter. 
Central echocardiography reports will be provided by the central echocardiography vendor 
to the investigator/delegate. In the event of specific echocardiography abnormalities, the 
central echocardiography vendor will alert the sponsor and the site personnel. All 
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echocardiography reports must be reviewed, signed, and dated by the investigator/delegate 
within 10 working days of receipt and filed with the source documentation.  
Incidental clinically relevant findings on echocardiographies will be reported in the 
Medical History or as an AE in the eCRF, as applicable. 
The measures/assessments evaluated by the central echocardiography vendor include but 
are not limited to: 
• LVMI for height2.7 (g/m2.7); 
• Posterior wall thickness (mm); 
• Left ventricular mean wall thickness (mm); 
• LVEF (%); 
• Left ventricular end diastolic volume (mL); 
• Left ventricular end systolic volume (mL); 
• Left atrial volume (mL). 
Details on echocardiography procedures (recording, transfer of data and reporting) will be 
provided in the echocardiography manual. 
7.2.2.8 Exit interview (US and Canada) 
English-speaking subjects in US and Canada will be contacted by an external CRO to set 
an interview as soon as possible after the end of study treatment phase or EOT visit, ideally 
within 2 weeks. The interviews will be conducted via telephone by qualified staff from the 
CRO following the semi-structured interview guide (“Discussion Guide for the Exit 
Interview”). The interviews will take approximately 45 minutes and will be audio-recorded 
and then transcribed; the audio files and transcripts will be de-identified and securely 
transferred to the sponsor by the CRO.  
The purpose of exit interviews is to further explore what constitutes meaningful changes 
on the neuropathic pain (assess with modified BPI-SF3) and GI symptom (diarrhea and 
abdominal pain) questions from a subject’s perspective. Subjects will also be asked about 
meaningful change on the PGIC and PGIS questions.  
Further details are provided in the separate documents “Exit interview sub-study protocol” 
and “Discussion Guide for the Exit Interview”. After the first 5 interviews are completed, 
the CRO staff will meet with the sponsor to review the de-identified data, discuss the 
findings at that stage, and adjust the interview process, if needed. 
The interviews will be analyzed and interpreted by the CRO and reported in a separate 
report. 
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7.2.3 Safety assessments 
The definitions, reporting and follow-up of AEs/SAEs and pregnancies are described in 
Section 9. 
Unless otherwise specified, the date of each safety assessment will be collected in the 
eCRF. 
7.2.3.1 Physical examination 
Physical examination at screening includes the examination of the general appearance 
(heart, lungs, abdomen, skin, extremities, eyes, ears, nose, throat, lymph nodes, nervous 
system, etc.). At subsequent visits, physical examination includes, as a minimum, the 
examination of skin, heart, lungs, eyes, and ears. 
Each physical examination must include a complete skin examination performed by the 
investigator/delegate. In the event of findings other than regular skin findings relevant to 
FD (e.g., angiokeratoma, hyperkeratosis), a dermatologist will conduct further examination 
per local standard practice, including performing skin biopsies if required to rule out or 
confirm a diagnosis. 
Other examinations will be performed if indicated, based on medical history and/or 
symptoms. 
Information for all physical examinations must be included in the source documentation at 
the study site.  
The physical examination will be reported in the eCRF as either normal or abnormal; in 
the latter case, the investigator should specify whether it is clinically relevant. Clinically 
relevant physical abnormalities present at the time of signing of the ICF must be reported 
on the medical history or Fabry disease forms of the eCRF. Physical examination findings, 
which meet the definition of an AE [Section 9.1.1] and are made after signing of the ICF, 
must be recorded on the AE form of the eCRF. 
7.2.3.2 Vital signs 
HR, SBP, and DBP will be measured at each visit in a supine or sitting position and 
recorded in the eCRF. It is recommended to allow the subject to rest for at least 5 minutes, 
and to use the same arm and position (supine or sitting) throughout the study for an 
individual subject. 
The date and exact actual clock time of vital sign assessments will be entered in the eCRF. 
7.2.3.3 Weight and height 
Height will be measured without shoes at screening.  
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Body weight will be measured in indoor clothing but without shoes at screening and each 
visit thereafter.  
Body weight and height data will be recorded in the eCRF. 
7.2.3.4 Electrocardiogram assessment 
A standard pre-dose 12-lead ECG will be performed at all scheduled visits. At the Month 1 
visit, 2 additional 12-lead ECGs will be performed 2 h and 4 h after study treatment 
administration. 
A re-test may be performed if the result for an ECG is missing or to repeat an abnormal 
ECG. A re-test does not need to be reported as an unscheduled visit see Section 7.1.2. 
ECGs will be performed with the subject in a fully rested supine position after the subject 
has been allowed to rest for a minimum of 5 minutes prior to the measurement. The date 
and exact clock time of ECGs will be entered in the eCRF. 
A central ECG vendor (see ECG manual for contact details) will be used for the evaluation 
of all protocol-mandated ECGs, including re-tests due to ECG abnormalities and ECGs 
performed at unscheduled visits. The site personnel will electronically transmit the ECGs 
to the central ECG vendor for central reading. 
The following variables will be evaluated by the central ECG vendor: HR (bpm), PR (ms), 
QRS (ms), QT (ms), QTc according to Bazett’s formula (QTcB) (ms), QTcF (ms) and any 
ECG findings. QTc (ms) will be calculated according to Bazett’s and Fridericia’s formula 
(QTcB = QT/[RR]½ and QTcF = QT/[RR]⅓, respectively). 
ECG reports will be provided by the central ECG vendor to the investigator/delegate. 
If specific (pre-defined in the ECG manual) ECG abnormalities are observed, the central 
ECG vendor will alert the sponsor and the site personnel. 
All ECG reports must be reviewed, signed and dated by the investigator or delegate within 
10 working days of receipt and filed with the source documentation. The 
investigator/delegate must indicate on the ECG report whether abnormal values or findings 
are considered clinically relevant or not. Clinically relevant ECG findings that are known 
at the time of signing of the ICF must be recorded in the medical history or FD forms of 
the eCRF. Any clinically relevant ECG abnormalities detected after signing of the ICF 
must be reported as an AE or SAE as appropriate [see Section 9], and must be followed 
until the finding returns to normal, is considered stable, or until the change is no longer 
clinically relevant. 
Details on ECG procedures (recording, transfer of data and reporting) will be provided in 
the ECG manual. 
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7.2.4 Laboratory assessments 
7.2.4.1 Type of laboratory 
A central laboratory (see laboratory manual for contact details) will be used for all 
protocol-mandated laboratory tests (with the exception of urine pregnancy tests), including 
re-tests due to laboratory abnormalities and laboratory tests performed at unscheduled 
visits. 
Local laboratory results of the parameters described in Section 7.2.4.2 will only be 
collected in exceptional circumstances (e.g., hospitalization of the subject due to a medical 
emergency, and missing central laboratory results from a scheduled or unscheduled visit). 
The local laboratory results (with the corresponding normal ranges) must be recorded in 
the eCRF. 
If two or more consecutive central laboratory samples are lost or cannot be analyzed for 
whatever reason, the investigator will collect an additional sample as soon as possible to 
repeat the analysis, unless a local laboratory sample was collected within the same 
time-window and these test results are available. 
Laboratory reports will be provided by the central laboratory to the investigator/delegate. 
In the event of specific (pre-defined in the laboratory manual) laboratory abnormalities, the 
central laboratory will alert the sponsor and the site personnel.  
All laboratory reports must be reviewed, signed and dated by the investigator/delegate 
within 10 working days of receipt and filed with the source documentation. 
A re-test may be performed if the laboratory result is missing or to repeat an abnormal 
laboratory result. A re-test does not need to be reported as an unscheduled visit see 
Section 7.1.2.  
The investigator/delegate must indicate on the laboratory report whether abnormal values 
are considered clinically relevant or not. Clinically relevant laboratory findings that are 
known at the time of signing of the ICF must be recorded in the medical history or FD 
forms of the eCRF. Any clinically relevant laboratory abnormalities as per investigator 
judgment detected after signing of the ICF must be reported as an AE or SAE as appropriate 
[see Section 9], and must be followed until the value returns to within the normal range or 
is considered stable and no longer clinically relevant. 
Details about the collection, sampling, storage, shipment procedures, and reporting of 
results and abnormal findings can be found in the laboratory manual. 
7.2.4.2 Laboratory tests 
Unless otherwise specified, the date of each laboratory sample will be collected in the 
eCRF. 
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7.2.4.2.1 Blood tests 
Blood samples will be drawn under fastedb condition (i.e., skipping breakfast) and when 
applicable before the morning administration of the study treatment at all scheduled and 
unscheduled visits. 
Hematology: 
• Hemoglobin (g/L); 
• Hematocrit (%); 
• Erythrocyte count (reticulocyte count) (1012/L); 
• Leukocyte count with differential counts (109/L); 
• Platelet count (109/L). 
Blood chemistry: 
• ALT (U/L), AST (U/L), alkaline phosphatase (U/L); 
• Total and direct bilirubin (μmol/L); 
• Creatinine (μmol/L) measured using an enzymatic assay; 
• eGFR* (mL/min/1.73 m2); 
• Blood urea nitrogen (mmol/L); 
• Uric acid (μmol/L); 
• Albumin (g/L), protein total (g/L); 
• Glucose (mmol/L), HbA1c (%); 
• Cholesterol (mmol/L), triglycerides (mmol/L); 
• Sodium, potassium, chloride, calcium (mmol/L); 
• N-terminal pro-brain natriuretic peptide (ng/L). 
*eGFR will be estimated using the CKD-EPIcreatinine equation Levey 2009 as follows: 
eGFRcreatinine = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 (if female) × 
1.159 (if black)  
where: 
Scr = serum creatinine in mg/dL  
κ = 0.7 for females, κ = 0.9 for males,  
                                                 
b Subjects must not be requested to be in a fasted state (for the purpose of the study) at the screening visit unless the ICF 
has already been fully signed. 
 
