Clinical trial NCT02489344
Conditions: Fabry Disease
Sponsor: Genzyme, a Sanofi Company
Start date: 2015-07-07; Completion date: 2018-11-20
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary Objective:

To assess the long-term safety of GZ/SAR402671 in adult male participants with Fabry disease who previously completed study ACT13739 (NCT02489344).

Secondary Objective:

To assess the long-term effect of GZ/SAR402671 on pharmacodynamic and exploratory efficacy endpoints in adult male participants with Fabry disease who previously completed study ACT13739.

Detailed description:
The total duration of this extension study (LTS14116) was up to 31 months (30 months of treatment and one month post-treatment follow-up).

Arms: arm 1: Participants received GZ/SAR402671 15 milligrams (mg) once daily orally for 30 months in this extension study (LTS14116).
Interventions: intervention 1: GZ/SAR402671
Intervention descriptions: intervention 1: Pharmaceutical form:capsule

Route of administration: oral

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-003152-VERSION N°2.0 (28-JUN-2013)  
AMENDED CLINICAL TRIAL PROTOCOL 04 
COMPOUND: GZ/SAR402671  
TITLE: An  open-label, multicenter, multinational extension study of the long-term 
safety, pharmacodynamics and exploratory efficacy of GZ/SAR402671 in adult 
male patients diagnosed with Fabry disease  
STUDY NUMBER: LTS14116  
VERSION DATE / STATUS: 10-Nov-2017/ Approved 
CLINICAL STUDY DIRECTOR: 
Protocol Amendment 04 
Version number: 1 (electronic 1.0) 
Date : 10-Nov-2017 
Amended Clinical Trial Protocol 03 
Version number: 1 (electronic 4.0) 
Date : 19-Sep-2016 
Protocol Amendment 03 
Version number: 1 (electronic 1.0) 
Date : 19-Sep-2016 
Amended Clinical Trial Protocol 2 
Version number: 1 (electronic 3.0) 
Date : 14-Jan-2016 
Protocol Amendment 2 
Version number: 2 (electronic 2.0) 
Date : 14-Jan-2016 
Amended Clinical Trial Protocol 1 
Version number: 1 (electronic 1.0) 
Date : 12-May-2015 
Protocol Amendment 1 
Version number: 1 (electronic 1.0) 
Date : 12-May-2015 
Clinical Trial Protocol 
Version number: 1 (electronic 1.0) 
Date : 19-Jan-2015 
EudraCT or IND number : 2014-004995-49 
IND number: 114640 
(electronic 1.0)
NCT Number: NCT02489344


Amended Clinical Trial Protocol 04 
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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
Name: 
Address: 
Tel: 
Fax: 
E-mail: 
MONITORING TEAM’S 
REPRESENTATIVE 
Name: 
Address: 
Tel: 
Fax: 
E-mail: 
SPONSOR 
Company: 
Address: 
Sanoi Genzyme  
500 Kendall Street, 
Cambridge, MA, 02142, USA 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
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CLINICAL TRIAL SUMMARY 
 
COMPOUND: GZ/SAR402671 STUDY No: GZ402671/LTS14116  
TITLE 
An  open-label, multicenter, multinational extension study of the long-term 
safety, pharmacodynamics, and exploratory efficacy of GZ/SAR402671 in 
adult male patients diagnosed with Fabry disease 
INVESTIGATOR/TRIAL LOCATION 
Sites that participated  in study ACT13739 
PHASE OF DEVELOPMENT 
2 
STUDY OBJECTIVE(S) 
 
Primary objective: To assess the long-term safety of GZ/SAR402671 in 
adult male patients with Fabry disease who previously completed study 
ACT13739. 
Secondary objective(s): To assess the long-term effect of 
GZ/SAR402671 on pharmacodynamic and exploratory efficacy endpoints in 
adult male patients with Fabry disease who previously completed study 
ACT13739.    
STUDY DESIGN 
Open-label, multicenter, multinational extension study of the long-term safety, 
pharmacodynamics and exploratory efficacy of daily, oral GZ/SAR402671 
administration in adult male patients with Fabry disease who have completed 
study ACT13739. 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria  
• 
Male patient with Fabry disease who previously completed study 
ACT13739. 
• 
The patient is willing and able to provide signed informed consent.  
• 
Sexually active patient is willing to practice true abstinence in line 
with their preferred and usual lifestyle or use two acceptable 
effective methods of contraception. 
Exclusion criteria 
• 
The patient, in the opinion of the investigator, is unable to adhere to 
the requirements of the study. 
Total expected number of patients 
This is an extension study, and therefore, the number of patients will be 
determined by patients completing study ACT13739. 
STUDY TREATMENT(s) 
 
Investigational medicinal 
product(s) 
 
Formulation 
GZ/SAR402671 
 
GZ/SAR402671 is provided in capsule formulations containing 15 mg or 4 mg 
of GZ/SAR402671 
Route(s) of administration 
Oral 
Dose regimen 
Patients will continue to receive once daily, oral GZ/SAR402671 at the same 
dose level administered at the end of study ACT13739 (ie, 15 mg or 4 mg in 
the event the GZ/SAR402671 dose was reduced in ACT13739). 
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ENDPOINT(S) 
 
Primary endpoint 
Safety as measured by: 
• 
Assessment of adverse events (AEs)/ treatment-emergent 
AEs (TEAEs)  
• 
Physical examination 
• 
Neurological examination 
• 
Clinical laboratory evaluations including hematology, biochemistry, 
and urinalysis 
• 
Vital signs and body weight 
• 
Ophthalmology exam 
• 
12-lead electrocardiogram (ECG) 
Secondary Endpoint(s): 
Pharmacodynamics as measured by: 
• 
Plasma globotriaosylceramide (GL-3), lyso GL-3, glucosylceramide 
(GL-1) and  monosialodihexosylganglioside (GM3) 
• 
Exploratory blood and urine biomarkers including, but not limited to 
high sensitivity cardiac troponin T, plasma chitotriosidase assay 
(plus chitotriosidase genotyping for interpretation) and podocyturia  
• 
Urine GL-3 
Exploratory efficacy as measured by: 
• 
GL-3 in skin biopsy  
• 
Patient reported outcomes 
• 
Urinary albumin and protein  [albumin to creatinine ratio (ACR) and 
protein to creatinine ratio (PCR)] 
• 
Echocardiogram 
• 
Brain magnetic resonance imaging (MRI) 
• 
Estimated glomerular filtration rate (eGFR) 
ASSESSMENT SCHEDULE 
See Study Flow Chart. 
When possible, demographic, medical/surgical history, Fabry disease history 
including GLA (αGAL gene) mutations as well as safety, pharmacodynamic 
and exploratory efficacy assessments collected prior to first GZ/SAR402671 
administration in ACT13739 will be imported from the ACT13739 study 
database into the LTS14116 database. LTS14116 study entry visit may occur 
at the same time as the ACT13739 week 26 clinical visits.  
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
The maximum enrollment possible for this study will be determined by the 
final number of patients who completed study ACT13739. 
Analysis population: 
The Full Analysis Set (FAS) and the Safety Set will include all patients who 
receive at least 1 dose of study treatment in this study.  
Analysis of primary endpoints:  
Safety: Out of range laboratory values, vital signs, and ECGs will be flagged 
by the investigator as clinically significant or non-clinically significant 
abnormalities. The clinically significant abnormalities will be recorded as AEs 
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and included in the TEAE counts.  
TEAEs and SAEs will be tabulated (counts and percentages). 
Discontinuations due to AEs will be summarized.  
Descriptive statistics for actual values and changes from baseline will be 
generated by time point for selected safety parameters of interest. Data may 
also be plotted. For the purpose of analysis, baseline will be prior to the first 
dose GZ/SAR402671 in study ACT13739.  
Analysis of secondary endpoints 
Pharmacodynamics and exploratory efficacy: Descriptive statistics for actual 
values and change from treatment baseline will be generated by time point for 
selected pharmacodynamic and exploratory efficacy endpoints as 
appropriate. For the purpose of analysis, treatment baseline will be prior to 
the first dose GZ/SAR402671 in study ACT13739. 
Pharmacokinetics: GZ/SAR402671 plasma concentrations will be reported 
including patient number, visit and time relative to GZ/SAR402671 
administration. 
DURATION OF STUDY PERIOD (per 
patient)  
The maximum duration per patient is approximately 31 months as follows: 
Treatment period: up to 30 months 
Post-treatment follow up: 1 month (± 7 days) 
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1 
FLOW CHART 
1.1 
GRAPHICAL STUDY DESIGN 
15 mg
4 mg 
GZ/SAR402671
dose level: 
ACT13739
LTS14116
Safety, 
pharmacodynamic &/or 
exploratory efficacy 
assessments at:
Month 3
Month 6 
Month 9
Month 12
Month 18  
Month 30
End of Treatment follow 
up visit 
15 mg
4 mg
GZ/SAR402671
dose level: 
OR
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1.2 
STUDY FLOW CHART 
Treatment period 
Post-treatment observations 
Study entrya 
3 Month 
(± 14 days) 
6 Month 
(± 14 days) 
9 Month 
(± 14 days) 
12 Month 
(± 14 days) 
18 Month 
(± 14 days) 
30 Month 
(± 14 days) 
Early  
withdrawal 
End of treatment 
follow upb  
(1 month ± 7 days) 
Informed consent for extension 
X  
Inclusion/exclusion criteria 
X  
Visit at clinical site 
X 
Xf
Xf
Xf
Xf
Xf 
X
X
X
Study treatment administration 
GZ/SAR402671 
Once daily oral dosing 
Distribution of patient diary 
X 
Review of patient diary 
X 
X 
X 
X 
X 
X 
X 
Collection of patient diary 
X 
X 
Safety Assessments 
Vital signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination
X
X
X
X
X
X 
X
Neurological examination
X
X
X
X
X
X 
X
Ophthalmology exam 
X
Xc 
X
X
Xc
Xc 
Xc 
Electrocardiogram
X
X
X
X
X
X 
X
Biochemistry, hematology & 
urinalysis 
X
X
X
X
X
X 
X
Concomitant 
medications/therapies 
<
-
-
-
-
-
- 
-
>
Adverse event recording 
< 
- 
- 
- 
- 
- 
- 
- 
> 
Pharmacokinetics 
Plasma sampled 
X 
X
X 
X
X
Pharmacodynamics 
Plasma samples for GL-3, lyso 
GL-3, GM3, GL-1 
X
X
X 
X
X
High sensitivity cardiac troponin T 
X
X
X 
X
Urine GL-3
X
X
X 
X
X
Exploratory biomarkers – blood 
and plasma 
X
X
X 
X
X
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Treatment period 
Post-treatment observations 
 
Study entrya 
3 Month 
(± 14 days) 
6 Month 
(± 14 days) 
9 Month 
(± 14 days) 
12 Month 
(± 14 days) 
18 Month 
(± 14 days) 
30 Month 
(± 14 days) 
Early  
withdrawal 
End of treatment 
follow upb  
(1 month ± 7 days) 
Exploratory biomarkers – urine 
 
 
X 
 
 
X 
X 
X 
X 
Podocyturia 
 
 
 
 
 
 
X 
 
 
Exploratory efficacy 
GL-3 in skin biopsy 
 
 
Xg           
 
 
 
X 
X 
 
Patient reported outcomes 
 
 
Xh 
 
 
Xh 
Xh 
Xh 
 
Urinary albumin and protein : 
ACR & PCRe 
 
 
X, X, X 
 
 
X, X, X 
X, X, X 
 
 
Echocardiogram 
 
 
X 
 
 
X 
X 
X 
 
Brain MRI    
 
 
 
 
 
 
X 
X 
 
eGFR 
 
 
X 
 
 
X 
X 
 
 
Abbreviations: ACR, albumin to creatinine ratio; eGFR, estimated glomerular filtration rate; GL 1, glucosylceramide; GL 3, globotriaosylceramide; GM3, monosialodihexosylganglioside; IMP, 
investigational medicinal product; MRI, magnetic resonance imaging; PCR, protein to creatinine ratio.  
a When possible, demographic, medical/surgical history, Fabry disease history including GLA (αGAL gene) mutations as well as safety, pharmacodynamic and exploratory efficacy assessments collected 
prior to first GZ/SAR402671 administration in ACT13739 will be imported from the ACT13739 study database into the LTS14116 database. LTS14116 study entry visit may occur at the same time as 
the ACT13739 week 26 clinical visit.    
b End of treatment follow up on site visit 1 month (± 7 days) after the last GZ/SAR402671 administration.  
c Eye dilation required for examination.  
d One pharmacokinetic sample to be collected at each visit indicated within 1 to 8 hours following oral administration of GZ/SAR402671. Pharmacokinetic sample during the early withdrawal (if applicable) 
and post treatment follow up visit will be collected at any time during the visit. 
e Urine ACR/PCR: 3 overnight urine samples to be collected with 4 to 7 days between each collection. All urine samples are to be collected within a 16-day period.  
f 
IMP kits will be supplied to patients at site visits or may also be supplied directly to patient’s home ( Direct To Patient) 
g Skin biopsy at month 6 is optional- to be performed on the day of month 6 visit or at any other day during the following 30 days 
h BDI-II is part of protocol amendment #3 and will be conducted starting at the first patient visit after amendment approval and thereafter in subsequent visits 
 
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2 
TABLE OF CONTENTS 
 
1 
FLOW CHART.................................................................................................................................6 
1.1 
GRAPHICAL STUDY DESIGN ........................................................................................................6 
1.2 
STUDY FLOW CHART ....................................................................................................................7 
2 
TABLE OF CONTENTS ..................................................................................................................9 
3 
LIST OF ABBREVIATIONS ..........................................................................................................14 
4 
INTRODUCTION AND RATIONALE.............................................................................................15 
4.1 
INTRODUCTION............................................................................................................................15 
4.2 
GZ/SAR402671..............................................................................................................................15 
4.3 
RATIONALE...................................................................................................................................15 
5 
STUDY OBJECTIVES ...................................................................................................................16 
5.1 
PRIMARY.......................................................................................................................................16 
5.2 
SECONDARY ................................................................................................................................16 
6 
STUDY DESIGN ............................................................................................................................17 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................17 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................17 
6.2.1 
Duration of study participation for each patient .............................................................................17 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................17 
6.3 
INTERIM ANALYSIS......................................................................................................................17 
6.4 
STUDY COMMITTEES..................................................................................................................17 
6.5 
SPECIFIC PARAMETERS.............................................................................................................18 
6.5.1 
Safety .............................................................................................................................................18 
6.5.2 
Pharmacodynamics........................................................................................................................18 
6.5.3 
Exploratory efficacy........................................................................................................................18 
6.5.4 
Pharmacokinetics...........................................................................................................................18 
7 
SELECTION OF PATIENTS..........................................................................................................19 
7.1 
INCLUSION CRITERIA..................................................................................................................19 
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7.2 
EXCLUSION CRITERIA ................................................................................................................19 
8 
STUDY TREATMENTS .................................................................................................................20 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................20 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................20 
8.3 
BLINDING PROCEDURES............................................................................................................20 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................20 
8.5 
PACKAGING AND LABELING ......................................................................................................20 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................21 
8.7 
RESPONSIBILITIES ......................................................................................................................21 
8.7.1 
Treatment accountability and compliance......................................................................................21 
8.7.2 
Return and/or destruction of treatments ........................................................................................21 
8.8 
CONCOMITANT MEDICATION.....................................................................................................22 
8.8.1 
CYP3A4 inducers or inhibitors.......................................................................................................22 
8.8.2 
Renin-Angiotensin-Aldosterone System (RAAS) blockers, pain medication and/or 
antidepressants..............................................................................................................................22 
8.8.3 
Forbidden cataractogenic medications ..........................................................................................22 
8.8.4 
Contraceptives ...............................................................................................................................23 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................24 
9.1 
PRIMARY ENDPOINT- SAFETY...................................................................................................24 
9.1.1 
Adverse events ..............................................................................................................................24 
9.1.2 
Physical exam................................................................................................................................25 
9.1.3 
Neurological exam .........................................................................................................................25 
9.1.4 
Laboratory safety variables............................................................................................................25 
9.1.5 
Vital signs and weight ....................................................................................................................26 
9.1.6 
Ophthalmology Examination..........................................................................................................26 
9.1.7 
Electrocardiogram variables ..........................................................................................................26 
9.2 
SECONDARY ENDPOINT – PHARMACODYNAMICS.................................................................27 
9.2.1 
Plasma samples for GL-3, lyso GL-3, GL-1, and GM3..................................................................27 
9.2.2 
High sensitivity cardiac troponin T .................................................................................................27 
9.2.3 
Urine samples for GL-3..................................................................................................................27 
9.2.4 
Exploratory biomarkers in blood and urine ....................................................................................28 
9.2.5 
Podocyturia ....................................................................................................................................28 
9.3 
SECONDARY ENDPOINT – EXPLORATORY EFFICACY...........................................................28 
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9.3.1 
Globotriaosylceramide in skin biopsy.............................................................................................28 
9.3.2 
Patient reported outcome questionnaires ......................................................................................29 
9.3.2.1 
Short Form-36................................................................................................................................29 
9.3.2.2 
Gastrointestinal questionnaire .......................................................................................................29 
9.3.2.3 
Beck Depression Inventory- Second Edition (BDI-II).....................................................................29 
9.3.3 
Protein excretion from urine...........................................................................................................29 
9.3.4 
Echocardiogram.............................................................................................................................30 
9.3.5 
Brain magnetic resonance imaging................................................................................................30 
9.3.6 
Estimated glomerular filtration rate ................................................................................................30 
9.4 
OTHER ENDPOINTS – PHARMACOKINETICS...........................................................................31 
9.4.1 
Sampling time ................................................................................................................................31 
9.4.2 
Pharmacokinetics handling procedure...........................................................................................31 
9.4.3 
Bioanalytical method......................................................................................................................31 
9.4.3.1 
Pharmacokinetics parameters .......................................................................................................31 
9.5 
ESTIMATED SAMPLED BLOOD VOLUME ..................................................................................32 
9.6 
FUTURE USE OF SAMPLES ........................................................................................................32 
10 
STUDY PROCEDURES ................................................................................................................33 
10.1 
VISIT SCHEDULE..........................................................................................................................33 
10.1.1 
Study entry visit..............................................................................................................................33 
10.1.2 
Treatment period............................................................................................................................33 
10.1.2.1 Month 6, month 18 and month 30 visits.........................................................................................33 
10.1.3 
Post treatment follow-up ................................................................................................................34 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................34 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................34 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................34 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................35 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................35 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................35 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................36 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................36 
10.4.1 
Definitions of adverse events.........................................................................................................36 
10.4.1.1 Adverse event ................................................................................................................................36 
10.4.1.2 Serious adverse event ...................................................................................................................36 
10.4.1.3 Adverse event of special interest...................................................................................................37 
10.4.2 
Evaluation of adverse events/serious adverse events...................................................................38 
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10.4.2.1 Relationship to Study Treatment....................................................................................................38 
10.4.2.2 Severity grading .............................................................................................................................38 
10.4.2.3 Outcome.........................................................................................................................................38 
10.4.2.4 Action taken regarding investigational medicinal product..............................................................39 
10.4.3 
General guidelines for reporting adverse events ...........................................................................39 
10.4.4 
Instructions for reporting serious adverse events ..........................................................................40 
10.4.5 
Guidelines for reporting adverse events of special interest...........................................................40 
10.4.6 
Guidelines for management of specific laboratory abnormalities ..................................................40 
10.5 
PREGNANCY REPORTING..........................................................................................................41 
10.6 
OBLIGATIONS OF THE SPONSOR .............................................................................................42 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................42 
11 
STATISTICAL CONSIDERATIONS..............................................................................................43 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................43 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................43 
11.3 
ANALYSIS POPULATIONS...........................................................................................................43 
11.4 
STATISTICAL METHODS .............................................................................................................44 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................44 
11.4.2 
Analyses of primary endpoints – safety .........................................................................................44 
11.4.2.1 Adverse events ..............................................................................................................................44 
11.4.2.2 Clinical laboratory tests..................................................................................................................45 
11.4.2.3 Physical examinations, neurological examinations, and ophthalmology examinations.................45 
11.4.2.4 Vital signs.......................................................................................................................................45 
11.4.2.5 Electrocardiograms ........................................................................................................................46 
11.4.3 
Analyses of secondary endpoints – pharmacodynamics...............................................................46 
11.4.4 
Analyses of secondary endpoints - exploratory efficacy................................................................46 
11.4.4.1 Echocardiograms ...........................................................................................................................46 
11.4.4.2 Analyses of Patient Reported Outcomes.......................................................................................46 
11.4.5 
Multiplicity considerations ..............................................................................................................46 
11.5 
INTERIM ANALYSIS......................................................................................................................46 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................47 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................47 
12.2 
INFORMED CONSENT .................................................................................................................47 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ..............47 
13 
STUDY MONITORING...................................................................................................................49 
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13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................49 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................49 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................49 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................50 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................50 
14 
ADDITIONAL REQUIREMENTS...................................................................................................51 
14.1 
CURRICULUM VITAE....................................................................................................................51 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................51 
14.3 
CONFIDENTIALITY .......................................................................................................................51 
14.4 
PROPERTY RIGHTS.....................................................................................................................52 
14.5 
DATA PROTECTION.....................................................................................................................52 
14.6 
INSURANCE COMPENSATION....................................................................................................52 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................53 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................53 
14.8.1 
By the sponsor ...............................................................................................................................53 
14.8.2 
By the investigator..........................................................................................................................54 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................54 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................54 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................55 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................56 
17 
APPENDICES................................................................................................................................58 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY ABNORMALITIES BY SANOFI .......59 
 