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α = −0.329 for females, α = −0.411 for males,  
min = the minimum of Scr /κ or 1, max = the maximum of Scr /κ or 1 
Cardiac enzymes: 
• High sensitivity troponin T (μg/L). 
-Galactosidase A: 
An extra blood sample will be collected at the screening visit and randomization visit to 
assess the -GalA in leukocytes (nmol/h/mg of protein). The samples will be shipped to 
the central laboratory for analysis. 
7.2.4.2.2 Urinalysis 
A midstream, clean-catch urine specimen will be collected for dipstick analysis and 
determination of creatinine (μmol/L), albumin (mg/L), UACR (mg/g) at all scheduled and 
unscheduled visits. The collected urine will be transferred into standard urine collection 
tube for shipment to central laboratory. 
7.2.4.2.3 Pregnancy tests 
A serum pregnancy test for women of childbearing potential will be performed at 
screening. A urine pregnancy test will be performed at randomization and monthly 
thereafter with locally approved kits provided by the site. If pregnancy is suspected during 
the study, a serum pregnancy test must be performed immediately.  
The results of the urine pregnancy tests will not be collected in the eCRF. Serum pregnancy 
tests will be sent to the central lab for analysis and the result will be sent to the 
investigator/delegate (see laboratory manual for details on collection, sampling, storage, 
shipment procedures, and reporting of results). 
Reporting procedures of pregnancy are described in Section 9.4.1.  
7.2.4.2.4 Fecal analyses 
A fecal sample will be collected at the screening visit in subjects who report diarrhea 
symptoms to assess subject eligibility (exclusion criteria #8b, see Section 4.4). 
If no stool is available on the day of the screening visit, the subject will be provided with 
collection material and instructed by the site personnel how to collect, store and ship a stool 
sample. The subject will record the date and time at which the sample was produced.  
The collected fecal samples will be transferred by the study personnel as described in the 
laboratory manual and study specific laboratory flowchart. 
Stool exam will include calprotectin test, fecal occult blood test, stool culture, and test for 
ova and parasites. 
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7.2.5 Quality of life assessments 
7.2.5.1 36-Item Short Form Health Survey Version 2  
The SF-36v2 questionnaire (SF-36v2 Health Survey 1996, 2000 by Medical 
Outcomes Trust and Quality Metric Incorporated) is used to assess the subject’s QoL. The 
SF-36v2 will be completed by the subject at the randomization visit and Month 6 
(Month 6 PTOP visit if subject is in the PTOP). using the eDiary see Section 7.2.2.1.  
In the SF-36v2 questionnaire, subjects are instructed to rate their health and capacity to 
perform activities of daily living in 8 domains including physical functioning, physical role 
limitations and mental health during the last 4 weeks. Raw domain scores are determined 
and transformed to a 0–100 scale as described in the SF-36v2 manual [Maruish 2011]. 
Individual domain scores are used to determine the physical and mental component 
summary scores as described in the SF-36v2 manual [Maruish 2011]. 
A sample of the SF-36v2 (in English) is provided in Appendix 6.  
The sponsor has been granted a license agreement for the use of the SF-36v2 
questionnaire. The individual questionnaires will be completed only in countries for which 
validated translations are available. 
7.2.6 Pharmacokinetic assessments 
7.2.6.1 Pharmacokinetic assessments 
Pre-dose blood samples for determination of PK will be collected for all subjects at the 
Month 1 visit and all subsequent visits to provide information about the study treatment 
exposure in the target population. 
In addition, post-dose (0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 6 h, 8 h, 10 h, and 12 h) 
blood samples will be collected at the Month 1 visit in a subset of 36 subjects to explore 
the 12 h PK profile of lucerastat and if necessary, to identify its potential metabolites.  
7.2.6.2 Sampling, labeling, storage and shipment 
The date and exact actual clock time of collection of each blood sample will be entered in 
the eCRF as well as the exact dates and time of the study treatment administration prior to 
and after blood draw. 
Details about the collection, sampling, storage, and shipment procedures can be found in 
the laboratory manual. 
7.2.6.3 Bioanalysis 
The analysis of lucerastat and if needed, possible metabolites in plasma will be performed 
using a validated liquid chromatography coupled to tandem mass spectrometry assay. 
The foreseen limit of quantification of lucerastat is 50 ng/mL. 
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The analysis of lucerastat and, if needed, its possible metabolites in plasma will be 
performed by the Idorsia bioanalytical laboratory. To minimize the possibility of 
systematic unblinding, the values of the PK parameters will not be communicated to the 
investigator and study personnel, subjects, CRAs, and sponsor and vendor/CRO personnel 
involved in the conduct of the study until the study database is locked.  
The samples will be destroyed upon signature of the CSR and if applicable, the metabolite 
profiling report. 
7.2.7 Biomarker assessments 
7.2.7.1 Biomarkers of Fabry disease and their metabolic precursors 
Plasma and urinary samples for analysis of biomarkers of FD and their metabolic 
precursors will be collected at all scheduled visits (pre-dose). The date and exact actual 
clock time of collection of each blood sample and urine sample will be entered in the eCRF. 
Gb3 and lysoGb3, along with the Gb3 metabolic precursors GlcCer and LacCer will be 
quantified in plasma. Gb3 and lysoGb3 will be quantified in urine and normalized to 
creatinine.  
A central laboratory (see laboratory manual for contact details) will be used for all 
protocol-mandated biomarker assessments. To minimize the possibility for systematic 
unblinding, biomarker laboratory results will not be communicated to investigator and 
study personnel, the subjects, CRAs, and any sponsor personnel and vendor/CRO 
personnel involved in the conduct of the study until the study database is locked.  
7.2.7.2 Other non-genetic research samples  
Extra plasma, serum and urine samples will be collected at trough at the randomization 
visit, Month 6 visit or EOT visit for additional non-genetic analyses including analysis of 
biomarkers that characterize FD or FD treatment characteristics (e.g., measurement of 
levels of antibodies against ERT, other analysis may be added after study closure, if 
scientific rationale has become available through new research). Those samples may be 
stored in the sponsor’s research biorepository for a maximum of 15 years. 
Study participants may request these samples be destroyed at any time. 
No genetic analysis will be conducted. 
Details about the collection, sampling, storage and shipment procedures can be found in 
the laboratory manual. 
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8 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
8.1 Study completion as per protocol  
Subjects who complete the 6-month, double-blind study treatment period, and if applicable 
FU1 and FU2, are considered to have completed the study as per protocol. 
8.2 Premature withdrawal from study  
Subjects may voluntarily withdraw from the study without justification for any reason at 
any time. Subjects are considered withdrawn if they state an intention to withdraw further 
participation in all components of the study (i.e., withdrawal of consent), die, or are lost to 
follow-up. If a subject withdraws consent, no further data will be collected in the eCRF 
from the date of withdrawal onward. The investigator may withdraw a subject from the 
study (without regard to the subject’s consent) if, on balance, he/she believes that continued 
participation in the study would be contrary to the best interests of the subject. Withdrawal 
from the study may also result from a decision by the sponsor for any reason, including 
premature termination or suspension of the study. 
Subjects are considered as lost to follow-up if all repeated attempts by the investigator to 
communicate with the individual have failed. The site must take preventive measures to 
avoid a subject being lost to follow-up (e.g., document different ways of contact such as 
telephone number, home address, email address, person to be contacted if the subject 
cannot be reached). If the subject cannot be reached, the site must make reasonable repeated 
efforts to contact the subject, document all attempts (date, time and type of contact made), 
and enter the loss of follow-up information into the eCRF. The following methods must be 
used: at least 3 contacts (e.g., telephone calls, or e-mails) must be placed to the last 
available telephone number or e-mail address) and 1 registered letter must be sent by post 
to the last available home address. Additional methods may be acceptable if they are 
compliant with local rules/regulations (e.g., a visit by site personnel to the subject’s home), 
respecting the subject’s right to privacy. If the subject is still unreachable after all contact 
attempts listed above he/she will be considered to be lost to follow-up. 
The reason for premature withdrawal from the study must be recorded in the eCRF. 
If for whatever reason (except death or loss-to-follow-up) a subject is withdrawn from the 
study, the investigator should make best efforts to schedule a last appointment / telephone 
call to assess the safety and well-being of the subject, collect unused study treatment and 
discuss follow-up medical care. Data obtained during this last appointment / telephone call 
will be recorded in the subjects’ medical records but it will not be collected in the eCRF. 
The investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care, as described 
in Section 8.4. 
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8.3 Premature termination or suspension of the study 
The sponsor reserves the right to terminate the study at any time globally or locally. 
Investigators can terminate the participation of their site in the study at any time. 
If a study is prematurely suspended or terminated, the sponsor will promptly inform the 
investigators, the IECs/IRBs, and health authorities, as appropriate, and provide the reasons 
for the suspension or termination. 
If the study is suspended or prematurely terminated for any reason, the investigator — in 
agreement with the sponsor — must promptly inform all enrolled subjects and ensure their 
appropriate treatment and follow-up, as described in Section 8.4. The sponsor may inform 
the investigator of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subjects’ interests. 
In addition, if the investigator suspends or terminates a study without prior agreement from 
the sponsor, the investigator must promptly inform the sponsor personnel and the IEC/IRB, 
and provide both with a detailed written explanation of the termination or suspension. 
If the IEC/IRB suspends or terminates its approval / favorable opinion of a study, the 
investigator must promptly notify the sponsor personnel and provide a detailed written 
explanation of the termination or suspension. 
8.4 Medical care of subjects after study completion / withdrawal from study 
After the subject’s study completion or premature withdrawal from the study, whichever 
applies, the investigator/delegate will explain to subjects what treatment(s) / medical care 
is necessary and available according to local medical practice and applicable guidelines. 
Such care may include: 
• Use of drugs which were forbidden during concomitant study treatment administration; 
• Enrollment in the OLE of this study conducted under a separate protocol, only for those 
subjects who have completed the 6-month double-blind treatment period, providing 
they fulfill the specific eligibility criteria of this separate study. 
Female subjects of childbearing potential and fertile male subjects will be reminded of the 
contraception requirements as described in Section 4.5 and 4.6, respectively. 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 Safety definitions 
9.1.1 Definition of adverse events  
An AE is any untoward medical occurrence, i.e., any unfavorable and unintended sign, 
including an abnormal laboratory finding, symptom, or disease that occurs in a subject 
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during the course of the study, whether or not considered by the investigator as related to 
study treatment. 
AEs include: 
• Exacerbation of a pre-existing disease if considered medically relevant. The evolution 
of the FD disease condition including worsening of symptoms (e.g., neuropathic pain, 
GI symptoms) will be evaluated and reported as AE only if considered medically 
significant based on investigator judgment; 
• Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition; 
• Disease or medical condition detected or diagnosed during the course of the study even 
though it may have been present prior to the start of the study; 
• Continuous persistent disease or symptoms present at study start that worsen following 
the signing of the ICF; 
• Abnormal change on physical examination, ECG findings, if they represent a clinically 
significant finding that was not present at study start or worsened during the course of 
the study as per investigator medical assessment; 
• Laboratory test abnormalities if they represent a clinically significant finding 
(symptomatic or not) which was not present at study start or worsened during the course 
of the study as per investigator judgment, led to dose reduction, interruption or 
permanent discontinuation of study treatment. 
9.1.2 Definition of serious adverse events 
An SAE is defined by the ICH guidelines as any AE fulfilling at least 1 of the following 
criteria: 
• Fatal; 
• Life-threatening: 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 that hypothetically might have caused death 
had it been more severe; 
• Requiring in-patient hospitalization or prolongation of existing hospitalization; 
• Resulting in persistent or significant disability or incapacity; 
• Congenital anomaly or birth defect; 
• Medically significant: refers to important medical events that may not immediately 
result in death, be life-threatening, or require hospitalization but may be considered 
medically significant based upon appropriate medical judgment, as they may 
jeopardize the subject, and/or may require medical or surgical intervention to prevent 
one of the outcomes listed in the definitions above. 
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The following reasons for hospitalization are not considered as SAEs: 
• Hospitalization for cosmetic elective surgery, or social and/or convenience reasons; 
• Hospitalization for pre-planned (i.e., planned prior to signing ICF) surgery or standard 
monitoring of a pre-existing disease or medical condition that did not worsen, e.g., 
hospitalization for coronary angiography in a subject with stable angina pectoris. 
However, complications that occur during hospitalization are AEs or SAEs (e.g., if a 
complication prolongs hospitalization). 
9.1.3 Definition of suspected unexpected serious adverse reactions 
The expectedness of an SAE is determined by the sponsor according to the reference safety 
information (RSI) section provided in the most recent version of the IB.  
Any SAE that is assessed as related and unexpected against the RSI is known as a SUSAR. 
9.1.4 Intensity of adverse events 
The intensity of AEs is graded on a three-point scale — mild, moderate, severe — as 
follows: 
❑ Mild 
The event may be noticeable to the subject. It does not usually influence daily activities, 
and normally does not require intervention. 
❑ Moderate 
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 
❑ Severe 
The event may cause noticeable discomfort and usually interferes with daily activities. The 
subject may not be able to continue in the study, and treatment or intervention is usually 
needed. 
A mild, moderate, or severe AE may or may not be serious [see Section 9.1.2]. These terms 
are used to describe the intensity of a specific event. Medical judgment should be used on 
a case-by-case basis. 
Seriousness, rather than intensity assessment, determines the regulatory reporting 
obligations see Section 9.3.2. 
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9.1.5 Relationship to study treatment  
Each AE/SAE must be assessed by the investigator as to whether or not there is a 
reasonable possibility of causal relationship to the study treatment, and reported as either 
related or unrelated.  
9.1.6 Relationship to protocol-mandated procedure  
An AE/SAE is defined as related to protocol-mandated procedure if it appears to have a 
reasonable possibility of a causal relationship to either the study design or to a 
protocol-mandated procedure. 
The determination of the likelihood that a protocol mandated procedure caused the 
AE/SAE will be provided by the investigator. 
9.2 Time period and frequency for adverse event / serious adverse event 
assessment and follow-up 
The occurrence of an AE/SAE may come to the attention of study personnel during study 
visits, telephone calls or interviews of study participants presenting for medical care.  
At each study visit (scheduled or unscheduled), the investigator will inquire about the 
occurrence of AE/SAEs since the last visit. 
9.2.1 Follow-up of adverse events  
AEs still ongoing at the EOS visit must be followed up until resolution, are no longer 
considered clinically relevant or until stabilization.  
9.2.2 Follow-up of serious adverse events 
SAEs still ongoing at the EOS visit must be followed up until resolution, stabilization, or 
until the event outcome is provided.  
9.3 Reporting procedures 
9.3.1 Reporting of adverse events  
All AEs with an onset date after signing of the ICF and up to 30 days after study treatment 
discontinuation or up to the last visit of the PTOP period (whichever is the latest) must be 
recorded on specific AE forms of the eCRF.  
Information to be collected in an AE form in the eCRF includes date of onset, action taken 
with the study treatment, outcome of AE, date of resolution (if applicable) and PI’s 
assessment of intensity, and relationship to study treatment, study design or protocol 
mandated procedures. 
Information on worsening of intensity will be collected on a new AE form. If the AE 
lessens in intensity, no change in the severity is required to be reported. 
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Follow-up information on ongoing AE obtained after the subject’s EOS visit will not be 
collected in the eCRF. 
9.3.2 Additional reporting procedure for serious adverse events 
All SAEs must be reported by the investigator to the sponsor’s Global Drug Safety 
department within 24 hours of the investigator’s first knowledge of the event. 
All SAEs occurring after signing of the ICF up to 30 days after study treatment 
discontinuation or up to the last visit of the PTOP period (whichever is the latest) must be 
recorded on an SAE form, regardless of the investigator-attributed causal relationship with 
study treatment or study-mandated procedures. 
The SAE forms must be sent to the sponsor’s Global Drug Safety department (see contact 
details on the SAE form). The investigator must complete the SAE form in English, and 
must assess the event’s causal relationship to the study treatment. 
Any relevant information from source documents regarding the SAE, e.g., hospital notes 
or discharge summaries, etc., must be summarized on the SAE form. 
Follow-up information about a previously reported SAE must also be reported within 
24 hours of receiving it. The sponsor’s Global Drug Safety personnel may contact the 
investigator to obtain further information. 
If the subject is hospitalized in a hospital other than that of the study site, it is the 
investigator’s responsibility to contact this hospital to obtain all SAE-relevant information 
and documentation. 
New SAEs occurring after the 30-day follow-up period or after the last visit of the PTOP 
period (whichever is the latest) must be reported to the sponsor’s Global Drug Safety 
department within 24 hours of the investigator’s knowledge of the event, only if considered 
by the investigator to be causally related to previous exposure to the study treatment. 
9.4 Pregnancy  
If a woman becomes pregnant while on study treatment, study treatment must be 
discontinued [see Section 5.1.10.1.  
The investigator must counsel the subject and discuss the risks of continuing with the 
pregnancy and the possible effects on the fetus. 
9.4.1 Reporting of pregnancy 
Any pregnancy occurring in a female subject after signing of the ICF and up to 30 days 
following study treatment discontinuation must be reported to the sponsor’s Global Drug 
Safety department within 24 hours of the investigator’s knowledge of the event. 
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Any pregnancy occurring in the female partner of a male subject during the treatment 
period and up to the EOS visit or FU2 visit (whichever is first) must be reported to the 
sponsor’s Global Drug Safety department within 24 hours of the investigator’s knowledge 
of the event.  
Pregnancies must be reported on the sponsor Pregnancy form, which is faxed to the 
sponsor’s Global Drug Safety department (see contact details provided on the Pregnancy 
form). 
The investigator must complete the Pregnancy form in English. 
9.4.2 Follow-up of pregnancy 
Any pregnancies must be followed-up to their conclusion and the outcome must be reported 
to the sponsor’s Global Drug Safety department.  
Any AE associated pregnancy of a female subject occurring up to the EOS visit must be 
reported on separate AE forms in the eCRF.  
Any SAE occurring during the pregnancy must be reported on an SAE form as described 
in Section 9.3.2. 
9.5 Reporting of study treatment overdose, misuse, abuse and medication 
errors 
Study treatment overdose (defined as higher than the dose of study treatment prescribed), 
and study treatment errors will be reported as an AE when associated with signs or 
symptoms. 
In addition, study treatment errors must be documented in the study drug log of the eCRF. 
Misuse and abuse of the study treatment will be reported as an AE/SAE as determined. 
9.6 Study safety monitoring  
Study safety information (AEs, SAEs, laboratory values, ECGs, vital signs, and 
study-specific examinations as required) is monitored and reviewed on a continuous basis 
by the sponsor (in charge of ensuring subjects’ safety as well as data quality).  
The sponsor may request additional data pertaining to the diagnostic work-up of an AE or 
SAE (e.g., medical imaging, local laboratory values) for the purpose of monitoring safety. 
Such additional data may be shared with external experts. 
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10 STATISTICAL METHODS 
10.1 Analysis sets 
10.1.1 Screened Analysis Set 
The Screened Analysis Set includes all subjects who have given informed consent to 
participate in the study and have a subject number. 
10.1.2 Full Analysis Set 
The Full Analysis Set (FAS) includes all subjects randomized to either lucerastat or 
placebo. In order to adhere to the intent-to-treat principle as much as possible: 
• Subjects will be evaluated according to their assigned study treatment (not actual 
treatment received) and stratum information as recorded in the IRT system; 
• Unless otherwise stated, all available efficacy data for the primary and secondary 
endpoints will be included in the analyses up to the planned analysis time point, 
regardless of study treatment discontinuation and/or switches to alternative FD 
treatments. 
10.1.3 Modified Full Analysis Set 
A modified FAS (mFAS) will be defined by including subjects from the FAS who took at 
least one dose of study treatment. As in the FAS, subjects will be analyzed based on the 
assigned study treatment. 
10.1.4 Modified Full Analysis Set-gastrointestinal symptoms 
The mFAS-gastrointestinal symptoms (mFAS-GIS) comprises all subjects from the mFAS 
who, during the 4 weeks prior to randomization, have experienced: 
• Abdominal pain of moderate to severe intensity at baseline defined as an average 
abdominal pain intensity score ≥ 3 on a NRS-11 scale; and/or 
• Diarrhea at baseline defined as having at least 1 stool of a BSS consistency Type 6 or 
7 on at least 8 days. 
10.1.5 Per-Protocol Analysis Set 
The Per-Protocol Analysis Set (PPS) includes all subjects from the mFAS without protocol 
deviations occurring prior to Month 6, which could affect the analysis of the primary 
endpoint variable.  
The precise reasons for excluding subjects from the PPS will be fully defined and 
documented in the statistical analysis plan (SAP) before breaking the randomization blind. 
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10.1.6 Safety Set 
The Safety Set (SAF) includes all subjects who received at least 1 dose of study treatment 
(as recorded in the eCRF). Subjects will be analyzed based on the treatment received. In 
the situation of accidental dispensation of both study treatments to the same subject, the 
subject will be counted as on lucerastat for the whole study. 
10.1.7 Other analysis sets 
Other analysis datasets will be defined in the SAP (or corresponding SAPs), e.g., PK set, 
sub-study sets, and subgroups of interest. 
10.1.8 Usage of the analysis sets 
The mFAS and the PPS are used for the analysis of the primary and secondary endpoint 
related to Gb3. Results based on the PPS will supplement those based on the mFAS to 
assess the robustness of the treatment effect. The primary and secondary endpoint analyses 
will also be produced on the FAS as sensitivity analyses if the FAS and mFAS differ by at 
least 5 subjects (approximately 5% of the total sample size).  
The secondary endpoints related to abdominal pain and diarrhea will be assessed on the 
mFAS-GIS. 
All safety data will be analyzed using the SAF. 
The usage of other analysis sets will be described in the SAP. 
10.2 Variables 
In this section, variables are defined in detail for the primary and secondary efficacy 
endpoints and for the safety endpoints. All variables for all other endpoints will be defined 
in detail in the SAP. 
10.2.1 Primary efficacy variable 
Baseline and Month 6 modified BPI-SF3 scores will be obtained by averaging the weekly 
modified BPI-SF3 scores over the 4 weeks prior to the corresponding visit of interest 
(randomization visit and Month 6 visit, respectively). At least 4 of the 7 daily scores should 
be non-missing to derive a valid weekly modified BPI-SF3 score and at least 3 valid weekly 
scores should be non-missing to derive a valid score for the relevant time period. 
All available daily scores will be used to derive the scores regardless of study treatment 
discontinuations or introductions of new medications. 
In addition, intermediate monthly modified BPI-SF3 scores from Month 1 to Month 5 will 
be derived with the same validity conditions. The selection of daily scores over 4 weeks 
for these time points will be described in the SAP. 
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10.2.2 Secondary efficacy variables 
The following 3 secondary efficacy endpoint variables are considered:  
• Change from baseline to Month 6 in the NRS-11 score of “abdominal pain at its worst 
in the last 24 hours” in subjects with GI symptoms at baseline; 
• Change from baseline to Month 6 in the number of days with at least 1 stool of a BSS 
consistency Type 6 or 7 in subjects with GI symptoms at baseline; 
• Change from baseline to Month 6 in plasma Gb3. 
10.2.2.1 Change from baseline to Month 6 in the 11-point numerical rating scale score 
of “abdominal pain at its worst in the last 24 hours” in subjects with 
gastrointestinal symptoms at baseline 
Using the abdominal pain intensity scores collected daily, the variable “change from 
baseline to Month 6 in the NRS-11 score of “abdominal pain at its worst in the last 24 
hours” will be derived using the same rules as those described for the primary efficacy 
variable [see Section 10.2.1]. The variable will be derived only for those subjects with GI 
symptoms at baseline as defined in Section 10.1.4. 
10.2.2.2 Change from baseline to Month 6 in the number of days with at least 1 stool of 
a Bristol Stool Scale consistency Type 6 or 7 in subjects with gastrointestinal 
symptoms at baseline 
Using the number of complete stool bowel movements with BSS consistency of Type 6 or 
7 collected daily, the variable “change from baseline to Month 6 in the number of days 
with at least one stool of a BSS consistency Type 6 or 7” will be derived using the following 
rules: 
The number of days with diarrhea at baseline and Month 6 will be calculated as the number 
of days observed with diarrhea over the 4 weeks prior to the corresponding visit of interest 
(randomization and Month 6, respectively) over the number of days with data available 
multiplied by 28, provided there are at least 21 measures available in the corresponding 
time period. 
The variable will be derived only for those subjects with GI symptoms at baseline as 
defined in Section 10.1.4.  
All available data will be used to derive the number of days with diarrhea regardless of 
study treatment discontinuations. In addition, the intermediate number of days with 
diarrhea from Month 1 to Month 5 will be derived with the same validity conditions. The 
selection of daily scores over 4 weeks for these time points will be described in the SAP. 
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10.2.2.3 Change from baseline to Month 6 in plasma globotriaosylceramide 
Using the plasma Gb3 data collected at baseline and Month 6, the variable “change from 
baseline to Month 6 in Gb3” will be calculated as follows: 
(Gb3 at Month 6 – Gb3 at baseline). 
10.2.3 Safety variables 
The variables described in this section are to be used for the derivation of the safety 
endpoints described in Section 6.2. 
Treatment-emergent laboratory values, vital signs or AEs are those with an assessment or 
onset date/time ≥ start date/time of study treatment and ≤ 30 days after study treatment 
discontinuation. 
Abnormalities for laboratory, vital signs and ECGs will be defined in the SAP. 
Laboratory analyses are based on data received from the central laboratory as well as local 
laboratories.  
All laboratory, vital signs and ECG data are taken into account regardless of whether they 
correspond to scheduled or unscheduled assessments. 
10.3 Description of statistical analyses 
All available data for each subject will be used in all statistical analyses unless otherwise 
specified.  
10.3.1 Overall testing strategy 
Comparisons of lucerastat vs placebo will be conducted for the primary and secondary 
endpoints assessed at Month 6. 
The Type I error rate will be controlled at a two-sided alpha of 5% for the testing of the 
four null hypotheses associated with the primary and secondary endpoint comparisons 
employing a fixed-sequence statistical testing strategy in the following order: 
1. 
Change from baseline to Month 6 in the “modified” BPI-SF3 score of “neuropathic 
pain at its worst in the last 24 hours”. 
2. 
Change from baseline to Month 6 in plasma Gb3. 
3. 
Change from baseline to Month 6 in the NRS-11 score of “abdominal pain at its worst 
in the last 24 hours” in subjects with GI symptoms at baseline; 
4. 
Change from baseline to Month 6 in the number of days with at least one stool of a 
BSS consistency Type 6 or 7 in subjects with GI symptoms at baseline. 
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The order of the fixed-sequence statistical testing strategy is depicted in Figure 2. In the 
event that the null hypothesis is not rejected for an endpoint in the sequence, claims for 
statistical significance cannot be made for endpoints that follow in the sequence. 
Figure 2 
Fixed-sequence statistical testing strategy 
 