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3 
LIST OF ABBREVIATIONS 
 
ACR: 
albumin to creatinine ratio 
AE: 
adverse event 
AESI: 
adverse event of special interest 
BDI: 
Beck Depression Inventory 
BDI-II: 
Beck Depression Inventory- Second Edition 
CL1: 
claudin 
CS: 
clinically significant 
CTCAE: 
Common Terminology Criteria for Adverse Events 
DMC: 
data monitoring committee 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
ERT: 
enzyme replacement therapy 
GCP: 
good clinical practice 
GL-1: 
glucosylceramide 
GL-3: 
globotriaosylceramide 
GM3: 
monosialodihexosylganglioside 
ICH: 
International Conference on Harmonisation 
IEC: 
independent ethics committee 
IMP: 
investigational medicinal product 
IRB: 
institutional review board 
LC-MS/MS: 
liquid chromatography tandem mass spectrometry 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MRI: 
magnetic resonance imaging 
NCI: 
National Cancer Institute 
NCS: 
not clinically significant 
PCR: 
protein to creatinine ratio 
PCX: 
podocalyxin 
PRO: 
patient reported outcome 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SF-36: 
Short Form-36 
TEAEs: 
treatment-emergent adverse events 
 
 
 
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4 
INTRODUCTION AND RATIONALE 
4.1 
INTRODUCTION 
Fabry disease is a rare, X-linked, genetic disorder caused by mutations in the gene that encodes 
the lysosomal enzyme, αGAL.  This enzymatic deficiency leads to the progressive accumulation 
of glycosphingolipids, most notably globotriaosylceramide (GL-3), in lysosomes of a variety of 
cell types and tissues.  Although multiple organ-specific cell types accumulate GL-3 and are 
important to consider, the systemic accumulation in capillary endothelial cells is believed to play 
a major role in the general pathological process that leads to the devastating renal, cardiac, and 
cerebrovascular clinical manifestations of the disease and to substantially decreased life 
expectancy (1, 2).    
Fabry disease is a progressive disorder that takes years to advance to end stage organ failure 
mainly in hemizygous male patients.  Although GLA (αGAL gene) mutations are carried by the X 
chromosome, female patients exhibit a variable phenotype, ranging from oligosymptomatic to a 
presentation as severe as that observed in male patients (3, 4, 5, 6).  The initial signs and 
symptoms of Fabry disease often begin during childhood and frequently include neuropathic pain 
in the extremities, hypohidrosis, angiokeratomas, and gastrointestinal discomfort (7, 8, 9).  Over a 
period of decades, the progressive accumulation of GL-3 impairs vital organ function, putting 
patients with Fabry disease at risk of developing renal failure, cardiovascular dysfunction, and 
stroke (10, 11, 12).  However, it is now clear that tissue damage, such as fibrosis in heart and 
kidney, starts well before the onset of organ failure (13, 14, 15).   
Because Fabry disease patients have deficient αGAL enzymatic activity, one therapeutic approach 
is enzyme replacement therapy (ERT).  There are currently two approved recombinant forms of 
human αGAL for Fabry disease, both administered as biweekly intravenous infusions.  Agalsidase 
beta, manufactured by Sanofi Genzyme is marketed under the brand name Fabrazyme.  
Agalsidase alfa, manufactured by Shire is marketed under the brand name Replagal. 
4.2 
GZ/SAR402671 
GZ/SAR402671 is a small molecule, a second generation glucosylceramide synthase inhibitor that 
blocks the first step in glycosphingolipids biosynthesis, the enzymatic conversion of ceramide, to 
glucosylceramide (GL-1).  By reducing the amount of GL-1, the central building block for the 
synthesis of more complex glycosphingolipids including GL-3, this substrate reduction therapy 
with GZ/SAR402671 offers a potential therapeutic strategy for Fabry disease and other 
glycosphingolipidosis disorders, as already demonstrated with eliglustat for Gaucher disease (16).   
Refer to the Investigator’s brochure for a complete summary of nonclinical experience with 
GZ/SAR402671 (17). 
4.3 
RATIONALE 
This open-label, 30 month (2.5 years) treatment study is being conducted to allow male Fabry 
disease patients who have previously completed study ACT13739 to continue receiving 
GZ/SAR402671. The primary objective of LTS14116 is to evaluate the long term safety of 
GZ/SAR402671 in this patient population; secondary endpoints include further evaluating 
GZ/SAR402671 pharmacodynamics and exploratory efficacy.   
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
To assess the long-term safety of GZ/SAR402671 in adult male patients with Fabry disease who 
previously completed study ACT13739. 
5.2 
SECONDARY 
To assess the long-term effect of GZ/SAR402671 on pharmacodynamic and exploratory efficacy 
endpoints in adult male patients with Fabry disease who previously completed study ACT13739.   
 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
LTS14116 is an open-label, multicenter, multinational extension study of the long-term safety, 
pharmacodynamics and exploratory efficacy of daily, oral GZ/SAR402671 administration in adult 
male patients with Fabry disease that completed ACT13739. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The maximum duration per patient is approximately 31 months as follows: 
• 
Treatment period: up to 30 months 
• 
Post-treatment follow up: 1 month (± 7 days). Patients who start commercial ERT, 
investigational or any other Fabry disease treatment within the 1-month (±7 days) follow 
up period will not be considered for follow up assessments. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the clinical trial will be determined by last patient last visit. 
6.3 
INTERIM ANALYSIS 
No interim analysis is planned.  
6.4 
STUDY COMMITTEES 
A data monitoring committee (DMC) will be established to provide independent review of safety 
data and to ensure that risk to patients is minimized. The DMC will periodically review all 
available data including laboratory results, physical and clinical examination findings, radiology, 
AEs, and serious adverse events (SAEs) for any safety trends that could impact the treatment of 
patients. The DMC will also review data on an ad hoc basis to assist in determining if AEs should 
preclude continued treatment with GZ/SAR402671.  
The specific responsibilities of the DMC will be described in the DMC Charter. 
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6.5 
SPECIFIC PARAMETERS 
6.5.1 Safety 
Safety assessments include adverse event (AE) reporting, physical, neurological and ophthalmic 
examinations, body weight, vital signs, hematology, biochemistry, urinalysis, and 
electrocardiograms (ECG). 
6.5.2 Pharmacodynamics 
GZ/SAR402671 pharmacodynamics will be further evaluated in this long term study. Blood 
and/or plasma samples will be collected to evaluate GL-3, lyso GL-3, GM3, and GL-1. Urine 
samples will be collected to evaluate GL-3 levels. Blood and/or plasma and urine samples will 
also be collected to evaluate exploratory biomarkers including but not limited to high sensitivity 
cardiac troponin T, Chitotriosidase activity (via plasma) and podocyturia (via urine).  
6.5.3 Exploratory efficacy 
The exploratory efficacy of GZ/SAR402671 will be further evaluated in this long term study 
through changes in GL-3 scores as evaluated by light microscopy in skin biopsy, patient reported 
outcome (PRO) questionnaires, and urinary albumin and protein [albumin to creatinine ratio 
(ACR) and protein to creatinine ratio (PCR)]. In addition, given the 36 month total treatment 
duration of ACT13739 and in LTS14116 combined, exploratory efficacy of GZ/SAR402671 will 
also be evaluated through changes in echocardiograms, brain magnetic resonance imaging (MRI) 
and estimated glomerular filtration rate (eGFR).  
6.5.4 Pharmacokinetics 
Single pharmacokinetic samples are to be collected at clinical visits. Resulting data will be used as 
part of the GZ/SAR402671 clinical development program in population-based modeling to 
identify common factors that contribute to GZ/SAR402671 pharmacokinetics.  
 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Patient with Fabry disease who previously completed study ACT13739. 
I 02. The patient is willing and able to provide informed consent.  
I 03. Sexually active patient is willing to practice true abstinence in line with their preferred and 
usual lifestyle or use two acceptable effective methods of contraception, including a barrier 
method such as a condom or occlusive cap (diaphragm or cervical/vault cap) with 
spermicidal foam/gel/film/cream/suppository.  
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be evaluated for 
the following exclusion criteria:  
E 01. The patient, in the opinion of the investigator, is unable to adhere to the requirements of 
the study. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
GZ/SAR402671 hard gelatin capsules will be supplied for once daily oral administration, 
containing 4 mg or 15 mg of GZ/SAR402671 (calculated with reference to the active moiety), and 
the following excipients: croscarmellose sodium, colloidal silicon dioxide, sodium stearyl 
fumarate, and microcrystalline cellulose.  Throughout this document, these doses will be referred 
to as 4 mg and 15 mg, respectively. 
GZ/SAR402671 can be administered without restriction to food. 
Between the protocol scheduled on site visits interim visits may be required for investigational 
medicinal product (IMP) dispensing.  As an alternative to between clinical visits, GZ/SAR402671 
may be supplied from the site to the patient via a sponsor-approved courier company where 
allowed by local regulations and approved by ethics committee, sponsor and the subject. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
Not applicable. 
8.3 
BLINDING PROCEDURES 
This study has an open-label design. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
All patients will receive GZ/SAR402671at the same dose level at the end of study ACT13739 (ie, 
15 mg or 4 mg in the event the GZ/SAR402671 dose was reduced in ACT13739). 
8.5 
PACKAGING AND LABELING 
GZ/SAR402671 is packaged according to good manufacturing practices and local regulatory 
specifications and requirements. 
The capsules are packaged in blister packs.  The content of the labeling is in accordance with the 
local regulatory specifications and requirements. 
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8.6 
STORAGE CONDITIONS AND SHELF LIFE 
GZ/SAR402671 must be stored between 15 to 25°C.  Investigators or other authorized persons 
(eg, pharmacists) are responsible for storing the IMP provided by the sponsor in a secure and safe 
place in accordance with local regulations, labeling specifications, policies and procedures. 
8.7 
RESPONSIBILITIES 
The investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the sponsor and in accordance with applicable regulatory requirements. 
All IMP will be dispensed in accordance with the protocol and it is the investigator's 
responsibility to ensure that an accurate record of IMP issued and returned is maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc.) should be promptly notified to the 
sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
sponsor. In this case, the investigator will be responsible for promptly addressing any request 
made by the sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical study protocol, or dispose of IMP in any other manner 
not approved of by the sponsor. 
8.7.1 Treatment accountability and compliance 
The investigator or designee will keep an accurate record of all IMP that is received, dispensed, 
and returned on a per patient basis using a IMP accountability log.  
A patient diary will be issued to the patient at the entry visit with instructions to record each dose 
received.  The patient should bring their diary and any remaining capsules to each clinic visit.  
The site staff will review the patient diary during each clinic visit and record excursions from 
treatment into the case report form (CRF).  The patient diary will be collected at the end of the 
treatment period or when GZ/SAR402671 treatment is permanently discontinued (whichever 
occurs first). 
8.7.2 Return and/or destruction of treatments 
Reconciliation of all used, partially-used or unused treatments must be performed at the site by the 
investigator or designee and the monitoring team using treatment log forms. 
Authorization for destruction will be given by the sponsor once the reconciliation has been 
completed.  This destruction can be performed at the site depending on local regulations and site 
specific capabilities; alternatively, study drug may be returned to the sponsor or designee for 
destruction. 
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8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment administered concurrently with the IMP to or by the 
patient concomitantly to any IMP(s). 
8.8.1 CYP3A4 inducers or inhibitors 
GZ/SAR402671 should not be administered concomitantly with any strong or moderate inducers 
or inhibitors of CYP3A4 per FDA classification (http://www.fda.gov/Drugs/ 
DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling).   
If a patient is inadvertently administered a strong or moderate CYP3A4 inducer or inhibitor, the 
investigator should contact the sponsor as soon as possible.  The investigator or physician should 
switch the patient to an alternative medication that is not a CYP3A4 inducer or inhibitor. 
8.8.2 Renin-Angiotensin-Aldosterone System (RAAS) blockers, pain medication and/or 
antidepressants 
If the patient is on RAAS blockers, pain medication and/or antidepressants, the investigator 
should maintain the dose recorded at screening through the duration of the study, except for safety 
reasons. 
8.8.3 Forbidden cataractogenic medications 
Given the preclinical lens findings (17), a chronic regimen (ie, more frequent than once every 2 
weeks) of any dose or route of the following medications are forbidden during the treatment 
period: 
•
Corticosteroids
However, corticosteroids may be used on a restricted basis in patients who require temporary use 
(≤1 week) for the treatment of any acute illness. Such medications must not be used on more than 
a total of 2 occasions (ie, up to 1 week per occasion) during the 30-month treatment period.  
•
Psoralens used in dermatology with ultraviolet light therapy (also known as PUVA)
•
Typical antipsychotics
- 
Atypical antipsychotics are allowed.
•
Glaucoma medications
The investigator should consider substituting medications listed above for non-
cataractogenic treatments, as appropriate.   
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8.8.4 Contraceptives 
Each patient will be required to either practice true abstinence consistent with his preferred and 
usual lifestyle or use double-contraceptive methods with their female partner for the entire 
duration of the treatment period until 90 days after last treatment with IMP: 
1. A barrier method such as a condom or occlusive cap (diaphragm or cervical/vault cap) 
with spermicidal foam/gel/film/cream/suppository, and  
2. An established non-barrier method such as oral, injected, or implanted hormonal methods, 
an intrauterine device or intrauterine system 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY ENDPOINT- SAFETY 
The primary endpoint of this study is safety. The following safety assessments will be collected 
and analyzed: 
• 
Assessment of adverse events (AEs)/treatment emergent AEs(TEAEs) 
• 
Physical examination 
• 
Neurological exam 
• 
Clinical laboratory evaluations, including hematology, biochemistry, and urinalysis 
• 
Vital signs and body weight 
• 
Ophthalmology exam 
• 
12-lead ECG  
9.1.1 Adverse events 
Adverse events, spontaneously reported by the patient or observed by the investigator, will be 
monitored throughout the study. The safety profile will be based on incidence, severity, and 
cumulative nature of TEAEs. TEAEs are defined as AEs that develop or worsen during the on-
treatment period. For this study, the on-treatment period will be defined as the period from the 
time of first dose of IMP to at least 1 month after the last administration of the IMP. For the 
purposes of the study, status of ongoing and new AEs will be assessed 1 month after the last study 
drug administration, or for patients who discontinue early, after their last completed study visit. 
Any new AE or SAE that occurs during the 1 month follow-up period and is assessed as related to 
the drug or study procedures will be reported/collected in the clinical database. 
Definitions of AEs, SAEs, and AEs of special interest (AESIs), including reporting procedures, 
can be found in Section 10.4 and Section 10.5. 
At each study visit, patients will be evaluated for new AEs and the status of existing AEs. The 
investigator may elicit symptoms using an open-ended question, followed by appropriate 
questions that clarify the patient’s verbatim description of AEs or change in concomitant 
medications. 
Adverse events will be summarized with respect to the type, frequency, severity, seriousness, and 
relatedness. Pretreatment and TEAEs will be coded to a “Preferred Term (PT)” and associated 
primary “System Organ Class (SOC)” using the Medical Dictionary for Regulatory Activities 
(MedDRA). All events will be managed and reported in compliance with all applicable 
regulations, and included in the final clinical study report. 
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9.1.2 Physical exam 
Whenever possible, the same physician should perform the physical examination at all study 
visits.  The findings of each examination will be recorded.  Each physical examination will 
include the following physical observations/measurements: 
General appearance 
Heart 
Skin 
Respiratory auscultation 
Mental status 
Head, eyes, ears, nose and 
throat 
Extremities/joints 
External genitalia 
Peripheral arterial pulses 
Lymph nodes 
Abdomen 
A site physician will assess the physical examination findings as normal, abnormal but not 
clinically significant (NCS), or abnormal and clinically significant (CS).   
9.1.3 Neurological exam 
Each neurological examination will include, but not be limited to, assessments of the patient’s 
mental, cranial nerves, motor system, deep tendon reflex, sensation, and cerebellum, and 
evaluations of pain.  The examination should be performed by the same neurologist throughout 
the study, if possible. 
9.1.4 Laboratory safety variables 
The following hematology, chemistry, and urinalysis samples will be obtained prior to 
administration of GZ/SAR402671: 
• 
Blood hematology:  Complete blood count, including white blood cell count, platelet 
count, hemoglobin, and hematocrit with absolute (not percentage) differential cell counts  
of lymphocytes, monocytes, neutrophils, basophils, eosinophils, and (if applicable) 
abnormal cells. 
• 
Blood chemistry: sodium, potassium, chloride, blood urea nitrogen, glucose, uric acid, 
calcium, phosphorus, magnesium, albumin, total protein, creatinine, aspartate 
aminotransferase, alanine aminotransferase, total bilirubin, direct bilirubin, lipase, alkaline 
phosphatase, and C reactive protein.   
• 
Urine biochemistry: Routine urinalysis (including but not limited to urine microscopy, 
metered pH, specific gravity), creatinine, total protein, and albumin. 
Analysis of all safety laboratory parameters will be conducted by a central laboratory.  Procedures 
for handling and shipment of all central laboratory samples will be included in the information 
provided by the central laboratory.  Specimens will be processed appropriately by the central 
laboratory facility and laboratory reports will be made available to the investigator in a timely 
manner to assure appropriate clinical review. 
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The investigator must score all abnormal laboratory values as either CS or NCS.  Because some 
laboratory values may be outside of the normal value range due to the underlying disease, the 
investigator should use clinical judgment when considering clinical significance.  Clinical 
significance is defined as any change in laboratory parameters from baseline, which has medical 
relevance. If CS worsening of laboratory values from baseline levels is noted, the changes will be 
documented as an AE, scored according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03 and documented on the electronic case 
report form (eCRF).   
The investigator will continue to monitor the patient with additional laboratory assessments until 
(1) values have reached normal range and/or baseline levels, or, (2) in the judgment of the 
investigator, abnormal values are not related to the administration of IMP or other protocol-
specific procedures. 
9.1.5 Vital signs and weight 
Vital signs including weight (in kg), respiratory rate, heart rate (in bpm), blood pressure 
(systolic/diastolic in mmHg), and temperature (in Celsius °C). Heart rate, systolic and diastolic 
blood pressure measured after 10 minutes in supine resting position and after 3 minutes in 
standing position.  
If a change from baseline is noted that meets the definition of an AE (see Section 10.4.1), the AE 
should be documented on the eCRF. 
9.1.6 Ophthalmology Examination 
The examination should be performed by the same ophthalmologist throughout the study, if 
possible, and will include but not be limited to, visual acuity, slit-lamp examination and 
examination of the cornea, lens, and retina. For month 6, month 18 and month 30 examinations, 
dilation of the pupils is required. Photography of the lens with broad beam and red reflex, and 
cornea with the broad beam should be done at month 30 for all patients. 
9.1.7 Electrocardiogram variables 
Standard 12-lead ECGs will be recorded using an electrocardiographic device after at least 5 
minutes in supine position.  
Electrocardiograms will be recorded in triplicate within 5 minutes with at least 1 minute between 
2 replicates.  
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Each ECG consists of a 10-second recording of the 12 leads simultaneously, leading to: 
• 
A single 12-lead ECG (25 mm/s, 10 mm/mV) printout with heart rate, PR, QRS, QT, QTc 
automatic correction evaluation, including date, time, initials, and number of the patient, 
signature of the research physician, and at least 3 complexes for each lead.  This printout 
will be retained at the site.    
• 
A digital storage that enables eventual further reading by an ECG reading center: each 
digital file will be identified by theoretical day and time, real date and real time (recorder 
time), sponsor study code, patient number (ie, 3 digits), date of birth, and site and country 
numbers, if relevant.  The digital recording, data storage, and transmission (whenever 
requested) need to comply with all applicable regulatory requirements (ie, FDA 21 CFR, 
part 11).  The central reading findings will be used for statistical analyses. 
9.2 
SECONDARY ENDPOINT – PHARMACODYNAMICS 
A secondary endpoint of this study is pharmacodynamics. The following pharmacodynamic 
endpoints will be collected and analyzed: 
• 
Plasma GL-3, lyso GL-3, GL-1 and  GM3 
• 
Urine GL-3 
• 
Exploratory blood/plasma and urine biomarkers including, but not limited to plasma high 
sensitivity cardiac troponin T, plasma Chitotriosidase assay (plus chitotriosidase 
genotyping for interpretation) and podocyturia  
9.2.1 Plasma samples for GL-3, lyso GL-3, GL-1, and GM3 
Plasma samples for GL-3, lyso GL-3, GL-1, and GM3 will be analyzed using a validated liquid 
chromatography tandem mass spectrometry (LC-MS/MS) method at a central laboratory.  Refer to 
the study manual for details on the collection, processing, storage, and shipment of these samples. 
9.2.2 High sensitivity cardiac troponin T 
Plasma samples to explore changes in high sensitivity cardiac troponin T will be analyzed at a 
central laboratory. Refer to the study manual for details on the collection, processing, storage, and 
shipment of these samples. 
9.2.3 Urine samples for GL-3 
Urine samples for GL-3 will be analyzed using a validated LC-MS/MS method at a central 
laboratory.  Refer to the study manual for details on the collection, processing, storage, and 
shipment of these samples. 
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9.2.4 Exploratory biomarkers in blood and urine 
Blood (plasma) and urine samples for exploratory biomarkers related to Fabry disease will be 
collected and analyzed later using appropriate platforms.  Refer to the study manual for details on 
the collection, processing, storage, and shipment of these samples. 
9.2.5 Podocyturia 
Urine samples will be processed to prepare cytospin slides, which will be stained for podocyte 
(podocalyxin, PCX) and parietal cell (claudin 1, CL1) markers. PCX +/CL1 − cells will be 
identified as podocytes and PCX +/CL1 + cells as parietal cells with podocyte phenotype. Cells 
with small/apoptotic and normal size nuclei will be counted separately. Terminal 
deoxynucleotidyl transferase dUTP nick end labeling staining will be performed for apoptosis. All 
counts will be corrected for urine creatinine.  
9.3 
SECONDARY ENDPOINT – EXPLORATORY EFFICACY 
A secondary endpoint of this study is exploratory efficacy. The following exploratory efficacy 
endpoints will be collected and analyzed: 
• 
GL-3 in skin biopsy 
• 
PRO questionnaires  
• 
Urinary albumin and protein  (ACR and PCR) 
• 
Echocardiogram 
• 
Brain MRI 
• 
eGFR 
9.3.1 Globotriaosylceramide in skin biopsy  
A skin biopsy will be performed for the scoring of GL-3 as evaluated by light microscopy 
optionally at month 6 and mandatorily at month 30 of the treatment period. Quantification of 
cellular GL-3 by histomorphometry through electron microscopy (EM) may also be evaluated.  
For each study site, a physician experienced in skin biopsy technique will be identified to ensure 
all tissue samples are correctly obtained and are appropriately processed for shipment.  Sample 
processing, storage, and shipment guidelines are provided in the study manual.   
Masked biopsy samples will be reviewed and scored by 3 independent pathologists using light 
microscopy.  GL-3 clearance is scored as none/trace (0), mild (1), moderate (2), or severe (3) GL-
3 accumulation/inclusions.  For superficial capillary endothelium, discrepant scoring will be 
resolved by an adjudication process in which the slide will be reread by the original independent 
pathology reviewers.  If a majority score cannot be derived from the adjudication process, then the 
median adjudicated score will be used.   
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9.3.2 Patient reported outcome questionnaires 
Upon arrival at applicable study visits, the patient will complete PRO questionnaires first.  PROs 
will be completed before dosing, before completing any other health data forms, and before 
participating in any clinical assessments by the investigator or other healthcare provider(s).  These 
questionnaires will be administered by individuals trained in the administration of standardized 
questionnaires.  Specific instructions for the administration of PRO questionnaires are provided in 
study manual. 
9.3.2.1 Short Form-36 
The Short Form-36 (SF-36) health survey is a patient-reported survey of patient health. The SF-36 
consists of eight scaled scores, which are the weighted sums of the questions in their section. Each 
scale is directly transformed into a 0-100 scale on the assumption that each question carries equal 
weight. The lower the score, the more the disability. The higher the score the less disability i.e. a 
score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. 
The eight sections are: vitality, physical functioning, bodily pain, general health perceptions, 
physical role functioning, emotional role functioning, social role functioning, mental health. 
9.3.2.2 Gastrointestinal questionnaire 
Gastrointestinal symptoms (degree and frequency of abdominal pain, bowel movements and stool 
consistency) of Fabry disease will be captured using a modified version of the inflammatory 
bowel severity scoring system (18). 
9.3.2.3 Beck Depression Inventory- Second Edition (BDI-II) 
The Beck Depression Inventory Second Edition is a 21-item self-report inventory intended to 
assess the existence and severity of symptoms of depression as listed in the American Psychiatric 
Association's Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV; 
1994) (19). Details of BDI-II will be described in the study manual. 
9.3.3 Protein excretion from urine  
Protein excretion will be evaluated from the median of 3 timed overnight urine samples collected 
between 4 to 7 days of each other. All urine samples must be collected within a 16-day period.  
All 3 samples must be collected regardless of the results. Specific parameters that will be 
measured and reported include ACR and PCR.   
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9.3.4 Echocardiogram 
A 2-dimensional and M-mode echocardiograph with Doppler will include but not be limited to: 
ventricular cavity size, valve characterization, ejection fraction, ventricular wall thickness, 
regional wall motion, diastolic function, and pericardium characterization.  Pulmonary blood 
pressure and blood flow will be determined by Doppler ultrasound. 
Two copies of the echocardiograph recording will be generated for each study time point.  One 
copy will be kept at the study site with a site physician interpretation.  A site physician will assess 
the echocardiograph in an overall conclusion as normal, abnormal but not CS, or abnormal and 
CS.  Wherever possible, the same physician should review all echocardiographs for a given 
patient.  If the investigator determines the echocardiograph is abnormal and CS and a change from 
Screening, the result will be documented as an AE. 
The second copy will be sent to the central laboratory for analysis.  The central laboratory 
findings will be used for statistical analyses.  Specific procedures for these tests are supplied in 
the study manual.  
9.3.5  Brain magnetic resonance imaging 
A brain MRI (without contrast agent) will include, but not be limited to assessments of number 
and volume of white matter lesions, stroke, Pulvinar sign and other significant abnormalities.  
Two copies of the MRI recording will be generated for each requested timepoint.  One copy will 
be kept at the study site with the interpretation of a site physician.  A site physician will assess the 
MRI and record an overall conclusion as normal, abnormal but not CS, or abnormal and CS.  If 
the investigator determines the MRI is abnormal and CS and a change from baseline, the result 
will be documented as an AE. 
The second copy will be sent to the central laboratory for analysis.  The central laboratory 
findings will prevail and be used for statistical analyses. 
See the study imaging manual for procedures for sending assessments to the central analysis 
laboratory. Brain MRI results will be reported to the investigator. 
9.3.6 Estimated glomerular filtration rate 
Estimated GFR will be calculated by the central laboratory using an isotope dilution mass 
spectrometry-calibrated serum creatinine assay and the Chronic Kidney Disease Epidemiology 
Collaboration equation (20).  
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9.4 
OTHER ENDPOINTS – PHARMACOKINETICS 
9.4.1 Sampling time 
One pharmacokinetic sample to be collected at each visit indicated in Section 1.2 within 1 to 8 
hours following oral administration of GZ/SAR402671. The time of GZ/SAR402671 
administration on the day of the PK sample collection as well as the time of the PK sample 
collection is to be recorded in the eCRF. PK sample during the early withdrawal (if applicable) 
and post treatment follow up visit will be collected at any time during the visit. 
9.4.2 Pharmacokinetics handling procedure 
Table 1 - Summary of plasma sample handling procedures 
 
GZ/SAR402671 
Blood sample volume 
4 mL 
Anticoagulant 
K2EDTA 
Handling procedures 
See study specific laboratory manual 
Plasma aliquot split 
Yes, 3 aliquots 
Plasma storage conditions 
Keep in upright position at -70°C 
Plasma shipment conditions 
Frozen, on dry ice 
 
9.4.3 Bioanalytical method 
GZ/SAR402671 plasma concentrations will be determined using a validated LC-MS/MS method 
(DMPK15-R012) with a lower limit of quantification of 0.5 ng/mL under the responsibility of 
QPS, Newark, Delaware, USA.  
9.4.3.1 Pharmacokinetics parameters 
Given that single pharmacokinetic samples will be collected at clinical visits, no pharmacokinetic 
parameters will be generated. Plasma concentration data will be used as part of the 
GZ/SAR402671 clinical development program in population-based modeling to identify common 
factors that contribute to GZ/SAR402671 pharmacokinetics. 
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9.5 
ESTIMATED SAMPLED BLOOD VOLUME 
Table 2 - Estimated sample blood volume 
Type 
Volume per sample 
Sample number 
Volume per study 
Hematology 
2 mL 
6 
12 mL 
Biochemistry (includes eGFR) 
10 mL 
6 
60 mL 
High sensitivity cardiac troponin T 
2 mL 
3 
6 mL 
Plasma GL-3, lyso GL-3, GM3 
10 mL 
4 
40 mL 
Exploratory biomarkers 
10 mL 
4 
40 mL 
Pharmacokinetics 
4 mL 
4 
16 mL 
Total 
 
 
174 mL 
 
 
9.6 
FUTURE USE OF SAMPLES 
For patients who have consented to it, left over samples following testing may be used for other 
research purposes (excluding genetic analysis) related to Fabry disease and/or to GZ/SAR402671.  
These other research analyses will help to further understand Fabry disease, drug response, to 
develop and/or validate a bioassay method, or to identify new drug targets or biomarkers. 
These samples will remain labeled with the same identifiers than the one used during the study 
(ie, subject ID). They will be transferred to a Sanofi site (or a subcontractor site) which could be 
located outside of the country where the study is conducted. The sponsor has included safeguards 
for protecting subject confidentiality and personal data (see Section 14.3 and Section 14.5). 
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10 
STUDY PROCEDURES 
This section describes the evaluations that are to take place during the study according to the 
schedule for the study procedures (Section 1.2). 
10.1 
VISIT SCHEDULE 
See Section 1.2 for the schedule study visits and study assessments. 
10.1.1 Study entry visit 
Patients enrolled in the study will have the following procedures performed at study entry. 
• 
The patient will receive information on the study objectives and procedures from the 
investigator.  
• 
The patient will have to sign the informed consent prior to any action related to the study.  
Patients who meet all the inclusion criteria and none of the exclusion criteria will be eligible for 
inclusion in the study. The study entry visit may occur at the same time as the ACT13739 week 
26 clinical visit. For the purposes of analysis in this study, data collected at screening and prior to 
first GZ/SAR402671 treatment in ACT13739 will be imported from the patient’s prior study file 
in the ACT13739 database.  Items to be imported into the LTS14116 database include 
demographic, medical/surgical history, Fabry disease history, including GLA mutations, as well as 
results from safety, pharmacodynamics, and exploratory efficacy assessments.  
10.1.2 Treatment period 
A patient diary will be issued to the patient with instructions to record each dose that will be self- 
administered, and to bring their diary and any remaining capsules to subsequent clinic visits. At 
each visit, the patient diary and remaining capsules will be reviewed and dosing information will 
be recorded in the eCRF.   
For all clinical visits during the treatment period (as indicated in Section 1.2):  
• 
the patient will take  GZ/SAR402671 in the clinic;  
• 
Blood and urine samples are to be collected before the oral administration of 
GZ/SAR402671.  
10.1.2.1 Month 6, month 18 and month 30 visits 
On the scheduled visiting days, upon arrival, the patient will complete PRO questionnaires first.  
PROs are to be completed before dosing, before completing any other health data forms, and 
before participating in any clinical assessments by the investigator or other healthcare provider(s).  
One pharmacokinetic sample is to be collected at each visit indicated in Section 1.2 within 1 to 8 
hours following oral administration of GZ/SAR402671. 
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10.1.3 Post treatment follow-up 
Patients will be followed-up during a site visit that takes place 1 month (± 7 days) after the last 
GZ/SAR402671 administration.  
This visit is to evaluate the Fabry disease biomarkers and pharmacokinetics. Patient is required to 
give blood and urine samples for analysis of these biomarkers as described in Section 1.2. 
Patients who start commercial ERT, investigational or any other FD treatment within the 1-month 
(±7 days) follow up period will not be considered for follow up assessments. 
During the follow up period TEAE will continue to be collected up to the end of the period the 
date of start of new treatment. 
10.2 
DEFINITION OF SOURCE DATA 
Source data includes all information in original records and certified copies of original records of 
clinical findings, observations, or other activities necessary for the reconstruction and evaluation 
of the trial.  Source data are contained in source documents. 
Source documents are original documents, data and records (eg, hospital records, clinical and 
office charts, laboratory reports and notes, memoranda, patient diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcripts 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, patient files, and records kept at the pharmacy, at the 
laboratories, and at medical-technical departments) involved in the clinical study.  Source 
documentation must be maintained to support information provided in the eCRF. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible.  If the IMP is stopped, then it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the eCRF. In any case, the 
patient should remain in the study as long as possible. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation because of suspected AEs may be considered by the 
investigator after discussions with the sponsor. After close and appropriate clinical/and or 
laboratory monitoring, once the investigator considers, according to his/her best medical judgment 
that the occurrence of the concerned event was unlikely due to the IMP, the safety of the patient is 
not affected, and if the selection criteria for the study are still met (refer to Section 7.1 and 
Section 7.2).  Treatment with the IMP may be re-initiated after discussion with the sponsor.  For 
all temporary treatment discontinuations, the duration should be recorded by the investigator in 
the appropriate eCRF pages.  
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10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the investigator or the patient not to re-expose the patient to the IMP at 
any time. 
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the investigator’s decision.  All efforts should be made 
to document the reasons for treatment discontinuation and this should be documented in the 
eCRF. 
The following may be justifiable reasons for the investigator or sponsor to discontinue a patient 
from treatment: 
• 
The patient was erroneously included in the study (ie, was found to not have met the 
inclusion/exclusion criterion). 
• 
The patient experiences an intolerable or unacceptable AE. 
• 
The patient is unable to comply with the requirements of the protocol, including failure to 
appear at study visits or refusal of clinical study material administration. 
• 
The study is terminated by the sponsor. 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation before making a decision of permanent discontinuation of the IMP for the concerned 
patient.  
10.3.4 Handling of patients after permanent treatment discontinuation 
If a patient decides to discontinue participation in the study, he should be contacted by the 
investigator in order to obtain information about the reason(s) for discontinuation and collection 
of information regarding any potential AEs. 
Patients will be followed-up according to the study procedures as specified in this protocol up to 
the scheduled date of study completion including follow up phone calls at 1 month ±7 days after 
the last GZ/SAR402671 administration, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. Patients who discontinue 
GZ/SAR402671 and start commercial ERT, investigational or any other Fabry disease treatment 
within the 1-month (±7 days) follow up period will not be contacted for follow up.  
If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedure normally planned for the early withdrawal visit. 
All cases of permanent treatment discontinuation should be recorded by the investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
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10.3.5 Procedure and consequence for patient withdrawal from study  
A patient may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason.  
Withdrawal of consent for treatment should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-patient contact follow-up (eg, medical 
records check). Patients requesting withdrawal should be informed that withdrawal of consent for 
follow-up may jeopardize the public health value of the study.  
If possible, the patient is to complete the procedures planned for early withdrawal visit. 
For patients who fail to return to the site, the investigator should make the best effort to contact 
the patient (eg, contacting patient’s family or private physician, reviewing available registries or 
health care databases), and to determine his health status, including at least his vital status. 
Attempts to contact such patients must be documented in the patient’s records (eg, times and dates 
of attempted telephone contact, receipt for sending a registered letter).   The statistical analysis 
plan (SAP) will specify how these patients lost to follow-up for their primary endpoints will be 
considered. 
Patients who have withdrawn from the study cannot be retreated in the study. Their treatment 
numbers must not be reused. 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
10.4.1.2 Serious adverse event 
A SAE is any untoward medical occurrence that at any dose: 
• 
Results in death, or 
• 
Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• 
Results in persistent or significant disability/incapacity, or 
• 
Is a congenital anomaly/birth defect 
• 
Is a medically important event 
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Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
medical or surgical intervention (ie, specific measures or corrective treatment) to prevent one of 
the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered as a medically important event. The list is not 
intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence seizures, etc). 
- 
Development of drug dependence or drug abuse 
- 
ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN 
- 
Suicide attempt or any event suggestive of suicidality 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
- 
Bullous cutaneous eruptions 
- 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
(only if judged unusual/significant by the investigators in studies assessing specifically 
the effect of a study drug on these diseases). 
10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or non-serious) of scientific and medical concern specific to the 
sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
investigator to the sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added or removed 
during a study by protocol amendment. 
Adverse events of special interest for this study include: 
• 
Symptomatic overdose (serious or non-serious) with IMP 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
investigator or spontaneously notified by the patient (not based on systematic pills 
count) and defined  as any dose of IMP that exceeds the prescribed amount.  
- 
Of note, asymptomatic overdose has to be reported as a standard AE. 
• 
New or worsening lens opacities and cataracts 
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• 
Increase in ALT (see the “Increase in ALT” flow diagram in Section 17 (Appendix A) of 
the protocol) 
• 
Pregnancy of a female partner of a male patient enrolled in LTS14116.  
10.4.2 Evaluation of adverse events/serious adverse events 
10.4.2.1 Relationship to Study Treatment 
Assessment of the association between the AE and study exposure is important for regulatory 
reporting.  For each AE the investigator determines whether there is a reasonable possibility that 
the AE may have been caused by the study treatment according to the categories below: 
• 
Not Related: There is no suspicion of a causal relationship between exposure and the AE. 
• 
Unlikely Related: There is no evidence for a causal relationship between exposure and the 
AE; however, such a relationship cannot be ruled out. 
• 
Possibly Related: There is some evidence supporting the possibility of a causal 
relationship between exposure and the AE. 
• 
Related: There is strong evidence that there is a causal relationship between exposure and 
the AE. 
A relationship to the IMP must be given for each AE recorded, even if there is only limited 
information at the time. 
The investigator may change his/her opinion of causality in light of follow-up information, 
amending the AE report accordingly. 
10.4.2.2 Severity grading 
Adverse events and laboratory abnormalities will be assessed according to the NCI CTCAE 
v4.03, which will be provided in the study manual and may be accessed through the NCI website 
at http://ctep.info.nih.gov/reporting/ctc.html. 
Note that severity grading is not the same as “seriousness,” which is defined in Section 10.4.1. 
Seriousness serves as a guide for regulatory reporting obligations. 
10.4.2.3 Outcome 
Outcome describes the status of the AE. The investigator will provide information regarding the 
patient outcome of each AE. 
Definitions for possible results of an AE outcome: 
• 
Fatal: The termination of life as a result of an AE. 
• 
Not recovered/not resolved: The patient has not recuperated or the AE has not improved. 
• 
Recovering/resolving: The patient is recuperating or the AE is improving. 
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• 
Recovered/resolved: The patient has recuperated or the AE has resolved. 
• 
Recovered with sequelae/resolved with sequelae: The AE has resolved, but the patient has 
been left with symptoms or pathology. 
• 
Unknown: Not known, not observed, not recorded, or refused. 
10.4.2.4 Action taken regarding investigational medicinal product 
The investigator will be required to provide the action taken regarding IMP in response to the AE.  
Options include: 
• 
Dose not changed: No change in administration of the IMP. 
• 
Dose reduced: Reduction in the frequency, strength or amount of IMP administered. 
• 
Drug (IMP) interrupted: Temporary interruption (termination) in administration of the 
IMP. 
• 
Drug (IMP) withdrawn: Administration of the IMP terminated (no further dosing). 
• 
Not applicable: Determination of a value is not relevant in the current context. 
• 
Unknown: Not known, not observed, not recorded, or refused. 
10.4.3 General guidelines for reporting adverse events 
• 
All AEs, regardless of seriousness or relationship to IMP, spanning from the signature of 
the informed consent form until the end of the study as defined by the protocol for that 
patient, are to be recorded on the corresponding page(s) or screen(s) of the eCRF. 
• 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s).  
• 
The investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the sponsor.  
• 
When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
• 
Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
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Instructions for AE reporting are summarized in Table 3.  
10.4.4 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the investigator must immediately: 
•
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of
the eCRF; the system will automatically send a notification to the monitoring team after
approval of the investigator within the eCRF or after a standard delay.
•
SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the
dates on which these examinations were performed, to the representative of the monitoring
team whose name, fax number, and email address appear on the clinical trial protocol.
Care should be taken to ensure that the patient's identity is protected and the patient's
identifiers in the clinical trial are properly mentioned on any copy of a source document
provided to the sponsor. For laboratory results, include the laboratory normal ranges.
•
All further data updates should be recorded in the eCRF as appropriate, and further
documentation as well as additional information (for laboratory data, concomitant
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team
within 24 hours of knowledge of the SAE. In addition, every effort should be made to
further document any SAE that is fatal or life threatening within a week (7 days) of the
initial notification.
•
A back-up plan (using a paper CRF process) is available and should be used when the
eCRF system does not work.
Any SAE brought to the attention of the investigator at any time after the end of the study by the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.5 Guidelines for reporting adverse events of special interest 
For AESIs, the sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.4, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the eCRF. Instructions for AE 
reporting are summarized in Table 3. 
10.4.6 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by the sponsor are provided 
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Table 3 - Summary of adverse event reporting instructions 
Case Report Form completion 
Event category 
Reporting 
timeframe 
Specific events in this 
category 
AE 
form 
Safety 
Complementary 
Form 
Other 
specific 
forms 
Adverse Event (non-
SAE, non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse 
Event (non-AESI or 
AESI) 
Expedited (within 
24 hours) 
Any AE meeting seriousness criterion 
per Section 10.4.1.2 
Yes 
Yes 
No 
Adverse Event of 
Special Interest  
Expedited (within 
24 hours) 
Symptomatic overdose 
Yes 
Yes 
No 
 