The primary hypothesis related to H1 is initially assigned the local two-sided statistical 
significance level alpha = 0.05, whereas H2a through H2c from the secondary family of 
endpoints are assigned the local statistical significance level 0. If H1 is rejected, the local 
statistical significance level α is passed on to H2a and so on as long as hypotheses are 
rejected. 
10.3.2 Analysis of the primary efficacy variable 
10.3.2.1 Hypotheses 
Hypotheses for the primary endpoint are formulated in terms of the mean differences in 
change from baseline to Month 6. 
H0: Lucerastat - Placebo = 0 
is the null hypothesis that there is no difference between treatments. 
HA: Lucerastat - Placebo ≠ 0 
is the alternative hypothesis that a difference in change from baseline to Month 6 exists 
between treatments. 
The hypotheses for the secondary endpoints related to abdominal pain and plasma Gb3 are 
defined in the same way. 
The null hypothesis for the secondary endpoint related to stool consistency is that both 
groups are from identical distributions while the alternative hypothesis is that the 
distributions differ with respect to location. 
10.3.2.2 Primary statistical analysis 
The primary statistical analysis will be performed on the mFAS, according to the 
intent-to-treat approach. All available data will be used regardless of occurrence of ICEs 
such as premature treatment discontinuation or changes in background medication. 
H1
Neuropathic 
pain
a=0.05
H2a
Gb3
0
H2b
Abdominal 
pain
0
H2c
Stool 
consistency
0
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The null hypothesis will be tested at the two-sided alpha level = 0.05, using the following 
method: 
Missing data will be imputed applying a control-based multiple imputation (MI) assuming 
MNAR using the Copy Reference (CR) approach [Carpenter 2013]. Instead of imputing a 
single value for each missing observation, a set of values is generated from the model, 
resulting in as many distinct complete datasets without missing data. The imputation model 
includes the baseline value, the two stratification factors (sex and ERT treatment status at 
screening) and all post-baseline monthly scores up to Month 6. Missing data for subjects 
from both treatment arms will be imputed using data from the placebo arm. This approach 
assumes that subjects with missing data in the lucerastat arm have outcomes trending 
towards outcomes observed in the placebo arm, i.e., the imputations result in a treatment 
effect that gradually diminishes towards the placebo arm. 
An analysis of covariance (ANCOVA) model will be used to analyze this endpoint on each 
imputed dataset. The following terms will be included in the model: baseline value, the two 
stratification factors (sex and ERT treatment status at screening), and the treatment group. 
Uncertainty in the imputations will be reflected appropriately in the analysis by combining 
the results on each imputed dataset using Rubin’s methodology [Rubin 1987]. 
The mean difference in changes from baseline to Month 6 between lucerastat and placebo 
together with its two-sided 95% CI and p-value will be reported. 
10.3.2.3 Handling of missing data  
Some missing data may occur in the daily measurements, possibly translating into missing 
monthly scores. In the next sections “missing data” will refer to missing monthly modified 
BPI-SF3 scores. 
The missing data will be described via: 
• Visual inspection of missing data patterns; 
• Characterization of missing data patterns according to reason, (e.g., lack of efficacy, 
safety and tolerability, etc.). 
10.3.2.4 Sensitivity analyses for missing data  
The robustness of inferences from the primary endpoint analysis to deviations from its 
underlying modelling assumptions will be explored using the following sensitivity 
analyses: 
• Model based analyses relying on the missing at random (MAR) assumptions: 
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Missing monthly modified BPI-SF3 scores will be imputed using a MI method 
Rubin 1987 based on a model including the baseline modified BPI-SF3 score, 
stratification factors, all available post-baseline monthly scores up to Month 6 and 
treatment group. In contrast to the CR approach described in Section 10.3.2.2, 
treatment group is included in the imputation model and therefore, missing data for 
subjects from the lucerastat arm will be imputed using data from the lucerastat arm.  
• Model based analyses relying on “missing not at random” (MNAR) scenarios: 
Missing monthly modified BPI-SF3 scores will be imputed using a MI assuming 
MNAR using the Jump to Reference (J2R) approach [Carpenter 2013]. The J2R 
approach assumes that subjects with missing data in the lucerastat group have 
outcomes similar to outcomes from the placebo group, starting from the point of 
monotone missing data. In contrast to CR, for subjects in the lucerastat group, 
non-missing earlier values are ignored in the prediction of later missing values. 
Therefore, the treatment difference from the lucerastat group in subjects with missing 
data disappears immediately after the point where missing data occurs.  
10.3.2.5 Supportive analyses 
A series of additional analyses based on the modified BPI-SF3 score data are presented 
below and will support the primary endpoint results by analyzing the primary endpoint 
variable using various other methods and assumptions. 
Responder analysis 
Using subject responses from the modified BPI-SF3, a response variable (yes/no) will be 
calculated based on a reduction of at least 30% from baseline to Month 6 in the modified 
BPI-SF3. Subjects who have a missing modified BPI-SF3 score at Month 6 for any reason 
will be considered as non-responders. 
The Cochran-Mantel-Haenszel (CMH) test stratified by sex and ERT treatment status at 
screening (treated vs not treated) will be used to test for a difference in the proportions of 
responders at Month 6 between treatment groups. 
The treatment effect (lucerastat vs placebo) will be expressed in terms of the common odds 
ratio (ORc) and corresponding 95% CI. An ORc > 1 will indicate a response to treatment 
in favor of lucerastat as compared to placebo. 
Homogeneity of the treatment effect across strata will be investigated using the 
Breslow-Day test.  
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Impact of the use of different analysis sets 
An analysis on the PPS will be performed in order to assess the impact of important 
protocol deviations on the assessment of the primary endpoint. This analysis will especially 
address the issue about the lack of adherence to protocol or compliance to study treatment.  
An analysis on the FAS may also be performed and will assess the impact of being 
randomized but not treated see Section 10.1.8. 
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Impact of data collected during use of significant rescue pain therapy 
The modified BPI-SF3 scores of “neuropathic pain at its worst in the last 24 hours” on the 
days that a subject received any significant rescue pain therapy are substituted by the worst 
score of that subject during the double-blind treatment period. Monthly scores are then 
derived as described in Section 10.2.1 and the same analysis model as described in 
Section 10.3.2.2 will be applied.  
Characterization of treatment effect over time 
The treatment effect over time will be investigated by means of a mixed model for repeated 
measures (MMRM) on the available monthly scores. 
Use of different cut-offs for the definition of a responder at Month 6 
A supportive analysis will derive the response at Month 6 by using different cut-offs for 
response (20%, 40%, 50%). The cut-offs of 40% and 50% have been identified in several 
neuropathic pain indications as substantial benefit to the subjects [Dworkin 2008]. 
The new response variables will then be analyzed using the CMH test as described above. 
The cumulative distribution by treatment group of the percentage of subjects achieving a 
reduction in pain of x% at Month 6 will be presented descriptively for x ranging from 
0 to 100. 
Clinically important changes in modified BPI-SF3 
A range of important individual subject-level changes (absolute and percentage) from 
baseline to Month 6 in modified BPI-SF3 will be determined using anchor-based methods 
Farrar 2010, McLeod 2011. The following four anchors will be used: 
• PGIC-DS and PGIC-PS [see Section 7.2.2.5]; 
• PGIS-D and PGIS-P [see Section 7.2.2.4]. 
An analysis of the correlations between outcome (modified BPI-SF3 changes, percentage 
changes or absolute values at a given time point) and PGIS-P, PGIC-PS, PGIS-D and 
PGIC-DS will be performed in order to select the most relevant anchors to use for the 
determination of clinically relevant changes in modified BPI-SF3. Plots, displaying both 
polyserial and Spearman correlation coefficients, will be provided to assess the relationship 
between changes in modified BPI-SF3 and the various anchors. In order to help with the 
interpretation of a clinically meaningful change in modified BPI-SF3, the empirical 
probability density function (ePDF) and the empirical cumulative distribution function 
(eCDF) of the change in modified BPI-SF3 will be graphically represented for each anchor 
category. Adjacent anchor categories may be collapsed if the sample size within a 
particular anchor category is small; however, both the non-collapsed and collapsed plots 
will be provided. The ePDF will show the probability of observing a given BPI-SF3 change 
(on the y-axis) vs the change in modified BPI-SF3 (on the x-axis) and will be presented on 
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the same plot for each anchor category. The eCDF will show the cumulative proportion of 
subjects who reach a given modified BPI-SF3 change or more (on the y-axis) vs the change 
in modified BPI-SF3 (on the x-axis) and will be presented on the same plot for each anchor 
category. The eCDF plots will primarily be used to determine a reasonable range of 
meaningful change thresholds by estimating the 25th, 50th and 75th percentile change in 
modified BPI-SF3 among the improvement categories of the anchors. 
In addition, supportive receiver operator characteristic curve analyses will be conducted 
using logistic regressions on the pre-specified response criteria defined by the anchor 
variables and the change in modified BPI-SF3 as explanatory variable. 
Associations between change in neuropathic pain and other manifestations of FD 
In order to show that improvement in neuropathic pain is not associated with deterioration 
of other manifestations of FD, an analysis of the correlation between the percent change 
from baseline in modified BPI-SF3 at Month 6 and endpoints related to GI symptoms will 
be provided graphically by means of a scatter plot displaying the coefficient of correlation. 
10.3.2.6 Sub-group analyses 
The aim of these exploratory subgroup analyses, classifying subjects according to 
important baseline characteristics, is to explore the consistency of treatment effect in a 
variety of relevant subject subgroups to support the efficacy evaluation of lucerastat in this 
indication. 
The study is stratified by the following subgroup variables: 
• Sex (male/female); 
• ERT treatment status (“pseudo-naïve” / “treatment naïve” vs “switch”) at screening. 
The following pre-specified subgroups may also be considered for the analyses (details 
will be provided in the SAP):  
• Geographical region (Europe, North America); 
• Age (< 65 years vs ≥ 65 years); 
• eGFR at screening visit (≥ 60 mL/min/1.73 m2 vs < 60 mL/min/1.73 m2); 
• UACR at screening visit (> 30 mg/g vs ≤ 30 mg/g); 
• FD complications (history of myocardial infarction, stroke, TIA, chronic kidney 
disease) at screening (yes/no); 
• Background pain medications (none vs monotherapy vs combinations):  
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Monotherapy is defined as the use of pain medications belonging to one single class of 
pain medication. Classes of pain medication include anti-epileptics, TCAs, SNRIs, 
SSRIs, opioid analgesics, non-opioid analgesics see Section 5.2.3.2; 
• Background opioids (Yes/No); 
• Background TCAs (Yes/No); 
• Background antiepileptics (Yes/No).  