 
ALT ≥ 3 ULN or ALT ≥ 2X treatment 
baseline value 
Yes 
Yes 
Yes 
 
 
Lens opacities and cataracts 
Yes 
Yes 
No 
 
 
Pregnancy 
Yes 
Yes 
Yes 
AE: adverse event; AESI: adverse event of special interest; ALT: alanine aminotransferase; AST: aspartate aminotransferase; SAE: serious 
adverse event; ULN: upper limit of normal. 
10.5 
PREGNANCY REPORTING  
Male patients will be instructed to notify the investigator immediately if they discover that their 
female sexual partner is pregnant. 
If the investigator learns of a report of pregnancy at any time after signing the informed consent, 
the investigator should follow the instructions in Section 10.4.4 to contact the sponsor within 
24 hours; however, the investigator will be asked to complete the Pregnancy forms in addition to 
AE forms.  The pregnancy will be followed until the outcome of the pregnancy is known (eg, live 
birth or stillbirth).  The investigator will be responsible for this follow-up. 
If not otherwise established, the investigator will inform the patient that the sponsor is required to 
gather information regarding the course and outcome of the pregnancy after exposure to a study 
product.  The progress of the pregnancy must be followed until the outcome of the pregnancy is 
known (ie, delivery, elective termination, or spontaneous abortion).  If the pregnancy results in the 
birth of a child, additional follow-up information may be requested. 
The investigator will be asked to obtain follow-up information no later than 2 months after the 
gestational period to obtain maternal/fetal/neonatal outcome and any other relevant information. 
Follow-up information may be requested at additional time points.  All study related 
visits/contacts involving a known pregnancy should include pregnancy status assessment until 
pregnancy outcome is known. 
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10.6 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the sponsor will report in an expedited manner: 
• 
All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, independent ethics committees (IECs)/institutional review 
boards (IRBs) as appropriate and to the investigators.    
• 
All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
Any other AE not listed as an expected event in the Investigator’s brochure or in this protocol will 
be considered unexpected. 
The sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
 
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11 
STATISTICAL CONSIDERATIONS 
The data collected in this study represents an additional 30 months of extended treatment in 
patients who completed their first 6 months of treatment in study ACT13739. As the intention is 
to evaluate up to 36 months of GZ/SAR402671, baseline for this study will represent the 
GZ/SAR402671 treatment baseline and will be defined as the last assessment prior to the first 
GZ/SAR402671 administration. Therefore all baseline assessment values used in the calculations 
for this study will be those imported from ACT13739 study database.  
A SAP will be written and finalized prior to database lock to give guidance to the statistical 
analysis. It will be in compliance with the International Conference on Harmonisation (ICH) and 
Food and Drug Administration’s Guidance for Industry: Statistical Principles for Clinical Trials. 
The sponsor or its designee will perform the statistical analysis of the data from this study. The 
analysis will be performed using the SAS® statistical software system Version 9.1 3 or higher. 
All eCRF data, as well as any outcomes derived from the data, will be displayed in patient data 
listings.  Patient data listings will be presented for all patients enrolled into the study.  Categorical 
variables will be summarized using frequencies and percentages, and continuous variables will be 
summarized using descriptive statistics (number of patients with observation, mean, standard 
deviation, median, minimum, and maximum).  Graphical displays will be presented as 
appropriate.  
11.1 
DETERMINATION OF SAMPLE SIZE 
The maximum enrollment possible for this study will be determined by the final number of 
patients completing study ACT13739. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who signed the informed consent.  
All screened patients will be included in a summary of patient accountability for this study, 
including patient disposition.  Patient enrollment and disposition will be summarized for the 
overall patient set.  Summary of patient disposition will include the frequency and percentages of 
patients who enrolled, received study treatment, completed/discontinued study treatment 
(including reasons for discontinuation), and completed/discontinued the post-treatment safety 
follow-up. 
11.3 
ANALYSIS POPULATIONS 
The full analysis set and the Safety Set will include all patients who receive at least 1 dose of 
study treatment in this study.  No Per-Protocol Set (PPS) will be defined for this study; however, 
selected outcomes may be summarized for the ACT13739 PPS, as defined in the SAP of that 
study, if applicable.  
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11.4 
STATISTICAL METHODS 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure will be assessed and summarized will be presented for all 
patients as detailed in the SAP.  
11.4.2 Analyses of primary endpoints – safety 
The safety evaluation will be based upon the review of the individual values (clinically significant 
abnormalities), descriptive statistics (summary tables, graphics) and if needed on statistical 
analysis (appropriate estimations, confidence intervals). See Section 9.1 for additional details on 
safety assessments.  
All the safety analyses will be performed using the safety population. 
11.4.2.1 Adverse events 
11.4.2.1.1 Definitions 
AEs will be coded according to MedDRA. 
The AEs will be classified into pre-defined standard categories according to chronological 
criteria: 
• 
Treatment-emergent AEs (TEAEs): AEs that occurred or worsened during the on-
treatment period of this study; 
• 
Post-treatment AEs: AEs that occurred or worsened during the post-treatment period. 
If the start date of an AE is incomplete or missing, then the AE will be considered as a TEAE 
unless a partial date shows it as a post-treatment event. 
All AEs reported in the study will be listed, sorted by subject, onset date.  
11.4.2.1.2 Treatment-emergent adverse events 
Subjects presenting TEAEs will be listed sorted by treatment group, system-organ class and 
preferred term. 
The number and the percentage of subjects with at least one TEAE, severe TEAE, serious TEAE 
and TEAE leading to treatment discontinuation will be summarized by treatment. 
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Treatment-emergent AEs will be summarized by treatment, tabulating: 
• 
The number and percent of subjects with at least one TEAE within each and overall 
system organ class(es); 
• 
The number and percent of subjects experiencing each preferred term in each system 
organ class; 
• 
The number of occurrences of all preferred terms within each and overall system-
organ class(es); 
• 
The number of occurrences of each preferred term in each system-organ class. 
11.4.2.1.3  Deaths, serious, and other significant adverse events 
Any deaths and SAEs will be listed. 
11.4.2.1.4 Adverse events leading to treatment discontinuation 
Any AEs leading to treatment discontinuation will be listed. 
11.4.2.1.5 Adverse events of special interest 
Adverse events of special interest will be listed.  
11.4.2.2 Clinical laboratory tests 
Observed values and changes from treatment baseline to study time points will be summarized 
descriptively.  All laboratory values will be classified as normal, above normal, or below normal 
based on normal ranges provided by the laboratory.  Frequencies of clinically significant 
abnormal values and shifts from baseline to study time points will be summarized. Patient listings 
will be provided. 
11.4.2.3 Physical examinations, neurological examinations, and ophthalmology 
examinations 
The frequencies and percent of patients with normal/abnormal findings at clinical visits will be 
summarized. 
11.4.2.4 Vital signs  
For vital signs, descriptive statistics (N, mean, standard deviation, median, minimum, and 
maximum) will be presented for temperature (°C), blood pressure, heart rate, respiratory rate, and 
weight (kg) at each visit. Changes from treatment baseline to each visit will also be presented. 
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11.4.2.5 Electrocardiograms 
Electrocardiogram variables as well as changes from treatment baseline in these variables, using 
descriptive statistics (N, mean, standard deviation, median, minimum and maximum); will be 
presented for appropriate visits. Likewise, ECGs variables will be summarized using frequencies 
and percents at appropriate visits. 
11.4.3 Analyses of secondary endpoints – pharmacodynamics 
Pharmacodynamic parameters will be summarized for each visit using descriptive statistics. 
Change from treatment baseline will be calculated and summarized. See Section 9.2 for 
additional information on pharmacodynamic assessments.   
11.4.4 Analyses of secondary endpoints - exploratory efficacy 
Change from treatment baseline and 95% CIs for exploratory endpoints will be summarized using 
descriptive statistics as appropriate. See Section 9.3 for additional information exploratory 
efficacy assessments.  
11.4.4.1 Echocardiograms 
Continuous echocardiogram variables as well as changes from treatment baseline in these 
variables, using descriptive statistics (N, mean, standard deviation, median, minimum and 
maximum); will be presented for appropriate visits. Likewise, categorical echocardiogram 
variables will be summarized using frequencies and percents at appropriate visits. 
11.4.4.2 Analyses of Patient Reported Outcomes  
All quality of life data will be summarized by questionnaire, relevant scale or summary scores, 
and time point. No statistical inference will be performed. 
11.4.5 Multiplicity considerations 
No adjustments for multiple testing will be utilized. 
11.5 
INTERIM ANALYSIS 
No interim analysis is planned.  
 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the sponsor, the investigator, delegated investigator staff 
and subinvestigator, in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, and the ICH guidelines for good clinical practice (GCP), all applicable laws, rules 
and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with sponsor public disclosure commitments.  
12.2 
INFORMED CONSENT 
The investigator (according to applicable regulatory requirements), or a person designated by the 
investigator, and under the investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the Ethics Committee (IRB/IEC). All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent form should be 
signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written informed consent form will be provided to the patient.  
The informed consent form used by the investigator for obtaining the patient's informed consent 
must be reviewed and approved by the sponsor prior to submission to the appropriate Ethics 
Committee (IRB/IEC) for approval/favorable opinion. 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the investigator or the sponsor must submit this clinical trial 
protocol to the appropriate IRB/IEC, and is required to forward to the respective other party  a 
copy of the written and dated approval/favorable opinion signed by the Chairman with  IRB/IEC 
composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s brochure, investigator’s 
curriculum vitae [CV], etc) and the date of the review should be clearly stated on the written 
(IRB/IEC) approval/favorable opinion. 
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IMP will not be released at the study site and the investigator will not start the study before the 
written and dated approval/favorable opinion is received by the investigator and the sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the IRB/IEC before implementation, unless the change is necessary to eliminate an 
immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as 
possible. It should also be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical trial, in particular any change in safety. All updates to the 
Investigator’s brochure will be sent to the IRB/IEC. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the sponsor (including security rules). The 
investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The investigator may appoint such other individuals as he/she may deem appropriate as 
subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All subinvestigators shall be appointed and listed in a timely manner. The 
subinvestigators will be supervised by and work under the responsibility of the investigator. The 
investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the CRFs. Thus, the main duty of 
the monitoring team is to help the investigator and the sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The informed 
consent form will include a statement by which the patient allows the sponsor’s duly authorized 
personnel, the Ethics Committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records  which support the data on the CRFs (eg, patient's medical file, 
appointment books, original laboratory records, etc). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
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13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the sponsor to record (according to sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the sponsor may generate additional requests (DRF) to 
which the investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the eCRF.  
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the sponsor and investigator study files. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each investigator and subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
Ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The subinvestigators shall be bound by the same obligation as the investigator. The investigator 
shall inform the subinvestigators of the confidential nature of the clinical trial. 
The investigator and the subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The investigator shall not and shall cause the delegated investigator staff /subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the investigator and/or the subinvestigators shall provide all assistance 
required by the Sponsor, at the sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
• 
The patient's personal data, which are included in the sponsor database shall be treated in 
compliance with all applicable laws and regulations; 
• 
When archiving or processing personal data pertaining to the investigator and/or to the 
patients, the sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
• 
The sponsor also collects specific data regarding investigator as well as personal data from 
any person involved in the study which may be included in the sponsor’s databases, shall 
be treated by both the sponsor and the investigator in compliance with all applicable laws 
and regulations. 
• 
Patient race or ethnicity (ethnicity: not Hispanic or Latino; race: American Indian or 
Alaska native, Asian, Black, Native Hawaiian or other Pacific Islander, White and ‘not 
reported’) will be collected in this study because these data are required by several health 
authorities. 
14.6 
INSURANCE COMPENSATION 
The sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship.  This insurance policy is in accordance with local laws and requirements. 
The insurance of the sponsor does not relieve the investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
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14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, Good Clinical Practice and 
applicable regulatory requirements, the investigator should permit auditing by or on the behalf of 
the sponsor and inspection by regulatory authorities. 
The investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the investigator is notified of a planned inspection by the authorities, he will inform 
the sponsor and authorize the sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the investigator to the sponsor. 
The investigator shall take appropriate measures required by the sponsor to take corrective actions 
for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the sponsor  
The sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• 
The information on the product leads to doubt as to the benefit/risk ratio; 
• 
Patient enrollment is unsatisfactory; 
• 
The investigator has received from the sponsor all IMP, means and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon; 
• 
Non-compliance of the investigator or subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP. 
In any case the sponsor will notify the investigator of its decision by written notice. 
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14.8.2 By the investigator 
The investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the sponsor’s written consent, being understood that the sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the sponsor agrees that, consistent with scientific 
standards, a primary presentation or publication of the study results based on global study 
outcomes shall be sought. However, if no multicenter publication is submitted, underway or 
planned within twelve (12) months of the completion of this study at all sites, the investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other investigators and stakeholders. The investigator shall provide the sponsor with a copy of any 
such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication.  In addition, if requested by the sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 90 
days, to allow for filing of a patent application or such other justified measures as the sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The investigator shall not use the name(s) of the sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the sponsor. The sponsor 
shall not use the name(s) of the investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the investigator and by the sponsor and the signed amendment will be filed with this 
clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the informed consent form. The 
investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
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16 
BIBLIOGRAPHIC REFERENCES 
 1. Desnick RJ, Ioannou YA, Eng CM. a-Galactosidase A Deficiency: Fabry Disease. In: Valle D, 
Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballani A, Gibson K, Mitchell G. 
ed. OMMBID - The Online Metabolic and Molecular Bases of Inherited Diseases. New 
York,NY: McGraw-Hill;2014. 
http://ommbid.mhmedical.com/conent.apsx?bookid=474&Sectionid=45374153. Accessed 
July 31, 2014. 
2. Tsakiris D, Simpson HK, Jones EH, Briggs JD, Elinder CG, Mendel S, et al.  Report on 
management of renal failure in Europe, XXVI, 1995. Rare diseases in renal replacement 
therapy in the ERA-EDTA Registry.Nephrol Dial Transplant. 1996;11 suppl 7:4-20. 
3. Deegan PB, Baehner AF, Barba Romero MA, Hughes DA, Kampmann C, Beck M, et al. 
Natural history of Fabry disease in females in the Fabry Outcome Survey. J Med Genet. 2006 
Apr;43(4):347-52. 
4. Gupta S, Ries M, Kotsopoulos S, Schiffmann R. The relationship of vascular glycolipid 
storage to clinical manifestations of Fabry disease: a cross-sectional study of a large cohort of 
clinically affected heterozygous women. Medicine. 2005 Sep;84(5):261-8. 
5. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and 
impact of disease in a cohort of 60 obligate carrier females. J Med Genet. 2001 
Nov;38(11):769-75. 
6. Whybra C, Kampmann C, Willers I, Davies J, Winchester B, Kriegsmann J, et al. Anderson-
Fabry disease: clinical manifestations of disease in female heterozygotes. J Inherit Metab Dis. 
2001 Dec;24(7):715-24. 
7. Ries M, Ramaswami U, Parini R, Lindblad B, Whybra C, Willers I, et al. The early clinical 
phenotype of Fabry disease: a study on 35 European children and adolescents. Eur J Pediatr. 
2003 Nov;162(11):767–72. 
8. Ramaswami U, Whybra C, Parini R, Pintos-Morell G, Mehta A, Sunder-Plassmann G, et al. 
Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey. 
Acta Paediatr. 2006 Jan;95(1):86–92. 
9. Hopkin RJ, Bissler J, Banikazemi M, Clarke L, Eng CM, Germain DP, et al.  Characterization 
of Fabry disease in 352 pediatric patients in the Fabry Registry. Pediatr Res. 2008 
Nov;64(5):550-5. 
10. Wilcox WR, Oliveira JP, Hopkin RJ, Ortiz A, Banikazemi M, Feldt-Rasmussen U, et al. 
Females with Fabry disease frequently have major organ involvement: Lessons from the Fabry 
Registry. Mol Genet Metab. 2008 Feb;93(2):112-28. 
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11. Schiffmann R, Warnock DG, Banikazemi M, Bultas J, Linthorst GE, Packman S, et al. Fabry
disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events
before enzyme replacement therapy. Nephrol. Dial. Transplant. 2009 Jul;24(7):2102-11.
12. Zarate YA, Hopkin RJ. Fabry’s disease. Lancet. 2008 Oct 18;372(9647):1427-35.
13. Tøndel C, Bostad L, Hirth A, Svarstad E. Renal biopsy findings in children and adolescents
with Fabry disease and minimal albuminuria. Am J Kidney Dis. 2008 May;51(5):767-76.
14. Weidemann F, Niemann M, Breunig F, Herrmann S, Beer M, Störk S, et al. Long-term effects
of enzyme replacement therapy on Fabry cardiomyopathy: evidence for a better outcome with
early treatment. Circulation. 2009 Feb 3;119(4):524–9.
15. Najafian B, Svarstad E, Bostad L, Gubler MC, Tøndel C, Whitley C, et al. Progressive
podocyte injury and GL-3 accumulation are progressive in young patients with Fabry disease.
Kidney Int. 2011 March;79(6):663-70.
16. Lukina E, Watman N, Arreguin EA, Dragosky M, Iastrebner M, Rosenbaum H, et al.
Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1
with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study.  Blood.
2010 Nov 18;116(20):4095-8.
17. Sanofi. Investigator's Brochure - GZ/SAR402671. Edition 8. Aug 2017
18. Francis CY, Morris J, Whorwell PJ. The irritable bowel severity scoring system: a simple
method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol
Ther.1997 Apr;11(2):395-402.
19. Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory II. San Antonio,
(1996). TX: Psychological Corporation.
20. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, et al. A new
equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604-12.
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APPENDICES 
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General Guidance for the follow-up of laboratory abnormalities by Sanofi  
Neutrophils < 1500/mm3 or according to ethnic 
group
NEUTROPENIA
Repeat immediately a full blood count if value 
close to 1500/mm3
Neutrophils < 1500/mm3 confirmed 
with signs of infection  
Neutrophils < 1500/mm3 confirmed 
with no signs of infection  
1.
DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.
PERFORM biological 
investigations for infection
1.
DISCONTINUE
Investigational 
Medicinal Product
2.
INVESTIGATE for 
infection
In both situations
3.
INFORM the local monitor
4.
INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X-rays, etc.
5.
PERFORM and collect the following investigations (results): 
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella
6.
DECISION for bone marrow aspiration: to be taken in specialized unit
7.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
8.
MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
Note: 
•The procedures described in the above flowchart are to be discussed with the patient only in case 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
•For individuals of African descent, the relevant value of concern is <1000/mm3
Neutropenia is to be recorded as AE only if at least one of the criteria listed in Section 10.4.3 is met
 
(electronic 
 
 
 
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Platelets < 100 000/mm3 (rule out EDTA – induced 
pseudo-thrombocytopenia)
THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample)
Platelets  < 100 000/mm3 confirmed 
with bleeding  
Platelets  < 100 000/mm3 confirmed 
with no bleeding
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE for 
bleeding
In both situations
3.
INFORM the local Monitor
4.
QUESTION about last intake of quinine (drinks), alcoholism, heparin administration
5.
PERFORM or collect the following investigations: 
•
Complete blood count, schizocytes, creatinine
•
Bleeding time and coagulation test (fibrinogen, INR or PT, aPTT), Fibrin 
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
7.
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 1 in the case of associated anemia and/or leukopenia
•
On Day 8 if platelets remain < 50 000/mm3
8.
MONITOR the platelet count every day for at least one week and then regularly 
until it returns to normal
Note: 
The procedures above flowchart are to be discussed with the patient only in case described in the 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
Thrombocytopenia is to be recorded as AE only if at least one of the criteria listed in Section 10.4.3 
is met
 
(electronic 
 
 
 
1.0)


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INCREASE IN ALT
ALT ≥3 ULN (if baseline ALT <ULN) 
Or, ALT ≥2 times the baseline value 
(if baseline ALT ≥ULN)
ALT ≤5 ULN
(if baseline ALT < ULN)
Or, ALT ≤3 times the baseline 
value
(If baseline ALT ≥ULN)
ALT > 5 ULN
(if baseline ALT < ULN)
Or, ALT > 3 times the 
baseline value
(if baseline ALT ≥ULN)
Total bilirubin ≤2 ULN
Total bilirubin > 2 ULN
DISCONTINUE 
ADMINISTRATION OF 
INVESTIGATIONAL 
MEDICINAL PRODUCT
In ANY CASE, FOLLOW the instructions #1 to 7 listed in the box below. 
1. INVESTIGATE THE CLINICAL CONTEXT in the previous 72 hours, specifically for malaise with or without 
loss of consciousness, dizziness, and/or hypotension and/or episode of arrhythmia; rule out muscular injury
2. PERFORM the following tests: 
- LFTs : AST, ALT, Alkaline Phosphatase, Total and Conjugated Bilirubin and Prothrombin Time / INR 
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM, anti-HCV and HCV RNA , anti-CMV IgM and anti-HEV IgM antibodies, and 
depending on the clinical context, check for recent infections, eg, EBV, Herpes viruses and toxoplasma 
- Hepatobiliary ultrasonography (can be completed by other imaging investigations if needed)
3. CONSIDER auto-antibodies: anti-nuclear, anti-DNA, anti-smooth muscle, anti-LKM
4. CONSIDER consultation with hepatologist
5. CONSIDER patient hospitalization if INR>2 (or PT<50%) and/or central nervous system disturbances suggesting 
hepatic encephalopathy
6. MONITOR LFTs
- If investigational medicinal product is continued: every 48 hours until return to normal (<2ULN) or 
baseline. If ALT elevation persists beyond 2 weeks then perform LFTs every 2 weeks and 15 to 30 days after 
the last dose according to the study protocol.
- If investigational medicinal product is discontinued: as closely as possible to every 48 hours until 
stabilization then every 2 weeks until return to normal (<2ULN) or baseline or for at least 3 months, whichever 
comes last.
7. COLLECT/STORE one sample following handling procedures described in PK sections (for studies with PK 
sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of investigational medicinal product).
COMPLETE the 
specific CRF form for 
“ALT increase” 
And INFORM the 
Monitoring Team 
within 24 hours
Monitor LFTs 
every 48 hours
If Not Possible
Investigational Medicinal Product 
administration can be continued, as 
long as – under close monitoring –
conditions for stopping are not met
 
NOTE: ALT ≥ 3 ULN (IF BASELINE ALT < ULN) OR ALT ≥ 2 TIMES THE BASELINE VALUE (IF BASELINE ALT ≥ ULN) 
SHOULD BE NOTIFIED WITHIN 24 HOURS TO THE MONITORING TEAM (SEE SECTIONS 10.4.1.3, 10.4.5, AND 10.4.6). 
IN ADDITION, IF ALT < 3 ULN MEETS A SERIOUSNESS CRITERION, THE EVENT SHOULD BE NOTIFIED 
WITHIN 24 HOURS TO THE MONITORING TEAM 
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Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below
50 mL/mn
ACUTE RENAL FAILURE
Can be rapidly reversed:
• By volume repletion
• Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: anemia, 
hyperkalemia, hyperuricemia, metabolic 
acidosis, cardiac insufficiency, 
pulmonary edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
Investigational Medicinal Product by 
renal route
1.
Investigational Medicinal 
Product may be continued
2.
MONITOR serum creatinine 
until return to baseline level
1.
INFORM the local monitor
2.
DISCONTINUE
Investigational Medicinal Product 
administration
3.
HOSPITALIZATION should be 
considered and seek for nephrologic  
advice
4.
PERFORM the following 
examinations: 
•
BP, HR, hydration status, ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
COLLECT/STORE one sample 
following handling procedures 
described in PK sections (for studies 
with PK sampling) and freeze one 
serum sample (5 mL) on Day 1 
(cessation of investigational 
medicinal product)
6.
MONITOR renal function until 
return to baseline level (every day at 
the beginning, then every week)
Acute renal failure is to be recorded as AE only if at least one of the criteria listed in 
Section 10.4.3 is met
 
 
(electronic 
 
 
 
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If Increase in CPK (expressed in ULN)
> 3 ULN
Repeat immediately the count.
If confirmed, inform the local monitor and
INVESTIGATE for the origin:
- PERFORM:
•
ECG
•
CPK-MB -MM 
•
Troponin
•
Creatinine
•
Iono (k+, Ca2+)
•
Transaminases + Total and conjugated bilirubin
•
Myoglobin (serum and urines)
- COLLECT/STORE one sample following handling procedures described in PK sections (for 
studies with PK sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of 
investigational medicinal product). 
- INTERVIEW the patient about a recent intensive muscular effort, trauma, convulsions, electrical 
injury, injury or stress to the skeletal muscle, multiple intramuscular injections, recent surgery, 
concomitant medications, consumption of alcohol, morphine, cocaine.
- SEARCH for alternative causes to cardiac or muscular toxicity, ie: stroke, pulmonary infarction, 
dermatomyositis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular 
dystrophies.
If either the cardiac origin or the 
rhabdomyolysis is confirmed or if CPK 
> 10 ULN:
1. DISCONTINUE Investigational 
Medicinal Product administration
2. MONITOR CPK every 3 days for the 
first week then once weekly until return 
to normal or for at least 3 months
3. HOSPITALIZATION should be 
considered
If the cardiac origin or the rhabdomyolysis is 
ruled out and if CPK ≤10 ULN:
MONITOR CPK every 3 days for the first week 
then once weekly until return to normal or for 
at least 3 months
Muscular symptoms (myalgia, pain, weakness, 
dark urines)
Systematic CPK assessment as per 
protocol
Perform CPK
SUSPICION OF RHABDOMYOLYSIS
Suspicion of rhabdomyolysis is to be recorded as AE only if at least one of the criteria listed in Section 10.4.3 
is met
 
 
(electronic 
 
 
 
1.0)


 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
LTS14116 Amended Protocol 04
Clinical Approval
10-Nov-2017 17:32 GMT+0100
Regulatory Approval
10-Nov-2017 17:44 GMT+0100
Clinical Approval
14-Nov-2017 14:04 GMT+0100

SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) 
Page 1
STATISTICAL ANALYSIS PLAN 
An open-label, multicenter, multinational extension study of the long-term 
safety, pharmacodynamics and exploratory efficacy of GZ/SAR402671 in adult 
male patients diagnosed with Fabry disease 
GZ/SAR402671-ACT13739-LTS14116 
STATISTICIAN: 
DATE OF ISSUE: 09-Apr-2018 
Total number of pages: 
50 
NCT Number: NCT02489344


Statistical Analysis Plan  
09-Apr-2018 
GZ/SAR402671-ACT13739-LTS14116  
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 7 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 7 
1.2 
OBJECTIVES ................................................................................................................................... 7 
1.2.1 
Primary objectives ............................................................................................................................ 7 
1.2.2 
Secondary objectives ....................................................................................................................... 7 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 8 
1.4 
STUDY PLAN ................................................................................................................................... 9 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ................................ 10 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 10 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 11 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 11 
2.1.1 
Demographic and baseline characteristics .................................................................................... 11 
2.1.2 
Prior or concomitant medications ................................................................................................... 12 
2.1.3 
Efficacy endpoints .......................................................................................................................... 12 
2.1.3.1 
Primary efficacy endpoint(s) .......................................................................................................... 13 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 13 
2.1.4 
Safety endpoints ............................................................................................................................ 15 
2.1.4.1 
Adverse events variables ............................................................................................................... 16 
2.1.4.2 
Deaths ............................................................................................................................................ 16 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 17 
2.1.4.4 
Vital signs variables ....................................................................................................................... 17 
2.1.4.5 
Electrocardiogram variables .......................................................................................................... 17 
2.1.4.6 
Physical examination variables ...................................................................................................... 18 
2.1.4.7 
Neurological examination variables ............................................................................................... 18 
2.1.4.8 
Ophthalmology examination variables ........................................................................................... 18 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 18 
2.1.6 
Pharmacodynamic/genomics endpoints ........................................................................................ 19 


Statistical Analysis Plan  
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Page 3 
2.1.7 
Quality-of-life endpoints ................................................................................................................. 19 
2.1.8 
Health economic endpoints ............................................................................................................ 24 
2.1.9 
Further therapy after discontinuation of investigational medicinal product administration 
during the study .............................................................................................................................. 24 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 24 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 25 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 26 
2.3.1 
Efficacy populations ....................................................................................................................... 26 
2.3.2 
Safety population ........................................................................................................................... 26 
2.4 
STATISTICAL METHODS ............................................................................................................. 26 
2.4.1 
Demographics and baseline characteristics .................................................................................. 26 
2.4.2 
Prior or concomitant medications ................................................................................................... 27 
2.4.3 
Extent of investigational medicinal product exposure and compliance ......................................... 27 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 27 
2.4.3.2 
Compliance .................................................................................................................................... 28 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 28 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................ 28 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 28 
2.4.4.3 
Multiplicity issues ........................................................................................................................... 29 
2.4.4.4 
Additional efficacy analysis(es) ...................................................................................................... 29 
2.4.5 
Analyses of safety data .................................................................................................................. 30 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 30 
2.4.5.2 
Deaths ............................................................................................................................................ 33 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 33 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 34 
2.4.5.5 
Analyses of electrocardiogram variables ....................................................................................... 34 
2.4.5.6 
Analysis of physical examination variables .................................................................................... 34 
2.4.5.7 
Analysis of neurological examination variables ............................................................................. 35 
2.4.5.8 
Analysis of ophthalmology examination variables ......................................................................... 35 
2.4.6 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 35 
2.4.7 
Analyses of quality of life/health economics variables ................................................................... 35 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 36 
2.5.1 
General conventions ...................................................................................................................... 36 
2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 37 
2.5.3 
Missing data ................................................................................................................................... 37 
2.5.4 
Windows for time points ................................................................................................................. 39 
2.5.5 
Unscheduled visits ......................................................................................................................... 39 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 39 


Statistical Analysis Plan  
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Page 4 
2.5.7 
Statistical technical issues ............................................................................................................. 39 
3 
INTERIM ANALYSIS ..................................................................................................................... 40 
4 
DATABASE LOCK ........................................................................................................................ 41 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 42 
6 
REFERENCES ............................................................................................................................... 43 
7 
LIST OF APPENDICES ................................................................................................................. 44 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 45 


Statistical Analysis Plan  
09-Apr-2018 
GZ/SAR402671-ACT13739-LTS14116  
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Page 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ACR:  
 
albumin/creatinine ratio 
AE: 
 
 
adverse event(s) 
AESI:  
 
adverse event(s) of special interest 
ALP:  
 
alkaline phosphatase 
ALT:  
 
alanine aminotransferase 
AST:  
 
aspartate aminotransferase 
ATC:  
 
anatomic Therapeutic Chemical Classification System 
BDI:  
 
Beck Depression Inventory 
BMI:  
 
body mass index 
BQL:  
 
below quantifiable limit 
CKD-EPI: 
 
Chronic Kidney Disease Epidemiology Collaboration 
CRF:  
 
case report form 
CS: 
 
 
clinically significant 
CSR:  
 
clinical study report 
DMC:  
 
data monitoring committee 
eCRF:  
 
electronic case report form 
ECG:  
 
electrocardiogram 
eGFR:  
 
estimated glomerular filtration rate 
EM: 
 
 
electron microscopy 
ERT:  
 
enzyme replacement therapy 
GL-1:  
 
glucosylceramide 
GL-3:  
 
globotriaosylceramide 
GM3:  
 
monosialodihexosylganglioside 
HEENT: 
 
head, eyes, ears, nose, throat 
HLGT: 
 
high-level group term 
HLT:  
 
high-level term 
IDMS:  
 
isotope dilution mass spectrometry 
IMP:  
 
investigational medicinal product 
LC-MS/MS:  
liquid chromatography tandem mass spectrometry 
LLT:  
 
lower-level term 
MedDRA: 
 
Medical Dictionary for Regulatory Activities 
MRI:  
 
magnetic resonance imaging 
NA: 
 
 
not applicable 
NCS:  
 
not clinically significant 
PCR:  
 
protein/creatinine ratio 
PK: 
 
 
pharmacokinetic 
PRO:  
 
patient reported outcome 
PT: 
 
 
preferred term 


Statistical Analysis Plan  
09-Apr-2018 
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Version number: 1 
 
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Page 6 
SAE:  
 
serious adverse event 
SAP:  
 
statistical analysis plan 
SD: 
 
 
standard deviation 
SF36:  
 
short Form-36 
SOC:  
 
system organ class 
TEAE:  
 
treatment emergent adverse event 
WBC:  
 
white blood cell 
WHO-DD: 
 
World Health Organization-Drug Dictionary 


Statistical Analysis Plan  
09-Apr-2018 
GZ/SAR402671-ACT13739-LTS14116  
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 7 
1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION 
LTS14116 is an open-label, multicenter, multinational extension study of GZ/SAR402671 in adult 
male Fabry disease patients who previously completed study ACT13739 and satisfy the eligibility 
criteria. In this extension study, patient will  continue to receive once daily, oral GZ/SAR402671 
at the same dose level administered at the end of study ACT13739. 
This extension study consists of an enrollment visit, where study entry in the extension should 
occur at the same time as the ACT13739 week 26 clinical visit, followed by a treatment period up 
to 30 months (2.5 years) and 1 month follow-up for all patients completing or discontinuing the 
study medication. Patients who start commercial enzyme replacement therapy (ERT) within the  
1-month follow up period will not be considered for follow up. The maximum duration of 
participation per patient in the extension study will be approximately 31 months. 
The safety data and the results of the study will be periodically reviewed by Data Monitoring 
Committee (DMC).  
Eleven (11) adult male Fabry disease patients from 5 sites were enrolled into the ACT13739 
study, of which 8 entered the extension study LTS14116.  
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of the LTS14116 extension study is to assess the long-term safety of 
GZ/SAR402671 in adult male Fabry disease patients who previously completed study ACT13739. 
1.2.2 Secondary objectives 
The secondary objective of the LTS14116 extension study is to assess the long-term effect of 
GZ/SAR402671 on pharmacodynamic and exploratory efficacy endpoints in adult male Fabry 
disease patients who previously completed study ACT13739. 
Pharmacodynamics as measured by: 
• 
Plasma globotriaosylceramide (GL-3), lyso GL-3, glucosylceramide (GL-1) and 
monosialodihexosylganglioside (GM3) 
• 
Exploratory blood and urine biomarkers including, but not limited to, high sensitivity 
cardiac troponin T, plasma chitotriosidase assay (plus chitotriosidase genotyping for 
interpretation) and podocyturia 
• 
Urine GL-3 


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Page 8 
Exploratory efficacy as measured by: 
• 
GL-3 in skin biopsy 
• 
Urinary albumin and protein [albumin to creatinine ratio (ACR) and protein to creatinine 
ratio (PCR)] 
• 
Echocardiogram 
• 
Brain magnetic resonance imaging (MRI) 
• 
Estimated glomerular filtration rate (eGFR) 
• 
Health-related quality of life, a measure of the impact of the patient's health on his 
well-being as assessed by the patient reported Short Form generic health survey (36 items) 
(SF-36) questionnaire, Gastrointestinal questionnaire, Beck Depression Inventory- Second 
Edition (BDI-II) 
1.3 
DETERMINATION OF SAMPLE SIZE 
Eleven (11) patients were enrolled in ACT13739 study of which 9 patients completed. Therefore, 
9 is the maximum number of patients available to participate in the extension period. In total, 8 
patients gave informed consent and entered the extension study LTS14116. 