Results of the subgroup analyses will be displayed in a forest plot as described in 
[Cuzick 2005] and will include: 
1. An estimate of the treatment effect (least squares mean differences for lucerastat vs 
placebo) with its 95% CI for each level of each subgroup. It will be calculated using an 
ANCOVA as described for the primary analysis [Section 10.3.2.1]. The ANCOVA will 
also include the subgroup and the subgroup * treatment interaction.  
2. A p-value for the interaction tests obtained from the ANCOVA described above.  
3. A vertical reference line displayed at the level of the overall treatment effect. 
The study is not designed or powered to detect interactions but an arbitrary two-sided 
significance level of alpha = 0.10 will be used for the interpretation of the interaction test. 
No multiplicity adjustment is introduced as the subgroup analyses are exploratory in nature. 
10.3.3 Analysis of the secondary efficacy variables 
10.3.3.1 Change from baseline to Month 6 in the 11-point numerical rating scale score 
of “abdominal pain at its worst in the last 24 hours” in subjects with 
gastrointestinal symptoms at baseline 
This endpoint will be analyzed using the mFAS-GIS. All available data will be used 
regardless of occurrence of ICEs such as premature treatment discontinuation or changes 
in background medication. 
Missing data will be imputed applying a control-based MI assuming MNAR using the CR 
approach, as described for the primary endpoint in Section 10.3.2.2. 
An ANCOVA model will be used to analyze this endpoint on each imputed dataset. 
The following terms will be included in the model: baseline value, the two stratification 
factors (sex and ERT treatment status at screening), and the treatment group.  
Uncertainty in the imputations will be reflected appropriately in the analysis by combining 
the results on each imputed dataset using Rubin’s methodology [Rubin 1987]. 
The mean difference in changes from baseline to Month 6 between lucerastat and placebo 
together with its two-sided 95% CI and p-value will be reported. 
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To explore the robustness of inferences from the main analysis described above to 
deviations from its underlying assumptions regarding the nature of missing data, a 
control-based MI assuming MNAR using the J2R approach [Carpenter 2013] will be 
applied, as described in Section 10.3.2.4. 
A supportive analysis using an MMRM approach will be conducted to characterize the 
treatment effect over time such that the monthly average NRS-11 scores will be analyzed 
on all available data from all monthly visits without replacement of missing values.  
The model will enable: 
• Estimation of the treatment difference (lucerastat minus placebo) in the mean changes 
from baseline to Month 6 along with the corresponding 95% CIs; 
• Characterization of the patterns of change over time in the mean change from baseline 
in “abdominal pain at its worst in the last 24 hours” by treatment group. 
A supportive dichotomous responder analysis will be conducted using the CMH test as 
described in Section 10.3.2.5. Response to study treatment on abdominal pain will be 
defined as a reduction from baseline to Month 6 of at least 50% in the NRS-11 score 
(“abdominal pain at its worst in the last 24 hours”) in subjects with abdominal pain of 
moderate to severe intensity at baseline. 
10.3.3.2 Change from baseline to Month 6 in the number of days with at least 1 stool of 
a Bristol Stool Scale consistency Type 6 or 7 in subjects with gastrointestinal 
symptoms at baseline 
This endpoint will be analyzed using the mFAS-GIS. All available data will be used 
regardless of occurrence of intercurrent events such as premature treatment discontinuation 
or changes in background medication. Subjects with a missing baseline value will be 
excluded from the analysis. 
The change from baseline to Month 6 in the number of days with at least 1 stool of a Bristol 
Stool Scale consistency Type 6 or 7 will be analyzed using a non-parametric rank analysis 
of covariance [Quade 1967, Koch 1982, Koch 1990, Stokes 2012] adjusted for the baseline 
value and stratified by sex and ERT treatment status at screening, as follows: 
1. Produce standardized ranks for the baseline variable (covariate) and the change 
from baseline to Month 6 variable (response) within each stratum. Standardized 
ranks are used to adjust for the fact that the number of subjects differ among strata.  
2. Fit a separate linear regression model for each stratum with the standardized ranks 
of the baseline variable and the change from baseline to Month 6 variable as 
independent and dependent variable, respectively. Retain the regression residuals. 
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3. Apply the stratified Cochran-Mantel-Haenszel mean score test using the residuals 
as scores to compare treatment groups. The p-value from this test will be used to 
test the null hypothesis. 
An example SAS code to perform the three steps above will be provided in the SAP. 
The rank analysis of covariance does not provide an interpretable treatment effect estimate. 
Therefore, the magnitude of the treatment effect will be estimated using the unadjusted 
non-parametric win ratio [Wang 2016] between lucerastat and placebo with corresponding 
95% CI. The rejection of the null hypothesis will be solely based on the p-value from the 
rank analysis of covariance and not the 95% CI of the unadjusted win ratio estimator. 
Aligned with the treatment policy strategy, all subjects with a valid value for the change 
from baseline to Month 6 will be ranked based on these values (such that larger decreases 
are associated with better ranks). Subjects with a missing value for the change from 
baseline to Month 6 will be assigned worse ranks than subjects with available change from 
baseline to Month 6 values based on their last available change from baseline value prior 
to Month 6. Subjects with a non-missing baseline value but no post-baseline data will be 
assigned the worst rank. Mid-ranks are used in case of ties. 
To explore the robustness of inferences from the main analysis described above to 
deviations from its assumptions regarding missing data, the above analysis will be repeated 
as a sensitivity analysis using the following rules for ranking of subjects with missing data. 
As above, subjects with a missing value for the change from baseline to Month 6 will be 
assigned worse ranks than subjects with available change from baseline to Month 6 values, 
based on their last available change from baseline value prior to Month 6. However, these 
subjects will then be divided into four quarters using the first quartile, median and third 
quartile of their last available change from baseline value. Within each quarter, lucerastat 
subjects will be assigned worse ranks than placebo subjects. Lucerastat subjects with a 
non-missing baseline value but no post-baseline data will be assigned the worst rank. 
Placebo subjects with a non-missing baseline value but no post-baseline data will be 
assigned the second worst rank. Mid-ranks are used in case of ties. 
The supportive responder analysis described in Section 10.3.3.1 will also be applied to this 
endpoint.  
10.3.3.3 Change from baseline to Month 6 in plasma globotriaosylceramide 
This endpoint will be analyzed using the mFAS. All available data will be used regardless 
of occurrence of ICEs such as premature treatment discontinuation or changes in 
background medication. 
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Missing data will be imputed applying an MI approach assuming MAR. The imputation 
model includes the baseline value, the two stratification factors (sex and ERT treatment 
status at screening), all post-baseline monthly scores up to Month 6 and treatment group. 
The MAR assumption can be considered reasonable for this endpoint as it is an objective 
assessment and not subject-reported and therefore less likely to be related to reasons for 
study withdrawal. In addition, subjects, site staff as well as the sponsor are blinded to the 
plasma Gb3 results until after database lock and a lower amount of missing data is expected 
compared to the abdominal pain and stool consistency endpoints. 
After imputation, the analysis will be performed using an ANCOVA as described in 
Section 10.3.2.2. 
A two-sided 95% CI will be calculated for the difference in the mean changes from baseline 
to Month 6 between lucerastat and placebo. 
To explore the robustness of inferences from the main analysis described above to 
deviations from its underlying assumptions regarding the nature of missing data, 
control-based MI assuming MNAR using the CR (described in section 10.3.2.2) and J2R 
approaches (described in section 10.3.2.4) will be applied. 
A supportive analysis using an MMRM approach will be conducted to characterize the 
treatment effect over time such that change in plasma Gb3 will be analyzed on all available 
data from all monthly visits without replacement of missing values. 
The model will enable: 
• Estimation of the treatment difference (lucerastat minus placebo) in the mean changes 
from baseline to Month 6 along with the corresponding 95% CI; 
• Characterization of the patterns of change over time in the mean change from baseline 
in Gb3 by treatment group. 
10.3.4 Analysis of other efficacy variables 
The analyses of all other efficacy variables will be described in detail in the SAP. Other 
variables may also be analyzed by subgroups. Other efficacy endpoints will be analyzed at 
each relevant time point listed in the visit and assessment schedule see Table 5 and 
Table 6 along with any data from unscheduled visits as appropriate.  
10.3.5 Analysis of the safety variables  
The SAF will be used to perform all safety analyses. 
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If not otherwise stated, only treatment-emergent safety data will be considered in tables 
and figures. All safety data will be included in listings, with flags for safety data not 
considered to be treatment-emergent.  
10.3.5.1 Adverse events 
10.3.5.1.1 Treatment-emergent adverse events and serious adverse events 
Treatment-emergent AEs and SAEs will be tabulated by study treatment, system organ 
class (SOC) and preferred terms within each SOC: the number and percentage of subjects 
who experienced at least one (S)AE, at least one (S)AE within each SOC and at least 
one (S)AE within each preferred term will be displayed. (S)AEs will also be summarized 
by decreasing frequency of preferred term. (S)AEs will also be tabulated by maximum 
intensity and relationship to lucerastat or placebo. 
10.3.5.1.2 Adverse events leading to premature discontinuation of study drug 
(S)AEs leading to premature discontinuation of study drug will be summarized in a similar 
manner as that described in Section 10.3.5.1.1. 
10.3.5.2 Vital signs 
Descriptive summary statistics by visit and study treatment will be provided for observed 
treatment-emergent values and absolute changes from baseline in HR, SBP, DBP, MAP 
and body weight.  
Treatment-emergent notable blood pressure abnormalities will also be summarized 
descriptively. 
10.3.5.3 Electrocardiography 
Descriptive summary statistics by visit and study treatment will be provided for observed 
treatment-emergent values and absolute changes from baseline in numeric 12-lead ECG 
values (HR, PR, QRS, QT, QTcB, and QTcF).  
Changes in 12-lead ECG variables (HR, PR, QRS, QT, QTcB, and QTcF) from pre-dose 
to 2 h and 4 h post dose will be summarized at the Month 1 visit.  
Treatment-emergent marked abnormalities for 12-lead ECG variables (HR, PR, QRS, QT, 
QTcB, and QTcF) will be summarized at all visits and pre/post-dose time points.  
In addition, summaries of treatment-emergent morphological ECG abnormalities that were 
not present before first study treatment intake (using data from the ECG provider) will be 
provided.  
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10.3.5.4 Laboratory data 
10.3.5.4.1 Changes from baseline in laboratory variables 
Descriptive summary statistics by visit and study treatment will be provided for observed 
treatment-emergent values and absolute and percentage changes from baseline for 
laboratory tests (hematology, blood chemistry, cardiac enzyme, urinalysis). 
Data will be displayed in SI units whenever possible and graphical approaches will be 
applied for certain variables.  
10.3.5.4.2 Treatment-emergent marked laboratory abnormalities 
Laboratory abnormalities will be summarized descriptively by study treatment as 
categorical variables.  
10.3.6 Analysis of other variables 
A full description of all other analyses will be described in the SAP.  
10.4 Interim analyses 
No interim analysis is planned for efficacy and/or futility for this study.  
10.5 Sample size 
The planned sample size for this study is 99 subjects using a 2:1 allocation ratio 
(66 lucerastat, 33 placebo) and is primarily based on a test for the mean difference between 
lucerastat and placebo in the change from baseline to Month 6 in the “modified” BPI-SF3 
score.  
The sample size calculation for the primary endpoint analysis is based on the following 
assumptions: a clinically relevant difference of 2 points on the 11-point scale (0−10) 
between lucerastat and placebo, a corresponding SD of 3 points, a two-sided type I error 
of 5%, and equal group variances. These assumptions come from an expected mean 
decrease from baseline to Month 6 in BPI-SF3 in the lucerastat group of 1.0-1.5 (2-year 
data for subjects on ERT; [Hoffmann 2007b]), and an expected mean increase from 
baseline in the placebo group of approximately 0.5 to 1.0 [Weidemann 2014]. Following 
these assumptions 99 subjects will provide a power of 87.2% to detect a treatment 
difference between lucerastat and placebo on the primary endpoint. The calculations were 
conducted using East 6.5 based on a two-sided t-test for independent samples. 
For the analysis of the secondary efficacy endpoints, it is expected that about 70% of the 
randomized subjects will be included in the mFAS-GIS. Under this assumption the 
assessment of the secondary endpoints may be carried out on about 69 subjects 
(approximately 46 on lucerastat and 23 on placebo). Little is known from the literature on 
the expected effect size that might be observed for these endpoints however a reasonable 
treatment effect on the abdominal pain endpoint (NRS-11) could be a difference (delta) of 
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1.5–2.5 points on that scale with an expected variability (SD) in the region of 2.5–3.5. 
For illustration purposes, and in absence of missing data, the power to detect such an effect 
with this sample size for the analysis of a continuous endpoint is shown in Table 7. 
Table 7 
Power to detect a treatment difference for continuous secondary 
endpoints analyzed on the mFAS-GIS for a range of deltas and SDs 
(n = 69 subjects) 
alpha = 5% two-sided 
delta 
SD = 2.5 
SD = 3.0 
SD = 3.5 
1.5 
63.9% 
48.8% 
38.0% 
2.0 
87.0% 
73.0% 
59.7% 
2.5 
97.1% 
89.5% 
78.7% 
SD = standard deviation. 
11 DATA HANDLING 
11.1 Data collection, data transfer procedure and data access 
The investigator/delegate is responsible for ensuring the accuracy, completeness and on 
time reporting of subject data. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation and traceability of the data. Data reported in the 
eCRF derived from source documents must be consistent with the source documents. 
eCRF data will be captured via Electronic Data Capture. The investigator and site 
personnel will be trained to enter and edit the data via a secure network, with secure access 
features (username, password, and identification — an electronic password system). A 
complete electronic audit trail will be maintained. The investigator/delegate will approve 
the data (i.e., confirm the accuracy of the data recorded) using an electronic signature (ref. 
to US 21 CFR Part 11). 
Entries recorded by the subject in the eDiary are considered source data. All records on the 
eDiary will be date and time stamped. Each time the subject makes an entry into the eDiary, 
he/she will be required to enter his/her own confidential password. The eDiary device will 
transfer data to the eDiary vendor’s central server automatically on a nightly basis. The 
communication software ensures a secure transfer of data by encryption. The data will 
remain in an encrypted state during transmission to the server. The transfer process is 
validated to ensure that the data on the central server is an accurate and complete copy of 
the eDiary data. Once the data are on the central server, the site staff, eDiary vendor, and 
sponsor representatives can access the data in a view-only mode on a 24 hours per day, 
7 days per week basis. This data access is role-based and strictly view-only. Access to the 
data on the server requires a valid user identification and password combination. Site 
personnel will review and ensure completeness of the subjects’ entries. 
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For each subject enrolled, regardless of study treatment initiation, an eCRF must be 
completed and signed by the investigator/delegate. This also applies to those subjects who 
fail to complete the study.  
11.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On eCRFs or 
other documents (e.g., documents attached to SAE forms / Pregnancy forms) submitted to 
the sponsor and any vendors or CROs, subjects must be identified only by number and 
never by their name or initials, date of birth, hospital numbers, or any other personal 
identifier. An exception will be made for the vendor in charge of the exit interviews who 
will obtain subject’s name and contact details from the investigator/delegate. The 
investigator/delegate must keep a subject identification code list at the site, showing the 
screening/randomization number, the subject’s name, date of birth, and address or any 
other locally accepted identifiers. Documents identifying the subjects (e.g., signed ICFs) 
must not be sent to the sponsor, any vendor or CROs, and must be kept in strict confidence 
by the investigator/delegate.  
In the eDiary, there will be no possibility to enter any personal identifier and the subject 
will only be identified by the study site and subject number. The eDiary device will be 
authenticated when it attempts to transfer data to the vendor’s central server; the 
authentication will be based upon subject identification (i.e., site and subject number) 
pre-loaded in the vendor’s server. The server will verify both the serial number of the 
eDiary device and the subject identifier before any data can be transferred into the system.  
11.3 Database management  
eCRFs will be used for all subjects. The investigators will have access to the site eCRF 
data until the database is locked. The eCRF must be kept current to reflect subject status at 
any time point during the course of the study. 
While entering the data, the investigator/delegate will be instantly alerted to data queries 
by validated programmed checks. Additional data review will be performed by the sponsor 
personnel on an ongoing basis to look for unexpected patterns in data and for study 
monitoring. Should discrepant data be detected, a query specifying the matter and 
requesting clarification will be issued and visible to the investigator/delegate via the eCRF. 
All electronic queries visible in the system either require a data correction (when 
applicable) and a response from the investigator/delegate to clarify the queried data directly 
in the eCRF, or simply a data correction in the eCRF. The investigator/delegate must, on 
request, supply the sponsor with any required background data from the study 
documentation or clinical records. This is particularly important when errors in data 
transcription are suspected. In the case of health authority queries, it is also necessary to 
have access to the complete study records, provided that subject confidentiality is 
protected. 
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This process will continue until database lock. 
The test results of laboratory samples, ECGs, echocardiographies, eDiary, processed 
through a central laboratory or vendor and the results of the randomized subjects will be 
electronically sent to the sponsor at pre-specified intervals with a final transfer prior to 
database lock. During the course of the study, the site staff and sponsor representatives can 
access the data in a view-only mode on the central server of the respective vendor see also 
Section 11.1. 
AEs and medical history are coded according to the latest MedDRA version used by the 
sponsor or its delegate. Medications are coded according to the latest WHODrug 
Dictionary version used by the sponsor or its delegate. 
After the database has been declared complete and accurate, the database will be locked. 
Any changes to the database after that time may only be made as described in the 
appropriate sponsor QS docs. After database lock, the investigator will have read-only 
access to the site eCRF subject data, until receipt of an electronic copy of the site eCRFs 
(including the audit trail) on electronic media. 
12 PROCEDURES AND GOOD CLINICAL PRACTICE 
12.1 Ethics and Good Clinical Practice 
The sponsor personnel and the investigators will ensure that the study is conducted in full 
compliance with ICH GCP guidelines, the principles of the “Declaration of Helsinki”, and 
with the laws and regulations of the country in which the study is conducted. 
12.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document(s) provided to the 
subject (such as the ICF) to an IEC/IRB. Approval from the committee/board must be 
obtained before starting the study and must be documented in a dated letter to the 
investigator, clearly identifying the study, the documents reviewed, and the date of 
approval. 
Modifications made to the protocol or the ICF after receipt of the approval must also be 
submitted as amendments by the investigator to the IEC/IRB in accordance with local 
procedures and regulations [see Section 12.6]. 
A list of members participating in the IEC/IRB meetings must be provided, including the 
names, qualifications, and functions of these members. If that is not possible, the attempts 
made to obtain this information along with an explanation as to why it cannot be obtained 
or disclosed must be documented in the study documentation.  
If a member of the site study personnel was present during an IEC/IRB meeting, it must be 
clear that this person did not vote. 
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12.3 Informed consent 
It is the responsibility of the investigator/delegate to obtain informed consent according to 
ICH GCP and Declaration of Helsinki guidelines and local regulations from each 
individual subject participating in this study and/or his/her legally designated 
representative. The investigator/delegate must explain to subjects that they are completely 
free to refuse to enter the study, or to voluntarily withdraw from the study at any time for 
any reason without having to provide any justification. Special attention shall be paid to 
the information needs of specific subject populations and of individual subjects, as well as 
to the methods used to give the information. Adequate time shall be given for the subject 
to consider his or her decision to participate in the study and it shall be verified that the 
subject has understood the information (e.g., by asking the subject to explain what is going 
to happen). In the US and Canada, the ICF will include a description of the exit interview 
component of the study. 
The ICF will be provided in the country local language(s). 
Site personnel authorized (according to local regulation) to participate in the consent 
process and/or to obtain consent from the subject will be listed on the Delegation of 
Authority form. 
The subject and authorized site personnel listed on the Delegation of Authority form must 
sign, personally date, and time (if the first study-mandated procedure is to be performed on 
the same day informed consent is obtained) the ICF before any study-related procedures 
(i.e., any procedures required by the protocol) begin.  
If pregnancy of a male participant’s female partner is reported as defined in Section 9.4.1, 
she will be asked to sign a specific ICF allowing the collection, storage and use of data 
about the pregnancy and the birth of the child. The ICF will be provided in the country 