Statistical Analysis Plan  
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Page 9 
1.4 
STUDY PLAN 
The following figure describes an overview of the study design. 
Figure 1 – Overview of the study design 
 
The LTS14116 study comprises of the following timepoints/periods: 
• 
The study entry visit may occur at the same time as the week 26 clinical visit of the core 
study (ACT13739). The patients who complete study ACT13739 will sign the informed 
consent prior to any action related to the study. For the purpose of analysis in this study, 
data collected at screening and prior to the first GZ/SAR402671 administration in 
ACT13739 (including demographic, medical/surgical history, Fabry disease history, GLA 
mutations, results from safety, pharmacodynamics, and exploratory efficacy assessments) 
will be imported into the extension study (LTS14116) database.  
• 
A treatment period of 30 months. During this treatment period, the patient will take once 
daily oral dose of 15 mg or 4 mg of GZ/SAR402671 treatment on scheduled site visits 
(Months 3, 6, 9, 12, 18, and 30) as well as daily self-administer at home. A patient diary 
will be issued to patients with instructions to record each dose that will be self-
administered, and to bring their diary and any remaining capsules to subsequent clinic 
visits. At each visit, the patient diary and remaining capsules will be reviewed and dosing 


Statistical Analysis Plan  
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Page 10 
information will be recorded in the electronic case report form (eCRF). The study 
assessment clinical visits are scheduled based on the study entry day and have a ±14 day 
window period. All clinical data will be collected at specific time points according to the 
study procedure and schedule of assessments. On the clinical visits during the treatment 
period, the patient will complete any PROs before completing any other health data forms, 
and before participating in any clinical assessments. Blood and urine samples will also be 
collected before taking the treatment dose of GZ/SAR402671. An independent DMC will 
oversee safety in this study through periodic and ad-hoc reviews of study data. 
• 
A follow-up visit with a site visit 1 month (±7 days) after the last GZ/SAR402671 
administration. Patients who start commercial ERT within the 1-month follow up period 
will not be considered for follow up. 
The protocol Section 10 and the protocol Section 1.2 (Study Flow Chart) provide further details 
on the conduct and timing of study assessments.  
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
The statistical section of the protocol was never changed in an amendment. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
NA 


Statistical Analysis Plan  
09-Apr-2018 
GZ/SAR402671-ACT13739-LTS14116  
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Page 11 
2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
As LTS14116 is the extension study of the ACT13739 study, the baseline values from the 
ACT13739 study will be utilized in the analysis of the collected data from the combined 
ACT13739 and LTS14116 study periods. Therefore, in the planned analysis the baseline value is 
defined as the last available value before the first investigational medicinal product (IMP) intake 
in ACT13739 study, unless otherwise specified. Data collected in the ACT13739 study will be 
imported into the LTS14116 database, and all 11 patients who received IMP treatment in the 
ACT13739 study, regardless of whether the patient entered the LTS14116 extension study, will be 
presented in the analysis, in order to have a more complete picture of the responses over time of 
the GZ/SAR403671 treated Fabry patients..  
All baseline safety and efficacy parameters (apart from those listed below) will be presented along 
with the summary statistics in the efficacy and safety sections (Section 2.4.4 and Section 2.4.5). 
Demographic characteristics 
Demographic variables are age in years, sex (Male), race (Caucasian/White, Black, 
Asian/Oriental, Other). The demographic data collected in ACT13739 will be imported into the 
LTS14116 database. 
Medical or surgical history  
Medical/surgical parameters include body system, system/condition/diagnosis, start and stop 
dates, and ongoing status. In addition, Fabry medical history collected from the ACT13739 study 
for prespecified abnormalities, including the diagnosis date, Fabry medical history abnormality, 
description of abnormality, start and stop dates, and ongoing status, will be imported into the 
LTS14116 database. 
This information will be coded using the version of Medical Dictionary for Regulatory Activities 
(MedDRA) in effect at Sanofi at the time of LTS14116 database lock. 
Disease characteristics at baseline  
Specific disease history includes age at Fabry diagnosis in years, Leukocyte αGAL activity  
(<4.0, ≥4.0 nmol/hr/mg), Plasma αGAL activity (<1.5, ≥1.5 nmol/hr/mL), and Genotyping will be 
imported from the ACT13739 study.  


Statistical Analysis Plan  
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Vital signs  
Vital signs parameters include weight, height, and body mass index (BMI) at baseline. 
Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5. 
2.1.2 Prior or concomitant medications  
Concomitant medications taken during the LTS14116 study are to be reported in the LTS14116 
case report form (CRF) pages. All medications collected for the 11 patients who participated in 
the ACT13739 study will be imported into the LTS14116 database in order to show an overall 
profile of the patients’ long term medication use. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD), 
using the version in effect at Sanofi at the time of LTS14116 database lock. 
• 
Prior medications are those medications which the patient used prior (within 30 days 
before screening) to the first IMP intake in ACT13739 study. Prior medications could be 
discontinued before the first administration of IMP or could be ongoing during the 
treatment phase. 
• 
Concomitant medications are any treatments received by the patient concomitantly with 
the IMP, i.e., from the first IMP intake in the ACT13739 study through the day of last IMP 
intake in the LTS14116 study. A given medication can be classified both as a prior 
medication and as a concomitant medication. Concomitant medications do not include 
medications started during the residual treatment epoch or the posttreatment epoch in 
LTS14116 (as defined in the observation period in Section 2.1.4). 
• 
Posttreatment medications are those the patients took during the period starting from the 
day after the last IMP intake in the combined ACT13739/LTS14116 study period up 
through the end of follow-up phase. Medications started during the residual treatment or 
posttreatment epoch are not concomitant medications, though medications that started 
during the treatment epoch and continued into the residual epoch and posttreatment epoch 
may be classified as both concomitant and posttreatment medications. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints 
Evaluation schedule for efficacy variables is presented in protocol Section 1.2. 
All efficacy evaluations up to study closeout measurement (visit) will be included for analysis 
unless otherwise specified. Baseline for the efficacy variable is defined as the last non-missing 
value on or before the first IMP intake in ACT13739 study. 


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2.1.3.1 Primary efficacy endpoint(s) 
LTS14116 is an extension study of ACT13739. The primary objective is to evaluate the long-term 
safety of GZ/SAR402671; therefore, no primary efficacy endpoint is defined.  
2.1.3.2 Secondary efficacy endpoint(s) 
Secondary endpoint - pharmacodynamics  
The following pharmacodynamic endpoints will be collected and analyzed (see study flowchart in 
protocol Section 1.2). 
• 
Plasma GL-3, lyso GL-3, GL-1 and GM3 
• 
Urine GL-3 
• 
Exploratory blood/plasma and urine biomarkers including, but not limited to plasma high 
sensitivity cardiac troponin T, plasma Chitotriosidase assay (plus chitotriosidase 
genotyping for interpretation) and podocyturia 
Plasma samples for GL-3, lyso GL-3, GL-1, and GM3 and urine sample for GL-3 levels will be 
analyzed using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) 
method at a central laboratory.  
Plasma samples will be collected to explore changes in high sensitivity cardiac troponin T 
analyzed at a central laboratory. Blood (plasma) and urine samples for exploratory biomarkers 
related to Fabry disease will be collected and analyzed later using appropriate platforms.  
Urine samples will be processed to prepare cytospin slides, which will be stained for podocyte 
(podocalyxin, PCX) and parietal cell (claudin 1, CL1) markers. PCX +/CL1 − cells will be 
identified as podocytes and PCX +/CL1 + cells as parietal cells with podocyte phenotype.  
Secondary endpoints - exploratory efficacy 
The secondary exploratory efficacy endpoints are as follows: 
GL-3 clearance from skin 
A skin biopsy will be performed for the scoring of GL-3 as evaluated by light microscopy 
optionally at month 6 and mandatorily at month 30 of the treatment period. Quantification of 
cellular GL-3 by histomorphometry through electron microscopy (EM) may also be evaluated. 
For each study site, a physician experienced in skin biopsy technique will be identified to ensure 
all tissue samples are correctly obtained and are appropriately processed for shipment. Sample 
processing, storage, and shipment guidelines are provided in the study manual. Masked biopsy 
samples will be reviewed and scored by 3 independent pathologists using light microscopy. GL-3 
clearance is scored as none/trace (0), mild (1), moderate (2), or severe (3) GL-3 
accumulation/inclusions. 


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A majority score will be determined for each slide and cell type based on the individual scores of 
each pathologist. If there is a difference >1 between any 2 of the 3 pathologist’s scores, this will 
be considered as a discrepant scoring. For the evaluation of superficial skin capillary endothelium, 
the discrepant scoring of a slide will be resolved by an adjudication process in which the slide will 
be re-read by the original independent pathology reviewers. If a majority score cannot be derived 
from the adjudication process, then the median adjudicated score will be used. For other skin cell 
types evaluated, the discrepant scoring will be resolved by using the median score. In some 
instances, scores may not be available from all 3 pathologists for a given slide and cell type. If 
scores are provided by 2 of the 3 pathologists, the majority score is the score given by each 
pathologist (if they agree) or the higher of the two individual scores (if they disagree). If only one 
pathologist provides a score, the value for the majority score is set to missing. 
Protein excretion  
Protein excretion will be evaluated from the median of 3 timed overnight urine samples, that will 
be collected with 4 to 7 days between each collection (see study flowchart in protocol  
Section 1.2). All urine samples must be collected within a 16-day period. All 3 samples must be 
collected regardless of the results. Specific parameters that will be measured and reported include 
ACR and PCR. 
Echocardiogram  
A 2-dimensional and M-mode echocardiograph with Doppler will be performed at the study visits 
specified in study flowchart in protocol Section 1.2. The variables will include, but not be limited 
to, ventricular cavity size, valve characterization, ejection fraction, ventricular wall thickness, 
regional wall motion, diastolic function, and pericardium characterization, pulmonary blood 
pressure and blood flow will be determined by Doppler ultrasound. 
Two copies of the echocardiograph recording will be generated for each study time point. One 
copy will be kept at the study site with a site physician interpretation. A site physician will assess 
the echocardiograph and provide an overall conclusion as normal, abnormal but not clinically 
significant (NCS), or abnormal and clinically significant (CS). 
The second copy will be sent to the central laboratory for analysis. The central laboratory findings 
will be used for statistical analyses. Specific procedures for these tests are supplied to each study 
investigator in the study manual. 
Brain MRI 
Brain MRI (without contrast agent) assessments include: number and volume of white matter 
lesions, stroke, pulvinar sign, and other significant abnormalities. 
Two copies of the MRI recording will be generated for each requested timepoint (see study 
flowchart in protocol Section 1.2). One copy will be kept at the study site with the interpretation 
of a site physician. A site physician will assess the MRI and record an overall conclusion as 
normal, abnormal but NCS, or abnormal and CS. If the study investigator determines the MRI is 
abnormal and CS and a change from screening, the result will be documented as an AE. 


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The second copy will be sent to the central laboratory for analysis. The central laboratory findings 
will be used for statistical analyses. 
eGFR  
eGFR will be calculated by the central laboratory using an isotope dilution mass 
spectrometry(IDMS)-calibrated serum creatinine assay and the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation (see Section 2.5.1 for CKD-EPI formula). 
2.1.4 Safety endpoints 
The primary endpoint of this study is safety. The safety analysis will be based on the reported 
adverse events (AEs) and other safety information, such as clinical laboratory data, vital signs, 
electrocardiograms (ECGs), physical examinations, neurological examination and ophthalmologic 
examination. The LTS14116 study represents an additional 30 months of treatment of 
GZ/SAR402671 in patients who completed their 6 months of treatment of in the ACT13739 
study. As the intention is to evaluate data of up to 36 months of GZ/SAR402671 treatment, the 
safety data from the ACT13739 study will be imported into the LTS14116 database. In order to 
have a fuller picture of the treatment effect, data from all 11 patients who participated in the 
ACT13739 study, regardless of time of study termination, will be included in the safety analysis.  
Observation period  
The observation period of the analysis combining the ACT13739 and LTS14116 will be divided 
into 4 epochs: 
• 
The pre-treatment epoch is defined as the time from the signed informed consent date up 
to the day prior to the first IMP administration in the ACT13739 study. 
• 
 The on-treatment epoch is defined as the time from the first administration of the IMP in 
the ACT13739 study to the last administration of the IMP in the combined 
ACT13739/LTS14116 treatment period, including any temporary treatment 
discontinuation period, if any. 
• 
The residual treatment epoch is defined as the time from the day after the last IMP 
administration, whether during the ACT13739 or the LTS14116 study, plus 30 days or last 
study visit, whichever occurs first. 
The treatment-emergent adverse event (TEAE) period will include both the on-treatment and 
the residual treatment epochs. 
• 
The posttreatment epoch is defined as the period of time starting the day after the end of 
the TEAE period up to the end of the study (defined as either the last study visit for 
patients who start commercial ERT within 1 month after the last IMP treatment, or the 1 
month (±7 days) follow-up site visit for the rest of the patients). 
The on-study observation period includes the pre-treatment, on-treatment, residual treatment, and 
the posttreatment epochs. 


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2.1.4.1 Adverse events variables 
Adverse event observation period  
In the case of an AE that worsened or became serious, each part of the event is considered in the 
Study Data Tabulation Model (SDTM) as a separate record, with the date the AE worsened or 
became serious as the start date of the new record and linked by the initial AE reference number. 
(A single end date/time and outcome will be used for both records.) 
 The emergence is determined for each record of the AEs as follows: 
• 
Pre-treatment AEs are defined as AEs that developed, worsened, or became serious from 
the signed informed consent date up to first administration of IMP 
• 
Treatment-emergent adverse events (TEAEs) are adverse events that developed, worsened, 
or became serious during the TEAE period (as defined in Section 2.1.4) 
• 
Posttreatment adverse events are adverse events that developed, worsened, or became 
serious during the posttreatment period 
All adverse events (including SAEs and adverse events of special interest (AESI)) will be coded 
to a lower-level term (LLT), preferred term (PT), high-level term (HLT), high-level group term 
(HLGT), and associated primary system organ class (SOC) using the version of MedDRA in 
effect at Sanofi at the time of database lock. 
Adverse events (including serious adverse events) will be recorded from the time of signed 
informed consent in the ACT13739 until the completion of the LTS14116 study. 
AESIs include the following categories listed in the Adverse Event Log form in the eCRF: 
• 
Symptomatic overdose 
• 
Alanine aminotransferase (ALT) increase 
• 
New or worsening lens opacities and cataracts 
• 
Pregnancy of a female partner of a male patient enrolled in ACT13739/LTS14116 
AEs that fall into any AESI category will be checked off on the Adverse Event Log form in the 
eCRF by the site investigator, and flagged in the database. 
2.1.4.2 Deaths 
The deaths observation period are per the observation periods defined above.  
• 
Death on-treatment:  deaths occurring during the TEAE period (as defined in  
Section 2.1.4) 
• 
Death posttreatment:  deaths occurring after the end of the TEAE period  


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2.1.4.3 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including, hematology, blood chemistry and 
urine biochemistry. Clinical laboratory values after conversion will be analyzed into standard 
international units and international units will be used in all listings and tables. 
Blood samples for clinical laboratories will be taken at the scheduled visits listed in study 
flowchart in protocol Section 1.2. The laboratory parameters will be classified as follows: 
• 
Hematology 
- 
Complete blood count, including hematocrit with absolute (not percentage) differential 
cell counts of lymphocytes, hemoglobin, platelets, erythrocytes, basophils, eosinophils, 
lymphocytes, monocytes, neutrophils, leukocytes, and (if applicable) abnormal cells 
• 
Blood chemistry 
- 
albumin, alkaline phosphatase (ALP), alanine aminotransferase, aspartate 
aminotransferase, direct bilirubin, total bilirubin, blood urea nitrogen, calcium, 
chloride, creatinine,  glucose,  potassium, lipase, magnesium, phosphorus, total 
protein, sodium, uric acide, C-reactive protein 
Urine samples will be collected as follows 
- 
Urine biochemistry: albumin, creatinine, total protein, and routine urinalysis (including 
but not limited to sediment examination, specific gravity, metered pH.) 
2.1.4.4 Vital signs variables 
Vital signs taken include: heart rate (supine, standing), systolic and diastolic blood pressure 
(supine, standing), temperature (supine), respiratory rate (supine). In addition, height at the 
baseline visit and weight at every visit will be taken (see study flowchart in protocol Section 1.2). 
2.1.4.5 Electrocardiogram variables 
Standard 12-lead ECGs will be recorded using an electrocardiographic device after at least 
5 minutes in the supine position at the investigator site (see study flowchart in protocol  
Section 1.2). Triplicate ECG will be recorded within 5 minutes with at least 1 minute between 
2 replicates. 
The printout of the recording will be retained at the site and manually read by the study site 
cardiologist or qualified investigator to determine whether the result is normal, abnormal but 
NCS, or abnormal and CS.  
The ECG recordings will also be digitally transmitted to ECG reading center for the central 
reading of the ECG parameters. ECG parameters include RR interval, PR interval, QT interval, 
QTc (according to Bazett and Fridericia formulae) interval, QRS duration, and HR. 