local language(s). 
12.4 Compensation to subjects and investigators 
The sponsor provides insurance in order to indemnify (with both legal and financial 
coverage) the investigator/site against claims arising from the study, except for claims that 
arise from malpractice and/or negligence. 
The compensation of the subject in the event of study-related injuries will comply with 
applicable regulations. 
12.5 Protocol adherence/compliance 
The investigator must conduct the study in compliance with the IEC/IRB and/or the 
regulatory authority-approved version of the protocol and must not implement any 
deviation/change from the protocol, except when deviation is necessary to eliminate an 
immediate hazard to the subject. 
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If a protocol deviation occurs, the investigator/delegate will inform the sponsor or its 
representative in a timely manner. The investigator/delegate must document and explain 
any deviation from the approved protocol. Deviations considered to be a violation of ICH 
GCP must be reported to the IEC/IRB and regulatory authorities according to the sponsor 
or (overruling) local requirements. 
All protocol deviations will be reported in the CSR. IECs/IRBs will be provided with 
listings of protocol deviations as per local requirements. 
12.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. 
An amended protocol must be submitted to the IEC/IRB and regulatory authorities, 
according to their requirements. 
12.7 Essential documents and retention of documents 
The investigator/delegate must maintain adequate records necessary for the reconstruction 
and evaluation of the study. A number of attributes are considered of universal importance 
to source data and the records that hold those data. These include that the data and records 
are accurate, legible, contemporaneous, original (or certified copy), attributable, complete, 
consistent, enduring, and available when needed. 
These records are to be classified into 2 different categories of documents: ISF and 
subjects’ source documents. 
These records must be kept by the investigator for as long as is necessary to comply with 
the sponsor’s requirements (i.e., as specified in the clinical study agreement), and national 
and/or international regulations, whichever would be the longest period. If the investigator 
cannot guarantee this archiving requirement at the site for any or all of the documents, 
special arrangements, respecting the data confidentiality, must be made between the 
investigator and the sponsor to store these documents outside the site, so that they can be 
retrieved in the event of a regulatory inspection. No study document should be destroyed 
without prior written approval from the sponsor. Should the investigator wish to assign the 
study records to another party, or move them to another location, the sponsor must be 
notified in advance. 
If the site is using an electronic/computerized system to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 or 
equivalent standard) and if the CRA has been provided personal and restricted access to 
study subjects only, to verify consistency between electronic source data and the eCRF 
during monitoring visits. 
If the site is using an electronic/computerized system to store subject medical records but 
it could not be confirmed that the system is validated or if the CRA could not be provided 
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access to the system, the site is requested to print the complete set of source data needed 
for verification by the CRA. The print-outs must be numbered, stapled together with a 
coversheet, signed and dated by the investigator/delegate to confirm that these certified 
copies are exact copies having the same information as the original source data. The 
printouts will be considered as the official clinical study records and must be filed either 
with the subject’s medical records or with the subject’s eCRF. 
In order to verify that the process the site uses to prepare certified copies is reliable, the 
CRA must be able to observe this process and confirm that the comparison of the source 
documents and the certified copy did not reveal inconsistencies. The CRA does not need 
to verify this process for all data of all subjects but at least for some of them (e.g., first 
subject; regular check during the study of critical data like inclusion/exclusion criteria, 
endpoints for some subjects) as per the sponsor instructions. If it were not possible for the 
CRA to observe this process, it would not be possible to rely on the site’s certified copies 
and therefore the site cannot be selected for the clinical study. 
12.8 Monitoring 
Prior to study start, at a site, all required approvals must be obtained. A site initiation visit 
(SIV) will be performed after the required essential study documents are approved by the 
sponsor. The study treatment will be shipped to the site upon approval of the required 
essential documents. 
The PI must ensure that all site personnel involved in the study are present during the SIV 
and will dedicate enough time to it. Site Information Technology support should also be 
available during the SIV to assess the use of the eCRF. 
The SIV must be completed before the site can start the screening of study subjects. 
Following the SIV, a copy of the completed initiation visit report and follow-up letter will 
be provided to the PI and filed in the ISF. 
During the study, the CRA will contact and visit the site regularly and must be permitted, 
on request, to have access to study facilities and all source documents needed to verify 
adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered in the eCRFs and other protocol-related documents. The sponsor monitoring 
standards require full verification that informed consent has been provided, verification of 
adherence to the inclusion/exclusion criteria, documentation of SAEs, and the recording of 
the main efficacy, safety, and tolerability endpoints. Additional checks of the consistency 
of the source data with the eCRFs will be performed according to the study-specific 
monitoring guidelines. The frequency of the monitoring visits will be based on subject 
recruitment rate and critical data-collection times. 
The PI must ensure that the eCRF is completed after a subject’s visit (site visit or telephone 
call), and that all requested subject files (e.g., ICFs, medical notes/charts, other 
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documentation verifying the activities conducted for the study) are available for review by 
the CRA. The required site personnel must be available during monitoring visits and allow 
adequate time to meet with the CRA to discuss study-related issues. 
The investigator agrees to cooperate with the CRA(s) to ensure that any issues detected in 
the course of these monitoring visits are resolved. If the subject is hospitalized or dies in a 
hospital other than the study site, the investigator is responsible for contacting that hospital 
in order to document the SAE, in accordance with local regulations. 
A close-out visit will be performed for any initiated site when there are no more active 
subjects and all follow-up issues have been resolved. If a site does not enroll any subjects, 
the close-out visit may be performed prior to study closure at the discretion of the sponsor. 
12.9 Investigator Site File 
Each site will be provided with an ISF prior to the SIV. It will contain all the essential 
documents that are required to be up-to-date and filed at site as per ICH GCP section 8. 
The ISF will include a table of content listing the essential documents. All study-related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the CRA regarding the filing of the study 
documents outside the ISF. It should be clearly documented where each document is filed. 
This note to file should be present in the specific tab of the document in the ISF. 
The ISF must be stored in a secure and access-restricted area during and after the study. 
The ISF must be kept by the site for as long as is necessary to comply with the sponsor’s 
requirements (i.e., as specified in the clinical study agreement), ICH GCP and national 
and/or international regulations, whichever would be the longest period. If the site needs 
to transfer the ISF to another location and/or if site facility can no longer store the ISF, the 
PI must immediately inform the sponsor. 
If the PI will change, or if the site will relocate, the CRA must be notified as soon as 
possible. 
12.10 Audit 
The sponsor representatives may audit the investigator site (during the study or after its 
completion). The purpose of this visit will be to determine the investigator’s adherence to 
ICH GCP, the protocol, and applicable regulations; adherence to the sponsor requirements 
(e.g., standard operating procedures) will also be verified. Prior to initiating this audit, the 
investigator will be contacted by the sponsor to arrange a time for the audit. 
The investigator and site personnel must cooperate with the auditor(s) and allow access to 
all study documentation (e.g., subject records) and facilities. 
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12.11 Inspections 
Health authorities and/or IEC/IRB may also conduct an inspection of this study (during the 
study or after its completion) at the site. 
Should an inspection be announced by a health authority and/or IEC/IRB, the investigator 
must immediately inform the sponsor (usually via the CRA) that such a request has been 
made. 
The investigator and site personnel must cooperate with inspector(s) and allow access to 
all study documentation (e.g., subject records) and study facilities. 
12.12 Reporting of study results and publication 
The sponsor will post the key elements of this protocol and the summary of results within 
the required timelines on publicly accessible databases (e.g., clinicaltrials.gov, EU 
database), as required by law and regulation. 
Study results will be documented in a CSR that will be signed by the sponsor’s 
representatives and the coordinating investigator. 
In accordance with the Good Publication Practices and ethical practice as outlined in 
internationally recognized guidance documents (e.g., European Medical Writers 
Association, American Medical Writers Association, International Society for Medical 
Publication Professionals), the results of the study will be submitted for publication in a 
peer-reviewed journal. Study results can be submitted for presentation at a congress before 
submission to a peer-reviewed journal. 
The coordinating investigator and the Steering Committee, if any, will have the opportunity 
to review the analysis of the data and to discuss the interpretation of the study results with 
the sponsor personnel prior to submission to a peer-reviewed journal or presentation at a 
congress. 
Authorship will be determined in accordance with the International Committee of Medical 
Journal Editors criteria, and be based on: 
• substantial contributions to the conception or design of the study, or the acquisition, 
analysis, or interpretation of data; and 
• drafting of the publication or critical review for important intellectual content; and 
• providing final approval of the version to be published; and 
• agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved. 
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The list of authors of any publication of study results may include representatives of the 
sponsor and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted to 
the sponsor for review at least 30 days prior to submission for publication or presentation 
at a congress. Upon review, the sponsor may provide comments, and may also request 
alterations and/or deletions for the sole purpose of protecting its confidential information 
and/or patent rights. Neither the institution nor the investigator should permit publication 
during such a review period. 
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[Carpenter 2013] Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials 
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14 APPENDICES 
Appendix 1 
Individualized Pain Management Plan template 
Subject name: 
 
IPMP version: 
 
Subject number: 
 
Date: 
 
 
Study Doctor 
Study Nurse / Coordinator 
Name: 
 
Name: 
 
Medical institution: 
 
Medical institution: 
 
Address / E-mail: 
 
Address / E-mail: 
 
Telephone: 
 
Telephone: 
 
In order to help you manage your pain, it is important that you continue taking the following 
medications as prescribed by your study doctor: 
Pain medication (name) 
Dose 
Frequency 
Additional instructions 
 
 
 
 
 
 
 
 
 
 
 
 
 
If you suffer from unbearable pain despite using the medication(s) listed above, it is 
important to follow the steps below: 
1. Contact your doctor/study nurse as soon as possible. Note that your doctor/study nurse may 
invite you to go back to the hospital. 
2. Take the rescue pain medication according to the instructions listed below; you may need to get 
the rescue pain medication using the prescription provided to you by the doctor/study nurse. 
3. In the evening, complete your electronic diary as usual. Remember to enter the use of rescue 
pain medication in the eDiary. 
4. After 72 hours, your doctor/study nurse will contact you to check your pain status. Note that your 
doctor/study nurse may invite you to go back to the hospital to discuss alternative treatments.  
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Rescue pain medication (name) 
Dose 
Frequency 
Additional 
instructions 
 
 
 
 
 
 
 
 
 
 
 
 
 
I, the undersigned, have been informed of the purpose of the Individual Pain Management Plan 
and I acknowledge I fully understand the instructions on how to apply it. I am aware that I will 
receive a copy of this signed Individual Pain Management Plan and that the information will be 
entered in my eDiary as well. 
 
Study patient: 
 
 
 
 
 
 
 
 
Print Name 
 
Signature 
 
Date 
 
Time 
 
I, the undersigned, have informed the study participant named above about the purpose and the 
relevant details to implement this Individual Pain Management. 
Study 
or delegate: 
 
 
 
 
 
 
 
 
Print Name 
 
Signature 
 
Date 
 
Time 
 
Reminder: A copy of this IPMP must be given to the participant.  
 
 
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Instructions for the investigator/delegate (not to be given to the patient) 
During the screening visit: 
1. 
Discuss with your patient the possibility to use pain medications during the study. 
2. 
Complete the IPMP version 1: 
a. Indicate which pain medication the subject is currently taking and should 
continue taking. 
b. Indicate which rescue pain medication should be used by the subject if they 
are experiencing unbearable pain (see list below). Take into account the 
patient’s background pain medications and his/her previous response to pain 
medication. 
3. 
Instruct the patient to continue taking his/her pain medication(s) and, in the case of 
unbearable pain, to follow the rescue pain medication plan listed in the IPMP. 
4. 
Instruct the patient to contact the study nurse or the study doctor, in the case of 
unbearable pain. Ensure the contact details for nurse and physician are completed 
in the IPMP.  
5. 
Ensure the patient got the prescription needed to obtain pain medication (including 
rescue pain medication) listed in the IPMP.  
6. 
Both patient and investigator must sign the IPMP and a copy should be provided to 
the patient. 
During the randomization visit and any subsequent study visits: 
1. 
Check whether patient is compliant with the IPMP and eDiary completion. 
2. 
Check whether patient considers his/her pain to be adequately managed.  
3. 
If needed, update the IPMP (e.g., IPMP version 2).  
4. 
Ensure the patient got the prescription needed to obtain pain medication (including 
rescue pain medication) listed in the IPMP.  
5. 
Both patient and investigator must sign the updated IPMP version and a copy 
should be provided to the patient. 
In the event of of subject phone call due to unbearable pain: 
1. 
Check if the patient has continued to take his/her pain medication as listed in the 
IPMP. 
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2. 
Ask the patient if he/she has completed the eDiary. 
3. 
Remind the patient of the rescue pain medication, of what he/she should take as per 
IPMP. Remind the patient to enter the use of all pain medications in the eDiary. 
4. 
Schedule a phone call with the patient, 72 hours after this phone call. 
72-hour phone call: 
1. 
Ask the patient whether the pain symptoms have improved, worsened or remained 
stable. 
2. 
Check whether the eDiary was completed (pain intensity and use of pain 
medications). 
3. 
Ask the patient if he/she considered is pain is adequately managed with the rescue 
pain medication. If not, advise the patient if any adjustment on pain medication 
dose is required. You may also consider scheduling a visit to the site to update the 
IPMP (e.g., adding a new rescue pain medication to the IPMP). 
During unscheduled site visit due to unbearable pain: 
1. 
Review the IPMP with the patient; discuss additional rescue pain medications. 
2. 
If needed, update the IPMP (IPMP version 2) by adding/replacing or increasing the 
dose of rescue pain medications. 
3. 
Ensure the patient got the prescription needed to obtain pain medication (including 
rescue pain medication) listed in the IPMP.  
4. 
Both patient and investigator must sign the updated IPMP version and a copy 
should be provided to the patient. 
Example of potential rescue therapy for unbearable pain [see protocol section 5.2.3.2.2]: 
• Initiation or dose escalation of adjuvant pain medication (i.e., anti-epileptics, tricyclic 
antidepressants, antidepressants belonging to SNRIs/SSRIs); 
• Initiation or dose escalation of opioid analgesic drugs;  
• Initiation or dose escalation of non-opioid analgesics (i.e., NSAIDs, topical 
analgesics). 
 
 
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Appendix 2 
Bristol Stool Scale 
 
 
 
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Appendix 3 
Brief Pain Inventory-Short Form – English version (24 h) 
 
 
 
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Appendix 4 
Patient Global Impression questionnaires 
Patient Global Impression of Severity of neuropathic Pain (PGIS-P) 
The following question refers to the neuropathic pain you may experience due to your 
Fabry disease. 
Please choose the response that best describes the overall severity of the neuropathic pain 
you may have experienced due to your Fabry disease over the past 7 days (week): 
• 1=None 
• 2=Mild 
• 3=Moderate 
• 4=Severe 
Patient Global Impression of Change in neuropathic Pain Severity (PGIC-PS) 
The following question refers to the neuropathic pain you may experience due to your 
Fabry disease. 
Please choose the response that best describes the change in the overall severity of the 
neuropathic pain you may have experienced due to your Fabry disease since you started 
study treatment: 
• 1 = Very Much Improved 
• 2 = Much Improved 
• 3 = Minimally Improved 
• 4 = No change 
• 5 = Minimally worse 
• 6 = Much Worse 
• 7 = Very Much Worse  
Patient Global Impression of Severity of Disease (PGIS-D) 
The following question refers to symptoms (e.g., neuropathic pain, abdominal pain, 
diarrhea, constipation) you may experience due to your Fabry disease. 
Please choose the response that best describes the overall severity of the symptoms you 
may have experienced due to your Fabry disease over the past 7 days (week): 
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• 1=None 
• 2=Mild 
• 3=Moderate 
• 4=Severe 
Patient Global Impression of Change in Disease Severity (PGIC-DS) 
The following question refers to symptoms (e.g., neuropathic pain, abdominal pain, 
diarrhea, constipation) you may experience due to your Fabry disease. 
Please choose the response that best describes the change in overall severity of the 
symptoms you may have experienced due to your Fabry disease since you started study 
treatment: 
• 1 = Very Much Improved 
• 2 = Much Improved 
• 3 = Minimally Improved 
• 4 = No change 
• 5 = Minimally worse 
• 6 = Much Worse 
• 7 = Very Much Worse  
 
 
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Appendix 5 
Center for Epidemiologic Studies Depression Scale Revised 
 
 
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Center for Epidemiologic Studies Depression Scale – Revised (CESD-R) 
 
Below is a list of the ways you might have felt or 
behaved. Please check the boxes to tell me how often 
you have felt this way in the past week or so. 
Last Week 
Nearly 
every 
day for    
2 weeks 
Not at 
all  or     
Less 
than 1 
day 
1 - 2 
days 
3 - 4 
days 
5 - 7 
days 
My appetite was poor.  
0 
1 
2 
3 
4 
I could not shake off the blues.  
0 
1 
2 
3 
4 
I had trouble keeping my mind on what I was doing.  
0 
1 
2 
3 
4 
I felt depressed.  
0 
1 
2 
3 
4 
My sleep was restless.  
0 
1 
2 
3 
4 
I felt sad.  
0 
1 
2 
3 
4 
I could not get going.  
0 
1 
2 
3 
4 
Nothing made me happy.  
0 
1 
2 
3 
4 
I felt like a bad person.  
0 
1 
2 
3 
4 
I lost interest in my usual activities.  
0 
1 
2 
3 
4 
I slept much more than usual.  
0 
1 
2 
3 
4 
I felt like I was moving too slowly.  
0 
1 
2 
3 
4 
I felt fidgety.  
0 
1 
2 
3 
4 
I wished I were dead.  
0 
1 
2 
3 
4 
I wanted to hurt myself.  
0 
1 
2 
3 
4 
I was tired all the time.  
0 
1 
2 
3 
4 
I did not like myself.  
0 
1 
2 
3 
4 
I lost a lot of weight without trying to.  
0 
1 
2 
3 
4 
I had a lot of trouble getting to sleep.  
0 
1 
2 
3 
4 
I could not focus on the important things.  
0 
1 
2 
3 
4 
 
REFERENCE: Eaton, W. W., Smith, C., Ybarra, M., Muntaner, C., Tien, A. (2004). Center for 
Epidemiologic Studies Depression Scale: review and revision (CESD and CESD-R). In ME 
Maruish (Ed.). The Use of Psychological Testing for Treatment Planning and Outcomes 
Assessment (3rd Ed.), Volume 3: Instruments for Adults, pp. 363-377. Mahwah, NJ: Lawrence 
Erlbaum. 
 
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Appendix 6 
36-Item Short Form Health Survey Version 2 
 
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