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2.1.4.6 Physical examination variables 
Physical examination will be performed at study visits specified in study flowchart in protocol 
Section 1.2 The findings of each examination will be recorded. Each physical examination will 
include the following physical observations/measurements: 
• 
General appearance 
• 
Heart 
• 
Skin 
• 
Respiratory auscultation 
• 
Mental status 
• 
HEENT (head, eyes, ears, nose, throat) 
• 
Extremities/Joints 
• 
External genitalia 
• 
Peripheral atrial pulses 
• 
Lymph nodes 
• 
Abdomen 
A site physician will assess the physical examination findings as normal, abnormal but NCS, or 
abnormal and CS. 
2.1.4.7 Neurological examination variables 
Neurological examination variables will include: mental, cranial nerves, motor system, deep 
tendon reflex, sensation, and cerebellum, and evaluations of pain. It will be performed at study 
visits specified in study flowchart in protocol Section 1.2. 
2.1.4.8 Ophthalmology examination variables 
A standard ophthalmology examination will be performed at the scheduled visits specified in 
study flowchart in protocol Section 1.2. The examination should be performed by the same 
ophthalmologist throughout the study, if possible, and will include but not be limited to, visual 
acuity, slit-lamp examination and examination of the cornea, lens, and retina. At Month 6, 
Month 18, Month 30, and in cases of Early Withdrawal, dilation of the pupils is required for 
examination. Photography of the lens with broad beam and red reflex, and cornea with the broad 
beam should be done at Month 30 for all patients. 
2.1.5 Pharmacokinetic variables  
Single pharmacokinetic samples will be collected at clinical visits (see study flowchart in protocol 
Section 1.2). As a result, no pharmacokinetic parameters will be generated.  


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2.1.6 Pharmacodynamic/genomics endpoints  
The pharmacodynamic endpoints (plasma GL-3, lyso GL-3, GL-1 and GM3, urine GL-3 and  
exploratory blood and urine biomarkers, high sensitivity cardiac troponin T, plasma 
chitotriosidase assay, and podocyturia) are considered as secondary endpoints in this study (see 
Section 2.1.3.2). 
2.1.7 Quality-of-life endpoints  
SF-36 
The SF-36v2® Health Status Survey (standard 4-week recall period) consists of 36 questions, 
each of which has a weighted response associated with it.  The 36 questions are combined into 
various groupings to form eight scales, which are then further combined to form two overall 
summary measures.  The scales and the items constituting the scales are as follows: 
• 
Physical Functioning (PF) – Items 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j 
• 
Role Limitations Due to Physical Health (RP) – Items 4a, 4b, 4c, 4d 
• 
Bodily Pain (BP) – Items 7, 8 
• 
General Health Perceptions (GH) – Items 1, 11a, 11b, 11c, 11d 
• 
Vitality (VT) – Items 9a, 9e, 9g, 9i 
• 
Social Functioning (SF) – Items 6, 10 
• 
Role Limitations Due to Emotional Problems (RE) – Items 5a, 5b, 5c 
• 
Mental Health (MH) – Items 9b, 9c, 9d, 9f, 9h 
Note: Item 2, a general health item formerly referred to as Reported Health Transition (Self-
Evaluated Transition (SET) in the current version of the health survey), is not used to score any of 
the eight health domain scales or component summary measures . 
Prior to any summary scores being calculated, values outside the range of acceptable item 
response values will be converted to missing scores.  Next, ten items in the questionnaire  
(items 1, 6, 7, 8, 9a, 9d, 9e, 9h, 11b, and 11d) will be reverse scored.  Reverse scoring of these 
items is required so that a higher item response value indicates better health for all SF -36v2® 
Healthy Survey items and summary measures.  In addition, items 1, 7, and 8 require further 
recalibration of the items scores according to the developer’s recommendation as follows: 
 


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Table 1 - Scoring for Item 1 
Response Choices 
Pre-coded Item Value 
Final Item Value 
 
Excellent 
1 
5.0 
Very Good 
2 
4.4 
Good 
3 
3.4 
Fair 
4 
2.0 
Poor 
5 
1.0 
 
Table 2 - Scoring for Item 7 
Response Choices 
Pre-coded Item Value 
Final Item Value 
None 
1 
6.0 
Very mild 
2 
5.4 
Mild 
3 
4.2 
Moderate 
4 
3.1 
Severe 
5 
2.2 
Very severe 
6 
1.0 
 
Table 3 – Scoring for Item 8 if Both Item 7 and Item 8 are answered 
Response Choices 
If Item 8 Pre-coded 
Item Value 
& Item 7 Pre-coded 
Item Value 
Then Final Item Value 
Not at all 
1 
1 
6 
Not at all 
1 
2 through 6 
5 
A little bit 
2 
1 through 6 
4 
Moderately 
3 
1 through 6 
3 
Quite a bit 
4 
1 through 6 
2 
Extremely 
5 
1 through 1 
1 
 
 


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Table 4 – Scoring for Item 8 if Item 7 is not Answered 
Response Choices 
Pre-coded Item Value 
Final Item Value 
Not at all 
1 
6.0 
A little bit 
2 
4.75 
Moderately 
3 
3.5 
Quite a bit 
4 
2.25 
Extremely 
5 
1.0 
Table 5 – Scoring for Item 6 
Response Choices 
Pre-coded Item Value 
Final Item Value 
Not at all 
1 
5 
Slightly 
2 
4 
Moderately 
3 
3 
Quite a bit 
4 
2 
Extremely 
5 
1 
 
Table 6 – Scoring for Items 9a, 9d, 9e, 9h 
Response Choices 
Pre-coded Item Value 
Final Item Value 
All of the time 
1 
5 
Most of the time 
2 
4 
Some of the time 
3 
3 
A little of the time 
4 
2 
None of the time 
5 
1 
 
Table 7 – Scoring for Items 11b and 11d 
Response Choices 
Pre-coded Item Value 
Final Item Value 
Definitely true 
1 
5 
Mostly true 
2 
4 
Don’t know 
3 
3 
Mostly false 
4 
2 
Definitely false 
5 
1 
 


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Raw scale scores are calculated using final item values only. A respondent has to have answered 
at least 50% of the items contributing to a particular scale for a raw scale score to be computed. If 
the respondent did not answer at least 50% of the items contributing to a particular scale, the raw 
scale score will be set to missing for that scale for that respondent for a particular timepoint. If a 
respondent has answered at least 50% of the items contributing to a particular scale but some of 
the items were not answered, the missing items will be estimated by the average score across the 
items that were answered.  
The raw scale scores will be computed by taking the sum of the items for that particular scale.  
Each raw scale score will then be transformed to a 0 to 100 scale using the following formula: 

100
range
 
score
 
raw
 
Possible
score
 
raw
 
possible
Lowest 
 - 
score
 
raw
 
Actual
Scale
 d
Transforme

=
 
This information is listed in Table 8. 
Table 8 - Lowest and highest possible raw scores and score range of the scales 
Scale 
Sum Final Item Values 
Lowest And Highest 
Possible Raw Scores 
Possible Raw Score 
Range 
Physical Functioning 
3a + 3b + 3c + 3d + 3e + 3f + 
3g + 3h + 3I + 3j 
10, 30 
20 
Role-Physical 
4a + 4b + 4c + 4d 
4, 20 
16 
Bodily Pain 
7 + 8 
2, 12 
10 
General Health 
1 + 11a + 11b + 11c + 11d 
5, 25 
20 
Vitality 
9a + 9e + 9g + 9i 
4, 20 
16 
Social Functioning 
6 + 10 
2, 10 
8 
Role-Emotional 
5a + 5b + 5c 
3, 15 
12 
Mental Health 
9b + 9c + 9d + 9f + 9h 
5, 25 
20 
 
The two overall summary scores will be calculated by first determining the standard deviation 
scores (also called z-scores) for the eight scales as follows: 
 
 
Specifically, the following numbers (Table 9) are used in the calculation of the eight z-scores: 


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Table 9 – Means and standard deviations used for the z-score calculations  
Scale 
Mean from the 1998 general 
population 
Standard deviation from the 1998 
general population 
Physical functioning 
83.29094 
23.75883 
Role-Physical 
82.50964 
25.52028 
Bodily Pain 
71.32527 
23.66224 
General Health 
70.84570 
20.97821 
Vitality 
58.31411 
20.01923 
Social Functioning 
84.30250 
22.91921 
Role-Emotional 
87.39733 
21.43778 
Mental Health 
74.98685 
17.75604 
The SF36v2 then utilizes a linear T-score transformation method so that scores for each of the 
health domain scales has a mean of 50 and a standard deviation of 10. For example: 
Physical functioning (PF) T-score = 50 + (PF z_score * 10) 
The z-scores for the raw scales will be combined to form the two aggregate raw summary scores 
by multiplying each one by its corresponding scoring coefficient derived from the 1990 general 
U.S. population and taking the sum of those values. If any of the component scale scores are 
missing, then the associated aggregate summary score is not computed.   
The following scoring coefficients (Table 10) are used in calculating the aggregate raw summary 
scores: 
 
Table 10 – Scoring coefficients used in calculating the aggregate raw summary scores 
Scale 
Coefficients used for raw PCS 
Coefficients used for raw MCS 
Physical functioning 
0.42402 
-0.22999 
Role-Physical 
0.35119 
-0.12329 
Bodily Pain 
0.31754 
-0.09731 
General Health 
0.24954 
-0.01571 
Vitality 
0.02877 
0.23534 
Social Functioning 
-0.00753 
0.26876 
Role-Emotional 
-0.19206 
0.43407 
Mental Health 
-0.22069 
0.48581 
 


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The physical component summary (PCS) and mental component summary (MCS) are then 
standardized: 
PCS = (raw PCS x 10) +50 
 
MCS = (raw MCS x 10) +50 
Gastrointestinal questionnaire 
Gastrointestinal symptoms (degree and frequency of abdominal pain, bowel movements and stool 
consistency) of Fabry disease will be captured using a modified version of the inflammatory 
bowel severity scoring system. 
BDI-II 
The BDI second edition is a 21-item self-report inventory intended to assess the existence and 
severity of symptoms of depression as listed in the American Psychiatric Association's Diagnostic 
and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV; 1994).  
The scale for the BDI was originally created by using descriptions of patient symptoms including 
mood, pessimism, sense of failure, self-dissatisfaction, guilt, suicidal ideas, crying, irritability, 
social withdrawal, insomnia, fatigue, appetite, weight loss, and self-accusation.  In the first 
portion of the test, psychological symptoms are assessed whereas the second portion assesses 
physical symptoms. Each question has a four-point scale ranging which ranges from 0 (symptom 
not present) to 3 (symptom very intense). The overall score constitutes the sum of 
all BDI item score, disregarding any missing item score. 
2.1.8 Health economic endpoints  
NA 
2.1.9 Further therapy after discontinuation of investigational medicinal product 
administration during the study 
NA 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Enrolled patients are defined as patients who signed the informed consent and enrolled in the 
ACT13739 study whether or not the said patients continue in the LTS14116 study.  


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For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary table. 
• 
Patient treated in ACT13739 study 
• 
Patients who completed ACT13739 study and did not enter LTS14116 study 
• 
Patients who enrolled in LTS14116  
• 
LTS14116 patients who completed the study treatment period as per protocol 
• 
LTS14116 patients who did not complete the study treatment period as per protocol 
- 
Breakdown of reasons for permanent treatment discontinuation in the LTS14116 study 
• 
LTS14116 patients who completed/discontinued the posttreatment safety follow-up visits 
Percentages will be calculated using the number of enrolled patients in the ACT13739 or 
LTS14116 as the denominator for milestones occurred in the respective studies, eg, number of 
patients completed the ACT13739 study will be based on the number of patients enrolled in the 
ACT13739. Reasons for treatment discontinuations will be supplied in table format giving 
numbers and percentages. A listing for all ACT13739/LTS14116 enrolled patients will also be 
provided. 
All major deviations, as recorded through standard Sanofi procedure, will be summarized in tables 
giving numbers and percentages of deviations. 
Additionally, the analysis populations (see Section 2.3.1) for safety and efficacy will be 
summarized in a table by number of patients on the enrolled population. 
• 
Efficacy population: full analysis set (FAS) 
• 
Safety population 
Patient disposition and patient populations will be summarized for all patients enrolled in 
ACT13739/LTS14116. 
2.2.1 Randomization and drug dispensing irregularities 
Inclusion and drug-dispensing irregularities occur whenever: 
1. An inclusion is not in accordance with the protocol-defined method, such as an ineligible 
patient is included; 
 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined method, such as a 
non-included patient is treated with IMP reserved for included patients. 
Inclusion and drug-dispensing irregularities will be monitored throughout the study and reviewed 
on an ongoing basis. 


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All inclusion and drug-dispensing irregularities will be documented in the clinical study report. If 
the number of irregularities is large enough to make a tabular summary useful, the irregularities 
will be categorized and summarized among enrolled patients (number and percentages). 
2.3 
ANALYSIS POPULATIONS 
2.3.1 Efficacy populations 
Patients treated without informed consent will not be included in the full analysis set (FAS). 
Full analysis set (FAS) 
The FAS includes all patients who receive at least 1 dose of IMP in the ACT13739 study. 
2.3.2 Safety population 
The safety population is defined as: all patients who received at least 1 dose of the IMP during the 
ACT13739 study. 
2.4 
STATISTICAL METHODS 
2.4.1 Demographics and baseline characteristics 
All patients who enrolled in ACT13739 and the subgroup who also enrolled in LTS14116 will be 
summarized separately on demographic and baseline characteristic data. 
Continuous data will be summarized using the number of available data, mean, standard deviation 
(SD), median, minimum, and maximum for treatment group. Categorical and ordinal data will be 
summarized using the number and percentage of patients in treatment group. 
Parameters described in Section 2.1.1 will be summarized using descriptive statistics and 
displayed in listings on the FAS. 
Medical/surgical and Fabry history will be summarized by primary SOC and PT for treatment 
group. The table will be sorted by SOC internationally agreed order followed by PT decreasing 
order based on the overall incidence in the treatment group. 
P-values on demographic and baseline characteristic data will not be calculated. 
No specific description of the safety/efficacy parameters will be provided at baseline. If relevant, 
the baseline values will be described along with each safety/efficacy analysis. 


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2.4.2 Prior or concomitant medications 
The prior and concomitant medications will be presented for the safety population. 
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomic category (ATC) class (anatomic category) and generic 
name. All ATC codes corresponding to a medication will be summarized, and patients will be 
counted once in each ATC anatomic category and generic name linked to the medication. 
Therefore patients may be counted more than once for the same medication. 
The tables for prior medications, concomitant medications and posttreatment medications will be 
sorted by decreasing frequency of ATC followed by all encompassed generic names based on the 
incidence in the treatment group. In case of equal frequency regarding ATCs (anatomic or generic 
names), alphabetical order will be used. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure will be assessed and summarized within the safety population 
(Section 2.3.2). 
2.4.3.1 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by the duration of IMP exposure, and recorded dose 
information. 
Duration of IMP exposure is defined as last dose date – first dose date (in ACT13739) + 1 day, 
regardless of unplanned intermittent discontinuations (see Section 2.5.1 for calculation in case of 
missing or incomplete data). 
Duration of IMP exposure from start of ACT13739 will be summarized (in weeks) descriptively 
as a quantitative variable (number, mean, SD, median, minimum, and maximum). In addition, 
duration of treatment exposure will also be summarized categorically by numbers and percentages 
for each of the following categories and cumulatively according to these categories: up to 
3months, >3 to 6 months, >6 to 9 months, >9 to 12 months, >12 to 18 months, >18 to 30 months, 
>30 to 36 months, and >36 months.  
Additionally, the cumulative duration of treatment exposure in the on-treatment epoch will be 
provided, defined as the sum of the duration of treatment exposure for all patients, and will be 
expressed in patient years. 
The total IMP per patient will be defined as the sum of the actual dose in mg received at all site 
visits and the actual dose in mg*(stop date – start date + 1) of each recorded week of at home 
administration. The total IMP per patient during the on-treatment epoch will be summarized 
descriptively (number, mean, SD, median, minimum, and maximum). 
The treatment exposure to IMP from the start of ACT13739 study through the end of the 
LTS14116 study will be displayed in listings as recorded on the CRF. 


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2.4.3.2 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data. Differences between the planned (intended) dose and the actual dose 
administered during a site visit may be shown in a listing along with the exposure data, or in a 
separate listing, depending on number of cases. Due to the design of the patient diary, a 
calculation of percentage of planned doses taken within a home administration period is not 
possible.   
Cases of overdose are reported in the AE e-CRF pages and will be described in the AE analysis. 
2.4.4 Analyses of efficacy endpoints 
The primary objective of this LTS14116 study is to assess long-term safety. Efficacy data will be 
summarized with appropriate measures of variability. All efficacy analyses will be performed 
using the FAS. 
2.4.4.1 Analysis of primary efficacy endpoint(s) 
No primary efficacy endpoint is defined for the LTS14116 study; therefore, no primary efficacy 
analysis is planned. 
2.4.4.2 Analyses of secondary efficacy endpoints 
The full analysis set will be used in the analysis of all secondary efficacy endpoints. The on-study 
observation period as defined in Section 2.1.4 will be used in the presentation of the data. 
Pharmacodynamics and biomarkers  
The result and change from baseline in pharmacodynamics and biomarkers data will be 
summarized using descriptive statistics (including number, mean, SD, median, minimum, and 
maximum) and 95% confidence intervals for each visit. Spaghetti plots of measured values over 
time will be provided for all pharmacodynamic parameters and biomarkers. In addition, mean 
with SD graph will be produced. The pharmacodynamic and biomarker results for each patient 
will also be listed. 
Skin GL-3 
The skin biopsy at all visit assessments will be summarized. Shifts from baseline in skin GL-3 
scores as assessed by light microscopy (LM) will be summarized by frequencies and percentages. 
In addition, the skin score will be categorized into the following groups: 0 to <2, 2 to 3. Shifts 
from baseline in grouped skin GL-3 scores will be summarized by frequencies and percentages at 
all visits.  
A listing of skin GL-3 accumulation scores as assessed by LM will be produced. 


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ACR and PCR 
Urinary protein excretion is assessed by examining the albumin to creatinine ratio (ACR) and 
protein to creatinine ratio (PCR). The median value of the 3 measurements at each scheduled visit 
will be used for the statistical analysis. The results and change from baseline will be summarized 
using descriptive statistics and 95% confidence intervals at each scheduled visit. The spaghetti 
plot of ACR and PCR over time and the mean with SD graph will be provided. In addition, the 
results will be provided in a listing. 
Echocardiogram 
The summary statistics of all continuous echocardiogram variables (central laboratory values and 
changes from baseline) will be calculated for each visit or study assessment (baseline, each 
post-baseline time point). The overall interpretation will be summarized by frequencies and 
percentages for normal, abnormal but NCS, or abnormal and CS categories. The spaghetti plot 
and mean with SD graph will be provided for important echocardiogram parameters. A listing of 
echocardiogram results will be presented by patient.  
MRI 
All continuous MRI variables will be summarized using descriptive statistics for each visit or 
study assessment (baseline, each post-baseline time point). The overall interpretation will be 
summarized by frequencies and percentages for normal, abnormal but NCS, or abnormal and CS 
categories. The MRI data listing will be provided by patient. 
eGFR 
The result and change from baseline will be summarized using descriptive statistics and 95% 
confidence intervals (t-distribution assumed) for each visit. Spaghetti plots of measured values 
over time and the mean with SD graph will be provided to illustrate trends over time. A listing 
will be provided by patient for eGFR data. 
2.4.4.3 Multiplicity issues 
Since the primary objective is to evaluate the long-term safety, no multiplicity adjustment will be 
made for testing multiple efficacy endpoints. 
2.4.4.4 Additional efficacy analysis(es) 
NA 


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2.4.5 Analyses of safety data 
General common rules 
The safety analysis will be conducted according to the Sanofi quality document BTD-009536 v3.0 
“Analysis and reporting of safety data from Clinical Trials through the Clinical Study Report.” 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
• 
Safety data in patients who do not belong to the safety population (eg, exposed but not 
enrolled) will be listed separately 
• 
The baseline value is defined in Section 2.1.1 
• 
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs, and ECG (PCSA version dated 24 May 2014 [Appendix A]) 
• 
PCSA criteria will determine which patients had at least 1 PCSA during the TEAE period, 
taking into account all evaluations performed during the TEAE period, including 
nonscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the on-treatment PCSA percentage. PCSA flags will be determined after 
rounded values according to Sanofi quality document BTD-009536 version 3.0.   
• 
The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter in the TEAE period by 
treatment group on the safety population. 
• 
For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit. 
• 
Unscheduled measurements will not be summarized in the safety analysis, instead it will 
be listed in data listings. 
• 
The analysis of the safety variables will be essentially descriptive and no systematic 
testing is planned. 
2.4.5.1 Analyses of adverse events 
Generalities 
The primary focus of AE reporting will be on TEAEs. Pretreatment and posttreatment adverse 
events, if any, will be described separately. 
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pretreatment, treatment-emergent, or 
posttreatment. The algorithm for imputing date/time of onset will be conservative and will classify 


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an AE as treatment emergent unless there is definitive information to determine it is pretreatment 
or posttreatment. Details on classification of AEs with missing or partial onset dates are provided 
in Section 2.5.3. 
AE incidence tables will present the number (n) and percentage (%) of patients experiencing an 
AE, as well as event counts, if specified. Patients with multiple occurrences of the same AE  
(eg, same preferred term) will be counted only once in the tables within a treatment phase, but all 
associated events will be counted, if events are presented in the table. The denominator for 
computation of percentages is the safety population. 
Sorting within tables ensures the same presentation for the set of all AEs within the observation 
period (pretreatment, treatment-emergent, and posttreatment). For that purpose, the tables of 
adverse events summarized by SOC and PT categories will be sorted by the internationally agreed 
SOC order and decreasing frequency of PTs within SOCs unless otherwise specified. 
The handling of intensity of AE is specified in Section 2.5.1. 
Analysis of all TEAEs 
The following TEAE summaries will be generated for the safety population. 
• 
Overview of TEAEs, summarizing number (%) of patients with any 
- 
TEAEs 
- 
Serious TEAEs 
- 
Severe or life-threatening TEAEs 
- 
Related TEAEs 
- 
TEAEs leading to death 
- 
TEAEs leading to permanent treatment discontinuation 
• 
All TEAEs by primary SOC and PT, showing the number (%) of patients with at least  
1 TEAE and number of events, sorted by the internationally agreed SOC order, with PT 
presented in alphabetical order within each SOC  
• 
All TEAEs regardless of relationship and related by primary SOC and PT, showing the 
number (%) of patients with at least 1 TEAE and number of events, sorted by the 
internationally agreed SOC order, with PT presented in alphabetical order within each 
SOC  
• 
All TEAEs by maximal intensity, presented by primary SOC and PT, showing the number 
(%) of patients with at least 1 TEAE by intensity (ie, mild, moderate, severe, life-
threatening, death), sorted by the internationally agreed SOC order and by decreasing 
incidence of PTs within each SOC. Patients experiencing multiple events of the same AE 
(eg, same preferred term) of different intensities will be counted only once under the 
category of the highest intensity experienced. 


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Listings of all TEAEs showing patient identifier, IMP first dose date, SOC decode, PT decode, 
diagnosis (verbatim), date and day of onset, end date, AESI with immediate notification, category 
of AESI, intensity, corrective treatment/therapy, action taken with study treatment, relationship to 
study treatment, outcome, date of death if any, AE seriousness criteria will be produced. 
Analysis of all treatment emergent SAE(s) 
• 
All treatment-emergent SAEs by primary SOC and PT, showing the number (%) of 
patients with at least 1 serious TEAE and number of events, sorted by the internationally 
agreed SOC order, with PT presented in alphabetical order within each SOC  
• 
All treatment-emergent SAEs regardless of relationship and related by primary SOC and 
PT, showing the number (%) of patients with at least 1 serious TEAE and number of 
events, sorted by the internationally agreed SOC order, with PT presented in alphabetical 
order within each SOC  
Listings of all SAEs showing patient identifier, IMP first dose date, SOC decode, PT decode, 
diagnosis (verbatim), date and day of onset, end date, AESI with immediate notification, category 
of AESI, intensity, corrective treatment/therapy, action taken with study treatment, relationship to 
study treatment, outcome, date of death if any, AE seriousness criteria will be produced. 
Analysis of all TEAE(s) leading to treatment discontinuation 
• 
All TEAEs leading to treatment discontinuation by primary SOC and PT, showing the 
number (%) of patients with at least 1 TEAE and number of events, sorted by the 
internationally agreed SOC order, with PT presented in alphabetical order within each 
SOC  
Listings of all AEs leading to treatment discontinuation showing patient identifier, IMP first dose 
date, SOC decode, PT decode, diagnosis (verbatim), date and day of onset, end date, AESI with 
immediate notification, category of AESI, intensity, corrective treatment/therapy, action taken 
with study treatment, relationship to study treatment, outcome, date of death if any, AE 
seriousness criteria will be produced. 
Analysis of AEs of special interest (AESI) 
• 
All AESIs by AESI category and PT, showing the number (%) of patients with at least 
1 treatment-emergent AESI and number of events, sorted by decreasing incidence of PT 
within each AESI category 
Listings of all AESIs showing patient identifier, IMP first dose date, SOC decode, PT decode, 
diagnosis (verbatim), date and day of onset, end date, AESI with immediate notification, category 
of AESI, intensity, corrective treatment/therapy, action taken with study treatment, relationship to 
study treatment, outcome, date of death if any, AE seriousness criteria will be produced. 


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Analysis of posttreatment AEs 
• 
All posttreatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 posttreatment AE and number of events, sorted by the internationally agreed 
SOC order, with PT presented in alphabetical order within each SOC 
Listings of all posttreatment AEs showing patient identifier, IMP first dose date, SOC decode, PT 
decode, diagnosis (verbatim), date and day of onset, end date, AESI with immediate notification, 
category of AESI, intensity, corrective treatment/therapy, action taken with study treatment, 
relationship to study treatment, outcome, date of death if any, AE seriousness criteria will be 
produced. 
2.4.5.2 Deaths 
The following summaries of deaths will be generated for the safety population. 
• 
Number (%) of patients who died by study period (on-study, on-treatment, posttreatment) 
• 
TEAE leading to death (death as an outcome on the AE case report form page as reported 
by the Investigator) by primary SOC and PT showing number (%) of patients sorted by 
internationally agreed SOC order, with PT presented in alphabetical order within each 
SOC 
2.4.5.3 Analyses of laboratory variables  
The summary statistics (including number, mean, median, SD, minimum, and maximum) of all 
laboratory variables (central laboratory values and changes from baseline) will be calculated for 
each visit or study assessment (baseline, each postbaseline time point). Spaghetti plots will be 
plotted over time (at same time points) for some special interest parameters like aspartate 
aminotransferase (AST), alkaline phosphatase (ALP) and alanine aminotransferase (ALT) etc.  
The incidence of PCSAs (list provided in Appendix A) at any time during the TEAE period will 
be summarized by biological function (red blood cells and platelets, white blood cells, 
metabolism, electrolytes, renal function, and liver function) whatever the baseline level and/or 
according to the following baseline status categories:  
• 
Normal/missing 
• 
Abnormal according to PCSA criterion or criteria 
A listing of patients with at least 1 postbaseline PCSA will be provided and will display the whole 
profile over time of all parameters of the corresponding biological function.  
For parameters for which no PCSA criterion is defined, similar table(s) using the normal range 
will be provided. All laboratory values will be classified as normal (‘Normal’), below normal 
(‘Low’), or above normal (‘High’) based on normal ranges supplied by the central laboratory. 
Frequencies of clinically abnormal values and shift tables comparing the baseline classification 
(Normal, Low, High) to the classification at each postbaseline visit will be presented. All clinical 
laboratory data will be presented in listings. 
The handling of <BQL values is specified in Section 2.5.1. 


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2.4.5.4 Analyses of vital sign variables 
The summary statistics (including number, mean, median, SD, minimum, and maximum) of all 
vital signs variables (central laboratory values and changes from baseline) will be calculated for 
each visit or study assessment (baseline, each postbaseline time point). All vital sign data will be 
presented in listings. 
The incidence of PCSAs at any time during the TEAE period will be summarized by vital sign 
parameters irrespective of the baseline level and/or according to the following baseline status 
categories:  
• 
Normal/missing 
• 
Abnormal according to PCSA criterion or criteria 
A listing of patients with at least 1 postbaseline PCSA will be provided and will display the whole 
profile over time of all parameters 
2.4.5.5 Analyses of electrocardiogram variables 
The summary statistics (including number, mean, median, SD, minimum, and maximum) of all 
continuous ECG variables (central laboratory values and changes from baseline) will be 
calculated for each visit or study assessment (baseline, each postbaseline time point). The mean of 
the triplicate ECG measurements at each visit will be used for the descriptive statistics. The 
handling of triplicate ECG interpretation is described in Section 2.5.1. Categorical variables will 
be summarized by frequencies and percentages. A listing of ECG results will be presented by 
patient. 
The incidence of PCSAs at any time during the TEAE period will be summarized by ECG 
parameters irrespective of the baseline level and/or according to the following baseline status 
categories:  
• 
Normal/missing 
• 
Abnormal according to PCSA criterion or criteria 
A listing of patients with at least 1 postbaseline PCSA will be provided and will display the whole 
profile over time of all parameters. 
2.4.5.6 Analysis of physical examination variables 
Frequencies and percentages of patients with normal or abnormal findings and CS change from 
baseline of physical examinations will be summarized by body system. A listing will be provided 
for physical examination results. 


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2.4.5.7 Analysis of neurological examination variables 
The frequencies and percentages of patients with normal/abnormal findings at baseline and 
succeeding visits will be summarized by site/system. In addition, listings will be provided for the 
same. 
2.4.5.8 Analysis of ophthalmology examination variables 
The ophthalmology examination results will be presented by frequencies and percentages. A 
listing will be provided for examination results 
2.4.6 Analyses of pharmacokinetic and pharmacodynamic variables 
Plasma concentrations of GZ/ GZ/SAR402671 will be summarized for using descriptive statistics 
(including number, arithmetic mean, SD, geometric mean, coefficient of variation (CV %), 
minimum, median, and maximum) for each visit. Listing and graph of plasma concentration will 
be provided. 
Pharmacodynamic variables that are included in the secondary endpoints specified in  
Section 2.1.3.2 will be analyzed as described in Section 2.4.4.2. 
2.4.7 Analyses of quality of life/health economics variables 
SF-36 
Eight scales (range between 0 and 100) and the two component summaries (PCS and MCS) will 
be analyzed. Results and change from baseline will be summarized using descriptive statistics 
(including number, mean, median, SD, minimum, and maximum) for each visit. Boxplots of the 
standardized scores over time for the 8 function scale scores and the 2 aggregate summary scores 
of SF-36 will be produced. 
GI 
The summary statistics (including number, mean, median, SD, minimum, and maximum) of 
questionnaire results will be calculated for each visit or study assessment (baseline, each 
postbaseline time point). Categorical variables will be summarized by frequencies and 
percentages. The bowel movement results will be derived as described in Section 2.5.1. Boxplots 
and bar graphs will be used to illustrate GI responses over time, as appropriate.  
BDI 
Baseline and change from baseline in BDI overall score will be summarized descriptively 
(including number, mean, median, SD, minimum, and maximum) for each visit (baseline, each 
postbaseline time point). Boxplots of the BDI overall score over time will be provided.  
The quality of life data will be listed by patient for SF-36, GI & BDI. 


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2.5 
DATA HANDLING CONVENTIONS 
The data handling conventions for the variables used in the statistical analysis are included in this 
section. 
2.5.1 General conventions 
The following formulas will be used for computation of parameters. 
Demographic formulas 
Age in years = integer part of ((date of informed consent – date of birth)/365.25) 
 
BMI = 
height(m)
weight(kg)
2  
Renal function formulas  
CKD-EPI equation (1): 
eGFR (mL/min/1.73 m2) = 141 * min(sCr/κ,1)α * max(sCr/κ,1)-1.209 * 0.993Age * 1.018 [if 
female] * 1.159 [if black] 
For the above, sCr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is –0.329 
for females and –0.411 for males, min indicates the minimum of sCr/κ or 1, and max indicates the 
maximum of sCr/κ or 1. All patients are males so the 1.018 correction factor will not be used. 
Handling of triplicate ECG interpretation 
If the ECG interpretation is recorded in triplicate, the derived categorical values will be used for 
statistical analysis.  For example, the ECG interpretation results reported as ‘normal’, ‘abnormal’ 
and ‘abnormal ECG, clinically significant’, then the derived values will be ‘only normal’, ‘ 
at least one abnormal but only non-clinically significant’ and ‘at least one abnormal and clinically 
significant’ respectively. 
Handling of <BQL laboratory values 
If the laboratory values are recorded as less than a quantifiable limit, the value halfway between  
0 and the BQL will be used for statistical analysis. For example, if the value is reported as <6.2, 
then the value 3.1 will be used. In cases of ratios, such as PCR and ACR, if one or both of the 
assayed parameters used to calculate a ratio has <BQL value, then the above mentioned 
imputation should be performed prior to the calculation of the ratio. 


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Handling of GI questionnaire   
If ‘Most number of times of bowel movement’ and “Least number of times of bowel movement’ 
results are recorded per week/month, then derived the results with per day frequency for the same. 
The per day frequency results for the above parameters will be used for statistical analysis.   
Handling of intensity of AEs 
If the intensity is ‘Severe’ or ‘Life-Threatening’, then combine these intensity categories  into a 
single category as ‘Severe and/or Life-Threatening’ for the analysis purpose..  
2.5.2 Data handling conventions for secondary efficacy variables 
NA 
2.5.3 Missing data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
For data listings, the character date will always be used to present the date collected in the CRF. 
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing  
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date 
of last administration reported on the end-of-treatment case report form page.  If this date is 
missing, the exposure duration should be left as missing.  
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and posttreatment medication. 
Handling of AEs with missing or partial date/time of onset 
Missing or partial AE onset dates and times will not be imputed. If the partial AE onset date/time 
information does not indicate that the AE started prior to treatment or after the treatment-emergent 
AE period, the AE will be classified as treatment-emergent.  No imputation of AE end dates/times 
will be performed.  This data categorization will be used for presenting treatment-emergent AE 
summary tables or listings.  No imputation is planned for date/time of AE resolution. 


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Handling of AEs when date and time of first investigational medicinal product administration 
is missing 
When the date and time of the first IMP administration is missing, all AEs that occurred on or 
after the day of randomization will be considered as TEAEs.  The exposure duration will be kept 
as missing in such cases. 
The last dose intake will be determined according to IMP administration dates collected in the 
case report form and will not be approximated by the last returned package date. 
Handling of missing assessment of relationship of AEs to investigational medicinal product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP will be 
assumed and the AE considered as such in the frequency tables of possibly related AEs, but no 
imputation will be done at the data level. 
Handling of missing intensity of AEs 
If the intensity is missing for 1 of the treatment-emergent occurrences of an AE, the maximal 
severity on the remaining occurrences will be considered.  If the severity is missing for all the 
occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is > 0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used.  
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values.   


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2.5.4 Windows for time points 
NA 
2.5.5 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will not be included in 
the by-visit summaries, but will be used for computation of baseline, as well as presented in 
listings. 
2.5.6 Pooling of centers for statistical analyses 
NA 
2.5.7 Statistical technical issues 
NA 


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3 
INTERIM ANALYSIS 
No interim analysis is planned. 


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4 
DATABASE LOCK 
The database is planned to be locked at approximately 70 days after last patient last visit. 


Statistical Analysis Plan  
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GZ/SAR402671-ACT13739-LTS14116  
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS version 9.2 or higher. 


Statistical Analysis Plan  
09-Apr-2018 
GZ/SAR402671-ACT13739-LTS14116  
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
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6 
REFERENCES 
1. Levey AS, Steven LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604-12.  


Statistical Analysis Plan  
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GZ/SAR402671-ACT13739-LTS14116  
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7 
LIST OF APPENDICES 
 
Appendix A: 
Potentially clinically significant abnormalities (PCSA) criteria 


Statistical Analysis Plan  
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GZ/SAR402671-ACT13739-LTS14116  
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Appendix A 
Potentially clinically significant abnormalities criteria  
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 – Version 3.0 –24-MAY-2014) 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
 
 
ALT 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not 
in IU/L.  
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
AST 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not 
in IU/L.  
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
Alkaline 
Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not 
in IU/L. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated 
Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-by-case 
basis. 


Statistical Analysis Plan  
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Page 46 
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 – Version 3.0 –24-MAY-2014) 
Parameter 
PCSA 
Comments 
ALT and Total 
Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, 
whatever the interval between measurement. 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
CLcr (mL/min) 
(Estimated 
creatinine 
clearance based 
on the Cokcroft-
Gault equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact 
on dosing and labeling 
eGFR 
(mL/min/1.73m2) 
(Estimate of 
GFR based on 
an MDRD 
equation)  
 
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact 
on dosing and labeling 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 17th Ed., 
2008. 
Blood Urea 
Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 


Statistical Analysis Plan  
09-Apr-2018 
GZ/SAR402671-ACT13739-LTS14116  
Version number: 1 
 
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Page 47 
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 – Version 3.0 –24-MAY-2014) 
Parameter 
PCSA 
Comments 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total 
Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count 
available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 17th Ed., 
2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline are 
more relevant than based on absolute value. 
Other categories for decrease from baseline can 
be used (≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 


Statistical Analysis Plan  
09-Apr-2018 
GZ/SAR402671-ACT13739-LTS14116  
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Property of the Sanofi Group - strictly confidential 
Page 48 
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 – Version 3.0 –24-MAY-2014) 
Parameter 
PCSA 
Comments 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug 
development, the analysis is redundant with that 
of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline 
≥20mmHg 
≥160 mmHg and increase from baseline ≥20 
mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 
mmHg 
≥110 mmHg and increase from baseline ≥10 
mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Orthostatic 
Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 


Statistical Analysis Plan  
09-Apr-2018 
GZ/SAR402671-ACT13739-LTS14116  
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 49 
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 – Version 3.0 –24-MAY-2014) 
Parameter 
PCSA 
Comments 
ECG 
Ref.: ICH E14 guidance (2005) and E14 Q&A (2012), 
and Cardiac Safety Research Consortium White Paper 
on PR and QRS (Nada et al. Am Heart J. 2013; 165(4) 
: 489-500) 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline ≥20bpm 
>100 bpm  
>100 bpm and increase from baseline ≥20bpm 
>120 bpm  
>120 bpm and increase from baseline ≥20 bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
> 220 ms 
>220 ms and increase from baseline ≥25% 
> 240 ms 
> 240 ms and increase from baseline ≥25% 
Categories are cumulative 
 
QRS 
>110 ms 
>110 msec and increase from baseline ≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative 
QT 
>500 ms 
 


Statistical Analysis Plan  
09-Apr-2018 
GZ/SAR402671-ACT13739-LTS14116  
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 50 
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 – Version 3.0 –24-MAY-2014) 
Parameter 
PCSA 
Comments 
QTc 
 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction formula.  
Absolute values categories are cumulative 
 
QTc >480 ms and QTc>60 ms are the 2 PCSA 
categories to be identified in individual subjects/patients 
listings.